Sex steroids in relation to sexual and skeletal maturation in obese male adolescents.

PubMed

Vandewalle, S; Taes, Y; Fiers, T; Van Helvoirt, M; Debode, P; Herregods, N; Ernst, C; Van Caenegem, E; Roggen, I; Verhelle, F; De Schepper, J; Kaufman, J M

2014-08-01

Childhood obesity is associated with an accelerated skeletal maturation. However, data concerning pubertal development and sex steroid levels in obese adolescents are scarce and contrasting. To study sex steroids in relation to sexual and skeletal maturation and to serum prostate specific antigen (PSA), as a marker of androgen activity, in obese boys from early to late adolescence. Ninety obese boys (aged 10-19 y) at the start of a residential obesity treatment program and 90 age-matched controls were studied cross-sectionally. Pubertal status was assessed according to the Tanner method. Skeletal age was determined by an x-ray of the left hand. Morning concentrations of total testosterone (TT) and estradiol (E2) were measured by liquid chromatography-tandem mass spectrometry, free T (FT) was measured by equilibrium dialysis, and LH, FSH, SHBG, and PSA were measured by immunoassays. Genital staging was comparable between the obese and nonobese groups, whereas skeletal bone advancement (mean, 1 y) was present in early and midadolescence in the obese males. Although both median SHBG and TT concentrations were significantly (P < .001) lower in obese subjects during mid and late puberty, median FT, LH, FSH, and PSA levels were comparable to those of controls. In contrast, serum E2 concentrations were significantly (P < .001) higher in the obese group at all pubertal stages. Obese boys have lower circulating SHBG and TT, but similar FT concentrations during mid and late puberty in parallel with a normal pubertal progression and serum PSA levels. Our data indicate that in obese boys, serum FT concentration is a better marker of androgen activity than TT. On the other hand, skeletal maturation and E2 were increased from the beginning of puberty, suggesting a significant contribution of hyperestrogenemia in the advancement of skeletal maturation in obese boys.

Automated analysis of whole skeletal muscle for muscular atrophy detection of ALS in whole-body CT images: preliminary study

NASA Astrophysics Data System (ADS)

Kamiya, Naoki; Ieda, Kosuke; Zhou, Xiangrong; Yamada, Megumi; Kato, Hiroki; Muramatsu, Chisako; Hara, Takeshi; Miyoshi, Toshiharu; Inuzuka, Takashi; Matsuo, Masayuki; Fujita, Hiroshi

2017-03-01

Amyotrophic lateral sclerosis (ALS) causes functional disorders such as difficulty in breathing and swallowing through the atrophy of voluntary muscles. ALS in its early stages is difficult to diagnose because of the difficulty in differentiating it from other muscular diseases. In addition, image inspection methods for aggressive diagnosis for ALS have not yet been established. The purpose of this study is to develop an automatic analysis system of the whole skeletal muscle to support the early differential diagnosis of ALS using whole-body CT images. In this study, the muscular atrophy parts including ALS patients are automatically identified by recognizing and segmenting whole skeletal muscle in the preliminary steps. First, the skeleton is identified by its gray value information. Second, the initial area of the body cavity is recognized by the deformation of the thoracic cavity based on the anatomical segmented skeleton. Third, the abdominal cavity boundary is recognized using ABM for precisely recognizing the body cavity. The body cavity is precisely recognized by non-rigid registration method based on the reference points of the abdominal cavity boundary. Fourth, the whole skeletal muscle is recognized by excluding the skeleton, the body cavity, and the subcutaneous fat. Additionally, the areas of muscular atrophy including ALS patients are automatically identified by comparison of the muscle mass. The experiments were carried out for ten cases with abnormality in the skeletal muscle. Global recognition and segmentation of the whole skeletal muscle were well realized in eight cases. Moreover, the areas of muscular atrophy including ALS patients were well identified in the lower limbs. As a result, this study indicated the basic technology to detect the muscle atrophy including ALS. In the future, it will be necessary to consider methods to differentiate other kinds of muscular atrophy as well as the clinical application of this detection method for early ALS detection and examine a large number of cases with stage and disease type.

Reactive oxygen species are involved in lipopolysaccharide-induced intrauterine growth restriction and skeletal development retardation in mice.

PubMed

Xu, De-Xiang; Chen, Yuan-Hua; Zhao, Lei; Wang, Hua; Wei, Wei

2006-12-01

Maternal infection is a cause of adverse developmental outcomes including embryonic resorption, intrauterine fetal death, and preterm labor. Lipopolysaccharide-induced developmental toxicity at early gestational stages has been well characterized. The purpose of the present study was to investigate the effects of maternal lipopolysaccharide exposure at late gestational stages on intrauterine fetal growth and skeletal development and to assess the potential role of reactive oxygen species in lipopolysaccharide-induced intrauterine fetal growth restriction and skeletal development retardation. The timed pregnant CD-1 mice were intraperitoneally injected with lipopolysaccharide (25 to 75 microg/kg per day) on gestational day 15 to 17. To investigate the role of reactive oxygen species on lipopolysaccharide-induced intrauterine fetal growth restriction and skeletal development retardation, the pregnant mice were injected with alpha-phenyl-N-t-butylnitrone (100 mg/kg, intraperitoneally) at 30 minutes before lipopolysaccharide (75 microg/kg per day, intraperitoneally), followed by an additional dose of alpha-phenyl-N-t-butylnitrone (50 mg/kg, intraperitoneally) at 3 hours after lipopolysaccharide. The number of live fetuses, dead fetuses, and resorption sites was counted on gestational day 18. Live fetuses in each litter were weighed. Crown-rump and tail lengths were examined and skeletal development was evaluated. Maternal lipopolysaccharide exposure significantly increased fetal mortality, reduced fetal weight and crown-rump and tail lengths of live fetuses, and retarded skeletal ossification in caudal vertebrae, anterior and posterior phalanges, and supraoccipital bone in a dose-dependent manner. Alpha-phenyl-N-t-butylnitrone, a free radical spin-trapping agent, almost completely blocked lipopolysaccharide-induced fetal death (63.2% in lipopolysaccharide group versus 6.5% in alpha-phenyl-N-t-butylnitrone + lipopolysaccharide group, P < .01). In addition, alpha-phenyl-N-t-butylnitrone significantly reversed lipopolysaccharide-induced intrauterine growth restriction and skeletal development retardation. However, aminoguanidine, a selective inhibitor of inducible nitric oxide synthase, had little effect. Furthermore, lipopolysaccharide-induced intrauterine fetal death, intrauterine fetal growth restriction, and skeletal development retardation were associated with lipid peroxidation and glutathione depletion in maternal liver, placenta, and fetal liver. Alpha-phenyl-N-t-butylnitrone significantly attenuated lipopolysaccharide-induced lipid peroxidation and glutathione depletion in maternal liver, placenta, and fetal liver. Maternal lipopolysaccharide exposure at late gestational stages results in intrauterine fetal growth restriction and skeletal development retardation in mice. Reactive oxygen species might be, at least in part, involved in lipopolysaccharide-induced intrauterine fetal growth restriction and skeletal development retardation.

Robust generation and expansion of skeletal muscle progenitors and myocytes from human pluripotent stem cells.

PubMed

Shelton, Michael; Kocharyan, Avetik; Liu, Jun; Skerjanc, Ilona S; Stanford, William L

2016-05-15

Human pluripotent stem cells provide a developmental model to study early embryonic and tissue development, tease apart human disease processes, perform drug screens to identify potential molecular effectors of in situ regeneration, and provide a source for cell and tissue based transplantation. Highly efficient differentiation protocols have been established for many cell types and tissues; however, until very recently robust differentiation into skeletal muscle cells had not been possible unless driven by transgenic expression of master regulators of myogenesis. Nevertheless, several breakthrough protocols have been published in the past two years that efficiently generate cells of the skeletal muscle lineage from pluripotent stem cells. Here, we present an updated version of our recently described 50-day protocol in detail, whereby chemically defined media are used to drive and support muscle lineage development from initial CHIR99021-induced mesoderm through to PAX7-expressing skeletal muscle progenitors and mature skeletal myocytes. Furthermore, we report an optional method to passage and expand differentiating skeletal muscle progenitors approximately 3-fold every 2weeks using Collagenase IV and continued FGF2 supplementation. Both protocols have been optimized using a variety of human pluripotent stem cell lines including patient-derived induced pluripotent stem cells. Taken together, our differentiation and expansion protocols provide sufficient quantities of skeletal muscle progenitors and myocytes that could be used for a variety of studies. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

The Effect of Conditional Inactivation of Beta 1 Integrins using Twist 2 Cre, Osterix Cre and Osteocalcin Cre Lines on Skeletal Phenotype

PubMed Central

Shekaran, Asha; Shoemaker, James T.; Kavanaugh, Taylor E.; Lin, Angela S.; LaPlaca, Michelle C.; Fan, Yuhong; Guldberg, Robert E.; García, Andrés J.

2014-01-01

Skeletal development and growth are complex processes regulated by multiple microenvironmental cues, including integrin-ECM interactions. The β1 sub-family of integrins is the largest integrin sub-family and constitutes the main integrin binding partners of collagen I, the major ECM component of bone. As complete β1 integrin integrin knockout results in embryonic lethality, studies of β1 integrin function in vivo rely on tissue-specific gene deletions. While multiple in vitro studies indicate that β1 integrins are crucial regulators of osteogenesis and mineralization, in vivo osteoblast-specific perturbations of β1 integrins have resulted in mild and sometimes contradictory skeletal phenotypes. To further investigate the role of β1 integrins on skeletal phenotype, we used the Twist2-Cre, Osterix-Cre and Osteocalcin-Cre lines to generate conditional β1 integrin deletions, where cre is expressed primarily in mesenchymal condensation, pre-osteoblast, and mature osteoblast lineage cells respectively within these lines. Mice with Twist2-specific β1 integrin disruption were smaller, had impaired skeletal development, especially in the craniofacial and vertebral tissues at E19.5, and did not survive beyond birth. Osterix-specific β1 integrin deficiency resulted in viable mice which were normal at birth but displayed early defects in calvarial ossification, incisor eruption and growth as well as femoral bone mineral density, structure, and mechanical properties. Although these defects persisted into adulthood, they became milder with age. Finally, a lack of β1 integrins in mature osteoblasts and osteocytes resulted in minor alterations to femur structure but had no effect on mineral density, biomechanics or fracture healing. Taken together, our data indicate that β1 integrin expression in early mesenchymal condensations play an important role in skeletal ossification, while β1 integrin-ECM interactions in pre-osteoblast, odontoblast- and hypertrophic chondryocyte- lineage cells regulate incisor eruption and perinatal bone formation in both intramembranously and endochondrally formed bones in young, rapidly growing mice. In contrast, the Osteocalcin-specific β1 integrin deletion had only minor effects on skeletal phenotype. PMID:25183373

[Size of lower jaw as an early indicator of skeletal class III development].

PubMed

Stojanović, Zdenka; Nikodijević, Angelina; Udovicić, Bozidar; Milić, Jasmina; Nikolić, Predrag

2008-08-01

Malocclusion of skeletal class III is a complex abnormality, with a characteristic sagital position of the lower jaw in front of the upper one. A higher level of prognatism of the lower jaw in relation to the upper one can be the consequence of its excessive length. The aim of this study was to find the differences in the length of the lower jaw in the children with skeletal class III and the children with normal sagital interjaw relation (skeletal class I) in the period of mixed dentition. After clinical and x-ray diagnostics, profile tele-x-rays of the head were analyzed in 60 examinees with mixed dentition, aged from 6 to 12 years. The examinees were divided into two groups: group 1--the children with skeletal class III and group 2--the children with skeletal class I. The length of the lower jaw, upper jaw and cranial base were measured. The proportional relations between the lengths measured within each group were established and the level of difference in the lengths measured and their proportions between the groups were estimated. No significant difference between the groups was found in the body length, ramus and the total length of the lower jaw. Proportional relation between the body length and the length of the lower jaw ramus and proportional relation between the forward cranial base and the lower jaw body were not significantly different. A significant difference was found in proportional relations of the total length of the lower jaw with the total lengths of cranial base and the upper jaw and proportional relation of the length of the lower and upper jaw body. Of all the analyzed parameters, the following were selected as the early indicators of the development of skeletal class III on the lower jaw: greater total length of the lower jaw, proportional to the total lengths of cranial base and theupper jaw, as well as greater length of the lower jaw body, proportional to the length of the upper jaw body.

[Molecular cloning, expression of rat Msx-1 and Msx-2 during early embryo genesis and roles for mandibular chondrogenesis].

PubMed

Ishiguro, S

1999-03-01

Quail-chick chimera experiments have shown a contribution of carnial neural crest cells to the craniofacial skeletal elements. Moreover, tissue interactions between epithelial-mesenchymal interaction during early facial process development are required for both skeletal differentiation and morphogenesis. In this study, it was observed that Msx homeobox containing genes expressed in the facial process were important molecules of cartilage morphogenesis. Rat cDNAs were isolated and encoded by Msx-1 and -2, and then the expression patterns using in situ hybridization were investigated during early rat face development. These genes were correlatively expressed in the cranial neural crest forming area (E 9.5 dpc) and the facial process (E 12.5 dpc). Antisence inhibition of Msx genes in the E 12.5 mandibular process exhibited the alteration of their gene expression and cartilage patterns. Antisence inhibition of Msx-1 induced lack of the medial portion of cartilage, and antisence inhibition of Msx-2 enhanced chondrogenesis of mandibular process under the organ culture condition. Thus it was concluded that expression of Msx genes during mandibular process development comprises important signals of chondrogenesis.

PubMed Central

Paolantonio, E.G.; Antonini, G.; Saulle, R.; La Torre, G.; Deli, R.

2016-01-01

SUMMARY The ratio of bad habits, mouth breathing and malocclusion is an important issue in view of prevention and early treatment of disorders of the craniofacial growth. While bad habits can interfere with the position of the teeth and normal pattern of skeletal growth, on the other hand obstruction of the upper airway, resulting in mouth breathing, changes the pattern of craniofacial growth causing malocclusion. Our crosssectional study, carried out on 3017 children using the ROMA index, was developed to verify if there was a significant correlation between bad habits/mouth breathing and malocclusion. The results showed that an increase in the degree of the index increases the prevalence of bad habits and mouth breathing, meaning that these factors are associated with more severe malocclusions. Moreover, we found a significant association of bad habits with increased overjet and openbite, while no association was found with crossbite. Additionally, we found that mouth breathing is closely related to increased overjet, reduced overjet, anterior or posterior crossbite, openbite and displacement of contact points. Therefore, it is necessary to intervene early on these aetiological factors of malocclusion to prevent its development or worsening and, if already developed, correct it by early orthodontic treatment to promote eugnatic skeletal growth. PMID:27958599

Resurgence of vitamin D: Old wine in new bottle

PubMed Central

Vaishya, Raju; Vijay, Vipul; Agarwal, Amit Kumar; Jahangir, Jabed

2015-01-01

There are early references of it in ancient text and physicians have discussed its importance and features of its deficiency in the past. Vitamin D has again regained interest with recent dramatic rise in the incidence of deficiency in the developing as well as developing world. In this review article, we discuss the biochemical and role of vitamin D in the skeletal system. We also discuss the recommended dietary requirements and features of skeletal deficiency. Extra-skeletal roles of vitamin D deficiency have been a matter of debate lately and it has also been discussed in detail in this article. In conclusion, it would not be wrong to label vitamin D as one of the most important vitamin involved in the metabolism of the musculoskeletal system and any clinician, especially the orthopaedician, should be well versed with its overall mechanism and roles in the human body. PMID:26155053

Serum PTHrP level as a biomarker in assessing skeletal maturation during circumpubertal development.

PubMed

Hussain, Mohammed Zahid; Talapaneni, Ashok Kumar; Prasad, Mandava; Krishnan, Ramalingam

2013-04-01

Many investigators have studied the cellular organization and the local and systemic factors regulating endochondral bone growth in the growth plate and condylar cartilage. Parathyroid hormone-related protein (PTHrP) and Indian hedgehog protein have been reported to regulate multiple steps during such skeletal morphogenesis. The aims of this study were to quantify serum PTHrP levels at 6 cervical vertebral stages and to correlate serum PTHrP levels to the 6 skeletal maturation stages for use as a biologic indicator of skeletal maturation. Mean serum PTHrP levels were measured in 90 subjects categorized into 6 cervical vertebral stages. Mean serum PTHrP levels were significantly higher in the late pubertal stages than in the early pubertal stages. Pearson correlation showed that serum PTHrP levels had a positive correlation with cervical vertebral maturation stages from the prepubertal to the late pubertal stages, and a negative correlation from the late pubertal to the postpubertal stages. Peak serum PTHrP levels do not correlate with early pubertal stages characterized by maximum growth increments. Hence, the validity of using serum PTHrP levels to predict peak growth velocity is questionable. Copyright © 2013 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

Enhanced Development of Skeletal Myotubes from Porcine Induced Pluripotent Stem Cells

PubMed Central

Genovese, Nicholas J.; Domeier, Timothy L.; Telugu, Bhanu Prakash V. L.; Roberts, R. Michael

2017-01-01

The pig is recognized as a valuable model in biomedical research in addition to its agricultural importance. Here we describe a means for generating skeletal muscle efficiently from porcine induced pluripotent stem cells (piPSC) in vitro thereby providing a versatile platform for applications ranging from regenerative biology to the ex vivo cultivation of meat. The GSK3B inhibitor, CHIR99021 was employed to suppress apoptosis, elicit WNT signaling events and drive naïve-type piPSC along the mesoderm lineage, and, in combination with the DNA methylation inhibitor 5-aza-cytidine, to activate an early skeletal muscle transcription program. Terminal differentiation was then induced by activation of an ectopically expressed MYOD1. Myotubes, characterized by myofibril development and both spontaneous and stimuli-elicited excitation-contraction coupling cycles appeared within 11 days. Efficient lineage-specific differentiation was confirmed by uniform NCAM1 and myosin heavy chain expression. These results provide an approach for generating skeletal muscle that is potentially applicable to other pluripotent cell lines and to generating other forms of muscle. PMID:28165492

Soft-Tissue Injuries Associated With High-Energy Extremity Trauma: Principles of Management.

PubMed

Norris; Kellam

1997-01-01

The management of high-energy extremity trauma has evolved over the past several decades, and appropriate treatment of associated soft-tissue injuries has proved to be an important factor in achieving a satisfactory outcome. Early evaluation of the severely injured extremity is crucial. Severe closed injuries require serial observation of the soft tissues and early skeletal stabilization. Open injuries require early aggressive debridement of the soft tissues followed by skeletal stabilization. Temporary wound dressings should remain in place until definitive soft-tissue coverage has been obtained. Definitive soft-tissue closure will be expedited by serial debridements performed every 48 to 72 hours in a sterile environment. Skeletal union is facilitated by early bone grafting and/or modification of the stabilizing device. Aggressive rehabilitation, includ-ing early social reintegration, are crucial for a good functional outcome. Adherence to protocols is especially beneficial in the management of salvageable severely injured extremities.

Advanced skeletal maturity in children and adolescents with myelomeningocele.

PubMed

Roiz, Ronald; Mueske, Nicole M; Van Speybroeck, Alexander; Ryan, Deirdre D; Gilsanz, Vicente; Wren, Tishya A L

2017-12-11

Atypical skeletal development is common in youth with myelomeningocele (MM), though the underlying reasons have not been fully elucidated. This study assessed skeletal maturity in children and adolescents with MM and examined the effects of sex, age, sexual development, ethnicity, anthropometrics and shunt status. Forty-three males and 35 females with MM, 6-16 years old, underwent hand radiographs for bone age determination. The difference between bone age and chronological age was evaluated using Wilcoxon sign rank tests. Relationships between age discrepancy (skeletal-chronological) and participant characteristics were assessed using multiple linear regression with forward selection. Overall, forty percent (31/78) of MM participants had an advanced bone age of 1 year or greater (median: 2.5 years), while 47% (37/78) were within 1 year above or below their chronological age (-0.001 years) and 13% (10/78) were delayed by more than 1 year (-1.4 years). Bone age was advanced compared to chronologic age in both males and females (p⩽ 0.024). Advanced bone age was observed in early to late puberty and after maturation (p⩽ 0.07), as well as in Hispanic participants (p= 0.003) and in those with a shunt (p= 0.0004). Advanced bone age was positively correlated with height, weight and body mass index (BMI) percentiles (p= 0.004). In multiple linear regression analysis, advanced bone age was most strongly associated with higher Tanner stage of sexual development, and higher weight, height or BMI percentile. Advanced skeletal maturity is common in children/adolescents with MM over 8 years of age who have reached puberty (65%), particularly those who are overweight (80%). Hormonal effects associated with adiposity and sexual maturity likely influence skeletal maturation. Clinicians may use Tanner stage and weight or BMI to gain insight into skeletal maturity.

Altered fetal skeletal muscle nutrient metabolism following an adverse in utero environment and the modulation of later life insulin sensitivity.

PubMed

Dunlop, Kristyn; Cedrone, Megan; Staples, James F; Regnault, Timothy R H

2015-02-12

The importance of the in utero environment as a contributor to later life metabolic disease has been demonstrated in both human and animal studies. In this review, we consider how disruption of normal fetal growth may impact skeletal muscle metabolic development, ultimately leading to insulin resistance and decreased insulin sensitivity, a key precursor to later life metabolic disease. In cases of intrauterine growth restriction (IUGR) associated with hypoxia, where the fetus fails to reach its full growth potential, low birth weight (LBW) is often the outcome, and early in postnatal life, LBW individuals display modifications in the insulin-signaling pathway, a critical precursor to insulin resistance. In this review, we will present literature detailing the classical development of insulin resistance in IUGR, but also discuss how this impaired development, when challenged with a postnatal Western diet, may potentially contribute to the development of later life insulin resistance. Considering the important role of the skeletal muscle in insulin resistance pathogenesis, understanding the in utero programmed origins of skeletal muscle deficiencies in insulin sensitivity and how they may interact with an adverse postnatal environment, is an important step in highlighting potential therapeutic options for LBW offspring born of pregnancies characterized by placental insufficiency.

Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: implications for the development of Turner syndrome.

PubMed

Kosho, T; Muroya, K; Nagai, T; Fujimoto, M; Yokoya, S; Sakamoto, H; Hirano, T; Terasaki, H; Ohashi, H; Nishimura, G; Sato, S; Matsuo, N; Ogata, T

1999-12-01

We report on clinical features in 14 Japanese patients (4 males and 10 females) with partial monosomy of the short arm pseudoautosomal region involving SHOX (n = 11) or total monosomy of the pseudoautosomal region with no involvement of disease genes on the sex-differential regions (n = 3). Skeletal assessment showed that three patients had no discernible skeletal abnormalities, one patient exhibited short 4th metacarpals and borderline cubitus valgus, and the remaining 10 patients had Madelung deformity and/or mesomelia characteristic of Léri-Weill dyschondrosteosis (LWD), together with short 4th metacarpals and/or cubitus valgus. Skeletal lesions were more severe in females and became obvious with age. Growth evaluation revealed that patients without LWD grew along by the -2 SD growth curve before puberty and showed a normal or exaggerated pubertal growth spurt, whereas those with LWD grew along by the standard growth curves before puberty but exhibited an attenuated pubertal growth spurt and resultant short stature. Maturational assessment indicated a tendency of relatively early maturation in patients with LWD. There was no correlation between the clinical phenotype and the deletion size. These findings suggest that haploinsufficiency of SHOX causes not only short stature but also Turner skeletal anomalies (such as short 4th metacarpals, cubitus valgus, and LWD) and that growth pattern is primarily dependent on the presence or absence of LWD. Because skeletal lesions have occurred in a female-dominant and age-influenced fashion, it is inferred that estrogens exert a maturational effect on skeletal tissues that are susceptible to premature fusion of growth plates because of haploinsufficiency of SHOX, facilitating the development of skeletal lesions.

Does skeletal muscle have an 'epi'-memory? The role of epigenetics in nutritional programming, metabolic disease, aging and exercise.

PubMed

Sharples, Adam P; Stewart, Claire E; Seaborne, Robert A

2016-08-01

Skeletal muscle mass, quality and adaptability are fundamental in promoting muscle performance, maintaining metabolic function and supporting longevity and healthspan. Skeletal muscle is programmable and can 'remember' early-life metabolic stimuli affecting its function in adult life. In this review, the authors pose the question as to whether skeletal muscle has an 'epi'-memory? Following an initial encounter with an environmental stimulus, we discuss the underlying molecular and epigenetic mechanisms enabling skeletal muscle to adapt, should it re-encounter the stimulus in later life. We also define skeletal muscle memory and outline the scientific literature contributing to this field. Furthermore, we review the evidence for early-life nutrient stress and low birth weight in animals and human cohort studies, respectively, and discuss the underlying molecular mechanisms culminating in skeletal muscle dysfunction, metabolic disease and loss of skeletal muscle mass across the lifespan. We also summarize and discuss studies that isolate muscle stem cells from different environmental niches in vivo (physically active, diabetic, cachectic, aged) and how they reportedly remember this environment once isolated in vitro. Finally, we will outline the molecular and epigenetic mechanisms underlying skeletal muscle memory and review the epigenetic regulation of exercise-induced skeletal muscle adaptation, highlighting exercise interventions as suitable models to investigate skeletal muscle memory in humans. We believe that understanding the 'epi'-memory of skeletal muscle will enable the next generation of targeted therapies to promote muscle growth and reduce muscle loss to enable healthy aging. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Forward Genetics Defines Xylt1 as a Key, Conserved Regulator of Early Chondrocyte Maturation and Skeletal Length

PubMed Central

Mis, Emily K.; Liem, Karel F.; Kong, Yong; Schwartz, Nancy B.; Domowicz, Miriam; Weatherbee, Scott D.

2014-01-01

The long bones of the vertebrate body are built by the initial formation of a cartilage template that is later replaced by mineralized bone. The proliferation and maturation of the skeletal precursor cells (chondrocytes) within the cartilage template and their replacement by bone is a highly coordinated process which, if misregulated, can lead to a number of defects including dwarfism and other skeletal deformities. This is exemplified by the fact that abnormal bone development is one of the most common types of human birth defects. Yet, many of the factors that initiate and regulate chondrocyte maturation are not known. We identified a recessive dwarf mouse mutant (pug) from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. pug mutant skeletal elements are patterned normally during development, but display a ~20% length reduction compared to wild-type embryos. We show that the pug mutation does not lead to changes in chondrocyte proliferation but instead promotes premature maturation and early ossification, which ultimately leads to disproportionate dwarfism. Using sequence capture and high-throughput sequencing, we identified a missense mutation in the Xylosyltransferase 1 (Xylt1) gene in pug mutants. Xylosyltransferases catalyze the initial step in glycosaminoglycan (GAG) chain addition to proteoglycan core proteins, and these modifications are essential for normal proteoglycan function. We show that the pug mutation disrupts Xylt1 activity and subcellular localization, leading to a reduction in GAG chains in pug mutants. The pug mutant serves as a novel model for mammalian dwarfism and identifies a key role for proteoglycan modification in the initiation of chondrocyte maturation. PMID:24161523

Early life vitamin D depletion alters the postnatal response to skeletal loading in growing and mature bone

PubMed Central

Buckley, Harriet; Owen, Robert; Marin, Ana Campos; Lu, Yongtau; Eyles, Darryl; Lacroix, Damien; Reilly, Gwendolen C.; Skerry, Tim M.; Bishop, Nick J.

2018-01-01

There is increasing evidence of persistent effects of early life vitamin D exposure on later skeletal health; linking low levels in early life to smaller bone size in childhood as well as increased fracture risk later in adulthood, independently of later vitamin D status. A major determinant of bone mass acquisition across all ages is mechanical loading. We tested the hypothesis in an animal model system that early life vitamin D depletion results in abrogation of the response to mechanical loading, with consequent reduction in bone size, mass and strength during both childhood and adulthood. A murine model was created in which pregnant dams were either vitamin D deficient or replete, and their offspring moved to a vitamin D replete diet at weaning. Tibias of the offspring were mechanically loaded and bone structure, extrinsic strength and growth measured both during growth and after skeletal maturity. Offspring of vitamin D deplete mice demonstrated lower bone mass in the non loaded limb and reduced bone mass accrual in response to loading in both the growing skeleton and after skeletal maturity. Early life vitamin D depletion led to reduced bone strength and altered bone biomechanical properties. These findings suggest early life vitamin D status may, in part, determine the propensity to osteoporosis and fracture that blights later life in many individuals. PMID:29370213

Early-onset type 2 diabetes impairs skeletal acquisition in the male TALLYHO/JngJ mouse.

PubMed

Devlin, M J; Van Vliet, M; Motyl, K; Karim, L; Brooks, D J; Louis, L; Conlon, C; Rosen, C J; Bouxsein, M L

2014-10-01

Type 2 diabetes (T2D) incidence in adolescents is rising and may interfere with peak bone mass acquisition. We tested the effects of early-onset T2D on bone mass, microarchitecture, and strength in the TALLYHO/JngJ mouse, which develops T2D by 8 weeks of age. We assessed metabolism and skeletal acquisition in male TALLYHO/JngJ and SWR/J controls (n = 8-10/group) from 4 weeks to 8 and 17 weeks of age. Tallyho mice were obese; had an approximately 2-fold higher leptin and percentage body fat; and had lower bone mineral density vs SWR at all time points (P < .03 for all). Tallyho had severe deficits in distal femur trabecular bone volume fraction (-54%), trabecular number (-27%), and connectivity density (-82%) (P < .01 for all). Bone formation was higher in Tallyho mice at 8 weeks but lower by 17 weeks of age vs SWR despite similar numbers of osteoblasts. Bone marrow adiposity was 7- to 50-fold higher in Tallyho vs SWR. In vitro, primary bone marrow stromal cell differentiation into osteoblast and adipocyte lineages was similar in SWR and Tallyho, suggesting skeletal deficits were not due to intrinsic defects in Tallyho bone-forming cells. These data suggest the Tallyho mouse might be a useful model to study the skeletal effects of adolescent T2D.

Association between oral habits, mouth breathing and malocclusion.

PubMed

Grippaudo, C; Paolantonio, E G; Antonini, G; Saulle, R; La Torre, G; Deli, R

2016-10-01

The ratio of bad habits, mouth breathing and malocclusion is an important issue in view of prevention and early treatment of disorders of the craniofacial growth. While bad habits can interfere with the position of the teeth and normal pattern of skeletal growth, on the other hand obstruction of the upper airway, resulting in mouth breathing, changes the pattern of craniofacial growth causing malocclusion. Our crosssectional study, carried out on 3017 children using the ROMA index, was developed to verify if there was a significant correlation between bad habits/mouth breathing and malocclusion. The results showed that an increase in the degree of the index increases the prevalence of bad habits and mouth breathing, meaning that these factors are associated with more severe malocclusions. Moreover, we found a significant association of bad habits with increased overjet and openbite, while no association was found with crossbite. Additionally, we found that mouth breathing is closely related to increased overjet, reduced overjet, anterior or posterior crossbite, openbite and displacement of contact points. Therefore, it is necessary to intervene early on these aetiological factors of malocclusion to prevent its development or worsening and, if already developed, correct it by early orthodontic treatment to promote eugnatic skeletal growth. © Copyright by Società Italiana di Otorinolaringologia e Chirurgia Cervico-Facciale, Rome, Italy.

Early Exercise Rehabilitation of Muscle Weakness in Acute Respiratory Failure Patients

PubMed Central

Berry, Michael J.; Morris, Peter E.

2013-01-01

Acute Respiratory Failure patients experience significant muscle weakness which contributes to prolonged hospitalization and functional impairments post-hospital discharge. Based on our previous work, we hypothesize that an exercise intervention initiated early in the intensive care unit aimed at improving skeletal muscle strength could decrease hospital stay and attenuate the deconditioning and skeletal muscle weakness experienced by these patients. Summary Early exercise has the potential to decrease hospital length of stay and improve function in Acute Respiratory Failure patients. PMID:23873130

Integrated diagenetic and sequence stratigraphy of a late Oligocene-early Miocene, mixed-sediment platform (Austral Basin, southern Patagonia): Resolving base-level and paleoceanographic changes, and paleoaquifer characteristics

NASA Astrophysics Data System (ADS)

Dix, George R.; Parras, Ana

2014-06-01

A condensed (~ 20-m-thick) marine transgressive-highstand succession comprises the upper San Julián Formation (upper Oligocene-lower Miocene) of the northern retroarc Austral Basin, southern Patagonia. Mixed-sediment facies identify a shelf-interior setting, part of an overall warm-temperate regional platform of moderate energy. Giant oyster-dominated skeletal-hiatal accumulations along the maximum flooding surface and forming high-energy event beds in the highstand succession preserve relict micrite in protected shelter porosity, and identify periods of reduced sediment accumulation. The stratigraphic distribution of marine-derived glaucony and diagenetic carbonates is spatially related to sequence development. Depositional siderite coincides with prominent marine transgression, defining transient mixing of marine and meteoric waters across coastal-plain deposits. Chemically evolved autochthonous glaucony coincides with periods of extended seafloor exposure and transgressions that bracket the marine succession, and within the oyster-dominated skeletal accumulations. Seafloor cement, likely once magnesian calcite, formed in association with an encrusting/boring biota along the maximum flooding surface in concert with incursion of cool (11-13 °C) water. The cement is present locally in skeletal event beds in the highstand succession suggesting a possible association with high-order base-level change and cooler water. As the highstand succession coincides with elevated global sea level in the late Oligocene-early Miocene, the locally marine-cemented glauconitic skeletal event beds in the highstand succession may identify higher order glacio-eustatic control. Local stratal condensation, however, is best explained by regional differences in basement subsidence. In the burial realm, carbonate diagenesis produced layers of phreatic calcrete coincident with skeletal-rich deposits. Zeolite (clinoptilolite-K) cement is restricted to the lowermost marine transgressive interval probably due to initial elevated metastability of reworked weathered silicates. Clay (illite)-cement is restricted to siliciclastic-rich intervals wherein skeletal carbonate did not buffer pore-water pH. Diagenetic carbonate geochemistry (Sr, Na, and δ18O and δ13C) shows that, with burial, the transgressive and highstand system tracts developed as distinct paleoaquifers resulting from different proximities to meteoric recharge zones.

Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system.

PubMed

Sabharwal, Rasna; Chapleau, Mark W

2014-04-01

New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of LV dysfunction and higher mortality in Sgcd-/- mice. Treatment of Sgcd-/- mice with the angiotensin type 1 receptor blocker losartan for 8-9 weeks, beginning at 3 weeks of age, decreased fibrosis and oxidative stress in skeletal muscle, increased locomotor activity and prevented autonomic dysfunction. Chronic infusion of the counter-regulatory peptide angiotensin-(1-7) resulted in similar protection. We conclude that activation of the renin-angiotensin system, at a young age, contributes to skeletal muscle and autonomic dysfunction in muscular dystrophy. We speculate that the latter is mediated via abnormal sensory nerve and/or cytokine signalling from dystrophic skeletal muscle to the brain and contributes to age-related LV dysfunction, dilated cardiomyopathy, arrhythmias and premature death. Therefore, correcting the early autonomic dysregulation and renin-angiotensin system activation may provide a novel therapeutic approach in muscular dystrophy.

Beyond sarcopenia: Characterization and integration of skeletal muscle quantity and radiodensity in a curable breast cancer population.

PubMed

Weinberg, Marc S; Shachar, Shlomit S; Muss, Hyman B; Deal, Allison M; Popuri, Karteek; Yu, Hyeon; Nyrop, Kirsten A; Alston, Shani M; Williams, Grant R

2018-05-01

Skeletal muscle loss, commonly known as sarcopenia, is highly prevalent and prognostic of adverse outcomes in oncology. However, there is limited information on adults with early breast cancer and examination of other skeletal muscle indices, despite the potential prognostic importance. This study characterizes and examines age-related changes in body composition of adults with early breast cancer and describes the creation of a novel integrated muscle measure. Female patients diagnosed with stage I-III breast cancer with abdominal computerized tomography (CT) scans within 12 weeks from diagnosis were identified from local tumor registry (N = 241). Skeletal muscle index (muscle area per height [cm 2 /m 2 ]), skeletal muscle density, and subcutaneous and visceral adipose tissue areas, were determined from CT L3 lumbar segments. We calculated a novel integrated skeletal measure, skeletal muscle gauge, which combines skeletal muscle index and density (SMI × SMD). 241 patients were identified with available CT imaging. Median age 52 years and range of 23-87. Skeletal muscle index and density significantly decreased with age. Using literature based cut-points, older adults (≥65 years) had significantly higher proportions of sarcopenia (63 vs 28%) and myosteatosis (90 vs 11%) compared to younger adults (<50 years). Body mass index was positively correlated with skeletal muscle index and negatively correlated with muscle density. Skeletal muscle gauge correlated better with increasing age (ρ = 0.52) than with either skeletal muscle index (ρ = 0.20) or density (ρ = 0.46). Wide variations and age-related changes in body composition metrics were found using routinely obtained abdominal CT imaging. Skeletal muscle index and density provide independent, complementary information, and the product of the two metrics, skeletal muscle gauge, requires further research to explore its impact on outcomes in women with curable breast cancer. © 2017 Wiley Periodicals, Inc.

Flapping before Flight: High Resolution, Three-Dimensional Skeletal Kinematics of Wings and Legs during Avian Development

PubMed Central

Heers, Ashley M.; Baier, David B.; Jackson, Brandon E.; Dial, Kenneth P.

2016-01-01

Some of the greatest transformations in vertebrate history involve developmental and evolutionary origins of avian flight. Flight is the most power-demanding mode of locomotion, and volant adult birds have many anatomical features that presumably help meet these demands. However, juvenile birds, like the first winged dinosaurs, lack many hallmarks of advanced flight capacity. Instead of large wings they have small “protowings”, and instead of robust, interlocking forelimb skeletons their limbs are more gracile and their joints less constrained. Such traits are often thought to preclude extinct theropods from powered flight, yet young birds with similarly rudimentary anatomies flap-run up slopes and even briefly fly, thereby challenging longstanding ideas on skeletal and feather function in the theropod-avian lineage. Though skeletons and feathers are the common link between extinct and extant theropods and figure prominently in discussions on flight performance (extant birds) and flight origins (extinct theropods), skeletal inter-workings are hidden from view and their functional relationship with aerodynamically active wings is not known. For the first time, we use X-ray Reconstruction of Moving Morphology to visualize skeletal movement in developing birds, and explore how development of the avian flight apparatus corresponds with ontogenetic trajectories in skeletal kinematics, aerodynamic performance, and the locomotor transition from pre-flight flapping behaviors to full flight capacity. Our findings reveal that developing chukars (Alectoris chukar) with rudimentary flight apparatuses acquire an “avian” flight stroke early in ontogeny, initially by using their wings and legs cooperatively and, as they acquire flight capacity, counteracting ontogenetic increases in aerodynamic output with greater skeletal channelization. In conjunction with previous work, juvenile birds thereby demonstrate that the initial function of developing wings is to enhance leg performance, and that aerodynamically active, flapping wings might better be viewed as adaptations or exaptations for enhancing leg performance. PMID:27100994

Skeletal development and abnormalities of the vertebral column and of the fins in hatchery-reared turbot Scophthalmus maximus.

PubMed

Tong, X H; Liu, Q H; Xu, S H; Ma, D Y; Xiao, Z Z; Xiao, Y S; Li, J

2012-03-01

To describe the skeletal development and abnormalities in turbot Scophthalmus maximus, samples were collected every day from hatching to 60 days after hatching (DAH). A whole-mount cartilage and bone-staining technique was used. Vertebral ontogeny started with the formation of anterior haemal arches at 5·1 mm standard length (L(S) ) c. 11 DAH, and was completed by the full attainment of parapophyses at 16·9 mm L(S) c. 31 DAH. Vertebral centra started to develop at 6·3 mm L(S) c. 16 DAH and ossification in all centra was visible at 11·0 mm L(S) c. 25 DAH. The caudal fin appeared at 5·1 mm L(S) c. 11 DAH and ossification was visible at 20·6 mm L(S) c. 37 DAH. The onset of dorsal and anal fin elements appeared at 5·8 mm L(S) c. 15 DAH and 6·3 mm L(S) c. 16 DAH, respectively. Ossifications of both dorsal fin and anal fin were visible at 20·6 mm L(S) c. 37 DAH. The pectorals were the only fins present before first feeding, their ossifications were completed at 23·5 mm L(S) c. 48 DAH. Pelvic fins began forming at 7·2 mm L(S) c. 19 DAH and calcification of the whole structure was visible at 19·8 mm L(S) c. 36 DAH. In the present study, 24 types of skeletal abnormalities were observed. About 51% of individuals presented skeletal abnormalities, and the highest occurrence was found in the haemal region of the vertebral column. As for each developmental stage, the most common abnormalities were in the dorsal fin during early metamorphic period (stage 2), vertebral fusion during climax metamorphosis (stage 3) and caudal fin abnormality during both late-metamorphic period (stage 4) and post-metamorphic period (stage 5). Such research will be useful for early detection of skeletal malformations during different growth periods of reared S. maximus. © 2012 The Authors. Journal of Fish Biology © 2012 The Fisheries Society of the British Isles.

Genomic architecture of histone 3 lysine 27 trimethylation during late ovine skeletal muscle development.

PubMed

Byrne, K; McWilliam, S; Vuocolo, T; Gondro, C; Cockett, N E; Tellam, R L

2014-06-01

The ruminant developmental transition from late foetus to lamb is associated with marked changes in skeletal muscle structure and function that reflect programming for new physiological demands following birth. To determine whether epigenetic changes are involved in this transition, we investigated the genomic architecture of the chromatin modification, histone 3 lysine 27 trimethylation (H3K27me3), which typically regulates early life developmental processes; however, its role in later life processes is unclear. Chromatin immunoprecipitation coupled with next-generation sequencing was used to map H3K27me3 nucleosomes in ovine longissimus lumborum skeletal muscle at 100 days of gestation and 12 weeks post-partum. In both states, H3K27me3 modification was associated with genes, transcription start sites and CpG islands and with transcriptional silencing. The H3K27me3 peaks consisted of two major categories, promoter specific and regional, with the latter the dominant feature. Genes encoding homeobox transcription factors regulating early life development and genes involved in neural functions, particularly gated ion channels, were strongly modified by H3K27me3. Gene promoters differentially modified by H3K27me3 in the foetus and lamb were enriched for gated ion channels, which may reflect changes in neuromuscular function. However, most modified genes showed no changes, indicating that H3K27me3 does not have a large role in late muscle maturation. Notably, promyogenic transcription factors were strongly modified with H3K27me3 but showed no differences between the late gestation foetus and lamb, likely reflecting their lack of involvement in the myofibre fusion process occurring in this transition. H3K27me3 is a major architectural feature of the epigenetic landscape of ruminant skeletal muscle, and it comments on gene transcription and gene function in the context of late skeletal muscle development. © 2014 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.

Biological Maturation in Adolescence and the Development of Drinking Habits and Alcohol Abuse among Young Males: A Prospective Longitudinal Study.

ERIC Educational Resources Information Center

Andersson, Tommy; Magnusson, David

1990-01-01

The relationship between biological maturation, as evidenced by skeletal growth, during adolescence and the development of drinking habits and alcohol abuse was studied for a representative group of Swedish males (N=88). Early and late maturers had more advanced drinking habits at age 14 years than did normally maturing subjects. (TJH)

Infant formula increases bone turnover favoring bone formation

USDA-ARS?s Scientific Manuscript database

In the first year of life, the major infant food choices have traditionally been breast milk (BM), cow's milk formula (MF), or soy formula (SF). Studies examining the effects of infant formula on early life skeletal development are extremely limited. We have enrolled 120 healthy 6-month-old infants ...

Forward genetics defines Xylt1 as a key, conserved regulator of early chondrocyte maturation and skeletal length.

PubMed

Mis, Emily K; Liem, Karel F; Kong, Yong; Schwartz, Nancy B; Domowicz, Miriam; Weatherbee, Scott D

2014-01-01

The long bones of the vertebrate body are built by the initial formation of a cartilage template that is later replaced by mineralized bone. The proliferation and maturation of the skeletal precursor cells (chondrocytes) within the cartilage template and their replacement by bone is a highly coordinated process which, if misregulated, can lead to a number of defects including dwarfism and other skeletal deformities. This is exemplified by the fact that abnormal bone development is one of the most common types of human birth defects. Yet, many of the factors that initiate and regulate chondrocyte maturation are not known. We identified a recessive dwarf mouse mutant (pug) from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. pug mutant skeletal elements are patterned normally during development, but display a ~20% length reduction compared to wild-type embryos. We show that the pug mutation does not lead to changes in chondrocyte proliferation but instead promotes premature maturation and early ossification, which ultimately leads to disproportionate dwarfism. Using sequence capture and high-throughput sequencing, we identified a missense mutation in the Xylosyltransferase 1 (Xylt1) gene in pug mutants. Xylosyltransferases catalyze the initial step in glycosaminoglycan (GAG) chain addition to proteoglycan core proteins, and these modifications are essential for normal proteoglycan function. We show that the pug mutation disrupts Xylt1 activity and subcellular localization, leading to a reduction in GAG chains in pug mutants. The pug mutant serves as a novel model for mammalian dwarfism and identifies a key role for proteoglycan modification in the initiation of chondrocyte maturation. © 2013 Published by Elsevier Inc.

Stage specific effects of soluble copper and copper oxide nanoparticles during sea urchin embryo development and their relation to intracellular copper uptake.

PubMed

Torres-Duarte, Cristina; Ramos-Torres, Karla M; Rahimoff, René; Cherr, Gary N

2017-08-01

The effects of exposure to either soluble copper (copper sulfate) or copper oxide nanoparticles (nano-CuO) during specific early developmental stages of sea urchin embryos were analyzed. Soluble copper caused significant malformations in embryos (skeletal malformations, delayed development or gut malformations) when present at any given stage, while cleavage stage was the most sensitive to nano-CuO exposure causing skeletal malformations and decreased total antioxidant capacity. The stage specificity was linked to higher endocytic activity during the first hours of development that leads to higher accumulation of copper in specific cells critical for development. Results indicate that nano-CuO results in higher accumulation of copper inside of embryos and this intracellular copper is more persistent as compared to soluble copper. The possible implications later in development are discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

Osteoblast differentiation and skeletal development are regulated by Mdm2–p53 signaling

PubMed Central

Lengner, Christopher J.; Steinman, Heather A.; Gagnon, James; Smith, Thomas W.; Henderson, Janet E.; Kream, Barbara E.; Stein, Gary S.; Lian, Jane B.; Jones, Stephen N.

2006-01-01

Mdm2 is required to negatively regulate p53 activity at the peri-implantation stage of early mouse development. However, the absolute requirement for Mdm2 throughout embryogenesis and in organogenesis is unknown. To explore Mdm2–p53 signaling in osteogenesis, Mdm2-conditional mice were bred with Col3.6-Cre–transgenic mice that express Cre recombinase in osteoblast lineage cells. Mdm2-conditional Col3.6-Cre mice die at birth and display multiple skeletal defects. Osteoblast progenitor cells deleted for Mdm2 have elevated p53 activity, reduced proliferation, reduced levels of the master osteoblast transcriptional regulator Runx2, and reduced differentiation. In contrast, p53-null osteoprogenitor cells have increased proliferation, increased expression of Runx2, increased osteoblast maturation, and increased tumorigenic potential, as mice specifically deleted for p53 in osteoblasts develop osteosarcomas. These results demonstrate that p53 plays a critical role in bone organogenesis and homeostasis by negatively regulating bone development and growth and by suppressing bone neoplasia and that Mdm2-mediated inhibition of p53 function is a prerequisite for Runx2 activation, osteoblast differentiation, and proper skeletal formation. PMID:16533949

The relative expression levels of insulin-like growth factor 1 and myostatin mRNA in the asynchronous development of skeletal muscle in ducks during early development.

PubMed

Hu, Yan; Liu, Hongxiang; Shan, Yanju; Ji, Gaige; Xu, Wenjuan; Shu, Jingting; Li, Huifang

2015-08-10

Genetic selection is a powerful tool for modifying poultry muscle yield. Insulin-like growth factor I (IGF-I) and myostatin (MSTN) are important regulators of muscle growth, especially in the myogenesis stage. This study compared the developmental pattern of the pectoralis major (PM) and lateral gastrocnemius (LM) muscles, mRNA expression characterization of IGF-I and MSTN-A and their correlation between 14 days in ovo and 1 week post-hatch in two Chinese local duck breeds. During early development, the growth of duck PM and LM followed an asynchronous pattern. Variations in PM growth rate observed with development followed the relative variations of MSTN and IGF-I expression; however, the same behavior was not observed in LM. Moreover, the profile of IGF-I expression in duck skeletal muscles indicated that genetic selection for high meat-yield poultry has altered the temporal expression of IGF-I and affected cellular characteristics and mass by hatch in a PM-specific manner. The MSTN-A expression profile showed synchronization with the growth of skeletal muscle and peaks of myofiber proliferation. The expression patterns of IGF-I and MSTN suggest that duck pectoralis fibers are prioritized for proliferation in embryogenesis. The IGF-1/MSTN-A mRNA ratios in PM and LM presented very similar trends in the changes of myofiber characteristics, and differences in the IGF-1/MSTN-A mRNA ratio in PM between the two breeds corresponded to the timing of differences in PM mass between the varieties. Our results support the hypothesis that relative levels of IGF-I and MSTN mRNA may participate in ordering muscle growth rates with selected development. Copyright © 2015 Elsevier B.V. All rights reserved.

MyoD and Myf6 gene expression patterns in skeletal muscle during embryonic and posthatch development in the domestic duck (Anas platyrhynchos domestica).

PubMed

Li, H; Zhu, C; Tao, Z; Xu, W; Song, W; Hu, Y; Zhu, W; Song, C

2014-06-01

The MyoD and Myf6 genes, which are muscle regulatory factors (MRFs), play major roles in muscle growth and development and initiate muscle fibre formation via the regulation of muscle-specific gene translation. Therefore, MyoD and Myf6 are potential candidate genes for meat production traits in animals and poultry. The objective of this study was to evaluate MyoD and Myf6 gene expression patterns in the skeletal muscle during early developmental stage of ducks. Gene expression levels were detected using the quantitative RT-PCR method in the breast muscle (BM) and leg muscle (LM) at embryonic days 13, 17, 21, 25, 27, as well as at 1 week posthatching in Gaoyou and Jinding ducks (Anas platyrhynchos domestica). The MyoD and Myf6 gene profiles in the two duck breeds were consistent during early development, and MyoD gene expression showed a 'wave' trend in BM and an approximate 'anti-√' trend in LM. Myf6 gene expression in BM showed the highest level at embryonic day 21, which subsequently decreased, although remained relatively high, while levels at embryonic days 13, 17 and 21 were higher in LM. The results of correlation analysis showed that MyoD and Myf6 gene expression levels were more strongly correlated in LM than in BM in both duck breeds. These results indicated that different expression patterns of the MyoD and Myf6 genes in BM and LM may be related to muscle development and differentiation, suggesting that MyoD and Myf6 are integral to skeletal muscle development. © 2013 Blackwell Verlag GmbH.

The Origin and Early Radiation of Archosauriforms: Integrating the Skeletal and Footprint Record.

PubMed

Bernardi, Massimo; Klein, Hendrik; Petti, Fabio Massimo; Ezcurra, Martín D

2015-01-01

We present a holistic approach to the study of early archosauriform evolution by integrating body and track records. The ichnological record supports a Late Permian-Early Triassic radiation of archosauriforms not well documented by skeletal material, and new footprints from the Upper Permian of the southern Alps (Italy) provide evidence for a diversity not yet sampled by body fossils. The integrative study of body fossil and footprint data supports the hypothesis that archosauriforms had already undergone substantial taxonomic diversification by the Late Permian and that by the Early Triassic archosauromorphs attained a broad geographical distribution over most parts of Pangea. Analysis of body size, as deduced from track size, suggests that archosauriform average body size did not change significantly from the Late Permian to the Early Triassic. A survey of facies yielding both skeletal and track record indicate an ecological preference for inland fluvial (lacustrine) environments for early archosauromorphs. Finally, although more data is needed, Late Permian chirotheriid imprints suggest a shift from sprawling to erect posture in archosauriforms before the end-Permian mass extinction event. We highlight the importance of approaching palaeobiological questions by using all available sources of data, specifically through integrating the body and track fossil record.

The Origin and Early Radiation of Archosauriforms: Integrating the Skeletal and Footprint Record

PubMed Central

Bernardi, Massimo; Klein, Hendrik; Petti, Fabio Massimo; Ezcurra, Martín D.

2015-01-01

We present a holistic approach to the study of early archosauriform evolution by integrating body and track records. The ichnological record supports a Late Permian–Early Triassic radiation of archosauriforms not well documented by skeletal material, and new footprints from the Upper Permian of the southern Alps (Italy) provide evidence for a diversity not yet sampled by body fossils. The integrative study of body fossil and footprint data supports the hypothesis that archosauriforms had already undergone substantial taxonomic diversification by the Late Permian and that by the Early Triassic archosauromorphs attained a broad geographical distribution over most parts of Pangea. Analysis of body size, as deduced from track size, suggests that archosauriform average body size did not change significantly from the Late Permian to the Early Triassic. A survey of facies yielding both skeletal and track record indicate an ecological preference for inland fluvial (lacustrine) environments for early archosauromorphs. Finally, although more data is needed, Late Permian chirotheriid imprints suggest a shift from sprawling to erect posture in archosauriforms before the end-Permian mass extinction event. We highlight the importance of approaching palaeobiological questions by using all available sources of data, specifically through integrating the body and track fossil record. PMID:26083612

Low Skeletal Muscle Density Is Associated with Early Death in Patients with Perihilar Cholangiocarcinoma Regardless of Subsequent Treatment.

PubMed

van Vugt, Jeroen L A; Gaspersz, Marcia P; Vugts, Jaynee; Buettner, Stefan; Levolger, Stef; de Bruin, Ron W F; Polak, Wojciech G; de Jonge, Jeroen; Willemssen, François E J A; Groot Koerkamp, Bas; IJzermans, Jan N M

2018-02-16

Low skeletal muscle mass is associated with increased postoperative morbidity and worse survival following resection for perihilar cholangiocarcinoma (PHC). We investigated the predictive value of skeletal muscle mass and density for overall survival (OS) of all patients with suspected PHC, regardless of treatment. Baseline characteristics and parameters regarding disease and treatment were collected from all patients with PHC from 2002 to 2014. Skeletal muscle mass and density were measured at the level of the third lumbar vertebra on CT. The association between skeletal muscle mass and density with OS was investigated using the Kaplan-Meier method and Cox survival. Median OS in 233 included patients did not differ between those with and without low skeletal muscle mass (p = 0.203), whereas a significantly different median OS (months) was observed between patients with low (HR 7.0, 95% CI 4.7-9.3) and high (HR 12.1, 95% CI 8.1-16.1) skeletal muscle density (p = 0.004). Low skeletal muscle density was independently associated with decreased OS (HR 1.78, 95% CI 1.03-3.07, p = 0.040) within the first 6 months but not after 6 months (HR 0.68, 95% CI 0.44-1.07, p = 0.093), after adjusting for age, tumour size and suspected peritoneal or other distant metastases on imaging. A time-dependent effect of skeletal muscle density on OS was found in patients with PHC, regardless of subsequent treatment. Low skeletal muscle density may identify patients at risk for early death. © 2018 The Author(s) Published by S. Karger AG, Basel.

Skeletal Morphogenesis of Microbrachis and Hyloplesion (Tetrapoda: Lepospondyli), and Implications for the Developmental Patterns of Extinct, Early Tetrapods

PubMed Central

Olori, Jennifer C.

2015-01-01

The ontogeny of extant amphibians often is used as a model for that of extinct early tetrapods, despite evidence for a spectrum of developmental modes in temnospondyls and a paucity of ontogenetic data for lepospondyls. I describe the skeletal morphogenesis of the extinct lepospondyls Microbrachis pelikani and Hyloplesion longicostatum using the largest samples examined for either taxon. Nearly all known specimens were re-examined, allowing for substantial anatomical revisions that affect the scoring of characters commonly used in phylogenetic analyses of early tetrapods. The palate of H. longicostatum is re-interpreted and suggested to be more similar to that of M. pelikani, especially in the nature of the contact between the pterygoids. Both taxa possess lateral lines, and M. pelikani additionally exhibits branchial plates. However, early and rapid ossification of the postcranial skeleton, including a well-developed pubis and ossified epipodials, suggests that neither taxon metamorphosed nor were they neotenic in the sense of branchiosaurids and salamanders. Morphogenetic patterns in the foot suggest that digit 5 was developmentally delayed and the final digit to ossify in M. pelikani and H. longicostatum. Overall patterns of postcranial ossification may indicate postaxial dominance in limb and digit formation, but also more developmental variation in early tetrapods than has been appreciated. The phylogenetic position and developmental patterns of M. pelikani and H. longicostatum are congruent with the hypothesis that early tetrapods lacked metamorphosis ancestrally and that stem-amniotes exhibited derived features of development, such as rapid and complete ossification of the skeleton, potentially prior to the evolution of the amniotic egg. PMID:26083733

Congenital scoliosis of a bottlenose dolphin.

PubMed

DeLynn, Ruth; Lovewell, Gretchen; Wells, Randall S; Early, Greg

2011-10-01

There are many reports of cetaceans with deformed and twisted bodies. Skeletal pathology descriptions have shown changes to axial skeletons because of injury, trauma, or disease. We present a bottlenose dolphin (Tursiops truncatus) that shows characteristic patterns of congenital skeletal deformity, including malformed vertebrae, ribs, and sternum. These malformations were consistent with segmentation and formation defects arising during early embryonic development, with a resulting cascade of deformity and compensatory pathology. In spite of severe deformities, the dolphin lived 18 yr, raised two calves, and likely would have lived longer had she not succumbed to sepsis and the piercing of the aorta caused by a stingray barb.

[Calcium in the developing skeletal muscles of the chick embryo].

PubMed

Samosudova, N V; Enenko, S O; Larin, Iu S; Shungskaia, V E

1982-07-01

The osmium-pyroantimonate technique was used for the ultrastructural study of Ca2+-localization in two types of chick embryo skeletal muscles: m. pectoralis and m. soleus. In 8- and 12-day old embryos the pyroantimonate precipitate was found on plasmalemma, condensed chromatine and ribosomes and in N-lines of I-band. During myogenesis (15-, 21-day old embryos) the calcium precipitate is redistributed from the above mentioned sites to terminal cisternae and N-line of I-band. It is proposed that calcium of N-lines may be involved in the glycogenolysis, its association with the muscle contraction occurring particularly at early developmental stages.

A personal historic perspective on the role of chloride in skeletal and cardiac muscle.

PubMed

Hutter, Otto F

2017-03-01

During the early decades of the last century, skeletal muscle was held to be impermeable to chloride ions. This theory, based on shaky grounds, was famously falsified by Boyle and Conway in 1941. Two decades later and onwards, the larger part of the resting conductance of skeletal muscle was found to be due to chloride ions, sensitive to the chemical environment, and to be time-and-voltage dependent. So, much of the groundwork for the physiological role of chloride ions in skeletal muscle was laid before the game-changing discovery of chloride channels. The early history of the role of chloride in cardiac muscle, and work on the relative permeability to foreign anions of different muscles are also here covered from a personal perspective. © 2017 The Author. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Retrospective 25-year follow-up of treatment outcomes in angle Class III patients : Early versus late treatment.

PubMed

Wendl, B; Muchitsch, A P; Winsauer, H; Walter, A; Droschl, H; Jakse, N; Wendl, M; Wendl, T

2017-05-01

To assess early versus late treatment of Class III syndrome for skeletal and dental differences. Thirty-eight Class III patients treated with a chincup were retrospectively analyzed. Baseline data were obtained by reviewing pretreatment (T0) anamnestic records, cephalograms, and casts. The cases were assigned to an early or a late treatment group based on age at T0 (up to 9 years or older than 9 years but before the pubertal growth spurt). Both groups were further compared based on posttreatment data (T1) and long-term follow-up data collected approximately 25 years after treatment (T2). Early treatment was successful in 74% and late treatment in 67% of cases. More failures were noted among male patients. The late treatment group was characterized post therapeutically by significantly more pronounced skeletal parameters of jaw size relative to normal Class I values; in addition, a greater skeletal discrepancy between maxilla and mandible, higher values for mandibular length, Cond-Pog, ramus height, overjet, anterior posterior dysplasia indicator (APDI), lower anterior face height, and gonial angle were measured at T1. The angle between the AB line and mandibular plane was found to be larger at T0, T1, and T2, as well as more pronounced camouflage positions of the lower anterior teeth at T0. The early treatment group was found to exhibit greater amounts of negative overjet at T0 but more effective correction at T1. Early treatment of Class III syndrome resulted in greater skeletal changes with less dental compensation.

Role of reduced insulin-stimulated bone blood flow in the pathogenesis of metabolic insulin resistance and diabetic bone fragility.

PubMed

Hinton, Pamela S

2016-08-01

Worldwide, 387 million adults live with type 2 diabetes (T2D) and an additional 205 million cases are projected by 2035. Because T2D has numerous complications, there is significant morbidity and mortality associated with the disease. Identification of early events in the pathogenesis of insulin resistance and T2D might lead to more effective treatments that would mitigate health and monetary costs. Here, we present our hypothesis that impaired bone blood flow is an early event in the pathogenesis of whole-body metabolic insulin resistance that ultimately leads to T2D. Two recent developments in different fields form the basis for this hypothesis. First, reduced vascular function has been identified as an early event in the development of T2D. In particular, before the onset of tissue or whole body metabolic insulin resistance, insulin-stimulated, endothelium-mediated skeletal muscle blood flow is impaired. Insulin resistance of the vascular endothelium reduces delivery of insulin and glucose to skeletal muscle, which leads to tissue and whole-body metabolic insulin resistance. Second is the paradigm-shifting discovery that the skeleton has an endocrine function that is essential for maintenance of whole-body glucose homeostasis. Specifically, in response to insulin signaling, osteoblasts secret osteocalcin, which stimulates pancreatic insulin production and enhances insulin sensitivity in skeletal muscle, adipose, and liver. Furthermore, the skeleton is not metabolically inert, but contributes to whole-body glucose utilization, consuming 20% that of skeletal muscle and 50% that of white adipose tissue. Without insulin signaling or without osteocalcin activity, experimental animals become hyperglycemic and insulin resistant. Currently, it is not known if insulin-stimulated, endothelium-mediated blood flow to bone plays a role in the development of whole body metabolic insulin resistance. We hypothesize that it is a key, early event. Microvascular dysfunction is a primary cause of diabetic nephropathy, retinopathy and neuropathy and poor bone blood flow is associated with bone loss. Therefore, we also hypothesize that dysfunction of the bone vascular endothelium contributes to the bone fragility observed in T2D. The most important consequence of our-dual hypothesis is the public health significance. Namely, identification of the proximal cause of T2D and associated bone complications allows pursuit of the appropriate therapeutic target to treat and prevent T2D. If our hypothesis that reduced bone blood flow is an early event in the pathogenesis of T2D and diabetic bone fragility is correct, then the endothelium of the bone vasculature should be a therapeutic target. Copyright © 2016 Elsevier Ltd. All rights reserved.

Biomaterial-based delivery for skeletal muscle repair

PubMed Central

Cezar, Christine A.; Mooney, David J.

2015-01-01

Skeletal muscle possesses a remarkable capacity for regeneration in response to minor damage, but severe injury resulting in a volumetric muscle loss can lead to extensive and irreversible fibrosis, scarring, and loss of muscle function. In early clinical trials, the intramuscular injection of cultured myoblasts was proven to be a safe but ineffective cell therapy, likely due to rapid death, poor migration, and immune rejection of the injected cells. In recent years, appropriate therapeutic cell types and culturing techniques have improved progenitor cell engraftment upon transplantation. Importantly, the identification of several key biophysical and biochemical cues that synergistically regulate satellite cell fate has paved the way for the development of cell-instructive biomaterials that serve as delivery vehicles for cells to promote in vivo regeneration. Material carriers designed to spatially and temporally mimic the satellite cell niche may be of particular importance for the complete regeneration of severely damaged skeletal muscle. PMID:25271446

mTORC1 Plays an Important Role in Skeletal Development by Controlling Preosteoblast Differentiation

PubMed Central

Matthews, Mary P.; Martin, Sally K.; Xie, Jianling; Ooi, Soo Siang; Walkley, Carl R.; Codrington, John D.; Ruegg, Markus A.; Hall, Michael N.; Proud, Christopher G.; Gronthos, Stan; Zannettino, Andrew C. W.

2017-01-01

ABSTRACT The mammalian target of rapamycin complex 1 (mTORC1) is activated by extracellular factors that control bone accrual. However, the direct role of this complex in osteoblast biology remains to be determined. To investigate this question, we disrupted mTORC1 function in preosteoblasts by targeted deletion of Raptor (Rptor) in Osterix-expressing cells. Deletion of Rptor resulted in reduced limb length that was associated with smaller epiphyseal growth plates in the postnatal skeleton. Rptor deletion caused a marked reduction in pre- and postnatal bone accrual, which was evident in skeletal elements derived from both intramembranous and endochondrial ossification. The decrease in bone accrual, as well as the associated increase in skeletal fragility, was due to a reduction in osteoblast function. In vitro, osteoblasts derived from knockout mice display a reduced osteogenic potential, and an assessment of bone-developmental markers in Rptor knockout osteoblasts revealed a transcriptional profile consistent with an immature osteoblast phenotype suggesting that osteoblast differentiation was stalled early in osteogenesis. Metabolic labeling and an assessment of cell size of Rptor knockout osteoblasts revealed a significant decrease in protein synthesis, a major driver of cell growth. These findings demonstrate that mTORC1 plays an important role in skeletal development by regulating mRNA translation during preosteoblast differentiation. PMID:28069737

Early growth response-1 negative feedback regulates skeletal muscle postprandial insulin sensitivity via activating Ptp1b transcription.

PubMed

Wu, Jing; Tao, Wei-Wei; Chong, Dan-Yang; Lai, Shan-Shan; Wang, Chuang; Liu, Qi; Zhang, Tong-Yu; Xue, Bin; Li, Chao-Jun

2018-03-15

Postprandial insulin desensitization plays a critical role in maintaining whole-body glucose homeostasis by avoiding the excessive absorption of blood glucose; however, the detailed mechanisms that underlie how the major player, skeletal muscle, desensitizes insulin action remain to be elucidated. Herein, we report that early growth response gene-1 ( Egr-1) is activated by insulin in skeletal muscle and provides feedback inhibition that regulates insulin sensitivity after a meal. The inhibition of the transcriptional activity of Egr-1 enhanced the phosphorylation of the insulin receptor (InsR) and Akt, thus increasing glucose uptake in L6 myotubes after insulin stimulation, whereas overexpression of Egr-1 decreased insulin sensitivity. Furthermore, deletion of Egr-1 in the skeletal muscle improved systemic insulin sensitivity and glucose tolerance, which resulted in lower blood glucose levels after refeeding. Mechanistic analysis demonstrated that EGR-1 inhibited InsR phosphorylation and glucose uptake in skeletal muscle by binding to the proximal promoter region of protein tyrosine phosphatase-1B (PTP1B) and directly activating transcription. PTP1B knockdown largely restored insulin sensitivity and enhanced glucose uptake, even under conditions of EGR-1 overexpression. Our results indicate that EGR-1/PTP1B signaling negatively regulates postprandial insulin sensitivity and suggest a potential therapeutic target for the prevention and treatment of excessive glucose absorption.-Wu, J., Tao, W.-W., Chong, D.-Y., Lai, S.-S., Wang, C., Liu, Q., Zhang, T.-Y., Xue, B., Li, C.-J. Early growth response-1 negative feedback regulates skeletal muscle postprandial insulin sensitivity via activating Ptp1b transcription.

Testicular receptor 2, Nr2c1, is associated with stem cells in the developing olfactory epithelium and other cranial sensory and skeletal structures.

PubMed

Baker, Jennifer L; Wood, Bernard; Karpinski, Beverly A; LaMantia, Anthony-S; Maynard, Thomas M

2016-01-01

Comparative genomic analysis of the nuclear receptor family suggests that the testicular receptor 2, Nr2c1, undergoes positive selection in the human-chimpanzee clade based upon a significant increase in nonsynonymous compared to synonymous substitutions. Previous in situ analyses of Nr2c1 lacked the temporal range and spatial resolution necessary to characterize cellular expression of this gene from early to mid gestation, when many nuclear receptors are key regulators of tissue specific stem or progenitor cells. Thus, we asked whether Nr2c1 protein is associated with stem cell populations in the mid-gestation mouse embryo. Nr2c1 is robustly expressed in the developing olfactory epithelium. Its expression in the olfactory epithelium shifts from multiple progenitor classes at early stages to primarily transit amplifying cells later in olfactory epithelium development. In the early developing central nervous system, Nr2c1 is limited to the anterior telencephalon/olfactory bulb anlagen, coincident with Nestin-positive neuroepithelial stem cells. Nr2c1 is also seen in additional cranial sensory specializations including cells surrounding the mystacial vibrissae, the retinal pigment epithelium and Scarpa's ganglion. Nr2c1 was also detected in a subset of mesenchymal cells in developing teeth and cranial bones. The timing and distribution of embryonic expression suggests that Nr2c1 is primarily associated with the early genesis of mammalian cranial sensory neurons and craniofacial skeletal structures. Thus, Nr2c1 may be a candidate for mediating parallel adaptive changes in cranial neural sensory specializations such as the olfactory epithelium, retina and mystacial vibrissae and in non-neural craniofacial features including teeth. Copyright © 2015 Elsevier B.V. All rights reserved.

Oracle, a novel PDZ-LIM domain protein expressed in heart and skeletal muscle.

PubMed

Passier, R; Richardson, J A; Olson, E N

2000-04-01

In order to identify novel genes enriched in adult heart, we performed a subtractive hybridization for genes expressed in mouse heart but not in skeletal muscle. We identified two alternative splicing variants of a novel PDZ-LIM domain protein, which we named Oracle. Both variants contain a PDZ domain at the amino-terminus and three LIM domains at the carboxy-terminus. Highest homology of Oracle was found with the human and rat enigma proteins in the PDZ domain (62 and 61%, respectively) and in the LIM domains (60 and 69%, respectively). By Northern hybridization analysis, we showed that expression is highest in adult mouse heart, low in skeletal muscle and undetectable in other adult mouse tissues. In situ hybridization in mouse embryos confirmed and extended these data by showing high expression of Oracle mRNA in atrial and ventricular myocardial cells from E8.5. From E9.5 low expression of Oracle mRNA was detectable in myotomes. These data suggest a role for Oracle in the early development and function of heart and skeletal muscle.

Heat shock during early somitogenesis induces caudal vertebral column defects in Atlantic salmon (Salmo salar).

PubMed

Wargelius, Anna; Fjelldal, Per Gunnar; Hansen, Tom

2005-07-01

In several terrestrial vertebrates, heat shock (HS) during somitogenesis causes vertebral deformities. To determine if vertebral deformities can occur due to sudden temperature changes during early development in fish, Atlantic salmon embryos were HS treated during somitogenesis. Ten months later these individuals displayed a high prevalence of caudal vertebral column condensations (27-34%). The defects were located caudally of the abdominal cavity, displaying an even distribution in this region independent of time of HS. To determine if HS disturbed vertebral development during somitogenesis, two genes coding for markers of skeletal development were identified, namely, the secreted protein Shh (Sashh) and the transcription factor Twist (Satwist). These proteins are involved in the proliferation and specification of presumptive skeletal cells (sclerotome) in vertebrates. The spatial expression pattern of sashh and satwist in salmon indicated a functional conservation of these proteins. Furthermore, HS embryos displayed expressional disturbance in both sashh and satwist, indicating an effect of HS on sclerotomal cell patterning. However, the HS-protecting ability in embryos seems to be individually regulated because reduction in gene expression was not detected at all stages; in addition, HS did not induce somitic disturbance and vertebral deformity in all embryos.

A diminutive perinate European Enantiornithes reveals an asynchronous ossification pattern in early birds.

PubMed

Knoll, Fabien; Chiappe, Luis M; Sanchez, Sophie; Garwood, Russell J; Edwards, Nicholas P; Wogelius, Roy A; Sellers, William I; Manning, Phillip L; Ortega, Francisco; Serrano, Francisco J; Marugán-Lobón, Jesús; Cuesta, Elena; Escaso, Fernando; Sanz, Jose Luis

2018-03-05

Fossils of juvenile Mesozoic birds provide insight into the early evolution of avian development, however such fossils are rare. The analysis of the ossification sequence in these early-branching birds has the potential to address important questions about their comparative developmental biology and to help understand their morphological evolution and ecological differentiation. Here we report on an early juvenile enantiornithine specimen from the Early Cretaceous of Europe, which sheds new light on the osteogenesis in this most species-rich clade of Mesozoic birds. Consisting of a nearly complete skeleton, it is amongst the smallest known Mesozoic avian fossils representing post-hatching stages of development. Comparisons between this new specimen and other known early juvenile enantiornithines support a clade-wide asynchronous pattern of osteogenesis in the sternum and the vertebral column, and strongly indicate that the hatchlings of these phylogenetically basal birds varied greatly in size and tempo of skeletal maturation.

Endocrine regulation of fetal skeletal muscle growth: impact on future metabolic health

PubMed Central

Brown, Laura D.

2014-01-01

Establishing sufficient skeletal muscle mass is essential for lifelong metabolic health. The intrauterine environment is a major determinant of the muscle mass that is present for the life course of an individual, because muscle fiber number is set at the time of birth. Thus, a compromised intrauterine environment from maternal nutrient restriction or placental insufficiency that restricts development of muscle fiber number can have permanent effects on the amount of muscle an individual will live with. Reduced muscle mass due to fewer muscle fibers persists even after compensatory or “catch up” postnatal growth occurs. Furthermore, muscle hypertrophy can only partially compensate for this limitation in fiber number. Compelling associations link low birth weight and decreased muscle mass to future insulin resistance, which can drive the development of the metabolic syndrome and type 2 diabetes, and risk for cardiovascular events later in life. There are gaps in knowledge about the origins of reduced muscle growth at the cellular level and how these patterns are set during fetal development. By understanding the nutrient and endocrine regulation of fetal skeletal muscle growth and development, we can direct research efforts towards improving muscle growth early in life in order to prevent the development of chronic metabolic disease later in life. PMID:24532817

Dietary supplementation with β-hydroxy-β-methylbutyrate calcium during the early postnatal period accelerates skeletal muscle fibre growth and maturity in intra-uterine growth-retarded and normal-birth-weight piglets.

PubMed

Wan, Haifeng; Zhu, Jiatao; Su, Guoqi; Liu, Yan; Hua, Lun; Hu, Liang; Wu, Caimei; Zhang, Ruinan; Zhou, Pan; Shen, Yong; Lin, Yan; Xu, Shengyu; Fang, Zhengfeng; Che, Lianqiang; Feng, Bin; Wu, De

2016-04-01

Intra-uterine growth restriction (IUGR) impairs postnatal growth and skeletal muscle development in neonatal infants. This study evaluated whether dietary β-hydroxy-β-methylbutyrate Ca (HMB-Ca) supplementation during the early postnatal period could improve muscle growth in IUGR neonates using piglets as a model. A total of twelve pairs of IUGR and normal-birth-weight (NBW) male piglets with average initial weights (1·85 (sem 0·36) and 2·51 (sem 0·39) kg, respectively) were randomly allotted to groups that received milk-based diets (CON) or milk-based diets supplemented with 800 mg/kg HMB-Ca (HMB) during days 7-28 after birth. Blood and longissimus dorsi (LD) samples were collected and analysed for plasma amino acid content, fibre morphology and the expression of genes related to muscle development. The results indicate that, regardless of diet, IUGR piglets had a significantly decreased average daily weight gain (ADG) compared with that of NBW piglets (P<0·05). However, IUGR piglets fed HMB-Ca had a net weight and ADG similar to that of NBW piglets fed the CON diet. Irrespective of body weight (BW), HMB-Ca supplementation markedly increased the type II fibre cross-sectional area and the mRNA expression of mammalian target of rapamycin (mTOR), insulin-like growth factor-1 and myosin heavy-chain isoform IIb in the LD of piglets (P<0·05). Moreover, there was a significant interaction between the effects of BW and HMB on mTOR expression in the LD (P<0·05). In conclusion, HMB-Ca supplementation during the early postnatal period could improve skeletal muscle growth and maturity by accelerating fast-twitch glycolytic fibre development in piglets.

Time course of the MAPK and PI3-kinase response within 24 h of skeletal muscle overload

NASA Technical Reports Server (NTRS)

Carlson, C. J.; Fan, Z.; Gordon, S. E.; Booth, F. W.

2001-01-01

Knowledge of the molecular mechanisms by which skeletal muscle hypertrophies in response to increased mechanical loading may lead to the discovery of novel treatment strategies for muscle wasting and frailty. To gain insight into potential early signaling mechanisms associated with skeletal muscle hypertrophy, the temporal pattern of mitogen-activated protein kinase (MAPK) phosphorylation and phosphatidylinositol 3-kinase (PI3-kinase) activity during the first 24 h of muscle overload was determined in the rat slow-twitch soleus and fast-twitch plantaris muscles after ablation of the gastrocnemius muscle. p38alpha MAPK phosphorylation was elevated for the entire 24-h overload period in both muscles. In contrast, Erk 2 and p54 JNK phosphorylation were transiently increased by overload, returning to the levels of sham-operated controls by 24 h. PI3-kinase activity was increased by muscle overload only at 12 h of overload and only in the plantaris muscle. In summary, sustained elevation of p38alpha MAPK phosphorylation occurred early in response to muscle overload, identifying this pathway as a potential candidate for mediating early hypertrophic signals in response to skeletal muscle overload.

Early-onset and classical forms of type 2 diabetes show impaired expression of genes involved in muscle branched-chain amino acids metabolism.

PubMed

Hernández-Alvarez, María Isabel; Díaz-Ramos, Angels; Berdasco, María; Cobb, Jeff; Planet, Evarist; Cooper, Diane; Pazderska, Agnieszka; Wanic, Krzystof; O'Hanlon, Declan; Gomez, Antonio; de la Ballina, Laura R; Esteller, Manel; Palacin, Manuel; O'Gorman, Donal J; Nolan, John J; Zorzano, Antonio

2017-10-23

The molecular mechanisms responsible for the pathophysiological traits of type 2 diabetes are incompletely understood. Here we have performed transcriptomic analysis in skeletal muscle, and plasma metabolomics from subjects with classical and early-onset forms of type 2 diabetes (T2D). Focused studies were also performed in tissues from ob/ob and db/db mice. We document that T2D, both early and late onset, are characterized by reduced muscle expression of genes involved in branched-chain amino acids (BCAA) metabolism. Weighted Co-expression Networks Analysis provided support to idea that the BCAA genes are relevant in the pathophysiology of type 2 diabetes, and that mitochondrial BCAA management is impaired in skeletal muscle from T2D patients. In diabetic mice model we detected alterations in skeletal muscle proteins involved in BCAA metabolism but not in obese mice. Metabolomic analysis revealed increased levels of branched-chain keto acids (BCKA), and BCAA in plasma of T2D patients, which may result from the disruption of muscle BCAA management. Our data support the view that inhibition of genes involved in BCAA handling in skeletal muscle takes place as part of the pathophysiology of type 2 diabetes, and this occurs both in early-onset and in classical type 2 diabetes.

Consequences of early extraction of compromised first permanent molar: a systematic review.

PubMed

Saber, Afnan M; Altoukhi, Doua H; Horaib, Mariam F; El-Housseiny, Azza A; Alamoudi, Najlaa M; Sabbagh, Heba J

2018-04-05

The aim of this study was to systematically review the literature to determine the sequelae of early extraction of compromised first permanent molars (FPMs) with regard to the skeletal and dental development of 5- to 15-year-old children. Meta-analysis was conducted when applicable. Our research protocol included a search strategy, inclusion/exclusion criteria, and a data extraction plan. The search engines used were PubMed, Scopus, and Science Direct. Study selection was performed independently by three reviewers. Articles published from 1960 to 2017 were reviewed based on inclusion and exclusion criteria. Meta-analysis was performed to compare space closure between upper and lower arches. Eleven studies fulfilled the inclusion criteria. The consequences were decrease in post extraction space, accelerated development and eruption of second permanents molars (SPMs) and third molars, a decrease in caries and/or fillings on the proximal surfaces of adjacent teeth, lingual tipping and retrusion of incisors, and counter clockwise rotation of the occlusal plane. There were several consequences of early extraction of FPMs, which were related to skeletal and dental development. Our systematic review suggests that comprehensive evaluation of the compromised FPMs should be performed before planning an extraction. The ideal time for FPM extraction is when the SPM is at the early bifurcation stage in order to achieve complete closure of the extraction space by the SPM. Benefits should be weighed over the risks to decrease the risk of unfavorable outcomes as much as possible. However, due to the limited evidence on the outcomes and variables that influence them, high-quality prospective studies are needed.

Syntheses and evaluation of 68 Ga- and 153 Sm-labeled DOTA-conjugated bisphosphonate ligand for potential use in detection of skeletal metastases and management of pain arising from skeletal metastases.

PubMed

Chakraborty, Sudipta; Goswami, Dibakar; Chakravarty, Rubel; Mohammed, Sahiralam Khan; Sarma, Haladhar Deb; Dash, Ashutosh

2018-05-05

This article reports the syntheses and evaluation of 68 Ga- and 153 Sm-complexes of a new DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-conjugated geminal bisphosphonate, DOTA-Bn-SCN-BP, for their potential uses in the early detection of skeletal metastases by imaging and palliation of pain arising from skeletal metastases, respectively. The conjugate was synthesized in high purity following an easily adaptable three-step reaction scheme. Gallium-68- and 153 Sm-complexes were prepared in high yield (>98%) and showed excellent in vitro stability in phosphate-buffered saline (PBS) and human serum. Both the complexes showed high affinity for hydroxyapatite particles in in vitro binding study. In biodistribution studies carried out in normal Wistar rats, both the complexes exhibited rapid skeletal accumulation with almost no retention in any other major organ. The newly synthesized molecule DOTA-Bn-SCN-BP would therefore be a promising targeting ligand for the development of radiopharmaceuticals for both imaging skeletal metastases and palliation of pain arising out of it in patients with cancer when radiolabeled with 68 Ga and 153 Sm, respectively. A systematic comparative evaluation, however, showed that there was no significant improvement of skeletal accumulation of the 153 Sm-DOTA-Bn-SCN-BP complex over 153 Sm-DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid) as the later itself demonstrated optimal properties required for an agent for bone pain palliation. © 2018 John Wiley & Sons A/S.

Relationship between oxidative stress and muscle mass loss in early postmenopause: an exploratory study.

PubMed

Zacarías-Flores, Mariano; Sánchez-Rodríguez, Martha A; García-Anaya, Oswaldo Daniel; Correa-Muñoz, Elsa; Mendoza-Núñez, Víctor Manuel

2018-04-09

Endocrine changes due to menopause have been associated to oxidative stress and muscle mass loss. The study objective was to determine the relationship between both variables in early postmenopause. An exploratory, cross-sectional study was conducted in 107 pre- and postmenopausal women (aged 40-57 years). Levels of serum lipid peroxides and uric acid and enzymes superoxide dismutase and glutathione peroxidase, as well as total plasma antioxidant capacity were measured as oxidative stress markers. Muscle mass using bioelectrical impedance and muscle strength using dynamometry were also measured. Muscle mass, skeletal muscle index, fat-free mass, and body mass index were calculated. More than 90% of participants were diagnosed with overweight or obesity. Postmenopausal women had lower values of muscle mass and strength markers, with a negative correlation between lipid peroxide level and skeletal muscle index (r= -0.326, p<.05), and a positive correlation between uric acid and skeletal muscle index (r=0.295, p<.05). A multivariate model including oxidative stress markers, age, and waist circumference showed lipid peroxide level to be the main contributor to explain the decrease in skeletal muscle mass in postmenopause, since for every 0.1μmol/l increase in lipid peroxide level, skeletal muscle index decreases by 3.03 units. Our findings suggest an association between increased oxidative stress and muscle mass loss in early postmenopause. Copyright © 2018 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.

Short stature/short limb skeletal dysplasia with severe combined immunodeficiency and bowing of the femora: report of two patients and review.

PubMed Central

MacDermot, K D; Winter, R M; Wigglesworth, J S; Strobel, S

1991-01-01

We report two patients with severe combined immunodeficiency and short stature/short limb skeletal dysplasia. Case 1 presented at birth with rhizomelic shortening of the extremities and bowing of the femora. She developed clinical signs of severe combined immunodeficiency at 13 months and died at 21 months. Case 2 had severe prenatal shortening and bowing of the extremities and a small, malformed chest. Symptoms of severe combined immunodeficiency and severe failure to thrive developed soon after birth and she died at 5 months. The diagnosis of severe combined immunodeficiency in our patients was based on their clinical course and necropsy findings, supported in case 1 by the results of immune function tests. The results of investigation of immune function (immunoglobulins, lymphocyte subpopulations, lymphocyte function) are very variable in this syndrome as in other variants of severe combined immunodeficiency. Bone histopathology in both patients showed grossly irregular costochondral junctions, but normal transition of proliferating to hypertrophic chondrocytes. These cases belong to early lethal type 1 short limb skeletal dysplasia with severe combined immunodeficiency. Review of previously published cases with severe combined immunodeficiency and well documented skeletal findings show eight patients with prenatal onset of bowing and shortening of the extremities and metaphyseal abnormalities. These include two sib pairs concordant for the skeletal changes. In these cases, adenosine deaminase levels were not reported. An additional four published cases with associated adenosine deaminase deficiency had only mild metaphyseal abnormalities, but subsequently showed no linear growth.(ABSTRACT TRUNCATED AT 250 WORDS) Images PMID:1999827

Crosstalk between intestinal microbiota, adipose tissue and skeletal muscle as an early event in systemic low-grade inflammation and the development of obesity and diabetes.

PubMed

Bleau, Christian; Karelis, Antony D; St-Pierre, David H; Lamontagne, Lucie

2015-09-01

Obesity is associated with a systemic chronic low-grade inflammation that contributes to the development of metabolic disorders such as cardiovascular diseases and type 2 diabetes. However, the etiology of this obesity-related pro-inflammatory process remains unclear. Most studies have focused on adipose tissue dysfunctions and/or insulin resistance in skeletal muscle cells as well as changes in adipokine profile and macrophage recruitment as potential sources of inflammation. However, low-grade systemic inflammation probably involves a complex network of signals interconnecting several organs. Recent evidences have suggested that disturbances in the composition of the gut microbial flora and alterations in levels of gut peptides following the ingestion of a high-fat diet may be a cause of low-grade systemic inflammation that may even precede and predispose to obesity, metabolic disorders or type 2 diabetes. This hypothesis is appealing because the gastrointestinal system is first exposed to nutrients and may thereby represent the first link in the chain of events leading to the development of obesity-associated systemic inflammation. Therefore, the present review will summarize the latest advances interconnecting intestinal mucosal bacteria-mediated inflammation, adipose tissue and skeletal muscle in a coordinated circuitry favouring the onset of a high-fat diet-related systemic low-grade inflammation preceding obesity and predisposing to metabolic disorders and/or type 2 diabetes. A particular emphasis will be given to high-fat diet-induced alterations of gut homeostasis as an early initiator event of mucosal inflammation and adverse consequences contributing to the promotion of extended systemic inflammation, especially in adipose and muscular tissues. Copyright © 2014 John Wiley & Sons, Ltd.

Early effects of ageing on the mechanical performance of isolated locomotory (EDL) and respiratory (diaphragm) skeletal muscle using the work-loop technique.

PubMed

Tallis, Jason; James, Rob S; Little, Alexander G; Cox, Val M; Duncan, Michael J; Seebacher, Frank

2014-09-15

Previous isolated muscle studies examining the effects of ageing on contractility have used isometric protocols, which have been shown to have poor relevance to dynamic muscle performance in vivo. The present study uniquely uses the work-loop technique for a more realistic estimation of in vivo muscle function to examine changes in mammalian skeletal muscle mechanical properties with age. Measurements of maximal isometric stress, activation and relaxation time, maximal power output, and sustained power output during repetitive activation and recovery are compared in locomotory extensor digitorum longus (EDL) and core diaphragm muscle isolated from 3-, 10-, 30-, and 50-wk-old female mice to examine the early onset of ageing. A progressive age-related reduction in maximal isometric stress that was of greater magnitude than the decrease in maximal power output occurred in both muscles. Maximal force and power developed earlier in diaphragm than EDL muscle but demonstrated a greater age-related decline. The present study indicates that ability to sustain skeletal muscle power output through repetitive contraction is age- and muscle-dependent, which may help rationalize previously reported equivocal results from examination of the effect of age on muscular endurance. The age-related decline in EDL muscle performance is prevalent without a significant reduction in muscle mass, and biochemical analysis of key marker enzymes suggests that although there is some evidence of a more oxidative fiber type, this is not the primary contributor to the early age-related reduction in muscle contractility. Copyright © 2014 the American Physiological Society.

Effects of early sea-floor processes on the taphonomy of temperate shelf skeletal carbonate deposits

NASA Astrophysics Data System (ADS)

Smith, Abigail M.; Nelson, Campbell S.

2003-10-01

Cool-water shelf carbonates differ from tropical carbonates in their sources, modes, and rates of deposition, geochemistry, and diagenesis. Inorganic precipitation, marine cementation, and sediment accumulation rates are absent or slow in cool waters, so that temperate carbonates remain longer at or near the sea bed. Early sea-floor processes, occurring between biogenic calcification and ultimate deposition, thus take on an important role, and there is the potential for considerable taphonomic loss of skeletal information into the fossilised record of cool-water carbonate deposits. The physical breakdown processes of dissociation, breakage, and abrasion are mediated mainly by hydraulic regime, and are always destructive. Impact damage reduces the size of grains, removes structure and therefore information, and ultimately may transform skeletal material into anonymous particles. Abrasion is highly selective amongst and within taxa, their skeletal form and structure strongly influencing resistance to mechanical breakdown. Dissolution and precipitation are the end-members of a two-way chemical equilibrium operating in sea water. In cool waters, inorganic precipitation is rare. There is conflicting opinion about the importance of diagenetic dissolution of carbonate skeletons on the temperate sea floor, but test maceration and early loss of aragonite in particular are reported. Dissolution may relate to undersaturated acidic pore waters generated locally by a combination of microbial metabolisation of organic matter, strong bioturbation, and oxidation of solid phase sulphides immediately beneath the sea floor in otherwise very slowly accumulating skeletal deposits. Laboratory experiments demonstrate that surface-to-volume ratio and skeletal mineralogy are both important in determining skeletal resistance to dissolution. Biological processes on the sea floor include encrustation and bioerosion. Encrustation, a constructive process, may be periodic or seasonal, and can be reversed. It produces both information and material. Bioerosion, in contrast, is destructive and permanent. In temperate areas bioerosion may destroy even very large shells during their long residence at the sea floor, on the order of hundreds to thousands of years. Overall, processes on the temperate sea floor may combine to destroy more carbonate than they produce, and the preservation potential of temperate shelf carbonate into the rock record may be significantly affected. Where preservation does occur in such a destructive regime, the effects of early sea-floor processes will be key determinants of the deposit, resulting in a "taphofacies" characteristic of temperate shelf carbonate sediments.

Body size and pubertal development explain ethnic differences in structural geometry at the femur in Asian, Hispanic and white early adolescent girls living in the US

USDA-ARS?s Scientific Manuscript database

Variation in structural geometry is present in adulthood, but when this variation arises and what influences this variation prior to adulthood remains poorly understood. Ethnicity is commonly the focus of research of skeletal integrity and appears to explain some of the variation in quantification o...

Expansion/Facemask Treatment of an Adult Class III Malocclusion.

PubMed

Jackson, Gregory W; Kravitz, Neal D

2014-01-01

The orthodontic treatment of class III malocclusion with a maxillary deficiency is often treated with maxillary protraction with or without expansion. Skeletal and dental changes have been documented which have combined for the protraction of the maxilla and the correction of the class III malocclusion. Concerning the ideal time to treat a developing class III malocclusion, studies have reported that, although early treatment may be the most effective, face mask therapy can provide a viable option for older children as well. But what about young adults? Can the skeletal and dental changes seen in expansion/facemask therapy in children and adolescents be demonstrated in this age group as well, possibly eliminating the need for orthodontic dental camouflage treatment or orthognathic surgery? A case report is presented of an adult class III malocclusion with a Class III skeletal pattern and maxillary retrusion. Treatment was with nonextraction, comprehensive edgewise mechanics with slow maxillary expansion with a bonded expander and protraction facemask.

Evolution of Class III treatment in orthodontics.

PubMed

Ngan, Peter; Moon, Won

2015-07-01

Angle, Tweed, and Moyers classified Class III malocclusions into 3 types: pseudo, dentoalveolar, and skeletal. Clinicians have been trying to identify the best timing to intercept a Class III malocclusion that develops as early as the deciduous dentition. With microimplants as skeletal anchorage, orthopedic growth modification became more effective, and it also increased the scope of camouflage orthodontic treatment for patients who were not eligible for orthognathic surgery. However, orthodontic treatment combined with orthognathic surgery remains the only option for patients with a severe skeletal Class III malocclusion or a craniofacial anomaly. Distraction osteogenesis can now be performed intraorally at an earlier age. The surgery-first approach can minimize the length of time that the malocclusion needs to worsen before orthognathic surgery. Finally, the use of computed tomography scans for 3-dimensional diagnosis and treatment planning together with advances in imaging technology can improve the accuracy of surgical movements and the esthetic outcomes for these patients. Copyright © 2015 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

Biomarkers of cancer cachexia.

PubMed

Loumaye, Audrey; Thissen, Jean-Paul

2017-12-01

Cachexia is a complex multifactorial syndrome, characterized by loss of skeletal muscle and fat mass, which affects the majority of advanced cancer patients and is associated with poor prognosis. Interestingly, reversing muscle loss in animal models of cancer cachexia leads to prolong survival. Therefore, detecting cachexia and maintaining muscle mass represent a major goal in the care of cancer patients. However, early diagnosis of cancer cachexia is currently limited for several reasons. Indeed, cachexia development is variable according to tumor and host characteristics. In addition, safe, accessible and non-invasive tools to detect skeletal muscle atrophy are desperately lacking in clinical practice. Finally, the precise molecular mechanisms and the key players involved in cancer cachexia remain poorly characterized. The need for an early diagnosis of cancer cachexia supports therefore the quest for a biomarker that might reflect skeletal muscle atrophy process. Current research offers different promising ways to identify such a biomarker. Initially, the quest for a biomarker of cancer cachexia has mostly focused on mediators of muscle atrophy, produced by both tumor and host, in an attempt to define new therapeutic approaches. In another hand, molecules released by the muscle into the circulation during the atrophy process have been also considered as potential biomarkers. More recently, several "omics" studies are emerging to identify new muscular or circulating markers of cancer cachexia. Some genetic markers could also contribute to identify patients more susceptible to develop cachexia. This article reviews our current knowledge regarding potential biomarkers of cancer cachexia. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Characterising the proximal patellar tendon attachment and its relationship to skeletal maturity in adolescent ballet dancers

PubMed Central

Rudavsky, Aliza; Cook, Jillianne; Magnusson, Stig Peter; Kjaer, Michael; Docking, Sean

2017-01-01

Summary Background It is unknown how and when the proximal attachment of the patellar tendon matures; puberty may be key in ensuring normal tendon formation. The aim of this study was to investigate the features of the proximal patellar tendon attachment at different stages of skeletal maturity, to help gain an understanding of how and when the tendon attachment matures. Methods Sixty adolescent elite ballet students (ages 11–18) and eight mature adults participated. Peak height velocity (PHV) estimated skeletal maturity. Ultrasound tissue characterisation (UTC) scan was taken of the left knee and analysed for stability of echopattern. An image-based grading scale for greyscale ultrasound was developed to describe the tendon appearance. Anterior-posterior thickness was measured at the inferior pole of the patella, 1 and 2 centimetres distally. Outcomes were compared with skeletal maturity. Results Mid-portion patellar tendon thickness increased with skeletal maturity (p=0.001 at 1 cm and p=0.007 at 2 cm). There was more variance in structural appearance (greyscale classification and UTC echopattern) in pre and peri-PHV participants. Tendon attachment one-year post PHV appeared similar to mature tendons. Conclusions Early adolescence was associated with highly variable tendon appearance, whereas the tendon appeared mature after PHV. Adolescence may be a critical time for the formation of normal tendon attachment. Level of evidence IIb individual cohort study. PMID:29264342

Demonstration of a day-night rhythm in human skeletal muscle oxidative capacity.

PubMed

van Moorsel, Dirk; Hansen, Jan; Havekes, Bas; Scheer, Frank A J L; Jörgensen, Johanna A; Hoeks, Joris; Schrauwen-Hinderling, Vera B; Duez, Helene; Lefebvre, Philippe; Schaper, Nicolaas C; Hesselink, Matthijs K C; Staels, Bart; Schrauwen, Patrick

2016-08-01

A disturbed day-night rhythm is associated with metabolic perturbations that can lead to obesity and type 2 diabetes mellitus (T2DM). In skeletal muscle, a reduced oxidative capacity is also associated with the development of T2DM. However, whether oxidative capacity in skeletal muscle displays a day-night rhythm in humans has so far not been investigated. Lean, healthy subjects were enrolled in a standardized living protocol with regular meals, physical activity and sleep to reflect our everyday lifestyle. Mitochondrial oxidative capacity was examined in skeletal muscle biopsies taken at five time points within a 24-hour period. Core-body temperature was lower during the early night, confirming a normal day-night rhythm. Skeletal muscle oxidative capacity demonstrated a robust day-night rhythm, with a significant time effect in ADP-stimulated respiration (state 3 MO, state 3 MOG and state 3 MOGS, p < 0.05). Respiration was lowest at 1 PM and highest at 11 PM (state 3 MOGS: 80.6 ± 4.0 vs. 95.8 ± 4.7 pmol/mg/s). Interestingly, the fluctuation in mitochondrial function was also observed in whole-body energy expenditure, with peak energy expenditure at 11 PM and lowest energy expenditure at 4 AM (p < 0.001). In addition, we demonstrate rhythmicity in mRNA expression of molecular clock genes in human skeletal muscle. Our results suggest that the biological clock drives robust rhythms in human skeletal muscle oxidative metabolism. It is tempting to speculate that disruption of these rhythms contribute to the deterioration of metabolic health associated with circadian misalignment.

Gdf11 is a negative regulator of chondrogenesis and myogenesis in the developing chick limb.

PubMed

Gamer, L W; Cox, K A; Small, C; Rosen, V

2001-01-15

GDF11, a new member of the TGF-beta gene superfamily, regulates anterior/posterior patterning in the axial skeleton during mouse embryogenesis. Gdf11 null mice display skeletal abnormalities that appear to represent anterior homeotic transformations of vertebrae consistent with high levels of Gdf11 expression in the primitive streak, presomitic mesoderm, and tail bud. However, despite strong Gdf11 expression in the limb throughout development, this structure does not appear to be affected in the knockout mice. In order to understand this dichotomy of Gdf11 expression versus Gdf11 function, we identified the chicken Gdf11 gene and studied its role during limb formation. In the early limb bud, Gdf11 transcripts are detected in the subectodermal mesoderm at the distal tip, in a region overlapping the progress zone. At these stages, Gdf11 is excluded from the central core mesenchyme where precartilaginous condensations will form. Later in development, Gdf11 continues to be expressed in the distal most mesenchyme and can also be detected more proximally, in between the forming skeletal elements. When beads incubated in GDF11 protein were implanted into the early wing bud, GDF11 caused severe truncations of the limb that affected both the cartilage elements and the muscle. Limb shortening appeared to be the result of an inhibition of chondrogenesis and myogenesis and using an in vitro micromass assay, we confirmed the negative effects of GDF11 on both myogenic and chondrogenic cell differentiation. Analysis of molecular markers of skeletal patterning revealed that GDF11 induced ectopic expression of Hoxd-11 and Hoxd-13, but not of Hoxa-11, Hoxa-13, or the Msx genes. These data suggest that GDF11 may be involved in controlling the late distal expression of the Hoxd genes during limb development and that misregulation of these Hox genes by excess GDF11 may cause some of the observed alterations in skeletal element shape. In addition, GDF11 induced the expression of its own antagonist follistatin, indicating that the activity of GFD11 may be limited by a negative feedback mechanism. The data from our studies in the chick suggest that Gdf11 plays a role in the formation and development of the avian limb skeleton.

Relation of adrenal-derived steroids with bone maturation, mineral density and geometry in healthy prepubertal and early pubertal boys.

PubMed

Vandewalle, S; Taes, Y; Fiers, T; Toye, K; Van Caenegem, E; Kaufman, J-M; De Schepper, J

2014-12-01

Little is known about the effects of adrenal steroids on skeletal maturation and bone mass acquisition in healthy prepubertal boys. To study whether adrenal-derived steroids within the physiological range are associated with skeletal maturation, areal and volumetric bone mineral density (aBMD and vBMD) and bone geometry in healthy prepubertal and early pubertal boys. 98 healthy prepubertal and early pubertal boys (aged 6-14 y) were studied cross-sectionally. Androstenedione (A) and estrone (E1) were determined by liquid chromatography tandem mass spectrometry and DHEAS was determined by immunoassay. Whole body and lumbar spine aBMD and bone area were determined by dual-energy X-ray absorptiometry. Trabecular (distal site) and cortical (proximal site) vBMD and bone geometry were assessed at the non-dominant forearm and leg using peripheral QCT. Skeletal age was determined by X-ray of the left hand. Adrenal-derived steroids (DHEAS, A and E1) are positively associated with bone age in prepubertal and early pubertal children, independently of age. There are no associations between the adrenal-derived steroids and the studied parameters of bone size (lumbar spine and whole body bone area, trabecular or cortical area at the radius or tibia, periosteal circumference and cortical thickness at the radius or tibia) or BMD (aBMD or vBMD). In healthy prepubertal and early pubertal boys, serum adrenal-derived steroid levels, are associated with skeletal maturation, independently of age, but not with bone size or (v)BMD. Our data suggest that adrenal derived steroids are not implicated in the accretion of bone mass before puberty in boys. Copyright © 2014 Elsevier Inc. All rights reserved.

A diminutive perinate European Enantiornithes reveals an asynchronous ossification pattern in early birds

DOE PAGES

Knoll, Fabien; Chiappe, Luis M.; Sanchez, Sophie; ...

2018-03-05

Fossils of juvenile Mesozoic birds provide insight into the early evolution of avian development, however such fossils are rare. The analysis of the ossification sequence in these early-branching birds has the potential to address important questions about their comparative developmental biology and to help understand their morphological evolution and ecological differentiation. Here we report on an early juvenile enantiornithine specimen from the Early Cretaceous of Europe, which sheds new light on the osteogenesis in this most species-rich clade of Mesozoic birds. Consisting of a nearly complete skeleton, it is amongst the smallest known Mesozoic avian fossils representing post-hatching stages ofmore » development. Finally, comparisons between this new specimen and other known early juvenile enantiornithines support a clade-wide asynchronous pattern of osteogenesis in the sternum and the vertebral column, and strongly indicate that the hatchlings of these phylogenetically basal birds varied greatly in size and tempo of skeletal maturation.« less

A diminutive perinate European Enantiornithes reveals an asynchronous ossification pattern in early birds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knoll, Fabien; Chiappe, Luis M.; Sanchez, Sophie

Fossils of juvenile Mesozoic birds provide insight into the early evolution of avian development, however such fossils are rare. The analysis of the ossification sequence in these early-branching birds has the potential to address important questions about their comparative developmental biology and to help understand their morphological evolution and ecological differentiation. Here we report on an early juvenile enantiornithine specimen from the Early Cretaceous of Europe, which sheds new light on the osteogenesis in this most species-rich clade of Mesozoic birds. Consisting of a nearly complete skeleton, it is amongst the smallest known Mesozoic avian fossils representing post-hatching stages ofmore » development. Finally, comparisons between this new specimen and other known early juvenile enantiornithines support a clade-wide asynchronous pattern of osteogenesis in the sternum and the vertebral column, and strongly indicate that the hatchlings of these phylogenetically basal birds varied greatly in size and tempo of skeletal maturation.« less

Gene Expression and Structural Skeletal Responses to Long-Duration Simulated Microgravity in Rats

NASA Technical Reports Server (NTRS)

Shirazi-Fard, Yasaman; Rael, Victoria E.; Torres, Samantha; Steczina, Sonette; Bryant, Sheenah; Tahimic, Candice; Globus, Ruth K.

2017-01-01

In this study, we aim to examine skeletal responses to simulated long-duration spaceflight (90 days) and weight-bearing recovery on bone loss using the ground-based hindlimb unloading (HU) model in adolescent (3-month old) male rats. We hypothesized that simulated microgravity leads to the temporal regulation of oxidative defense genes and pro-bone resorption factors, where there is a progression and eventual plateau; furthermore, early transient changes in these pathways precede skeletal adaptations.

Loss of ATRX Does Not Confer Susceptibility to Osteoarthritis

PubMed Central

Solomon, Lauren A.; Russell, Bailey A.; Makar, David; Bérubé, Nathalie G.; Beier, Frank

2013-01-01

The chromatin remodelling protein ATRX is associated with the rare genetic disorder ATR-X syndrome. This syndrome includes developmental delay, cognitive impairment, and a variety of skeletal deformities. ATRX plays a role in several basic chromatin-mediated cellular events including DNA replication, telomere stability, gene transcription, and chromosome congression and cohesion during cell division. We have used a loss-of-function approach to directly investigate the role of Atrx in the adult skeleton in three different models of selective Atrx loss. We specifically targeted deletion of Atrx to the forelimb mesenchyme, to cartilage and to bone-forming osteoblasts. We previously demonstrated that loss of ATRX in forelimb mesenchyme causes brachydactyly while deletion in chondrocytes had minimal effects during development. We now show that targeted deletion of Atrx in osteoblasts causes minor dwarfism but does not recapitulate most of the skeletal phenotypes seen in ATR-X syndrome patients. In adult mice from all three models, we find that joints lacking Atrx are not more susceptible to osteoarthritis, as determined by OARSI scoring and immunohistochemistry. These results indicate that while ATRX plays limited roles during early stages of skeletal development, deficiency of the protein in adult tissues does not confer susceptibility to osteoarthritis. PMID:24386478

The suprachiasmatic nucleus drives day-night variations in postprandial triglyceride uptake into skeletal muscle and brown adipose tissue.

PubMed

Moran-Ramos, Sofía; Guerrero-Vargas, Natali N; Mendez-Hernandez, Rebeca; Basualdo, Maria Del Carmen; Escobar, Carolina; Buijs, Ruud M

2017-12-01

What is the central question of this study? What are the factors influencing day-night variations in postprandial triglycerides? What is the main finding and its importance? Rats show low postprandial plasma triglyceride concentrations early in the active period that are attributable to a higher uptake by skeletal muscle and brown adipose tissue. We show that these day-night variations in uptake are driven by the suprachiasmatic nucleus, probably via a Rev-erbα-mediated mechanism and independent of locomotor activity. These findings highlight that the suprachiasmatic nucleus has a major role in day-night variations in plasma triglycerides and that disturbances in our biological clock might be an important risk factor contributing to development of postprandial hyperlipidaemia. Energy metabolism follows a diurnal pattern, mainly driven by the suprachiasmatic nucleus (SCN), and disruption of circadian regulation has been linked to metabolic abnormalities. Indeed, epidemiological evidence shows that night work is a risk factor for cardiovascular disease, and postprandial hyperlipidaemia is an important contributor. Therefore, the aim of this work was to investigate the factors that drive day-night variations in postprandial triglycerides (TGs). Intact and SCN-lesioned male Wistar rats were subjected to an oral fat challenge during the beginning of the rest phase (day) or the beginning of the active phase (night). The plasma TG profile was evaluated and tissue TG uptake assayed. After the fat challenge, intact rats showed lower postprandial plasma TG concentrations early in the night when compared with the day. However, no differences were observed in the rate of intestinal TG secretion between day and night. Instead, there was a higher uptake of TG by skeletal muscle and brown adipose tissue early in the active phase (night) when compared with the rest phase (day), and these variations were abolished in rats bearing bilateral SCN lesions. Rev-erbα gene expression suggests this as a possible mediator of the mechanism linking the SCN and day-night variations in TG uptake. These findings show that the SCN has a major role in day-night variations in plasma TGs by promoting TG uptake into skeletal muscle and brown adipose tissue. Consequently, disturbance of the biological clock might be an important risk factor contributing to the development of hyperlipidaemia. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

Disturbances of bone growth and development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ledesma-Medina, J.; Newman, B.; Oh, K.S.

1988-03-01

''What is growth anyway. Can one talk about positive growth in childhood, neutral growth in maturity, and negative growth in old age. Our goal is to help promote normal positive growth in infants and children. To achieve this, we must be cognizant of the morphologic changes of both normal and abnormal bone formation as they are reflected in the radiographic image of the skeleton. The knowledge of the various causes and the pathophysiologic mechanisms of the disturbances of bone growth and development allows us to recognize the early radiographic manifestations. Endocrine and metabolic disorders affect the whole skeleton, but themore » early changes are best seen in the distal ends of the femurs, where growth rate is most rapid. In skeletal infections and in some vascular injuries two-or three-phase bone scintigraphy supercedes radiography early in the course of the disease. MRI has proved to be very helpful in the early detection of avascular bone necrosis, osteomyelitis, and tumor. Some benign bone tumors and many bone dysplasias have distinct and diagnostic radiographic findings that may preclude further studies. In constitutional diseases of bone, including chromosomal aberrations, skeletal surveys of the patient and all family members together with biochemical and cytogenetic studies are essential for both diagnosis and genetic counseling. Our role is to perform the least invasive and most informative diagnostic imaging modalities that corroborate the biochemical and histologic findings to establish the definitive diagnosis. Unrecognized, misdiagnosed, or improperly treated disturbance of bone growth can result in permanent deformity usually associated with disability. 116 references.« less

The effects of Capn1 gene inactivation on skeletal muscle growth, development, and atrophy, and the compensatory role of other proteolytic systems.

PubMed

Kemp, C M; Oliver, W T; Wheeler, T L; Chishti, A H; Koohmaraie, M

2013-07-01

Myofibrillar protein turnover is a key component of muscle growth and degeneration, requiring proteolytic enzymes to degrade the skeletal muscle proteins. The objective of this study was to investigate the role of the calpain proteolytic system in muscle growth development using μ-calpain knockout (KO) mice in comparison with control wild-type (WT) mice, and evaluate the subsequent effects of silencing this gene on other proteolytic systems. No differences in muscle development between genotypes were observed during the early stages of growth due to the up regulation of other proteolytic systems. The KO mice showed significantly greater m-calpain protein abundance (P < 0.01) and activity (P < 0.001), and greater caspase 3/7 activity (P < 0.05). At 30 wk of age, KO mice showed increased protein:DNA (P < 0.05) and RNA:DNA ratios (P < 0.01), greater protein content (P < 0.01) at the expense of lipid deposition (P < 0.05), and an increase in size and number of fast-twitch glycolytic muscle fibers (P < 0.05), suggesting that KO mice exhibit an increased capacity to accumulate and maintain protein in their skeletal muscle. Also, expression of proteins associated with muscle regeneration (neural cell adhesion molecule and myoD) were both reduced in the mature KO mice (P < 0.05 and P < 0.01, respectively), indicating less muscle regeneration and, therefore, less muscle damage. These findings indicate the concerted action of proteolytic systems to ensure muscle protein homeostasis in vivo. Furthermore, these data contribute to the existing evidence of the importance of the calpain system's involvement in muscle growth, development, and atrophy. Collectively, these data suggest that there are opportunities to target the calpain system to promote the growth and/or restoration of skeletal muscle mass.

The life cycle of chondrocytes in the developing skeleton

PubMed Central

Shum, Lillian; Nuckolls, Glen

2002-01-01

Cartilage serves multiple functions in the developing embryo and in postnatal life. Genetic mutations affecting cartilage development are relatively common and lead to skeletal malformations, dysfunction or increased susceptibility to disease or injury. Characterization of these mutations and investigation of the molecular pathways in which these genes function have contributed to an understanding of the mechanisms regulating skeletal patterning, chondrogenesis, endochondral ossification and joint formation. Extracellular growth and differentiation factors including bone morphogenetic proteins, fibroblast growth factors, parathyroid hormone-related peptide, extracellular matrix components, and members of the hedgehog and Wnt families provide important signals for the regulation of cell proliferation, differentiation and apoptosis. Transduction of these signals within the developing mesenchymal cells and chondrocytes results in changes in gene expression mediated by transcription factors including Smads, Msx2, Sox9, signal transducer and activator of transcription (STAT), and core-binding factor alpha 1. Further investigation of the interactions of these signaling pathways will contribute to an understanding of cartilage growth and development, and will allow for the development of strategies for the early detection, prevention and treatment of diseases and disorders affecting the skeleton. PMID:11879545

DNA damage checkpoint pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide.

PubMed

Zhang, Ying; Chen, Guangpei; Gu, Zhen; Sun, Haijian; Karaplis, Andrew; Goltzman, David; Miao, Dengshun

2018-01-01

We previously demonstrated that parathyroid hormone-related peptide (PTHrP) 1-84 knockin ( Pthrp KI) mice, which lacked a PTHrP nuclear localization sequence (NLS) and C-terminus, displayed early senescence, defective osteoblastic bone formation, and skeletal growth retardation. However, the mechanism of action of the PTHrP NLS and C-terminus in regulating development of skeleton is still unclear. In this study, we examined alterations of oxidative stress and DNA damage response-related molecules in Pthrp KI skeletal tissue. We found that ROS levels, protein expression levels of γ-H2AX, a DNA damage marker, and the DNA damage response markers p-Chk2 and p53 were up-regulated, whereas gene expression levels of anti-oxidative enzymes were down-regulated significantly. We therefore further disrupted the DNA damage response pathway by deleting the Chk2 in Pthrp KI (Chk2 -/- KI) mice and did comparison with WT, Chk2 -/- and Pthrp KI littermates. The Pthrp KI mice with Chk2 deletion exhibited a longer lifespan, improvement in osteoblastic bone formation and skeletal growth including width of growth plates and length of long bones, trabecular and epiphyseal bone volume, BMD, osteoblast numbers, type I collagen and ALP positive bone areas, the numbers of total colony-forming unit fibroblasts (CFU-f), ALP + CFU-f and the expression levels of osteogenic genes. In addition, the genes associated with anti-oxidative enzymes were up-regulated significantly, whereas the tumor suppressor genes related to senescence were down-regulated in Chk2 -/- KI mice compared to Pthrp KI mice. Our results suggest that Chk2 deletion in Pthrp KI mice can somewhat rescue defects in osteoblastic bone formation and skeletal growth by enhancing endochondral bone formation and osteogenesis. These studies therefore indicate that the DNA damage checkpoint pathway may be a target for the nuclear action of PTHrP to regulate skeletal development and growth.

Post-natal myogenic and adipogenic developmental

PubMed Central

Konings, Gonda; van Weeghel, Michel; van den Hoogenhof, Maarten MG; Gijbels, Marion; van Erk, Arie; Schoonderwoerd, Kees; van den Bosch, Bianca; Dahlmans, Vivian; Calis, Chantal; Houten, Sander M; Misteli, Tom

2011-01-01

A-type lamins are a major component of the nuclear lamina. Mutations in the LMNA gene, which encodes the A-type lamins A and C, cause a set of phenotypically diverse diseases collectively called laminopathies. While adult LMNA null mice show various symptoms typically associated with laminopathies, the effect of loss of lamin A/C on early post-natal development is poorly understood. Here we developed a novel LMNA null mouse (LMNAGT−/−) based on genetrap technology and analyzed its early post-natal development. We detect LMNA transcripts in heart, the outflow tract, dorsal aorta, liver and somites during early embryonic development. Loss of A-type lamins results in severe growth retardation and developmental defects of the heart, including impaired myocyte hypertrophy, skeletal muscle hypotrophy, decreased amounts of subcutaneous adipose tissue and impaired ex vivo adipogenic differentiation. These defects cause death at 2 to 3 weeks post partum associated with muscle weakness and metabolic complications, but without the occurrence of dilated cardiomyopathy or an obvious progeroid phenotype. Our results indicate that defective early post-natal development critically contributes to the disease phenotypes in adult laminopathies. PMID:21818413

VDR Haploinsufficiency Impacts Body Composition and Skeletal Acquisition in a Gender-Specific Manner

PubMed Central

de Paula, Francisco J. A.; Dick-de-Paula, Ingrid; Bornstein, Sheila; Rostama, Bahman; Le, Phuong; Lotinun, Sutada; Baron, Roland; Rosen, Clifford J.

2011-01-01

The vitamin D receptor (VDR) is crucial for virtually all of vitamin D’s actions and is thought to be ubiquitously expressed. We hypothesized that disruption of one allele of the VDR gene would impact bone development and would have metabolic consequences. Body composition and bone mass (BMD) in VDR heterozygous (VDR HET) mice were compared to those obtained in male and female VDR KO and WT mice at 8 weeks of age. Male mice were also evaluated at 16 weeks, and bone marrow mesenchymal stem cell (MSC) differentiation was evaluated in VDR female mice. Additionally, female VDR HET and WT mice received intermittent PTH treatment or vehicle (VH) for 4 weeks. BMD was determined at baseline and after treatment. MRI was done in vivo at the end of treatment; μCT and bone histomorphometry were performed after killing the animals. VDR HET male mice had normal skeletal development until 16 weeks of age but showed significantly less gain in fat mass than WT mice. In contrast, female VDR HET mice showed decreased total-body BMD at age 8 weeks but ad a normal skeletal response to PTH. MSC differentiation was also impaired in VDR HET female mice. Thus, female VDR HET mice show early impairment in bone acquisition, while male VDR HET mice exhibit a lean phenotype. Our results indicate that the VDR HET mouse is a useful model for studying the metabolic and skeletal impact of decreased vitamin D sensitivity. PMID:21637996

VDR haploinsufficiency impacts body composition and skeletal acquisition in a gender-specific manner.

PubMed

de Paula, Francisco J A; Dick-de-Paula, Ingrid; Bornstein, Sheila; Rostama, Bahman; Le, Phuong; Lotinun, Sutada; Baron, Roland; Rosen, Clifford J

2011-09-01

The vitamin D receptor (VDR) is crucial for virtually all of vitamin D's actions and is thought to be ubiquitously expressed. We hypothesized that disruption of one allele of the VDR gene would impact bone development and would have metabolic consequences. Body composition and bone mass (BMD) in VDR heterozygous (VDR HET) mice were compared to those obtained in male and female VDR KO and WT mice at 8 weeks of age. Male mice were also evaluated at 16 weeks, and bone marrow mesenchymal stem cell (MSC) differentiation was evaluated in VDR female mice. Additionally, female VDR HET and WT mice received intermittent PTH treatment or vehicle (VH) for 4 weeks. BMD was determined at baseline and after treatment. MRI was done in vivo at the end of treatment; μCT and bone histomorphometry were performed after killing the animals. VDR HET male mice had normal skeletal development until 16 weeks of age but showed significantly less gain in fat mass than WT mice. In contrast, female VDR HET mice showed decreased total-body BMD at age 8 weeks but had a normal skeletal response to PTH. MSC differentiation was also impaired in VDR HET female mice. Thus, female VDR HET mice show early impairment in bone acquisition, while male VDR HET mice exhibit a lean phenotype. Our results indicate that the VDR HET mouse is a useful model for studying the metabolic and skeletal impact of decreased vitamin D sensitivity.

Role of interleukin-6 as an early marker of fat embolism syndrome: a clinical study.

PubMed

Prakash, Shiva; Sen, Ramesh Kumar; Tripathy, Sujit Kumar; Sen, Indu Mohini; Sharma, R R; Sharma, Sadhna

2013-07-01

A few animal studies have shown that IL-6 can serve as an early marker of fat embolism syndrome. The degree to which this is true in human trauma victims is unknown. In this clinical study, we sought to determine (1) whether elevated serum IL-6 levels at 6, 12, and 24 hours in patients with skeletal trauma were associated with the development of fat embolism syndrome (FES) within 72 hours after injury, and (2) at what time after trauma peak IL-6 levels are observed. Forty-eight patients between 16 and 40 years old who presented to our tertiary trauma center within 6 hours of injury with long bone and/or pelvic fractures were included in this study. Serum IL-6 levels were measured at 6, 12, and 24 hours after injury. The patients were observed clinically and monitored for 72 hours for development of FES symptoms. Gurd's criteria were used to diagnose FES. Elevated serum IL-6 levels 12 hours after trauma correlated with an increased likelihood of having FES develop; no significant relationship was observed between IL-6 levels at 6 or 24 hours and the development of FES. Patients with FES had a mean IL-6 level of 131 pg/mL, whereas those without FES had a mean IL-6 level of 72 pg/mL. Peak IL-6 levels were observed at 12 hours. An elevated serum IL-6 level may be useful as an early marker of FES in patients with isolated skeletal trauma. Level II, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.

Expression profile of IGF-I-calcineurin-NFATc3-dependent pathway genes in skeletal muscle during early development between duck breeds differing in growth rates.

PubMed

Shu, Jingting; Li, Huifang; Shan, Yanju; Xu, Wenjuan; Chen, Wenfeng; Song, Chi; Song, Weitao

2015-06-01

The insulin-like growth factor I (IGF-I)-calcineurin (CaN)-NFATc signaling pathways have been implicated in the regulation of myocyte hypertrophy and fiber-type specificity. In the present study, the expression of the CnAα, NFATc3, and IGF-I genes was quantified by RT-PCR for the first time in the breast muscle (BM) and leg muscle (LM) on days 13, 17, 21, 25, and 27 of embryonic development, as well as at 7 days posthatching (PH), in Gaoyou and Jinding ducks, which differ in their muscle growth rates. Consistent expression patterns of CnAα, NFATc3, and IGF-I were found in the same anatomical location at different development stages in both duck breeds, showing significant differences in an age-specific fashion. However, the three genes were differentially expressed in the two different anatomical locations (BM and LM). CnAα, NFATc3, and IGF-I messenger RNA (mRNA) could be detected as early as embryonic day 13 (ED13), and the highest level appeared at this stage in both BM and LM. Significant positive relationships were observed in the expression of the studied genes in the BM and LM of both duck breeds. Also, the expression of these three genes showed a positive relationship with the percentage of type IIb fibers and a negative relationship with the percentage of type I fibers and type IIa fibers. Our data indicate differential expression and coordinated developmental regulation of the selected genes involved in the IGF-I-calcineurin-NFATc3 pathway in duck skeletal muscle during embryonic and early PH growth and development; these data also indicate that this signaling pathway might play a role in the regulation of myofiber type transition.

Skeletal anomaly assessment in diploid and triploid juvenile Atlantic salmon (Salmo salar L.) and the effect of temperature in freshwater.

PubMed

Amoroso, G; Adams, M B; Ventura, T; Carter, C G; Cobcroft, J M

2016-04-01

Triploid Atlantic salmon tend to develop a higher prevalence of skeletal anomalies. This tendency may be exacerbated by an inadequate rearing temperature. Early juvenile all-female diploid and triploid Atlantic salmon were screened for skeletal anomalies in consecutive experiments to include two size ranges: the first tested the effect of ploidy (0.2-8 g) and the second the effect of ploidy, temperature (14 °C and 18 °C) and their interaction (8-60 g). The first experiment showed that ploidy had no effect on skeletal anomaly prevalence. A high prevalence of opercular shortening was observed (average prevalence in both ploidies 85.8%) and short lower jaws were common (highest prevalence observed 11.3%). In the second experiment, ploidy, but not temperature, affected the prevalence of short lower jaw (diploids > triploids) and lower jaw deformity (triploids > diploids, highest prevalence observed 11.1% triploids and 2.7% diploids) with a trend indicating a possible developmental link between the two jaw anomalies in triploids. A radiological assessment (n = 240 individuals) showed that at both temperatures triploids had a significantly (P < 0.05) lower number of vertebrae and higher prevalence of deformed individuals. These findings (second experiment) suggest ploidy was more influential than temperature in this study. © 2016 John Wiley & Sons Ltd.

Tracing the evolutionary origin of vertebrate skeletal tissues: insights from cephalochordate amphioxus.

PubMed

Yong, Luok Wen; Yu, Jr-Kai

2016-08-01

Vertebrate mineralized skeletal tissues are widely considered as an evolutionary novelty. Despite the importance of these tissues to the adaptation and radiation of vertebrate animals, the evolutionary origin of vertebrate skeletal tissues remains largely unclear. Cephalochordates (Amphioxus) occupy a key phylogenetic position and can serve as a valuable model for studying the evolution of vertebrate skeletal tissues. Here we summarize recent advances in amphioxus developmental biology and comparative genomics that can help to elucidate the evolutionary origins of the vertebrate skeletal tissues and their underlying developmental gene regulatory networks (GRN). By making comparisons to the developmental studies in vertebrate models and recent discoveries in paleontology and genomics, it becomes evident that the collagen matrix-based connective tissues secreted by the somite-derived cells in amphioxus likely represent the rudimentary skeletal tissues in chordates. We propose that upon the foundation of this collagenous precursor, novel tissue mineralization genes that arose from gene duplications were incorporated into an ancestral mesodermal GRN that makes connective and supporting tissues, leading to the emergence of highly-mineralized skeletal tissues in early vertebrates. Copyright © 2016 Elsevier Ltd. All rights reserved.

Skeletal development in the African elephant and ossification timing in placental mammals

PubMed Central

Hautier, Lionel; Stansfield, Fiona J.; Allen, W. R. Twink; Asher, Robert J.

2012-01-01

We provide here unique data on elephant skeletal ontogeny. We focus on the sequence of cranial and post-cranial ossification events during growth in the African elephant (Loxodonta africana). Previous analyses on ossification sequences in mammals have focused on monotremes, marsupials, boreoeutherian and xenarthran placentals. Here, we add data on ossification sequences in an afrotherian. We use two different methods to quantify sequence heterochrony: the sequence method and event-paring/Parsimov. Compared with other placentals, elephants show late ossifications of the basicranium, manual and pedal phalanges, and early ossifications of the ischium and metacarpals. Moreover, ossification in elephants starts very early and progresses rapidly. Specifically, the elephant exhibits the same percentage of bones showing an ossification centre at the end of the first third of its gestation period as the mouse and hamster have close to birth. Elephants show a number of features of their ossification patterns that differ from those of other placental mammals. The pattern of the initiation of the ossification evident in the African elephant underscores a possible correlation between the timing of ossification onset and gestation time throughout mammals. PMID:22298853

The sarcomeric Z-disc component myopodin is a multiadapter protein that interacts with filamin and alpha-actinin.

PubMed

Linnemann, Anja; van der Ven, Peter F M; Vakeel, Padmanabhan; Albinus, Britta; Simonis, Dirk; Bendas, Gerd; Schenk, Jörg A; Micheel, Burkhard; Kley, Rudolf A; Fürst, Dieter O

2010-09-01

Here we introduce myopodin as a novel filamin C binding partner. Corroborative yeast two-hybrid and biochemical analyses indicate that the central part of myopodin that shows high homology to the closely related protein synaptopodin and that is common to all its currently known or predicted variants interacts with filamin C immunoglobulin-like domains 20-21. A detailed characterization of the previously described interaction between myopodin and alpha-actinin demonstrates for the first time that myopodin contains three independent alpha-actinin-binding sites. Newly developed myopodin-specific antibodies reveal expression at the earliest stages of in vitro differentiation of human skeletal muscle cells preceding the expression of sarcomeric alpha-actinin. Myopodin colocalizes with filamin and alpha-actinin during all stages of muscle development. By contrast, colocalization with its previously identified binding partner zyxin is restricted to early developmental stages. Genetic and cellular analyses of skeletal muscle provided direct evidence for an alternative transcriptional start site in exon three, corroborating the expression of a myopodin variant lacking the PDZ domain encoded by exons 1 and 2 in skeletal muscle. We conclude that myopodin is a multiadapter protein of the sarcomeric Z-disc that links nascent myofibrils to the sarcolemma via zyxin, and might play a role in early assembly and stabilization of the Z-disc. Mutations in FLNC, ACTN2 and several other genes encoding Z-disc-related proteins cause myopathy and cardiomyopathy. Its localization and its association with the myopathy-associated proteins filamin C and alpha-actinin make myopodin an interesting candidate for a muscle disease gene. Copyright 2010 Elsevier GmbH. All rights reserved.

Prevention, treatment, and rehabilitation of anterior cruciate ligament injuries in children

PubMed Central

Lang, Pamela J; Sugimoto, Dai; Micheli, Lyle J

2017-01-01

As more children and adolescents participate in competitive organized sports, there has been an increase in the reported incidence of anterior cruciate ligament (ACL) injuries in these age groups. ACL injuries in skeletally immature athletes present a challenge, as reconstruction must preserve the physis of the distal femur and of the proximal tibia to avoid growth disturbances. Historically, a skeletally immature athlete with an ACL injury was treated with a brace and activity modification until skeletal maturity, with ACL reconstruction being performed at that time in the “non-copers” who experienced instability. More recently, evidence has shown that delayed reconstruction may lead to increased damage to the meniscus and articular cartilage. As a result, early reconstruction is favored to protect the meniscus and allow continued physical activity. While adolescents at or those near skeletal maturity may be treated with standard reconstruction techniques, they may result in growth disturbances in younger athletes with significant growth remaining. In response to the growing need for ACL reconstruction techniques in skeletally immature individuals, physeal-sparing and physeal-respecting reconstruction techniques have been developed. In addition to the advancements in surgical technique, ACL injury prevention has also gained attention. This growing interest in ACL prevention is in part related to the high risk of ACL re-tear, either of the ACL graft or of the contralateral ACL, in children and adolescents. Recent reports indicate that well-designed neuromuscular training programs may reduce the risk of primary and subsequent ACL injuries. PMID:28652828

Role of FGFs/FGFRs in skeletal development and bone regeneration.

PubMed

Du, Xiaolan; Xie, Yangli; Xian, Cory J; Chen, Lin

2012-12-01

Fibroblast growth factor (FGF)/FGF (FGFR) signaling is an important pathway involved in skeletal development. Missense mutations in FGFs and FGFRs were found clinically to cause multiple congenital skeleton diseases including chondrodysplasia, craniosynostosis, syndromes with dysregulated phosphate metabolism. FGFs/FGFRs also have crucial roles in bone fracture repair and bone regeneration. Understanding the molecular mechanisms for the role of FGFs/FGFRs in the regulation of skeletal development, genetic skeletal diseases, and fracture healing will ultimately lead to better treatment of skeleton diseases caused by mutations of FGFs/FGFRs and fracture. This review summarizes the major findings on the role of FGF signaling in skeletal development, genetic skeletal diseases and bone healing, and discusses issues that remain to be resolved in applying FGF signaling-related measures to promote bone healing. This review has also provided a perspective view on future work for exploring the roles and action mechanisms of FGF signaling in skeletal development, genetic skeletal diseases, and fracture healing. Copyright © 2012 Wiley Periodicals, Inc.

Forecasting the timing of peak mandibular growth in males by using skeletal age.

PubMed

Hunter, W Stuart; Baumrind, Sheldon; Popovich, Frank; Jorgensen, Gertrud

2007-03-01

It is generally believed that the orthodontic treatment of a patient with a Class II malocclusion and a small mandible is enhanced by good growth at puberty, so that the timing of peak mandibular growth at puberty becomes of interest. To test the belief that skeletal age, whether early, average, or late, can be used to predict the timing of maximum growth of the mandible, whether early, average, or late, the predictive relationship between skeletal age and peak mandibular growth velocity (PMdV) at puberty was evaluated in 94 boys by using their longitudinal records from 4 to 18 years of age. Skeletal age was determined for each subject at ages 9 through 14 by using the method of Greulich and Pyle. At age 9, the Greulich and Pyle measurements predicted that 30 of the 94 subjects would have delayed PMdV equal to or exceeding 1 SD (of the mean age for PMdV), and 10 would have advanced PMdV equal to or exceeding 1 SD. When the actual age of PMdV was determined retrospectively from plots of annual mandibular growth increments, it was found that only 4 of the 30 in the delayed group had actually experienced delays in PMdV, and only 2 of the 10 in the advanced group had experienced accelerated PMdV. Skeletal age is not a reliable predictor of the timing of PMdV.

The elemental composition of purple sea urchin (Strongylocentrotus purpuratus) calcite and potential effects of pCO2 during early life stages

NASA Astrophysics Data System (ADS)

LaVigne, M.; Hill, T. M.; Sanford, E.; Gaylord, B.; Russell, A. D.; Lenz, E. A.; Hosfelt, J. D.; Young, M. K.

2013-06-01

Ocean acidification will likely have negative impacts on invertebrates producing skeletons composed of calcium carbonate. Skeletal solubility is partly controlled by the incorporation of "foreign" ions (e.g. magnesium) into the crystal lattice of these skeletal structures, a process that is sensitive to a variety of biological and environmental factors. Here we explore effects of life stage, oceanographic region of origin, and changes in the partial pressure of carbon dioxide in seawater (pCO2) on trace elemental composition in the purple sea urchin (Strongylocentrotus purpuratus). We show that, similar to other urchin taxa, adult purple sea urchins have the ability to precipitate skeleton composed of a range of biominerals spanning low- to high-Mg calcites. Mg / Ca and Sr / Ca ratios were substantially lower in adult spines compared to adult tests. On the other hand, trace elemental composition was invariant among adults collected from four oceanographically distinct regions spanning a range of carbonate chemistry conditions (Oregon, Northern California, Central California, and Southern California). Skeletons of newly settled juvenile urchins that originated from adults from the four regions exhibited intermediate Mg / Ca and Sr / Ca between adult spine and test endmembers, indicating that skeleton precipitated during early life stages is more soluble than adult spines and less soluble than adult tests. Mean skeletal Mg / Ca or Sr / Ca of juvenile skeleton did not vary with source region when larvae were reared under present-day, global-average seawater carbonate conditions (400 μatm; pHT = 8.02 ± 0.03 1 SD; Ωcalcite = 3.3 ± 0.2 1 SD). However, when reared under elevated pCO2 (900 μatm; pHT = 7.73 ± 0.03; Ωcalcite = 1.8 ± 0.1), skeletal Sr / Ca in juveniles exhibited increased variance across the four regions. Although larvae from the northern populations (Oregon, Northern California, Central California) did not exhibit differences in Mg or Sr incorporation under elevated pCO2 (Sr / Ca = 2.10 ± 0.06 mmol mol-1; Mg / Ca = 67.4 ± 3.9 mmol mol-1), juveniles of Southern California origin partitioned ~8% more Sr into their skeletons when exposed to higher pCO2 (Sr / Ca = 2.26 ± 0.08 vs. 2.09 ± 0.005 mmol mol-1 1 SD). Together these results suggest that the diversity of carbonate minerologies present across different skeletal structures and life stages in purple sea urchins does not translate into an equivalent geochemical plasticity of response associated with geographic variation or temporal shifts in seawater properties. Rather, composition of S. purpuratus skeleton precipitated during both early and adult life history stages appears relatively robust to spatial gradients and predicted future changes in carbonate chemistry. An exception to this trend may arise during early life stages, where certain populations of purple sea urchins may alter skeletal mineral precipitation rates and composition beyond a given pCO2 threshold. This potential for geochemical plasticity during early development in contrast to adult stage geochemical resilience adds to the growing body of evidence that ocean acidification can have differing effects across organismal life stages.

Environmental stress in the Early Mediaeval Slavic population at Borovce (Slovakia).

PubMed

Obertová, Zuzana

2005-01-01

Several palaeopathological indicators examined in skeletal samples are caused by stress during childhood and remain visible in adults. In this study, dental enamel hypoplasia was observed in 451 individuals from the Early Mediaeval (8th to beginning of 12th c. AD) Slavic skeletal series at Borovce (Slovakia). The presence of enamel hypoplasia was scored in all types of deciduous and permanent teeth. More than one-fourth (27.2%) of the individuals with preserved permanent teeth showed enamel hypoplasia. No significant differences in the occurrence of the enamel lesions were found between males and females. The age at development of hypoplasias was estimated for 74 individuals by measuring the distance of the defect from the cemento-enamel junction. The hypoplastic defects appeared most frequently between 2.5 and 3.0 years. Following the trends observed in the distribution of age at development of the enamel lesions between subadults and adults, individuals stressed earlier in life had a reduced ability to cope with later insults. High prevalence of enamel hypoplasia, especially among 10-14-year-old growing juveniles, has led to the assumption that the Borovce population lived a considerably long period under conditions of high environmental pathogen load, and probably also suffered from some nutritional deficiencies.

EFFECT OF MECHANICAL STIMULI ON SKELETAL REGENERATION AROUND IMPLANTS

PubMed Central

Leucht, Philipp; Kim, Jae-Beom; Wazen, Rima; Currey, Jennifer A.; Nanci, Antonio; Brunski, John B.; Helms, Jill A.

2007-01-01

Due to the aging population and the increasing need for total joint replacements, osseointegration is of a great interest for various clinical disciplines. Our objective was to investigate the molecular and cellular foundation that underlies this process. Here, we used an in vivo mouse model to study the cellular and molecular response in three distinct areas of unloaded implants: the periosteum, the gap between implant and cortical bone, and the marrow space. Our analyses began with the early phases of healing, and continued until the implants were completely osseointegrated. We investigated aspects of osseointegration ranging from vascularization, cell proliferation, differentiation, and bone remodeling. In doing so, we gained an understanding of the healing mechanisms of different skeletal tissues during unloaded implant osseointegration. To continue our analysis, we used a micromotion device to apply a defined physical stimulus to the implants, and in doing so, we dramatically enhanced bone formation in the peri-implant tissue. By comparing strain measurements with cellular and molecular analyses, we developed an understanding of the correlation between strain magnitudes and fate decisions of cells shaping the skeletal regenerate. PMID:17175211

Dwarfism and early death in mice lacking C-type natriuretic peptide

PubMed Central

Chusho, Hideki; Tamura, Naohisa; Ogawa, Yoshihiro; Yasoda, Akihiro; Suda, Michio; Miyazawa, Takashi; Nakamura, Kenji; Nakao, Kazuki; Kurihara, Tatsuya; Komatsu, Yasato; Itoh, Hiroshi; Tanaka, Kiyoshi; Saito, Yoshihiko; Katsuki, Motoya; Nakao, Kazuwa

2001-01-01

Longitudinal bone growth is determined by endochondral ossification that occurs as chondrocytes in the cartilaginous growth plate undergo proliferation, hypertrophy, cell death, and osteoblastic replacement. The natriuretic peptide family consists of three structurally related endogenous ligands, atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP), and is thought to be involved in a variety of homeostatic processes. To investigate the physiological significance of CNP in vivo, we generated mice with targeted disruption of CNP (Nppc−/− mice). The Nppc−/− mice show severe dwarfism as a result of impaired endochondral ossification. They are all viable perinatally, but less than half can survive during postnatal development. The skeletal phenotypes are histologically similar to those seen in patients with achondroplasia, the most common genetic form of human dwarfism. Targeted expression of CNP in the growth plate chondrocytes can rescue the skeletal defect of Nppc−/− mice and allow their prolonged survival. This study demonstrates that CNP acts locally as a positive regulator of endochondral ossification in vivo and suggests its pathophysiological and therapeutic implication in some forms of skeletal dysplasia. PMID:11259675

Atrogin-1 Deficiency Leads to Myopathy and Heart Failure in Zebrafish.

PubMed

Bühler, Anja; Kustermann, Monika; Bummer, Tiziana; Rottbauer, Wolfgang; Sandri, Marco; Just, Steffen

2016-01-30

Orchestrated protein synthesis and degradation is fundamental for proper cell function. In muscle, impairment of proteostasis often leads to severe cellular defects finally interfering with contractile function. Here, we analyze for the first time the role of Atrogin-1, a muscle-specific E3 ubiquitin ligase known to be involved in the regulation of protein degradation via the ubiquitin proteasome and the autophagy/lysosome systems, in the in vivo model system zebrafish (Danio rerio). We found that targeted inactivation of zebrafish Atrogin-1 leads to progressive impairment of heart and skeletal muscle function and disruption of muscle structure without affecting early cardiogenesis and skeletal muscle development. Autophagy is severely impaired in Atrogin-1-deficient zebrafish embryos resulting in the disturbance of the cytoarchitecture of cardiomyocytes and skeletal muscle cells. These observations are consistent with molecular and ultrastructural findings in an Atrogin-1 knockout mouse and demonstrate that the zebrafish is a suitable vertebrate model to study the molecular mechanisms of Atrogin-1-mediated autophagic muscle pathologies and to screen for novel therapeutically active substances in high-throughput in vivo small compound screens (SCS).

Anterior open bite treatment with magnets.

PubMed

Kiliaridis, S; Egermark, I; Thilander, B

1990-11-01

The aim of this study was to examine the effects of repelling magnets on the treatment of anterior open bite and compare them with the effects of acrylic posterior bite-blocks. Twenty patients, aged 9-16 years with skeletal anterior open bite, were randomly divided into two groups. In one group the patients wore posterior repelling magnet splints and in the other they wore acrylic posterior bite-blocks of the same thickness as the magnet splints. The patients were instructed to use their appliance as much as possible (the minimum accepted being 18 hours daily) during a 6-month period. Dental casts, intra-oral photos, and lateral cephalograms were taken before and after treatment, and the patients were also examined regularly to identify the development of any craniomandibular disorders. In the first group, the dental and skeletal vertical relation responded quickly to the magnet treatment. The open bite was generally closed in just under 4 months, especially in patients in early mixed dentition. Spacing in the labial segments decreased in some cases, while slight crowding was induced in others. Transverse problems, i.e. unilateral cross-bite, sometimes followed by scissor-bite on the opposite side, was observed in those patients who were in the early mixed dentition and had used the magnets intensively. The patients who wore acrylic posterior bite-blocks also showed improvement in the dental and skeletal vertical relationships, especially during the first months. This was followed by a 'plateau' period. No transverse problems were found in these patients.

Orthognathic Surgery for the Correction of Severe Skeletal Class III Malocclusion.

PubMed

Kafle, D; Upadhayaya, C; Chaurasia, N; Agarwal, A

2016-01-01

Skeletal Malocclusions results from the abnormal position of maxilla and mandible in relation with cranial base. These types of malocclusion are commonly treated by orthodontic teeth movement known as camouflage orthodontics. However severe skeletal malocclusions cannot be treated by orthodontics alone. Such cases need surgical intervention to align the position of the jaw along with orthodontic correction. This procedure is commonly known as Orthognathic Surgery. Orthognathic Surgery dates back to early eighteenth century but became popular on mid twentieth century. Though the prevalence of skeletal malocclusion is more than 1% the treatment facility was not available in Nepal till 2012. Here we present a case of Skeletal Class III malocclusion treated at Dhulikhel Hospital, Kathmandu University Hospital. For this case, double jaw surgery was performed by le-Fort I osteotomy and Bilateral Sagital Split Osteotomy. Orthognathic surgery has been routinely performed at this centre since then.

Contrasting roles for MyoD in organizing myogenic promoter structures during embryonic skeletal muscle development.

PubMed

Cho, Ok Hyun; Mallappa, Chandrashekara; Hernández-Hernández, J Manuel; Rivera-Pérez, Jaime A; Imbalzano, Anthony N

2015-01-01

Among the complexities of skeletal muscle differentiation is a temporal distinction in the onset of expression of different lineage-specific genes. The lineage-determining factor MyoD is bound to myogenic genes at the onset of differentiation whether gene activation is immediate or delayed. How temporal regulation of differentiation-specific genes is established remains unclear. Using embryonic tissue, we addressed the molecular differences in the organization of the myogenin and muscle creatine kinase (MCK) gene promoters by examining regulatory factor binding as a function of both time and spatial organization during somitogenesis. At the myogenin promoter, binding of the homeodomain factor Pbx1 coincided with H3 hyperacetylation and was followed by binding of co-activators that modulate chromatin structure. MyoD and myogenin binding occurred subsequently, demonstrating that Pbx1 facilitates chromatin remodeling and modification before myogenic regulatory factor binding. At the same time, the MCK promoter was bound by HDAC2 and MyoD, and activating histone marks were largely absent. The association of HDAC2 and MyoD was confirmed by co-immunoprecipitation, proximity ligation assay (PLA), and sequential ChIP. MyoD differentially promotes activated and repressed chromatin structures at myogenic genes early after the onset of skeletal muscle differentiation in the developing mouse embryo. © 2014 Wiley Periodicals, Inc.

Testing times: identifying puberty in an identified skeletal sample.

PubMed

Henderson, Charlotte Y; Padez, Cristina

2017-06-01

Identifying the onset of puberty in skeletal remains can provide evidence of social changes associated with the onset of adulthood. This paper presents the first test of a skeletal method for identifying stages of development associated with the onset of puberty in a skeletal sample of known age and cause of death. Skeletal methods for assessing skeletal development associated with changes associated with puberty were recorded in the identified skeletal collection in Coimbra, Portugal. Historical data on the onset of menarche in this country are used to test the method. As expected, females mature faster than their male counterparts. There is some side asymmetry in development. Menarche was found to have been achieved by an average age of 15. Asymmetry must be taken into account when dealing with partially preserved skeletons. Age of menarche is consistent, although marginally higher, than the age expected based on historical data for this time and location. Skeletal development in males could not be tested against historical data, due to the lack of counterpart historical data. The ill health known to be present in this prematurely deceased population may have delayed skeletal development and the onset of puberty.

Interleukin-2 therapy reverses some immunosuppressive effects of skeletal unloading

NASA Technical Reports Server (NTRS)

Armstrong, Jason W.; Balch, Signe; Chapes, Stephen K.

1994-01-01

Using antiorthostatic suspension, we characterized hematopoietic changes that may be responsible for the detrimental effect of skeletal unloading on macrophage development. Skeletally unloaded mice had suppressed macrophage development in unloaded and loaded bones, which indicated a systemic effect. Bone marrow cells from unloaded mice secreted less macrophage colony-stimulating factor and interleukin-6 than control mice. Additionally, T-lymphocyte proliferation was reduced after skeletal unloading. We show that polyethylene glycol-interleukin-2 therapy reversed the effects of skeletal unloading on macrophage development and cell proliferation.

Cardiac troponin T and fast skeletal muscle denervation in ageing

PubMed Central

Xu, Zherong; Feng, Xin; Dong, Juan; Wang, Zhong‐Min; Lee, Jingyun; Furdui, Cristina; Files, Daniel Clark; Beavers, Kristen M.; Kritchevsky, Stephen; Milligan, Carolanne; Jin, Jian‐Ping; Delbono, Osvaldo

2017-01-01

Abstract Background Ageing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast‐twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow‐twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre‐type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia. Cardiac troponin T (cTnT), the heart muscle‐specific isoform of TnT, is a key component of the mechanisms of muscle contraction. It is expressed in skeletal muscle during early development, after acute sciatic nerve denervation, in various neuromuscular diseases and possibly in ageing muscle. Yet the subcellular localization and function of cTnT in skeletal muscle is largely unknown. Methods Studies were carried out on isolated skeletal muscles from mice, vervet monkeys, and humans. Immunoblotting, immunoprecipitation, and mass spectrometry were used to analyse protein expression, real‐time reverse transcription polymerase chain reaction was used to measure gene expression, immunofluorescence staining was performed for subcellular distribution assay of proteins, and electromyographic recording was used to analyse neurotransmission at the NMJ. Results Levels of cTnT expression in skeletal muscle increased with ageing in mice. In addition, cTnT was highly enriched at the NMJ region—but mainly in the fast‐twitch, not the slow‐twitch, muscle of old mice. We further found that the protein kinase A (PKA) RIα subunit was largely removed from, while PKA RIIα and RIIβ are enriched at, the NMJ—again, preferentially in fast‐twitch but not slow‐twitch muscle in old mice. Knocking down cTnT in fast skeletal muscle of old mice: (i) increased PKA RIα and reduced PKA RIIα at the NMJ; (ii) decreased the levels of gene expression of muscle denervation markers; and (iii) enhanced neurotransmission efficiency at NMJ. Conclusions Cardiac troponin T at the NMJ region contributes to NMJ functional decline with ageing mainly in the fast‐twitch skeletal muscle through interfering with PKA signalling. This knowledge could inform useful targets for prevention and therapy of age‐related decline in muscle function. PMID:28419739

Gravity Plays an Important Role in Muscle Development and the Differentiation of Contractile Protein Phenotype

NASA Technical Reports Server (NTRS)

Adams, Gregory A.; Haddad, Fadia; Baldwin, Kenneth M.

2003-01-01

Several muscles in the body exist mainly to work against gravity. Whether gravity is important in the development of these muscles is not known. By examining the basic proteins that compose muscle, questions about the role of gravity in muscle development can be answered. Myosin heavy chains (MHCs) are a family of proteins critically important for muscle contraction. Several types of MHCs exist (e.g., neonatal, slow, fast), and each type is produced by a particular gene. Neonatal MHCs are produced early in life. Slow MHCs are important in antigravity muscles, and fast MHCs are found in fast-twitch power muscles. The gene that is turned on or expressed will determine which MHC is produced. Early in development, antigravity skeletal muscles (muscles that work against gravity) normally produce a combination of the neonatal/embryonic MHCs. The expression of these primitive MHCs is repressed early in development; and the adult slow and fast MHC genes become fully expressed. We tested the hypothesis that weightbearing activity is critical for inducing the normal expression of the slow MHC gene typically expressed in adult antigravity muscles. Also, we hypothesized that thyroid hormone, but not opposition to gravity, is necessary for expressing the adult fast IIb MHC gene essential for high-intensity muscle performance. Groups of normal thyroid and thyroid-deficient neonatal rats were studied after their return from the 16-day Neurolab mission and compared to matched controls. The results suggest: (1) Weightlessness impaired body and limb skeletal muscle growth in both normal and thyroid-deficient animals. Antigravity muscles were impaired more than those used primarily for locomotion andor nonweightbearing activity. (2) Systemic and muscle expression of insulin-like growth factor-I (IGF-I), an important body and tissue growth factor, was depressed in flight animals. (3) Normal slow, type I MHC gene expression was markedly repressed in the normal thyroid flight group. (4) Fast IIb MHC gene expression was enhanced in fast-twitch muscles of normal thyroid animals exposed to spaceflight; however, thyroid deficiency markedly repressed expression of this gene independently of spaceflight. In summary, the absence of gravity, when imposed at critical stages of development, impaired body and skeletal muscle growth, as well as expression of the MHC gene family of motor proteins. This suggests that normal weightbearing activity is essential for establishing body and muscle growth in neonatal animals, and for expressing the motor gene essential for supporting antigravity functions.

Expression of Pannexin 1 and Pannexin 3 during skeletal muscle development, regeneration, and Duchenne muscular dystrophy.

PubMed

Pham, Tammy L; St-Pierre, Marie-Eve; Ravel-Chapuis, Aymeric; Parks, Tara E C; Langlois, Stéphanie; Penuela, Silvia; Jasmin, Bernard J; Cowan, Kyle N

2018-05-10

Pannexin 1 (Panx1) and Pannexin 3 (Panx3) are single membrane channels recently implicated in myogenic commitment, as well as myoblast proliferation and differentiation in vitro. However, their expression patterns during skeletal muscle development and regeneration had yet to be investigated. Here, we show that Panx1 levels increase during skeletal muscle development becoming highly expressed together with Panx3 in adult skeletal muscle. In adult mice, Panx1 and Panx3 were differentially expressed in fast- and slow-twitch muscles. We also report that Panx1/PANX1 and Panx3/PANX3 are co-expressed in mouse and human satellite cells, which play crucial roles in skeletal muscle regeneration. Interestingly, Panx1 and Panx3 levels were modulated in muscle degeneration/regeneration, similar to the pattern seen during skeletal muscle development. As Duchenne muscular dystrophy is characterized by skeletal muscle degeneration and impaired regeneration, we next used mild and severe mouse models of this disease and found a significant dysregulation of Panx1 and Panx3 levels in dystrophic skeletal muscles. Together, our results are the first demonstration that Panx1 and Panx3 are differentially expressed amongst skeletal muscle types with their levels being highly modulated during skeletal muscle development, regeneration, and dystrophy. These findings suggest that Panx1 and Panx3 channels may play important and distinct roles in healthy and diseased skeletal muscles. © 2018 Wiley Periodicals, Inc.

The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen.

PubMed

Tribioli, C; Lufkin, T

1999-12-01

Our previous studies in both mouse and human identified the Bapx1 homeobox gene, a member of the NK gene family, as one of the earliest markers for prechondrogenic cells that will subsequently undergo mesenchymal condensation, cartilage production and, finally, endochondral bone formation. In addition, Bapx1 is an early developmental marker for splanchnic mesoderm, consistent with a role in visceral mesoderm specification, a function performed by its homologue bagpipe, in Drosophila. The human homologue of Bapx1 has been identified and mapped to 4p16.1, a region containing loci for several skeletal diseases. Bapx1 null mice are affected by a perinatal lethal skeletal dysplasia and asplenia, with severe malformation or absence of specific bones of the vertebral column and cranial bones of mesodermal origin, with the most severely affected skeletal elements corresponding to ventral structures associated with the notochord. We provide evidence that the failure of the formation of skeletal elements in Bapx1 null embryos is a consequence of a failure of cartilage development, as demonstrated by downregulation of several molecular markers required for normal chondroblast differentiation (&agr; 1(II) collagen, Fgfr3, Osf2, Indian hedgehog, Sox9), as well as a chondrocyte-specific alpha1 (II) collagen-lacZ transgene. The cartilage defects are correlated with failed differentiation of the sclerotome at the time when these cells are normally initiating chondrogenesis. Loss of Bapx1 is accompanied by an increase in apoptotic cell death in affected tissues, although cell cycling rates are unaltered.

Low-oxygen waters limited habitable space for early animals.

PubMed

Tostevin, R; Wood, R A; Shields, G A; Poulton, S W; Guilbaud, R; Bowyer, F; Penny, A M; He, T; Curtis, A; Hoffmann, K H; Clarkson, M O

2016-09-23

The oceans at the start of the Neoproterozoic Era (1,000-541 million years ago, Ma) were dominantly anoxic, but may have become progressively oxygenated, coincident with the rise of animal life. However, the control that oxygen exerted on the development of early animal ecosystems remains unclear, as previous research has focussed on the identification of fully anoxic or oxic conditions, rather than intermediate redox levels. Here we report anomalous cerium enrichments preserved in carbonate rocks across bathymetric basin transects from nine localities of the Nama Group, Namibia (∼550-541 Ma). In combination with Fe-based redox proxies, these data suggest that low-oxygen conditions occurred in a narrow zone between well-oxygenated surface waters and fully anoxic deep waters. Although abundant in well-oxygenated environments, early skeletal animals did not occupy oxygen impoverished regions of the shelf, demonstrating that oxygen availability (probably >10 μM) was a key requirement for the development of early animal-based ecosystems.

[Surprisingly old skeleton found at Bornheim-Uedorf (Rhein-Sieg-Kreis)--Research results in forensic medicine, anthropology and archaeology].

PubMed

Zesch, Stephanie; Doberentz, Elke; Schmauder, Michael; Rosendahl, Wilfried; Madea, Burkhard

2016-01-01

On April 15th 2014, human skeletal remains were found during digging activities for constructing a new building at Bornheim-Uedorf (Rhein-Sieg-Kreis) near the river Rhine (about 20 meters) in a pit measuring 10 by 10 meters and having a depth of about 150 cm. The skeletal remains were preserved quite well considering the fact that they were located so near to the Rhine, although several skeletal parts were missing. The preserved skeletal remains comprised some skull fragments (including two ear bones of the right side), right scapula, both humeri, left ulna, left radius, left metacarpal bone 2, right metacarpal bones 1, 3 and 4, rib fragments, three thoracic vertebrae, all lumbar vertebrae, one sacral vertebra, pelvis fragments, left femur, proximal part of the left tibial diaphysis, right tibia and diaphysis of both fibulae. The anthropological analysis revealed that the skeletal remains belonged to a 20-to-30-year-old presumably male individual with a body height of about 163 to 173 cm (depending on the formula used for body height estimation). Evidence of intense physical activity and traumatological findings could not be detected on the preserved bones. Periosteal reactions on the bone surface caused by nonspecific bacterial infection were found on the right humerus close to the elbow and on both tibiae, especially the left one. Besides the skeletal remains, metal fragments were recovered--among them an arrowhead, which was typologically classified as an early medieval finding (6th to 7th century). Radiocarbon dating of a bone sample revealed an age of 1561 ± 19 a BP corresponding to a calibrated age of 436 to 540 AD (1 sigma). So, the archaeological classification of the recovered skeleton into the early medieval period was verified. Amongst the human remains, there was also a metatarsal bone of cattle with cut marks. The animal bone as well as the metal fragments indicated that the find was part of an early medieval burial with typical grave goods.

Dynamical mechanisms for skeletal pattern formation in the vertebrate limb.

PubMed Central

Hentschel, H. G. E.; Glimm, Tilmann; Glazier, James A.; Newman, Stuart A.

2004-01-01

We describe a 'reactor-diffusion' mechanism for precartilage condensation based on recent experiments on chondrogenesis in the early vertebrate limb and additional hypotheses. Cellular differentiation of mesenchymal cells into subtypes with different fibroblast growth factor (FGF) receptors occurs in the presence of spatio-temporal variations of FGFs and transforming growth factor-betas (TGF-betas). One class of differentiated cells produces elevated quantities of the extracellular matrix protein fibronectin, which initiates adhesion-mediated preskeletal mesenchymal condensation. The same class of cells also produces an FGF-dependent laterally acting inhibitor that keeps condensations from expanding beyond a critical size. We show that this 'reactor-diffusion' mechanism leads naturally to patterning consistent with skeletal form, and describe simulations of spatio-temporal distribution of these differentiated cell types and the TGF-beta and inhibitor concentrations in the developing limb bud. PMID:15306292

Nanometer-Scale Chemistry of a Calcite Biomineralization Template: Implications for Skeletal Composition and Nucleation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Branson, Oscar; Bonnin, Elisa A.; Perea, Daniel E.

Biomineralizing organisms exhibit exquisite control over skeletal morphology and composition. The promise of understanding and harnessing this feat of natural engineering has motivated an intense search for the mechanisms that direct in vivo mineral self-assembly. We used atom probe tomography, a sub-nanometer 3D chemical mapping technique, to examine the chemistry of a buried organic-mineral interface in biomineral calcite from a marine foraminifer. The chemical patterns at this interface capture the processes of early biomineralization, when the shape, mineralogy, and orientation of skeletal growth are initially established. Sodium is enriched by a factor of nine on the organic side of themore » interface. Based on this pattern, we suggest that sodium plays an integral role in early biomineralization, potentially altering interfacial energy to promote crystal nucleation, and that interactions between organic surfaces and electrolytes other than calcium or carbonate could be a crucial aspect of CaCO3 biomineralization.« less

Nanometer-Scale Chemistry of a Calcite Biomineralization Template: Implications for Skeletal Composition and Nucleation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Branson, Oscar; Bonnin, Elisa A.; Perea, Daniel E.

2016-10-28

Biomineralizing organisms exhibit exquisite control over skeletal morphology and composition. The promise of understanding and harnessing this feat of natural engineering has motivated an intense search for the mechanisms that direct in vivo mineral self-assembly. We used atom probe tomography, a sub-nanometer 3D chemical mapping technique, to examine the chemistry of a buried organic-mineral interface in biomineral calcite from a marine foraminifer. The chemical patterns at this interface capture the processes of early biomineralization, when the shape, mineralogy, and orientation of skeletal growth are initially established. Sodium is enriched by a factor of nine on the organic side of themore » interface. Based on this pattern, we suggest that sodium plays an integral role in early biomineralization, potentially altering interfacial energy to promote crystal nucleation, and that interactions between organic surfaces and electrolytes other than calcium or carbonate could be a crucial aspect of CaCO3 biomineralization.« less

Nanometer-Scale Chemistry of a Calcite Biomineralization Template: Implications for Skeletal Composition and Nucleation

DOE PAGES

Branson, Oscar; Bonnin, Elisa A.; Perea, Daniel E.; ...

2016-10-28

Biomineralizing organisms exhibit exquisite control over skeletal morphology and composition. The promise of understanding and harnessing this feat of natural engineering has motivated an intense search for the mechanisms that direct in vivo mineral self-assembly. We used atom probe tomography, a sub-nanometer 3D chemical mapping technique, to examine the chemistry of a buried organic-mineral interface in biomineral calcite from a marine foraminifer. Here, the chemical patterns at this interface capture the processes of early biomineralization, when the shape, mineralogy, and orientation of skeletal growth are initially established. Sodium is enriched by a factor of nine on the organic side ofmore » the interface. Based on this pattern, we suggest that sodium plays an integral role in early biomineralization, potentially altering interfacial energy to promote crystal nucleation, and that interactions between organic surfaces and electrolytes other than calcium or carbonate could be a crucial aspect of CaCO 3 biomineralization.« less

Advances on microRNA in regulating mammalian skeletal muscle development.

PubMed

Li, Xin-Yun; Fu, Liang-Liang; Cheng, Hui-Jun; Zhao, Shu-Hong

2017-11-20

MicroRNA (miRNA) is a class of short non-coding RNA, which is about 22 bp in length. In mammals, miRNA exerts its funtion through binding with the 3°-UTR region of target genes and inhibiting their translation. Skeletal muscle development is a complex event, including: proliferation, migration and differentiation of skeletal muscle stem cells; proliferation, differentiation and fusion of myocytes; as well as hypertrophy, energy metabolism and conversion of muscle fiber types. The miRNA plays important roles in all processes of skeletal muscle development through targeting the key factors of different stages. Herein we summarize the miRNA related to muscle development, providing a better understanding of the skeletal muscle development.

Mice transgenic for HTLV-I LTR-tax exhibit tax expression in bone, skeletal alterations, and high bone turnover.

PubMed

Ruddle, N H; Li, C B; Horne, W C; Santiago, P; Troiano, N; Jay, G; Horowitz, M; Baron, R

1993-11-01

HTLV-I infection can result in adult T cell leukemia with accompanying hypercalcemia and increased bone resorption. A viral etiology has also been invoked for Paget's disease, a disease of high bone turnover. Delineation of pathogenetic mechanisms of viral-associated bone diseases has been impeded by the complexity of viral and host factors. In order to consider the relationship of HTLV-I infection to skeletal changes we have evaluated the role of a single viral gene in mice transgenic for HTLV-I tax under the control of the viral promoter. Tax mice exhibited severe skeletal abnormalities characterized by high bone turnover, increases in osteoblast and osteoclast numbers and activity, and myelofibrosis. These changes were apparent as early as two months of age. Tax mRNA and protein were highly expressed in bone but not in bone marrow nor in any other tissues except, as previously reported, salivary gland and neurofibromas when they did develop. Within bone, tax protein was detected in only two cell types, mature osteoclasts and spindle-shaped cells within the endosteal myelofibrosis. These observations suggest that local expression of the tax gene, which encodes a viral regulatory protein known to influence host gene expression, can induce within the bone environment marked changes in bone cell activity, resulting in profound skeletal alterations.

Diffusion-weighted imaging and the skeletal system: a literature review.

PubMed

Yao, K; Troupis, J M

2016-11-01

Diffusion-weighted imaging (DWI) is a magnetic resonance imaging (MRI) sequence that has a well-established role in neuroimaging, and is increasingly being utilised in other clinical contexts, including the assessment of various skeletal disorders. It utilises the variability of Brownian motion of water molecules; the differing patterns of water molecular diffusion in various biological tissues help determine the contrast obtained in DWI. Although early research on the clinical role of DWI focused mainly on the field of neuroimaging, there are now more studies demonstrating the promising role DWI has in the diagnosis and monitoring of various osseous diseases. DWI has been shown to be useful in assessing a patient's skeletal tumour burden, monitoring the post-chemotherapy response of various bony malignancies, detecting hip ischaemia in patients with Legg-Calvé-Perthes disease, as well as determining the quality of repaired articular cartilage. Despite its relative successes, DWI has several limitations, including its limited clinical value in differentiating chondrosarcomas from benign bone lesions, as well as osteoporotic vertebral compression fractures from compression fractures due to malignancy. This literature review aims to provide an overview of the recent developments in the use of DWI in imaging the skeletal system, and to clarify the role of DWI in assessing various osseous diseases. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Fibroblast growth factor signaling in skeletal development and disease

PubMed Central

Ornitz, David M.; Marie, Pierre J.

2015-01-01

Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored. PMID:26220993

Massage therapy during early postnatal life promotes greater lean mass and bone growth, mineralization, and strength in juvenile and young adult rats.

PubMed

Chen, H; Miller, S; Shaw, J; Moyer-Mileur, L

2009-01-01

The objects of this study were to investigate the effects of massage therapy during early life on postnatal growth, body composition, and skeletal development in juvenile and young adult rats. Massage therapy was performed for 10 minutes daily from D6 to D10 of postnatal life in rat pups (MT, n=24). Body composition, bone area, mineral content, and bone mineral density were measured by dual energy X-ray absorptiometry (DXA); bone strength and intrinsic stiffness on femur shaft were tested by three-point bending; cortical and cancellous bone histomorphometric measurements were performed at D21 and D60. Results were compared to age- and gender-matched controls (C, n=24). D21 body weight, body length, lean mass, and bone area were significantly greater in the MT cohort. Greater bone mineral content was found in male MT rats; bone strength and intrinsic stiffness were greater in D60 MT groups. At D60 MT treatment promoted bone mineralization by increasing trabecular mineral apposition rate in male and endosteal mineral surface in females, and also improved micro-architecture by greater trabeculae width in males and decreasing trabecular separation in females. In summary, massage therapy during early life elicited immediate and prolonged anabolic effects on postnatal growth, lean mass and skeletal developmental in a gender-specific manner in juvenile and young adult rats.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou Jun; Huang Kaixun, E-mail: hxxzrf@mail.hust.edu.c

Accumulating evidence suggests that peroxynitrite (ONOO{sup -}) is involved in the pathogenesis of insulin resistance. In the current study, we investigated whether insulin resistance in vivo could be mediated by nitration of proteins involved in the early steps of the insulin signal transduction pathway. Exogenous peroxynitrite donated by 3-morpholinosydnonimine hydrochloride (SIN-1) induced in vivo nitration of the insulin receptor beta subunit (IRbeta), insulin receptor substrate (IRS)-1, and protein kinase B/Akt (Akt) in skeletal muscle of mice and dramatically reduced whole-body insulin sensitivity and muscle insulin signaling. Moreover, in high-fat diet (HFD)-fed insulin-resistant mice, we observed enhanced nitration of IRbeta andmore » IRS-1 in skeletal muscle, in parallel with impaired whole-body insulin sensitivity and muscle insulin signaling. Reversal of nitration of these proteins by treatment with the peroxynitrite decomposition catalyst FeTPPS yielded an improvement in whole-body insulin sensitivity and muscle insulin signaling in HFD-fed mice. Taken together, these findings provide new mechanistic insights for the involvement of peroxynitrite in the development of insulin resistance and suggest that nitration of proteins involved in the early steps of insulin signal transduction is a novel molecular mechanism of HFD-induced muscle insulin resistance.« less

Exploring the multidimensionality of stature variation in the past through comparisons of archaeological and living populations.

PubMed

Vercellotti, Giuseppe; Piperata, Barbara A; Agnew, Amanda M; Wilson, Warren M; Dufour, Darna L; Reina, Julio C; Boano, Rosa; Justus, Hedy M; Larsen, Clark Spencer; Stout, Sam D; Sciulli, Paul W

2014-10-01

Adult stature variation is commonly attributed to differential stress-levels during development. However, due to selective mortality and heterogeneous frailty, a population's tall stature may be more indicative of high selective pressures than of positive life conditions. This article examines stature in a biocultural context and draws parallels between bioarchaeological and living populations to explore the multidimensionality of stature variation in the past. This study investigates: 1) stature differences between archaeological populations exposed to low or high stress (inferred from skeletal indicators); 2) similarities in growth retardation patterns between archaeological and living groups; and 3) the apportionment of variance in growth outcomes at the regional level in archaeological and living populations. Anatomical stature estimates were examined in relation to skeletal stress indicators (cribra orbitalia, porotic hyperostosis, linear enamel hypoplasia) in two medieval bioarchaeological populations. Stature and biocultural information were gathered for comparative living samples from South America. Results indicate 1) significant (P < 0.01) differences in stature between groups exposed to different levels of skeletal stress; 2) greater prevalence of stunting among living groups, with similar patterns in socially stratified archaeological and modern groups; and 3) a degree of regional variance in growth outcomes consistent with that observed for highly selected traits. The relationship between early stress and growth is confounded by several factors-including catch-up growth, cultural buffering, and social inequality. The interpretations of early life conditions based on the relationship between stress and stature should be advanced with caution. Copyright © 2014 Wiley Periodicals, Inc.

Fibroblast growth factor signaling in skeletal development and disease.

PubMed

Ornitz, David M; Marie, Pierre J

2015-07-15

Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored. © 2015 Ornitz and Marie; Published by Cold Spring Harbor Laboratory Press.

Development-related expression patterns of protein-coding and miRNA genes involved in porcine muscle growth.

PubMed

Wang, F J; Jin, L; Guo, Y Q; Liu, R; He, M N; Li, M Z; Li, X W

2014-11-27

Muscle growth and development is associated with remarkable changes in protein-coding and microRNA (miRNA) gene expression. To determine the expression patterns of genes and miRNAs related to muscle growth and development, we measured the expression levels of 25 protein-coding and 16 miRNA genes in skeletal and cardiac muscles throughout 5 developmental stages by quantitative reverse transcription-polymerase chain reaction. The Short Time-Series Expression Miner (STEM) software clustering results showed that growth-related genes were downregulated at all developmental stages in both the psoas major and longissimus dorsi muscles, indicating their involvement in early developmental stages. Furthermore, genes related to muscle atrophy, such as forkhead box 1 and muscle ring finger, showed unregulated expression with increasing age, suggesting a decrease in protein synthesis during the later stages of skeletal muscle development. We found that development of the cardiac muscle was a complex process in which growth-related genes were highly expressed during embryonic development, but they did not show uniform postnatal expression patterns. Moreover, the expression level of miR-499, which enhances the expression of the β-myosin heavy chain, was significantly different in the psoas major and longissimus dorsi muscles, suggesting the involvement of miR-499 in the determination of skeletal muscle fiber types. We also performed correlation analyses of messenger RNA and miRNA expression. We found negative relationships between miR-486 and forkhead box 1, and miR-133a and serum response factor at all developmental stages, suggesting that forkhead box 1 and serum response factor are potential targets of miR-486 and miR-133a, respectively.

Increase in relative skeletal muscle mass over time and its inverse association with metabolic syndrome development: a 7-year retrospective cohort study.

PubMed

Kim, Gyuri; Lee, Seung-Eun; Jun, Ji Eun; Lee, You-Bin; Ahn, Jiyeon; Bae, Ji Cheol; Jin, Sang-Man; Hur, Kyu Yeon; Jee, Jae Hwan; Lee, Moon-Kyu; Kim, Jae Hyeon

2018-02-05

Skeletal muscle mass was negatively associated with metabolic syndrome prevalence in previous cross-sectional studies. The aim of this study was to investigate the impact of baseline skeletal muscle mass and changes in skeletal muscle mass over time on the development of metabolic syndrome in a large population-based 7-year cohort study. A total of 14,830 and 11,639 individuals who underwent health examinations at the Health Promotion Center at Samsung Medical Center, Seoul, Korea were included in the analyses of baseline skeletal muscle mass and those changes from baseline over 1 year, respectively. Skeletal muscle mass was estimated by bioelectrical impedance analysis and was presented as a skeletal muscle mass index (SMI), a body weight-adjusted appendicular skeletal muscle mass value. Using Cox regression models, hazard ratio for developing metabolic syndrome associated with SMI values at baseline or changes of SMI over a year was analyzed. During 7 years of follow-up, 20.1% of subjects developed metabolic syndrome. Compared to the lowest sex-specific SMI tertile at baseline, the highest sex-specific SMI tertile showed a significant inverse association with metabolic syndrome risk (adjusted hazard ratio [AHR] = 0.61, 95% confidence interval [CI] 0.54-0.68). Furthermore, compared with SMI changes < 0% over a year, multivariate-AHRs for metabolic syndrome development were 0.87 (95% CI 0.78-0.97) for 0-1% changes and 0.67 (0.56-0.79) for > 1% changes in SMI over 1 year after additionally adjusting for baseline SMI and glycometabolic parameters. An increase in relative skeletal muscle mass over time has a potential preventive effect on developing metabolic syndrome, independently of baseline skeletal muscle mass and glycometabolic parameters.

Emerging new tools to study and treat muscle pathologies: genetics and molecular mechanisms underlying skeletal muscle development, regeneration, and disease.

PubMed

Crist, Colin

2017-01-01

Skeletal muscle is the most abundant tissue in our body, is responsible for generating the force required for movement, and is also an important thermogenic organ. Skeletal muscle is an enigmatic tissue because while on the one hand, skeletal muscle regeneration after injury is arguably one of the best-studied stem cell-dependent regenerative processes, on the other hand, skeletal muscle is still subject to many degenerative disorders with few therapeutic options in the clinic. It is important to develop new regenerative medicine-based therapies for skeletal muscle. Future therapeutic strategies should take advantage of rapidly developing technologies enabling the differentiation of skeletal muscle from human pluripotent stem cells, along with precise genome editing, which will go hand in hand with a steady and focused approach to understanding underlying mechanisms of skeletal muscle development, regeneration, and disease. In this review, I focus on highlighting the recent advances that particularly have relied on developmental and molecular biology approaches to understanding muscle development and stem cell function. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Immunology Guides Skeletal Muscle Regeneration.

PubMed

Sass, F Andrea; Fuchs, Michael; Pumberger, Matthias; Geissler, Sven; Duda, Georg N; Perka, Carsten; Schmidt-Bleek, Katharina

2018-03-13

Soft tissue trauma of skeletal muscle is one of the most common side effects in surgery. Muscle injuries are not only caused by accident-related injuries but can also be of an iatrogenic nature as they occur during surgical interventions when the anatomical region of interest is exposed. If the extent of trauma surpasses the intrinsic regenerative capacities, signs of fatty degeneration and formation of fibrotic scar tissue can occur, and, consequentially, muscle function deteriorates or is diminished. Despite research efforts to investigate the physiological healing cascade following trauma, our understanding of the early onset of healing and how it potentially determines success or failure is still only fragmentary. This review focuses on the initial physiological pathways following skeletal muscle trauma in comparison to bone and tendon trauma and what conclusions can be drawn from new scientific insights for the development of novel therapeutic strategies. Strategies to support regeneration of muscle tissue after injury are scarce, even though muscle trauma has a high incidence. Based on tissue specific differences, possible clinical treatment options such as local immune-modulatory and cell therapeutic approaches are suggested that aim to support the endogenous regenerative potential of injured muscle tissues.

Immunology Guides Skeletal Muscle Regeneration

PubMed Central

Sass, F. Andrea; Pumberger, Matthias; Geissler, Sven; Duda, Georg N.; Perka, Carsten; Schmidt-Bleek, Katharina

2018-01-01

Soft tissue trauma of skeletal muscle is one of the most common side effects in surgery. Muscle injuries are not only caused by accident-related injuries but can also be of an iatrogenic nature as they occur during surgical interventions when the anatomical region of interest is exposed. If the extent of trauma surpasses the intrinsic regenerative capacities, signs of fatty degeneration and formation of fibrotic scar tissue can occur, and, consequentially, muscle function deteriorates or is diminished. Despite research efforts to investigate the physiological healing cascade following trauma, our understanding of the early onset of healing and how it potentially determines success or failure is still only fragmentary. This review focuses on the initial physiological pathways following skeletal muscle trauma in comparison to bone and tendon trauma and what conclusions can be drawn from new scientific insights for the development of novel therapeutic strategies. Strategies to support regeneration of muscle tissue after injury are scarce, even though muscle trauma has a high incidence. Based on tissue specific differences, possible clinical treatment options such as local immune-modulatory and cell therapeutic approaches are suggested that aim to support the endogenous regenerative potential of injured muscle tissues. PMID:29534011

Insulin-like growth factor-1 (IGF-1) promotes myoblast proliferation and skeletal muscle growth of embryonic chickens via the PI3K/Akt signalling pathway.

PubMed

Yu, Minli; Wang, Huan; Xu, Yali; Yu, Debing; Li, Dongfeng; Liu, Xiuhong; Du, Wenxing

2015-08-01

During embryonic development, IGF-1 fulfils crucial roles in skeletal myogenesis. However, the involvement of IGF-1-induced myoblast proliferation in muscle growth is still unclear. In the present study, we have characterised the role of IGF-1 in myoblast proliferation both in vitro and in vivo and have revealed novel details of how exogenous IGF-1 influences myogenic genes in chicken embryos. The results show that IGF-1 significantly induces the proliferation of cultured myoblasts in a dose-dependent manner. Additionally, the IGF-1 treatment significantly promoted myoblasts entering a new cell cycle and increasing the mRNA expression levels of cell cycle-dependent genes. However, these effects were inhibited by the PI3K inhibitor LY294002 and the Akt inhibitor KP372-1. These data indicated that the pro-proliferative effect of IGF-1 was mediated in response to the PI3K/Akt signalling pathway. Moreover, we also showed that exogenous IGF-1 stimulated myoblast proliferation in vivo. IGF-1 administration obviously promoted the incorporation of BrdU and remarkably increased the number of PAX7-positive cells in the skeletal muscle of chicken embryos. Administration of IGF-1 also significantly induced the upregulation of myogenic factors gene, the enhancement of c-Myc and the inhibition of myostatin (Mstn) expression. These findings demonstrate that IGF-1 has strong activity as a promoter of myoblast expansion and muscle fiber formation during early myogenesis. Therefore, this study offers insight into the mechanisms responsible for IGF-1-mediated stimulation of embryonic skeletal muscle development, which could have important implications for the improvement of chicken meat production. © 2015 International Federation for Cell Biology.

Biochemical markers in the assessment of bone disease

NASA Technical Reports Server (NTRS)

Bikle, D. D.

1997-01-01

As the mean age of our population increases, increasing attention has been paid to the diseases associated with aging, including diseases of the skeleton such as osteoporosis. Effective means of treating and possibly preventing such skeletal disorders are emerging, making their early recognition an important goal for the primary care physician. Although bone density measurements and skeletal imaging studies remain of primary diagnostic importance in this regard, a large number of assays for biochemical markers of bone formation and resorption are being developed that promise to complement the densitometry measurements and imaging studies, providing an assessment of the rates of bone turnover and an earlier evaluation of the effects of therapy. In this review, emphasizing the recent literature, the major biochemical markers currently in use or under active investigation are described, and their application in a number of diseases of the skeleton including osteoporosis is evaluated.

Physical therapy intervention for an adolescent with a knee flexion contracture and diagnosis of multiple pterygium syndrome.

PubMed

Bellamy, Sandra Gail; Gibbs, Karen; Lazaro, Rolando

2007-01-01

The purpose of this case report is to describe a course of physical therapy for a client with a rare genetic condition, multiple pterygium syndrome (MPS). MPS is a rare genetic disorder characterized by connective tissue webbing across multiple joints, dysmorphic facies, and various visceral and skeletal deformities. Before the patient commenced physical therapy, surgical amputation was recommended for the client's knee flexion contracture. The client's treatment plan included stretching, manual therapy, and resisted exercise. Long-term outcomes were decreased back and knee pain and improved range of motion, strength, and ambulation. Therapists using techniques to improve joint range of motion in clients with MPS should be aware that pterygia may include contractile tissue, nerves, and blood vessels and there may be underlying skeletal deformity or weakness in these areas. Children with MPS are at high risk of developing scoliosis and should be appropriately assessed in early childhood.

Cardiac troponin T and fast skeletal muscle denervation in ageing.

PubMed

Xu, Zherong; Feng, Xin; Dong, Juan; Wang, Zhong-Min; Lee, Jingyun; Furdui, Cristina; Files, Daniel Clark; Beavers, Kristen M; Kritchevsky, Stephen; Milligan, Carolanne; Jin, Jian-Ping; Delbono, Osvaldo; Zhang, Tan

2017-10-01

Ageing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast-twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow-twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre-type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia. Cardiac troponin T (cTnT), the heart muscle-specific isoform of TnT, is a key component of the mechanisms of muscle contraction. It is expressed in skeletal muscle during early development, after acute sciatic nerve denervation, in various neuromuscular diseases and possibly in ageing muscle. Yet the subcellular localization and function of cTnT in skeletal muscle is largely unknown. Studies were carried out on isolated skeletal muscles from mice, vervet monkeys, and humans. Immunoblotting, immunoprecipitation, and mass spectrometry were used to analyse protein expression, real-time reverse transcription polymerase chain reaction was used to measure gene expression, immunofluorescence staining was performed for subcellular distribution assay of proteins, and electromyographic recording was used to analyse neurotransmission at the NMJ. Levels of cTnT expression in skeletal muscle increased with ageing in mice. In addition, cTnT was highly enriched at the NMJ region-but mainly in the fast-twitch, not the slow-twitch, muscle of old mice. We further found that the protein kinase A (PKA) RIα subunit was largely removed from, while PKA RIIα and RIIβ are enriched at, the NMJ-again, preferentially in fast-twitch but not slow-twitch muscle in old mice. Knocking down cTnT in fast skeletal muscle of old mice: (i) increased PKA RIα and reduced PKA RIIα at the NMJ; (ii) decreased the levels of gene expression of muscle denervation markers; and (iii) enhanced neurotransmission efficiency at NMJ. Cardiac troponin T at the NMJ region contributes to NMJ functional decline with ageing mainly in the fast-twitch skeletal muscle through interfering with PKA signalling. This knowledge could inform useful targets for prevention and therapy of age-related decline in muscle function. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Parenteral amino acids increase albumin and skeletal muscle protein fractional synthetic rates in premature newborn minipigs.

PubMed

Hellstern, Gerald; Kaempf-Rotzoll, Daisy; Linderkamp, Otwin; Langhans, Klaus-Dieter; Rating, Dietz

2002-09-01

Early administration of parenteral amino acids increases whole body nitrogen retention in premature infants. Tracer kinetic studies suggest an increase in whole body protein synthesis as a possible mechanism for this increase in nitrogen retention. However, the effect of early parenteral amino acids on synthesis of specific proteins remains uncertain. Using premature newborn minipigs as a model for human premature newborns, we investigated the effects of parenterally administered amino acids on albumin and skeletal muscle protein fractional synthetic rates. Fifteen Yucatan minipigs were delivered by cesarean section 6 days before the mean expected delivery date (day 106 of gestation; expected gestation, 111-113 days) and randomized to two groups immediately after birth: 7 piglets received a mixture of amino acids (0.4 g. kg. h ) and glucose (0.8 g. kg. h ) for 5 hours, and 8 piglets (control group) received glucose only. All piglets received a continuous primed infusion of 1-[ C]valine. Arterial plasma free C-valine enrichment was measured by gas chromatography/mass spectrometry, and protein synthetic rates were determined by measuring incorporation of C-valine into albumin and skeletal muscle protein using gas chromatography/combustion/isotope ratio mass spectrometry. Administration of amino acids increased albumin (87.0% +/- 42.1% [mean +/- SD] vs. 37.6% +/- 6.8% per 24 hours; < 0.05) and skeletal muscle fractional synthetic rates (11.60% +/- 6.9% vs. 6.5% +/- 1.5% per 24 hours; < 0.05). We conclude that parenteral amino acids increase albumin and skeletal muscle fractional synthetic rates in premature piglets on the first day of life.

Microgravity effects of sea urchin fertilization and development

NASA Technical Reports Server (NTRS)

Steffen, S.; Simerly, C.; Schatten, H.; Schatten, G.; Fiser, R.

1992-01-01

Gravity has been a pervasive influence on all living systems and there is convincing evidence to suggest that it alters fertilization and embryogenesis in several developmental systems. Notwithstanding the global importance of gravity on development, it has only been recently possible to begin to design experiments which might directly investigate the specific effects of this vector. The goal of this research program is to explore and understand the effects of gravity on fertilization and early development using sea urchins as a model system. Sea urchin development has several advantages for this project including the feasibility of maintaining and manipulating these cells during spaceflight, the high percentage of normal fertilization and early development, and the abundant knowledge about molecular, biochemical, and cellular events during embryogenesis which permits detailed insights into the mechanism by which gravity might interfere with development. Furthermore, skeletal calcium is deposited into the embryonic spicules within a day of fertilization permitting studies of the effects of gravity on bone calcium deposition.

Chondrocyte-Specific Inhibition of β-Catenin Signaling Leads to Dysplasia of the Caudal Vertebrae in Mice

PubMed Central

Shu, Bing; Li, Tian-Fang; Li, Xiao-Feng; Tang, De-Zhi; Zhang, Yejia; Shi, Qi

2013-01-01

Study Design. To inhibit β-catenin specifically signaling in chondrocytes Col2-ICAT transgenic mice were generated. Anomalies in caudal vertebrae were detected during embryonic and postnatal stages of Col2-ICAT transgenic mice. Objective. To determine the role of canonical β-catenin signaling in caudal vertebral development. Summary of Background Data. β-catenin signaling plays a critical role in skeletal development. Col2-ICAT transgenic mice were generated to selectively block β-catenin signaling by overexpression of the ICAT gene in chondrocytes. Methods. Tails of E16.5 transgenic embryos and adult Col2-ICAT transgenic mice and their wild-type littermates were collected and analyzed. Skeletal preparation, 3-dimensional micro-computed tomographic and histological analyses were performed to evaluate changes in the structure of caudal vertebrae. Bromodeoxyuridine labeling was performed to evaluate changes in chondrocyte proliferation in caudal vertebrae. Results. Skeletal preparation and 3-dimensional micro-computed tomographic analyses revealed bone deformation and angulated deformities in tail tissue in Col2-ICAT transgenic mice. Histological studies revealed abnormal bone development and dysplastic caudal vertebrae in Col2-ICAT transgenic mice. Inhibition of β-catenin signaling in cartilage resulted in vertebral dysplasia leading to aberrant resegmenting process. Thus, 2 poorly developed sclerotomes failed to fuse to form a complete vertebrae. BrdU labeling revealed a decreased chondrocyte proliferation in both cartilageous templates of transgenic embryos and the growth plate of adult Col2-ICAT transgenic mice. Conclusion. Wnt/β-catenin signaling plays an important role in vertebral development. Inhibition of β-catenin signaling in chondrocytes results in caudal vertebra deformity in mice, which may occur as early as in the stage of sclerotome formation. Level of Evidence: N/A PMID:24026150

Muscle-targeted hydrodynamic gene introduction of insulin-like growth factor-1 using polyplex nanomicelle to treat peripheral nerve injury.

PubMed

Nagata, Kazuya; Itaka, Keiji; Baba, Miyuki; Uchida, Satoshi; Ishii, Takehiko; Kataoka, Kazunori

2014-06-10

The recovery of neurologic function after peripheral nerve injury often remains incomplete because of the prolonged reinnervation process, which leads to skeletal muscle atrophy and articular contracture from disuse over time. To rescue the skeletal muscle and promote functional recovery, insulin-like growth factor-1 (IGF-1), a potent myogenic factor, was introduced into the muscle by hydrodynamic injection of IGF-1-expressing plasmid DNA using a biocompatible nonviral gene carrier, a polyplex nanomicelle. In a mouse model of sciatic nerve injury, the introduction of IGF-1 into the skeletal muscle of the paralyzed limb effectively alleviated a decrease in muscle weight compared with that in untreated control mice. Histologic analysis of the muscle revealed the IGF-1-expressing plasmid DNA (pDNA) to have a myogenic effect, inducing muscle hypertrophy with the upregulation of the myogenic regulatory factors, myogenin and MyoD. The evaluation of motor function by walking track analysis revealed that the group that received the hydrodynamic injection of IGF-1-expressing pDNA using the polyplex nanomicelle had significantly early recovery of motor function compared with groups receiving negative control pDNA and untreated controls. Early recovery of sensation in the distal area of sciatic nerve injury was also induced by the introduction of IGF-1-expressing pDNA, presumably because of the effect of secreted IGF-1 protein in the vicinity of the injured sciatic nerve exerting a synergistic effect with muscle hypertrophy, inducing a more favorable prognosis. This approach of introducing IGF-1 into skeletal muscle is promising for the treatment of peripheral nerve injury by promoting early motor function recovery. Copyright © 2014 Elsevier B.V. All rights reserved.

Early energy metabolism-related molecular events in skeletal muscle of diabetic rats: The effects of l-arginine and SOD mimic.

PubMed

Stancic, Ana; Filipovic, Milos; Ivanovic-Burmazovic, Ivana; Masovic, Sava; Jankovic, Aleksandra; Otasevic, Vesna; Korac, Aleksandra; Buzadzic, Biljana; Korac, Bato

2017-06-25

Considering the vital role of skeletal muscle in control of whole-body metabolism and the severity of long-term diabetic complications, we aimed to reveal the molecular pattern of early diabetes-related skeletal muscle phenotype in terms of energy metabolism, focusing on regulatory mechanisms, and the possibility to improve it using two redox modulators, l-arginine and superoxide dismutase (SOD) mimic. Alloxan-induced diabetic rats (120 mg/kg) were treated with l-arginine or the highly specific SOD mimic, M40403, for 7 days. As appropriate controls, non-diabetic rats received the same treatments. We found that l-arginine and M40403 restored diabetes-induced impairment of phospho-5'-AMP-activated protein kinase α (AMPKα) signaling by upregulating AMPKα protein itself and its downstream effectors, peroxisome proliferator-activated receptor-γ coactivator-1α and nuclear respiratory factor 1. Also, there was a restitution of the protein levels of oxidative phosphorylation components (complex I, complex II and complex IV) and mitofusin 2. Furthermore, l-arginine and M40403 induced translocation of glucose transporter 4 to the membrane and upregulation of protein of phosphofructokinase and acyl coenzyme A dehydrogenase, diminishing negative diabetic effects on limiting factors of glucose and lipid metabolism. Both treatments abolished diabetes-induced downregulation of sarcoplasmic reticulum calcium-ATPase proteins (SERCA 1 and 2). Similar effects of l-arginine and SOD mimic treatments suggest that disturbances in the superoxide/nitric oxide ratio may be responsible for skeletal muscle mitochondrial and metabolic impairment in early diabetes. Our results provide evidence that l-arginine and SOD mimics have potential in preventing and treating metabolic disturbances accompanying this widespread metabolic disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Implications of skeletal muscle loss for public health nutrition messages: a brief report.

PubMed

Levy, Louis B; Welch, Ailsa A

2015-11-01

Age-related skeletal muscle loss, sarcopenia, cachexia and wider malnutrition (under nutrition) are complex in aetiology with interaction of clinical, social and economic factors. Weight loss and loss of skeletal muscle mass in older people are associated with increased morbidity and mortality with implications for increasing health and social care costs. There is insufficient evidence to identify the ideal treatment options. However, preventing weight loss and loss of skeletal muscle in older age will be keys to reducing morbidity and mortality. This will require all those coming into contact with older people to identify and address weight loss early, including through diet, improving physical activity and increasing social interaction. Public health messages on diet should, in the main, continue to focus on older people achieving current UK dietary recommendations for their age as visually depicted in the eatwell plate together with associated messages regarding dietary supplements where appropriate.

Recurrent short rib polydactyly syndrome.

PubMed

Eleftheriades, M; Iavazzo, C; Manolakos, E; Hassiakos, D; Botsis, D; Petersen, M; Konstantinidou, A

2013-01-01

We present three consecutive cases of skeletal dysplasias of a non-consanguineous couple with five pregnancies. The diagnosis of short-rib polydactyly syndrome (SRPS) was feasible by ultrasound during the 1st trimester of pregnancy. SRPS represents a heterogeneous group of lethal skeletal dysplasias. It is characterised by short limb dwarfism complicated by thoracic hypoplasia, polydactyly and different anomalies of major organs such as congenital heart defects and renal dysplasia. Four major types of the SRPS have been described: type I (Saldino-Noonan); type II (Majewski); type III (Verma-Naumoff) and type IV (Beemar-Langer). However, there is phenotypic overlapping between four types and with those of non-lethal skeletal dysplasias (i.e. Ellis-van Creveld syndrome and Jeune syndrome). Our cases show the importance of the nuchal translucency (NT) scan that offers the opportunity to examine fetal anatomy in the 1st trimester and diagnose rare skeletal abnormalities early in pregnancy.

Management of skeletal Class III malocclusion with face mask therapy and comprehensive orthodontic treatment.

PubMed

Muthukumar, Kirthika; Vijaykumar, N M; Sainath, M C

2016-01-01

Orthopedic correction of skeletal Class III malocclusion in a growing patient is crucial as it can circumvent future surgical procedures. Further, as surgery is done only at a later stage, early treatment helps to avoid the detrimental effects produced by the facial disfigurement on the patient's social life. This case report describes the treatment of a child aged 9 years 6 months who had a skeletal Class III malocclusion. The treatment plan involved the use of a reverse pull headgear (facemask) and multibracket appliance therapy resulting in successful correction of the malocclusion. The treatment results were highly satisfactory resulting in improved facial esthetics, a skeletal Class I with a Dental Class I molar and canine relationship, an ideal overjet and overbite. Thus, dentoalveolar camouflage, if done in properly selected cases, alleviates the need for surgical intervention. The patient is being monitored until the end of growth to ensure the stability of treatment results.

Recent research on the growth plate: Advances in fibroblast growth factor signaling in growth plate development and disorders.

PubMed

Xie, Yangli; Zhou, Siru; Chen, Hangang; Du, Xiaolan; Chen, Lin

2014-08-01

Skeletons are formed through two distinct developmental actions, intramembranous ossification and endochondral ossification. During embryonic development, most bone is formed by endochondral ossification. The growth plate is the developmental center for endochondral ossification. Multiple signaling pathways participate in the regulation of endochondral ossification. Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling has been found to play a vital role in the development and maintenance of growth plates. Missense mutations in FGFs and FGFRs can cause multiple genetic skeletal diseases with disordered endochondral ossification. Clarifying the molecular mechanisms of FGFs/FGFRs signaling in skeletal development and genetic skeletal diseases will have implications for the development of therapies for FGF-signaling-related skeletal dysplasias and growth plate injuries. In this review, we summarize the recent advances in elucidating the role of FGFs/FGFRs signaling in growth plate development, genetic skeletal disorders, and the promising therapies for those genetic skeletal diseases resulting from FGFs/FGFRs dysfunction. Finally, we also examine the potential important research in this field in the future. © 2014 Society for Endocrinology.

mRNA-seq reveals skeletal muscle atrophy in response to handling stress in a marine teleost, the red cusk-eel (Genypterus chilensis).

PubMed

Aedo, Jorge E; Maldonado, Jonathan; Aballai, Víctor; Estrada, Juan M; Bastias-Molina, Macarena; Meneses, Claudio; Gallardo-Escarate, Cristian; Silva, Herman; Molina, Alfredo; Valdés, Juan A

2015-12-01

Fish reared under intensive conditions are repeatedly exposed to stress, which negatively impacts growth. Although most fish follow a conserved pattern of stress response, with increased concentrations of cortisol, each species presents specificities in the cell response and stress tolerance. Therefore, culturing new species requires a detailed knowledge of these specific responses. The red cusk-eel (Genypterus chilensis) is a new economically important marine species for the Chilean aquaculture industry. However, there is no information on the stress- and cortisol-induced mechanisms that decrease skeletal muscle growth in this teleost. Using Illumina RNA-seq technology, skeletal muscle sequence reads for G. chilensis were generated under control and handling stress conditions. Reads were mapped onto a reference transcriptome, resulting in the in silico identification of 785 up-regulated and 167 down-regulated transcripts. Gene ontology enrichment analysis revealed a significant up-regulation of catabolic genes associated with skeletal muscle atrophy. These results were validated by RT-qPCR analysis for ten candidates genes involved in ubiquitin-mediated proteolysis, autophagy and skeletal muscle growth. Additionally, using a primary culture of fish skeletal muscle cells, the effect of cortisol was evaluated in relation to red cusk-eel skeletal muscle atrophy. The present data demonstrated that handling stress promotes skeletal muscle atrophy in the marine teleost G. chilensis through the expression of components of the ubiquitin-proteasome and autophagy-lysosome systems. Furthermore, cortisol was a powerful inductor of skeletal muscle atrophy in fish myotubes. This study is an important step towards understanding the atrophy system in non-model teleost species and provides novel insights on the cellular and molecular mechanisms that control skeletal muscle growth in early vertebrates.

[Fetal programming and the etiology of osteoporosis].

PubMed

Pieńkowski, Wojciech; Wolski, Hubert; Drews, Krzysztof; Seremak-Mrozikiewicz, Agnieszka

2015-08-01

Osteoporosis is a multifactorial skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in increased risk of fracture. Peak bone mass is an important predictor of later risk of osteoporosis. Epidemiological studies revealed that the risk of osteoporosis might be modified by exposure to environmental factors during intrauterine life and early postnatal period. This review summarizes the influence of fetal programming on the development of osteoporosis based on the epidemiological studies and potential mechanisms of epigenetic regulation of gene expression.

Skeletal muscle stem cells from animals I. Basic cell biology

USDA-ARS?s Scientific Manuscript database

Skeletal muscle stem cells from food-producing animals have been of interest to agricultural life scientists seeking to develop a better understanding of the molecular regulation of lean tissue (skeletal muscle protein hypertrophy) and intramuscular fat (marbling) development. Enhanced understanding...

MST1, a key player, in enhancing fast skeletal muscle atrophy

PubMed Central

2013-01-01

Background Skeletal muscle undergoes rapid atrophy upon denervation and the underlying mechanisms are complicated. FOXO3a has been implicated as a major mediator of muscle atrophy, but how its subcellular location and activity is controlled during the pathogenesis of muscle atrophy remains largely unknown. MST1 (Mammalian Sterile 20-like kinase 1) is identified as a central component of the Hippo signaling pathway. MST1 has been shown to mediate phosphorylation of FOXO3a at Ser207. Whether this MST1-FOXO signaling cascade exerts any functional consequence on cellular homeostasis remains to be investigated. Result We identified that MST1 kinase was expressed widely in skeletal muscles and was dramatically up-regulated in fast- but not slow-dominant skeletal muscles immediately following denervation. The results of our histological and biochemical studies demonstrated that deletion of MST1 significantly attenuated denervation-induced skeletal muscle wasting and decreased expression of Atrogin-1 and LC3 genes in fast-dominant skeletal muscles from three- to five-month-old adult mice. Further studies indicated that MST1, but not MST2, remarkably increased FOXO3a phosphorylation level at Ser207 and promoted its nuclear translocation in atrophic fast-dominant muscles. Conclusions We have established that MST1 kinase plays an important role in regulating denervation-induced skeletal muscle atrophy. During the early stage of muscle atrophy, the up-regulated MST1 kinase promoted progression of neurogenic atrophy in fast-dominant skeletal muscles through activation of FOXO3a transcription factors. PMID:23374633

Correlation of skeletal maturation stages determined by cervical vertebrae and hand-wrist evaluations.

PubMed

Flores-Mir, Carlos; Burgess, Corr A; Champney, Mitchell; Jensen, Robert J; Pitcher, Micheal R; Major, Paul W

2006-01-01

The aim of this study was to assess the correlation between the Fishman maturation prediction method (FMP) and the cervical vertebral maturation (CVM) method for skeletal maturation stage determination. Hand-wrist and lateral cephalograms from 79 subjects (52 females and 27 males) were used. Hand-wrist radiographs were analyzed using the FMP to determine skeletal maturation level (advanced, average, or delayed) and stage (relative position of the individual in the pubertal growth curve). Cervical vertebrae (C2, C3, and C4) outlines obtained from lateral cephalograms were analyzed using the CVM to determine skeletal maturation stage. Intraexaminer reliability (Intraclass correlation coefficient [ICC]) for both methods was calculated from 10 triplicate hand-wrist and lateral cephalograms from the same patients. An ICC coefficient of 0.985 for FMP and an ICC of 0.889 for CVM were obtained. A Spearman correlation value of 0.72 (P < .001) was found between the skeletal maturation stages of both methods. When the sample was subgrouped according to skeletal maturation level, the following correlation values were found: for early mature adolescents 0.73, for average mature adolescents 0.70, and for late mature adolescents 0.87. All these correlation values were statistically different from zero (P < .024). Correlation values between both skeletal maturation methods were moderately high. This may be high enough to use either of the methods indistinctively for research purposes but not for the assessment of individual patients. Skeletal level influences the correlation values and, therefore, it should be considered whenever possible.

Molecular cloning and expression of rat and mouse B61 gene: implications on organogenesis.

PubMed

Takahashi, H; Ikeda, T

1995-09-07

ECK is a member of EPH receptor protein-tyrosine kinase subfamily and human B61 has been identified as the ligand for ECK recently. In order to better understand the roles of B61-ECK signalling pathway in mammalian development, we have cloned rat and mouse B61 cDNA and examined the expression pattern during rat development. Sequence analysis has revealed that there is a considerable degree of identity among rat, mouse and human B61 (98.0% between rat and mouse, 86.3% between rat and human in amino acid level). Examination of B61 mRNA expression by in situ hybridization analysis revealed tight association of B61 with endothelial cells at an early stage and epithelial cells in various tissues including lung, kidney, intestine, skin at later stage of organogenesis. In the developing skeletal system, B61 is expressed in periosteum, perichondrium and hypertrophic chondrocytes and osteoblasts. In the developing nervous system, expression of B61 is restricted in the neurons of dorsal root ganglia. These expression profiles of B61 in epithelial cells of various organs, developing skeletal system and dorsal root ganglia match those of ECK. Our data suggest that B61 plays pivotal roles in organogenesis, especially vasculogenesis/angiogenesis and epithelial cell proliferation/differentiation.

Proteomics Analysis of Skeletal Muscle from Leptin-Deficient ob/ob Mice Reveals Adaptive Remodeling of Metabolic Characteristics and Fiber Type Composition.

PubMed

Schönke, Milena; Björnholm, Marie; Chibalin, Alexander V; Zierath, Juleen R; Deshmukh, Atul S

2018-03-01

Skeletal muscle insulin resistance, an early metabolic defect in the pathogenesis of type 2 diabetes (T2D), may be a cause or consequence of altered protein expression profiles. Proteomics technology offers enormous promise to investigate molecular mechanisms underlying pathologies, however, the analysis of skeletal muscle is challenging. Using state-of-the-art multienzyme digestion and filter-aided sample preparation (MED-FASP) and a mass spectrometry (MS)-based workflow, we performed a global proteomics analysis of skeletal muscle from leptin-deficient, obese, insulin resistant (ob/ob) and lean mice in mere two fractions in a short time (8 h per sample). We identified more than 6000 proteins with 118 proteins differentially regulated in obesity. This included protein kinases, phosphatases, and secreted and fiber type associated proteins. Enzymes involved in lipid metabolism in skeletal muscle from ob/ob mice were increased, providing evidence against reduced fatty acid oxidation in lipid-induced insulin resistance. Mitochondrial and peroxisomal proteins, as well as components of pyruvate and lactate metabolism, were increased. Finally, the skeletal muscle proteome from ob/ob mice displayed a shift toward the "slow fiber type." This detailed characterization of an obese rodent model of T2D demonstrates an efficient workflow for skeletal muscle proteomics, which may easily be adapted to other complex tissues. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Curve Modulation and Apex Migration Using Shilla Growth Guidance Rods for Early-onset Scoliosis at 5-Year Follow-up.

PubMed

Wilkinson, John T; Songy, Chad E; Bumpass, David B; McCullough, Francis L; McCarthy, Richard E

2017-04-03

The Shilla procedure was designed to correct and control early-onset spinal deformity while harnessing a child's remaining spinal growth. It allows for controlled axial skeletal growth within the construct, avoiding the need for frequent surgeries to lengthen implants. We hypothesized that curve characteristics evolve over time after initial apex fusion and placement of the Shilla implants. The purpose of this study was to identify trends in curve evolution after Shilla implantation and understand how these changes influence ultimate outcome. A single-center, retrospective review of all patients with Shilla implants in place for ≥5 years yielded 21 patients. Charts and radiographs were reviewed to compare coronal curve characteristics preoperatively, postoperatively, and at last follow-up to note changes in the apex of the primary curve. Also noted were the development of adjacent compensatory curves, the overall vertical spinal growth, and the need for definitive spinal fusion once skeletal maturity was reached. Of the 21 patients, the curve apex migrated caudally in 12 patients (57%) and cephalad in 1 patient (5%), with a mean migration of 2.7 vertebral levels. Two patients (10%) developed new, significant compensatory curves (1 caudal and 1 cephalad). All patients demonstrated spinal growth in T1-S1 length following index surgery (mean, 45 mm). At skeletal maturity, 10 patients underwent definitive posterior spinal fusion and instrumentation, and 3 underwent implant removal alone. This study constitutes the longest follow-up of Shilla patients evaluating curve and implant behavior. Results of this review suggest that the apex of the fused primary curve shifts in approximately 62% of patients, with nearly all of these (92%) involving a distal migration. Compensatory curves did develop after Shilla placement as well. Overall, these findings represent adding-on distal to the apex after Shilla instrumentation rather than a crankshaft phenomenon about the apex. A better understanding of spinal growth mechanics and outcomes after Shilla placement may improve our ability to appropriately select patients and instrumentation levels. Level III.

Comparative study of MSX-2, DLX-5, and DLX-7 gene expression during early human tooth development.

PubMed

Davideau, J L; Demri, P; Hotton, D; Gu, T T; MacDougall, M; Sharpe, P; Forest, N; Berdal, A

1999-12-01

Msx and Dlx family transcription factors are key elements of craniofacial development and act in specific combinations with growth factors to control the position and shape of various skeletal structures in mice. In humans, the mutations of MSX and DLX genes are associated with specific syndromes, such as tooth agenesis, craniosynostosis, and tricho-dento-osseous syndrome. To establish some relationships between those reported human syndromes, previous experimental data in mice, and the expression patterns of MSX and DLX homeogenes in the human dentition, we investigated MSX-2, DLX-5, and DLX-7 expression patterns and compared them in orofacial tissues of 7.5- to 9-wk-old human embryos by using in situ hybridization. Our data showed that MSX-2 was strongly expressed in the progenitor cells of human orofacial skeletal structures, including mandible and maxilla bones, Meckel's cartilage, and tooth germs, as shown for DLX-5. DLX-7 expression was restricted to the vestibular lamina and, later on, to the vestibular part of dental epithelium. The comparison of MSX-2, DLX-5, and DLX-7 expression patterns during the early stages of development of different human tooth types showed the existence of spatially ordered sequences of homeogene expression along the vestibular/lingual axis of dental epithelium. The expression of MSX-2 in enamel knot, as well as the coincident expression of MSX-2, DLX-5, and DLX-7 in a restricted vestibular area of dental epithelium, suggests the existence of various organizing centers involved in the control of human tooth morphogenesis.

A descriptive study of accidental skeletal injuries and non-accidental skeletal injuries of child maltreatment.

PubMed

Ghanem, Maha A H; Moustafa, Tarek A; Megahed, Haidy M; Salama, Naglaa; Ghitani, Sara A

2018-02-01

Lack of awareness and recognition of child maltreatment is the major reason behind underreporting. All victims often interact with the health care system for routine or emergency care. In several research works, non-accidental fractures are the second most common injury in maltreated children and it is represented up to one-third of cases. To determine the incidence of different types of accidental and non-accidental skeletal injuries among children, estimate the severity of injuries according to the modified injury severity score and to determine the degree of fractures either closed or opened (Gustiloe-Anderson open fracture classification). Moreover, identifying fractures resulting from child abuse and neglect. This aimed for early recognition of non-accidental nature of fractures in child maltreatment that can prevent further morbidity and mortality. A descriptive study was carried out on all children (109) with skeletal injuries who were admitted to both Main Alexandria and El-Hadara Orthopedic and Traumatology University Hospitals during six months. History, physical examination and investigations were done for the patients. A detailed questionnaire was taken to diagnose child abuse and neglect. Gustiloe-Anderson open fracture classification was used to estimate the degree of open fractures. Out of 109 children, twelve cases (11%) were categorized as child maltreatment. One case was physical abuse, eight cases (7.3%) were child neglect and three cases (2.8%) were labour exploitation. Road traffic accidents (RTA) was the commonest cause of skeletal injuries followed by falling from height. Regarding falls, they included 4 cases of stair falls in neglected children and another four cases of falling from height (balcony/window). The remaining 36 cases of falls were accidental. The skeletal injuries were in the form of fractures in 99 cases, dislocation in two cases, both fracture and/or dislocation in three cases, and bone deformity from brachial plexus injury in five cases. Fractures of the lower limb (42.2%) and both bones of the forearm (35%) represented the highest incidence of skeletal injuries in children. 54.5% of fractures due to neglect were lower limb fractures due to falling from height. Ninety-nine cases were diagnosed as long bone fractures and classified as the following; eighty patients as closed fractures, six patients as open grade I fractures, three patients as open grade II fractures, three patients as open grade IIIA fractures, four patients as open grade IIIB fractures and three patients as open grade IIIC fractures. Cases of neglect and child abuse represented 11% of all the studied cases, where neglect was the main cause. RTA and falling from height represented the most common cause of skeletal injury in children. Most fractures due to neglect were lower limb fractures resulting from falling from height. This demonstrates the need for early detection of neglect and child maltreatment aiming for early initiation of parental educational programs about child care and safety. Misinterpretation of skeletal injuries due to neglect or abuse can be avoided by proper training of orthopedic and traumatology staff on signs of child neglect and abuse. Copyright © 2017 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Androgens and bone health.

PubMed

Hansen, K A; Tho, S P

1998-01-01

Osteoporosis is one of the most common metabolic bone diseases in the adult population and its prevalence will continue to rise as our population grows older. In both sexes, hypogonadism is associated with accelerated loss of bone and development of osteoporosis. Adrenal and gonadal androgen levels decline with advancing age in both sexes. Androgens act by either directly binding to androgen receptors, or by aromatization of androgens to estrogens and subsequently interacting with estrogen receptors. Both pathways are important for skeletal health. Direct androgen binding to an androgen receptor may play a more important role in early skeletal development and determination of sexual dimorphic traits. While bone remodeling, which is important in maintaining healthy bone through life, is primarily stimulated by estrogen, studies in the rat and human support the complex action of androgens and estrogens in bone modeling and remodeling, and hence the development and maintenance of healthy bone. In postmenopausal females, the addition of androgens to hormone replacement therapy results in significant additional improvement in bone mineral density compared to estrogen replacement alone. Accumulating evidence indicate that androgens play an important role in the health of bone and the potential benefit of adding these agents to hormone replacement regimens.

Reduced osteoblast activity in the mice lacking TR4 nuclear receptor leads to osteoporosis.

PubMed

Lin, Shin-Jen; Ho, Hsin-Chiu; Lee, Yi-Fen; Liu, Ning-Chun; Liu, Su; Li, Gonghui; Shyr, Chih-Rong; Chang, Chawnshang

2012-06-07

Early studies suggested that TR4 nuclear receptor might play important roles in the skeletal development, yet its detailed mechanism remains unclear. We generated TR4 knockout mice and compared skeletal development with their wild type littermates. Primary bone marrow cells were cultured and we assayed bone differentiation by alkaline phosphatase and alizarin red staining. Primary calvaria were cultured and osteoblastic marker genes were detected by quantitative PCR. Luciferase reporter assays, chromatin immunoprecipitation (ChIP) assays, and electrophoretic mobility shift assays (EMSA) were performed to demonstrate TR4 can directly regulate bone differentiation marker osteocalcin. We first found mice lacking TR4 might develop osteoporosis. We then found that osteoblast progenitor cells isolated from bone marrow of TR4 knockout mice displayed reduced osteoblast differentiation capacity and calcification. Osteoblast primary cultures from TR4 knockout mice calvaria also showed higher proliferation rates indicating lower osteoblast differentiation ability in mice after loss of TR4. Mechanism dissection found the expression of osteoblast markers genes, such as ALP, type I collagen alpha 1, osteocalcin, PTH, and PTHR was dramatically reduced in osteoblasts from TR4 knockout mice as compared to those from TR4 wild type mice. In vitro cell line studies with luciferase reporter assay, ChIP assay, and EMSA further demonstrated TR4 could bind directly to the promoter region of osteocalcin gene and induce its gene expression at the transcriptional level in a dose dependent manner. Together, these results demonstrate TR4 may function as a novel transcriptional factor to play pathophysiological roles in maintaining normal osteoblast activity during the bone development and remodeling, and disruption of TR4 function may result in multiple skeletal abnormalities.

Differential regulation of myofilament protein isoforms underlying the contractility changes in skeletal muscle unloading

PubMed Central

Yu, Zhi-Bin; Gao, Fang; Feng, Han-Zhong; Jin, J-P

2006-01-01

Weight-bearing skeletal muscles change phenotype rapidly in response to unloading. Using the hind limb-suspension rat model, we investigated the regulation of myofilament protein isoforms in correlation to contractility. Four weeks of continuous hind limb unloading produced progressive atrophy and contractility changes in soleus but not extensor digitorum longus (EDL) muscle. The unloaded soleus muscle also had decreased fatigue resistance. Together with the decrease of myosin heavy chain (MHC) isoform I and IIa and increase of MHC IIb and IIx, coordinated regulation of thin filament regulatory protein isoforms were observed: γ- and β-tropomyosin decreased and α-tropomyosin increased, resulting in an α/β ratio similar to that in normal fast twitch skeletal muscle; troponin I and troponin T (TnT) both showed decrease in the slow isoform and increases in the fast isoform. The TnT isoform switching began after 7 days of unloading and TnI isoform showed detectable changes at 14 days while other protein isoform changes were not significant until 28 days of treatment. Correlating to the early changes in contractility, especially the resistance to fatigue, the early response of TnT isoform regulation may play a unique role in the adaptation of skeletal muscle to unloading. When the fast TnT gene expression was up-regulated in the unloaded soleus muscle, alternative RNA splicing switched to produce more high molecular weight acidic isoforms, reflecting a potential compensation for the decrease of slow TnT that is critical to skeletal muscle function. The results demonstrate that differential regulation of TnT isoforms is a sensitive mechanism in muscle adaptation to functional demands. PMID:17108008

Air-filled postcranial bones in theropod dinosaurs: physiological implications and the 'reptile'-bird transition.

PubMed

Benson, Roger B J; Butler, Richard J; Carrano, Matthew T; O'Connor, Patrick M

2012-02-01

Pneumatic (air-filled) postcranial bones are unique to birds among extant tetrapods. Unambiguous skeletal correlates of postcranial pneumaticity first appeared in the Late Triassic (approximately 210 million years ago), when they evolved independently in several groups of bird-line archosaurs (ornithodirans). These include the theropod dinosaurs (of which birds are extant representatives), the pterosaurs, and sauropodomorph dinosaurs. Postulated functions of skeletal pneumatisation include weight reduction in large-bodied or flying taxa, and density reduction resulting in energetic savings during foraging and locomotion. However, the influence of these hypotheses on the early evolution of pneumaticity has not been studied in detail previously. We review recent work on the significance of pneumaticity for understanding the biology of extinct ornithodirans, and present detailed new data on the proportion of the skeleton that was pneumatised in 131 non-avian theropods and Archaeopteryx. This includes all taxa known from significant postcranial remains. Pneumaticity of the cervical and anterior dorsal vertebrae occurred early in theropod evolution. This 'common pattern' was conserved on the line leading to birds, and is likely present in Archaeopteryx. Increases in skeletal pneumaticity occurred independently in as many as 12 lineages, highlighting a remarkably high number of parallel acquisitions of a bird-like feature among non-avian theropods. Using a quantitative comparative framework, we show that evolutionary increases in skeletal pneumaticity are significantly concentrated in lineages with large body size, suggesting that mass reduction in response to gravitational constraints at large body sizes influenced the early evolution of pneumaticity. However, the body size threshold for extensive pneumatisation is lower in theropod lineages more closely related to birds (maniraptorans). Thus, relaxation of the relationship between body size and pneumatisation preceded the origin of birds and cannot be explained as an adaptation for flight. We hypothesise that skeletal density modulation in small, non-volant, maniraptorans resulted in energetic savings as part of a multi-system response to increased metabolic demands. Acquisition of extensive postcranial pneumaticity in small-bodied maniraptorans may indicate avian-like high-performance endothermy. © 2011 The Authors. Biological Reviews © 2011 Cambridge Philosophical Society.

Progressive skeletal benefits of physical activity when young as assessed at the midshaft humerus in male baseball players.

PubMed

Warden, S J; Weatherholt, A M; Gudeman, A S; Mitchell, D C; Thompson, W R; Fuchs, R K

2017-07-01

Physical activity benefits the skeleton, but there is contrasting evidence regarding whether benefits differ at different stages of growth. The current study demonstrates that physical activity should be encouraged at the earliest age possible and be continued into early adulthood to gain most skeletal benefits. The current study explored physical activity-induced bone adaptation at different stages of somatic maturity by comparing side-to-side differences in midshaft humerus properties between male throwing athletes and controls. Throwers present an internally controlled model, while inclusion of control subjects removes normal arm dominance influences. Throwing athletes (n = 90) and controls (n = 51) were categorized into maturity groups (pre, peri, post-early, post-mid, and post-late) based on estimated years from peak height velocity (<-2, -2 to 2, 2 to 4, 4 to 10, and >10 years). Side-to-side percent differences in midshaft humerus cortical volumetric bone mineral density (Ct.vBMD) and bone mineral content (Ct.BMC); total (Tt.Ar), medullary (Me.Ar), and cortical (Ct.Ar) areas; average cortical thickness (Ct.Th); and polar Strength Strain Index (SSI P ) were assessed. Significant interactions between physical activity and maturity on side-to-side differences in Ct.BMC, Tt.Ar, Ct.Ar, Me.Ar, Ct.Th, and SSI P resulted from the following: (1) greater throwing-to-nonthrowing arm differences than dominant-to-nondominant arm differences in controls (all p < 0.05) and (2) throwing-to-nonthrowing arm differences in throwers being progressively greater across maturity groups (all p < 0.05). Regional analyses revealed greatest adaptation in medial and lateral sectors, particularly in the three post-maturity groups. Years throwing predicted 59% of the variance of the variance in throwing-to-nonthrowing arm difference in SSI P (p < 0.001). These data suggest that physical activity has skeletal benefits beginning prior to and continuing beyond somatic maturation and that a longer duration of exposure to physical activity has cumulative skeletal benefits. Thus, physical activity should be encouraged at the earliest age possible and be continued into early adulthood to optimize skeletal benefits.

Childhood-Adolescent Obesity in the Cardiorenal Syndrome: Lessons from Animal Models

PubMed Central

Hayden, Melvin R.; Sowers, James R.

2011-01-01

Background/Aims Childhood-adolescent overweight and obesity have grown to pandemic proportions during the past decade. The onset of obesity in younger adults will likely be manifested as earlier onset of myocardial and renal end-organ disease in younger adults. For the first time, it is estimated that the current generation may not live to be as old as their parents. Thus, it is important to develop animal models of childhood obesity to understand fundamental pathological organ changes. Methods In this regard, we utilize transmission electron microscopy evaluation to evaluate early remodeling changes of two adolescent rodent obesity models: the Zucker obese (fa/fa) rat and the db/db mouse models of obesity. We have concentrated on the initial ultrastructural remodeling (obese adipose tissue, skeletal muscle, and islet remodeling) and the associated changes in target end organs (including the myocardium and kidney) in young rodent models of obesity and insulin resistance, collectively manifesting as the cardiorenal metabolic syndrome (CRS). Results Briefly, tissues revealed the following ultrastructural remodeling abnormalities: inflammation, hypertrophy, and early fibrosis in adipose tissue; loss of mitochondria in skeletal muscles, hyperplasia, fibrosis, and depletion of insulin-secretory granules in pancreatic islets; increased intramyocardial lipid accumulation, fibrosis, and mitochondrial deposition in the myocardium, and obesity-related glomerulopathy and tubulopathy in the kidney. Conclusion Based on the current knowledge and ultrastructural observations of organ pathology, we propose mechanisms whereby obesity appears to be the driving force behind the development of the CRS. PMID:22294984

Actin genes and their expression in pacific white shrimp, Litopenaeus vannamei.

PubMed

Zhang, Xiaoxi; Zhang, Xiaojun; Yuan, Jianbo; Du, Jiangli; Li, Fuhua; Xiang, Jianhai

2018-04-01

Actin is a multi-functional gene family that can be divided into muscle-type actins and non-muscle-type actins. In this study, 37 unigenes encoding actins were identified from RNA-Seq data of Pacific white shrimp, Litopenaeus vannamei. According to phylogenetic analysis, four and three cDNAs belong to cytoplasmic- and heart-type actins and were named LvActinCT and LvActinHT, respectively. 10 cDNAs belong to the slow-type skeletal muscle actins, and 18 belong to the fast-type skeletal muscle actins; they were designated LvActinSSK and LvActinFSK, respectively. Some muscle actin genes formed gene clusters in the genome. Multiple alternative transcription starts sites (ATSSs) were found for LvActinCT1. Based on the early developmental expression profile, almost all LvActins were highly expressed between the early limb bud and post-larval stages. Using LvActinSSK5 as probes, slow-type muscle was localized in pleopod muscle and superficial ventral muscle. We also found three actin genes that were down-regulated in the hemocytes of white spot syndrome virus (WSSV)- and Vibrio parahaemolyticus-infected L. vannamei. This study provides valuable information on the actin gene structure of shrimp, furthers our understanding of the shrimp muscle system and helps us develop strategies for disease control and sustainable shrimp farming.

Aerobic Exercise and Pharmacological Therapies for Skeletal Myopathy in Heart Failure: Similarities and Differences

PubMed Central

Bacurau, Aline V.; Cunha, Telma F.; Souza, Rodrigo W.; Voltarelli, Vanessa A.; Gabriel-Costa, Daniele; Brum, Patricia C.

2016-01-01

Skeletal myopathy has been identified as a major comorbidity of heart failure (HF) affecting up to 20% of ambulatory patients leading to shortness of breath, early fatigue, and exercise intolerance. Neurohumoral blockade, through the inhibition of renin angiotensin aldosterone system (RAS) and β-adrenergic receptor blockade (β-blockers), is a mandatory pharmacological therapy of HF since it reduces symptoms, mortality, and sudden death. However, the effect of these drugs on skeletal myopathy needs to be clarified, since exercise intolerance remains in HF patients optimized with β-blockers and inhibitors of RAS. Aerobic exercise training (AET) is efficient in counteracting skeletal myopathy and in improving functional capacity and quality of life. Indeed, AET has beneficial effects on failing heart itself despite being of less magnitude compared with neurohumoral blockade. In this way, AET should be implemented in the care standards, together with pharmacological therapies. Since both neurohumoral inhibition and AET have a direct and/or indirect impact on skeletal muscle, this review aims to provide an overview of the isolated effects of these therapeutic approaches in counteracting skeletal myopathy in HF. The similarities and dissimilarities of neurohumoral inhibition and AET therapies are also discussed to identify potential advantageous effects of these combined therapies for treating HF. PMID:26904163

Early Life Conditions and Physiological Stress following the Transition to Farming in Central/Southeast Europe: Skeletal Growth Impairment and 6000 Years of Gradual Recovery

PubMed Central

Macintosh, Alison A.; Pinhasi, Ron; Stock, Jay T.

2016-01-01

Early life conditions play an important role in determining adult body size. In particular, childhood malnutrition and disease can elicit growth delays and affect adult body size if severe or prolonged enough. In the earliest stages of farming, skeletal growth impairment and small adult body size are often documented relative to hunter-gatherer groups, though this pattern is regionally variable. In Central/Southeast Europe, it is unclear how early life stress, growth history, and adult body size were impacted by the introduction of agriculture and ensuing long-term demographic, social, and behavioral change. The current study assesses this impact through the reconstruction and analysis of mean stature, body mass, limb proportion indices, and sexual dimorphism among 407 skeletally mature men and women from foraging and farming populations spanning the Late Mesolithic through Early Medieval periods in Central/Southeast Europe (~7100 calBC to 850 AD). Results document significantly reduced mean stature, body mass, and crural index in Neolithic agriculturalists relative both to Late Mesolithic hunter-gatherer-fishers and to later farming populations. This indication of relative growth impairment in the Neolithic, particularly among women, is supported by existing evidence of high developmental stress, intensive physical activity, and variable access to animal protein in these early agricultural populations. Among subsequent agriculturalists, temporal increases in mean stature, body mass, and crural index were more pronounced among Central European women, driving declines in the magnitude of sexual dimorphism through time. Overall, results suggest that the transition to agriculture in Central/Southeast Europe was challenging for early farming populations, but was followed by gradual amelioration across thousands of years, particularly among Central European women. This sex difference may be indicative, in part, of greater temporal variation in the social status afforded to young girls, in their access to resources during growth, and/or in their health status than was experienced by men. PMID:26844892

Indication for and frequency of early orthodontic therapy or interceptive measures.

PubMed

Schopf, Peter

2003-05-01

The early treatment of nonskeletal and skeletal orthodontic anomalies in the deciduous and early mixed dentition is intended to prevent the development of pronounced anomalies in the late mixed and permanent dentition with the ultimate aim of reducing or even eliminating the need for later orthodontic treatment. There is a general consensus in the international literature that early therapy is indicated in cases of anterior and lateral crossbite and Class III malocclusion, and possibly for extreme forms of mandibular retrognathism (overjet > or =10 mm) and of open bite. However, evidence of the efficiency of early orthodontic measures is just as rare as studies providing serviceable information on the incidence of tooth malalignments and malocclusions in the deciduous and early mixed dentition, some of whose findings are in any case highly divergent. This makes it substantially more difficult to draw conclusions on the extent to which early orthodontic therapy may be indicated. In order to obtain information on the incidence of nonskeletal and skeletal orthodontic problems constituting a treatment need, 2326 first-year schoolchildren aged between 6 and 7 years were examined in Frankfurt am Main and in the Rural District of Offenbach. In only 14.7% of the children were no relevant orthodontic findings recorded. 77.2% displayed mild to severe dysgnathic symptoms, though without early orthodontic therapy being considered indicated. Treatment with orthodontic appliances was considered urgent for 187 of the children (8.04%). With 8.3% and 7.9% respectively, lateral and anterior crossbite were top of the list of anomalies with an urgent treatment need. Among the patients with lateral crossbite, the prognostically less favorable unilateral form was recorded approximately four times more often than the bilateral form. Markedly increased sagittal overjet > or =10 mm) was registered in only 1.4% of the children, and negative overjet (Class III) (with the exception of edge-to-edge bite) in 1.9%. Extreme anterior open bite > or =6 mm) was recorded in only two children (0.09%). In 19.6% of the children, a supporting zone was reduced in at least one quadrant, necessitating interceptive measures such as the insertion of a space maintainer or later orthodontic treatment (space opening or extraction therapy).

Activity Participation Intensity Is Associated with Skeletal Development in Pre-Pubertal Children with Developmental Coordination Disorder

ERIC Educational Resources Information Center

Tsang, William W. N.; Guo, X.; Fong, Shirley S. M.; Mak, Kwok-Kei; Pang, Marco Y. C.

2012-01-01

Purpose: This study aimed (1) to compare the skeletal maturity and activity participation pattern between children with and without developmental coordination disorder (DCD); and (2) to determine whether activity participation pattern was associated with the skeletal development among children with DCD. Materials and methods: Thirty-three children…

MicroRNA in Skeletal Muscle: Its Crucial Roles in Signal Proteins, Mus cle Fiber Type, and Muscle Protein Synthesis.

PubMed

Zhang, Jing; Liu, Yu Lan

2017-01-01

Pork is one of the most economical sources of animal protein for human consumption. Meat quality is an important economic trait for the swine industry, which is primarily determined by prenatal muscle development and postnatal growth. Identification of the molecular mechanisms underlying skeletal muscle development is a key priority. MicroRNAs (miRNAs) are a class of small noncoding RNAs that have emerged as key regulators of skeletal muscle development. A number of muscle-related miRNAs have been identified by functional gain and loss experiments in mouse model. However, determining miRNA-mRNA interactions involved in pig skeletal muscle still remains a significant challenge. For a comprehensive understanding of miRNA-mediated mechanisms underlying muscle development, miRNAome analyses of pig skeletal muscle have been performed by deep sequencing. Additionally, porcine miRNA single nucleotide polymorphisms have been implicated in muscle fiber types and meat quality. The present review provides an overview of current knowledge on recently identified miRNAs involved in myogenesis, muscle fiber type and muscle protein metabolism. Undoubtedly, further systematic understanding of the functions of miRNAs in pig skeletal muscle development will be helpful to expand the knowledge of basic skeletal muscle biology and be beneficial for the genetic improvement of meat quality traits. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Familial osteochondritis dissecans associated with early osteoarthritis and disproportionate short stature.

PubMed

Stattin, E-L; Tegner, Y; Domellöf, M; Dahl, N

2008-08-01

Familial osteochondritis dissecans (OCD) is a rare disorder characterised by disturbed chondro-skeletal development, disproportionate growth and deformation of the skeleton. We identified a five-generation family with 15 living affected members from Northern Sweden. The disorder was diagnosed with a case definition of OCD in at least one joint. Main clinical findings consisted of OCD in knees and/or hips and/or elbows, disproportionate short stature and early osteoarthritis (OA). There were no radiological indications of epiphyseal dysplasia. Anthropometric measurements of affected individuals showed short stature, a high ratio between sitting height and total height, a relatively normal arm span and head circumference. In 12 of 15 cases, onset was during late childhood or adolescence and OA had developed in seven of those patients. Our observation suggests that OA is a frequent complication in familial OCD even though the lesions appear before closure of physis.

A unified anatomy ontology of the vertebrate skeletal system.

PubMed

Dahdul, Wasila M; Balhoff, James P; Blackburn, David C; Diehl, Alexander D; Haendel, Melissa A; Hall, Brian K; Lapp, Hilmar; Lundberg, John G; Mungall, Christopher J; Ringwald, Martin; Segerdell, Erik; Van Slyke, Ceri E; Vickaryous, Matthew K; Westerfield, Monte; Mabee, Paula M

2012-01-01

The skeleton is of fundamental importance in research in comparative vertebrate morphology, paleontology, biomechanics, developmental biology, and systematics. Motivated by research questions that require computational access to and comparative reasoning across the diverse skeletal phenotypes of vertebrates, we developed a module of anatomical concepts for the skeletal system, the Vertebrate Skeletal Anatomy Ontology (VSAO), to accommodate and unify the existing skeletal terminologies for the species-specific (mouse, the frog Xenopus, zebrafish) and multispecies (teleost, amphibian) vertebrate anatomy ontologies. Previous differences between these terminologies prevented even simple queries across databases pertaining to vertebrate morphology. This module of upper-level and specific skeletal terms currently includes 223 defined terms and 179 synonyms that integrate skeletal cells, tissues, biological processes, organs (skeletal elements such as bones and cartilages), and subdivisions of the skeletal system. The VSAO is designed to integrate with other ontologies, including the Common Anatomy Reference Ontology (CARO), Gene Ontology (GO), Uberon, and Cell Ontology (CL), and it is freely available to the community to be updated with additional terms required for research. Its structure accommodates anatomical variation among vertebrate species in development, structure, and composition. Annotation of diverse vertebrate phenotypes with this ontology will enable novel inquiries across the full spectrum of phenotypic diversity.

A Unified Anatomy Ontology of the Vertebrate Skeletal System

PubMed Central

Dahdul, Wasila M.; Balhoff, James P.; Blackburn, David C.; Diehl, Alexander D.; Haendel, Melissa A.; Hall, Brian K.; Lapp, Hilmar; Lundberg, John G.; Mungall, Christopher J.; Ringwald, Martin; Segerdell, Erik; Van Slyke, Ceri E.; Vickaryous, Matthew K.; Westerfield, Monte; Mabee, Paula M.

2012-01-01

The skeleton is of fundamental importance in research in comparative vertebrate morphology, paleontology, biomechanics, developmental biology, and systematics. Motivated by research questions that require computational access to and comparative reasoning across the diverse skeletal phenotypes of vertebrates, we developed a module of anatomical concepts for the skeletal system, the Vertebrate Skeletal Anatomy Ontology (VSAO), to accommodate and unify the existing skeletal terminologies for the species-specific (mouse, the frog Xenopus, zebrafish) and multispecies (teleost, amphibian) vertebrate anatomy ontologies. Previous differences between these terminologies prevented even simple queries across databases pertaining to vertebrate morphology. This module of upper-level and specific skeletal terms currently includes 223 defined terms and 179 synonyms that integrate skeletal cells, tissues, biological processes, organs (skeletal elements such as bones and cartilages), and subdivisions of the skeletal system. The VSAO is designed to integrate with other ontologies, including the Common Anatomy Reference Ontology (CARO), Gene Ontology (GO), Uberon, and Cell Ontology (CL), and it is freely available to the community to be updated with additional terms required for research. Its structure accommodates anatomical variation among vertebrate species in development, structure, and composition. Annotation of diverse vertebrate phenotypes with this ontology will enable novel inquiries across the full spectrum of phenotypic diversity. PMID:23251424

Sequence stratigraphy of the Lower Triassic Sinbad Formation, San Rafael Swell, east-central, Utah

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goodspeed, T.H.; Elrick, M.; Lucas, S.G.

1993-04-01

The Lower Triassic Sinbad Fm (20--30 m thick) in the San Rafael Swell of east-central Utah is high energy carbonate deposits that conformably overlie tidal flat/fluvial channel deposits of the Black Dragon Fm. The Torrey Fm conformably overlies the Sinbad Fm and consists primarily of siliciclastic tidal flat and fluvial deposits. Five facies (in ascending order) are characteristic of the Sinbad Fm: (1) bioturbated calcisiltite with calcite-replaced evaporite nodules and ripple laminations, (2) skeletal-oolitic-intraclastic packstone and grainstone, (3) slightly bioturbated, mechanically laminated, pelletal calcisiltite (5) trough cross-bedded, peloidal to oolitic grainstone, and (5) thin-bedded, skeletal-pelletal-oolitic grainstone with mud to wackestonemore » drapes. Regional facies relationships of the Sinbad Fm indicate initial deepening followed by shallowing. The skeletal-intraclastic packstone and grainstone facies represents maximum flooding. This facies thickens to the northwest and contains an open marine molluscan fauna of ammonites, bivalves, gastropods and scaphopods. The ammonites are indicative of the Tardus Zone of late Smithian age. Deposits above the maximum flooding zone (MFZ) are restricted foreshoal, pelletal calcisiltite, oolitic shoal, and backshoal skeletal-oolitic (with a restricted fauna of molluscs and ostracods) deposits. This shallowing-upward sequence represents the early HST. The Sinbad Fm represents the MFZ and early HST of a 150-m-thick depositional sequence of rocks with the Black Dragon FM representing the TST, and the Torrey Fm representing the late HST.« less

Therapies for the bone in mucopolysaccharidoses

PubMed Central

Tomatsu, Shunji; Alméciga-Díaz, Carlos J.; Montaño, Adriana M.; Yabe, Hiromasa; Tanaka, Akemi; Dung, Vu Chi; Giugliani, Roberto; Kubaski, Francyne; Mason, Robert W.; Yasuda, Eriko; Sawamoto, Kazuki; Mackenzie, William; Suzuki, Yasuyuki; Orii, Kenji E.; Barrera, Luis A.; Sly, William S.; Orii, Tadao

2014-01-01

Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis, leading to 1) stenosis of the upper cervical region, 2) restrictive small lung, 3) hip dysplasia, 4) restriction of joint movement, and 5) surgical complications. Patients often need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy through their lifetime. Current measures to intervene in bone disease progression are not perfect and palliative, and improved therapies are urgently required. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzyme to bone, especially avascular cartilage, to prevent or ameliorate the devastating skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion, and damage since the severity of skeletal dysplasia is associated with level of activity during daily life. This review illustrates a current overview of therapies and their impact for bone lesions in MPS including ERT, HSCT, gene therapy, and anti-inflammatory drugs. PMID:25537451

Musculo-Skeletal Abnormalities in Patients with Marfan Syndrome

PubMed Central

Al Kaissi, Ali; Zwettler, Elisabeth; Ganger, Rudolf; Schreiner, Simone; Klaushofer, Klaus; Grill, Franz

2013-01-01

Background A leptosomic body type is tall and thin with long hands. Marfanoid features may be familial in nature or pathological, as occurs in congenital contractual arachnodactyly (Beal’s syndrome) and Shprintzen-Goldberg syndrome mimicking some of the changes of Marfan syndrome, although not accompanied by luxation of lens and dissecting aneurysm of aorta. Methods In this article we collected eight patients who were consistent with the diagnosis of Marfan syndrome via phenotypic and genotypic characterization. Results Our patients manifested a constellation of variable presentations of musculo-skeletal abnormalities ranging from developmental dysplasia of the hip, protrusio acetabuli, leg length inequality, patellar instability, scoliosis, to early onset osteoarthritis. Each abnormality has been treated accordingly. Conclusion This is the first paper which includes the diagnosis and the management of the associated musculo-skeletal abnormalities in patients with Marfan syndrome, stressing that patients with Marfan syndrome are exhibiting great variability in the natural history and the severity of musculo-skeletal abnormalities. PMID:23399831

Short‐term disuse promotes fatty acid infiltration into skeletal muscle

PubMed Central

Pagano, Allan F.; Brioche, Thomas; Arc‐Chagnaud, Coralie; Demangel, Rémi; Chopard, Angèle

2017-01-01

Abstract Background Many physiological and/or pathological conditions lead to muscle deconditioning, a well‐described phenomenon characterized by a loss of strength and muscle power mainly due to the loss of muscle mass. Fatty infiltrations, or intermuscular adipose tissue (IMAT), are currently well‐recognized components of muscle deconditioning. Despite the fact that IMAT is present in healthy human skeletal muscle, its increase and accumulation are linked to muscle dysfunction. Although IMAT development has been largely attributable to inactivity, the precise mechanisms of its establishment are still poorly understood. Because the sedentary lifestyle that accompanies age‐related sarcopenia may favour IMAT development, deciphering the early processes of muscle disuse is of great importance before implementing strategies to limit IMAT deposition. Methods In our study, we took advantage of the dry immersion (DI) model of severe muscle inactivity to induce rapid muscle deconditioning during a short period. During the DI, healthy adult men (n = 12; age: 32 ± 5) remained strictly immersed, in a supine position, in a controlled thermo‐neutral water bath. Skeletal muscle biopsies were obtained from the vastus lateralis before and after 3 days of DI. Results We showed that DI for only 3 days was able to decrease myofiber cross‐sectional areas (−10.6%). Moreover, protein expression levels of two key markers commonly used to assess IMAT, perilipin, and fatty acid binding protein 4, were upregulated. We also observed an increase in the C/EBPα and PPARγ protein expression levels, indicating an increase in late adipogenic processes leading to IMAT development. While many stem cells in the muscle environment can adopt the capacity to differentiate into adipocytes, fibro‐adipogenic progenitors (FAPs) represent the population that appears to play a major role in IMAT development. In our study, we showed an increase in the protein expression of PDGFRα, the specific cell surface marker of FAPs, in response to 3 days of DI. It is well recognized that an unfavourable muscle environment drives FAPs to ectopic adiposity and/or fibrosis. Conclusions This study is the first to emphasize that during a short period of severe inactivity, muscle deconditioning is associated with IMAT development. Our study also reveals that FAPs could be the main resident muscle stem cell population implicated in ectopic adiposity development in human skeletal muscle. PMID:29248005

Abnormal lipid metabolism in skeletal muscle tissue of patients with muscular dystrophy: In vitro, high-resolution NMR spectroscopy based observation in early phase of the disease.

PubMed

Srivastava, Niraj Kumar; Yadav, Ramakant; Mukherjee, Somnath; Pal, Lily; Sinha, Neeraj

2017-05-01

Qualitative (assignment of lipid components) and quantitative (quantification of lipid components) analysis of lipid components were performed in skeletal muscle tissue of patients with muscular dystrophy in early phase of the disease as compared to control/normal subjects. Proton nuclear magnetic resonance (NMR) spectroscopy based experiment was performed on the lipid extract of skeletal muscle tissue of patients with muscular dystrophy in early phase of the disease and normal individuals for the analysis of lipid components [triglycerides, phospholipids, total cholesterol and unsaturated fatty acids (arachidonic, linolenic and linoleic acid)]. Specimens of muscle tissue were obtained from patients with Duchenne muscular dystrophy (DMD) [n=11; Age, Mean±SD; 9.2±1.4years; all were males], Becker muscular dystrophy (BMD) [n=12; Age, Mean±SD; 21.4±5.0years; all were males], facioscapulohumeral muscular dystrophy (FSHD) [n=11; Age, Mean±SD; 23.7±7.5years; all were males] and limb girdle muscular dystrophy-2B (LGMD-2B) [n=18; Age, Mean±SD; 24.2±4.1years; all were males]. Muscle specimens were also obtained from [n=30; Mean age±SD 23.1±6.0years; all were males] normal/control subjects. Assigned lipid components in skeletal muscle tissue were triglycerides (TG), phospholipids (PL), total cholesterol (CHOL) and unsaturated fatty acids (arachidonic, linolenic and linoleic acid)]. Quantity of lipid components was observed in skeletal muscle tissue of DMD, BMD, FSHD and LGMD-2B patients as compared to control/normal subjects. TG was significantly elevated in muscle tissue of DMD, BMD and LGMD-2B patients. Increase level of CHOL was found only in muscle of DMD patients. Level of PL was found insignificant for DMD, BMD and LGMD-2B patients. Quantity of TG, PL and CHOL was unaltered in the muscle of patients with FSHD as compared to control/normal subjects. Linoleic acids were significantly reduced in muscle tissue of DMD, BMD, FSHD and LGMD-2B as compared to normal/control individuals. Results clearly indicate alteration of lipid metabolism in patients with muscular dystrophy in early phase of the disease. Moreover, further evaluation is required to understand whether these changes are primary or secondary to muscular dystrophy. In future, these findings may prove an additional and improved approach for the diagnosis of different forms of muscular dystrophy. Copyright © 2017 Elsevier Inc. All rights reserved.

Brain and bone abnormalities of thanatophoric dwarfism.

PubMed

Miller, Elka; Blaser, Susan; Shannon, Patrick; Widjaja, Elysa

2009-01-01

The purpose of this article is to present the imaging findings of skeletal and brain abnormalities in thanatophoric dwarfism, a lethal form of dysplastic dwarfism. The bony abnormalities associated with thanatophoric dwarfism include marked shortening of the tubular bones and ribs. Abnormal temporal lobe development is a common associated feature and can be visualized as early as the second trimester. It is important to assess the brains of fetuses with suspected thanatophoric dwarfism because the presence of associated brain malformations can assist in the antenatal diagnosis of thanatophoric dwarfism.

In vivo longitudinal micro-CT study of bent long limb bones in rat offspring.

PubMed

De Schaepdrijver, Luc; Delille, Peter; Geys, Helena; Boehringer-Shahidi, Christian; Vanhove, Christian

2014-07-01

Micro-computed X-ray tomography (micro-CT) has been reported as a reliable method to assess ex vivo rat and rabbit fetal skeletons in embryo-fetal developmental toxicity studies. Since micro-CT is a non-invasive imaging modality it has the potential for longitudinal, in vivo investigation of postnatal skeletal development. This is the first paper using micro-CT to assess the reversibility of drug-induced bent long bones in a longitudinal study from birth to early adulthood in rat offspring. Analysis of the scans obtained on postnatal Day 0, 7, 21 and 80 showed complete recovery or repair of the bent long limb bones (including the scapula) within the first 3 weeks. When assessing risk the ability to demonstrate recovery is highly advantageous when interpreting such transient skeletal change. In summary, in vivo micro-CT of small laboratory animals can aid in non-clinical safety assessment, particularly for specific mechanistic purposes or to address a particular concern in developmental biology. Copyright © 2014 Elsevier Inc. All rights reserved.

Early development and osteoporosis and bone health.

PubMed

Dennison, E M; Cooper, C; Cole, Z A

2010-06-01

Osteoporosis is a skeletal disorder characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. Evidence is now accumulating from human studies that programming of bone growth might be an important contributor to the later risk of osteoporotic fracture. Body weight in infancy is a determinant of adult bone mineral content, as well as of the basal levels of activity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) and hypothalamo-pituitary-adrenal (HPA) axes, and recent work has suggested a central role for vitamin D. Epidemiological studies have shown that maternal smoking and nutrition during pregnancy influence intrauterine skeletal mineralization. Childhood growth rates have been directly linked to the risk of hip fracture many decades later, and now evidence is emerging from experimental animal studies that support these observational data. Recent studies have also highlighted epigenetic phenomena as potential mechanisms underlying the findings from epidemiological studies.

Early-progressive dilated cardiomyopathy in a family with Becker muscular dystrophy related to a novel frameshift mutation in the dystrophin gene exon 27.

PubMed

Tsuda, Takeshi; Fitzgerald, Kristi; Scavena, Mena; Gidding, Samuel; Cox, Mary O; Marks, Harold; Flanigan, Kevin M; Moore, Steven A

2015-03-01

We report a family in which two male siblings with Becker muscular dystrophy (BMD) developed severe dilated cardiomyopathy (DCM) and progressive heart failure (HF) at age 11 years; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device implantation at the same age. Genetic analysis of one sibling showed a novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAinsGG), in which seven base pairs are deleted and two are inserted. Although this predicts an amino-acid substitution and premature termination (p.Thr1260Argfs*8), muscle biopsy dystrophin immunostaining instead indicates that the mutation is more likely to alter splicing. Despite relatively preserved skeletal muscular performance, both the siblings developed progressive HF secondary to early-onset DCM. In addition, their 7-year-old nephew with delayed gross motor development, mild proximal muscle weakness and markedly elevated serum creatine kinase level (>13 000 IU l(-1)) at 16 months was recently demonstrated to have the familial DMD mutation. Here, we report a novel genotype of BMD with early-onset DCM and progressive lethal HF during early adolescence.

Effects of hypodynamic simulations on the skeletal system of monkeys

NASA Technical Reports Server (NTRS)

Young, D. R.; Tremor, J. W.

1977-01-01

A research and development program was undertaken to evaluate the skeletal losses of subhuman primates in hypodynamic environments. The goals of the program are: (1) to uncover the mechanisms by which weightlessness affects the skeletal system; (2) to determine the consequences and reversibility of bone mineral losses; and (3) to acquire a body of data needed to formulate an appropriate countermeasure program for the prevention of skeletal deconditioning. Space flight experiment simulation facilities are under development and will be tested for their capability in supporting certain of the requirements for these investigations.

Identification of morphological markers of sarcopenia at early stage of aging in skeletal muscle of mice.

PubMed

Sayed, Ramy K A; de Leonardis, Erika Chacin; Guerrero-Martínez, José A; Rahim, Ibtissem; Mokhtar, Doaa M; Saleh, Abdelmohaimen M; Abdalla, Kamal E H; Pozo, María J; Escames, Germaine; López, Luis C; Acuña-Castroviejo, Darío

2016-10-01

The gastrocnemius muscle (GM) of young (3months) and aged (12months) female wild-type C57/BL6 mice was examined by light and electron microscopy, looking for the presence of structural changes at early stage of the aging process. Morphometrical parameters including body and gastrocnemius weights, number and type of muscle fibers, cross section area (CSA), perimeter, and Feret's diameter of single muscle fiber, were measured. Moreover, lengths of the sarcomere, A-band, I-band, H-zone, and number and CSA of intermyofibrillar mitochondria (IFM), were also determined. The results provide evidence that 12month-old mice had significant changes on skeletal muscle structure, beginning with the reduction of gastrocnemius weight to body weight ratio, compatible with an early loss of skeletal muscle function and strength. Moreover, light microscopy revealed increased muscle fibers size, with a significant increase on their CSA, perimeter, and diameter of both type I and type II muscle fibers, and a reduction in the percentage of muscle area occupied by type II fibers. Enhanced connective tissue infiltrations, and the presence of centrally nucleated muscle fibers, were also found in aged mice. These changes may underlie an attempt to compensate the loss of muscle mass and muscle fibers number. Furthermore, electron microscopy discovered a significant age-dependent increase in the length of sarcomeres, I and H bands, and reduction on the overlapped actin/myosin length, supporting contractile force loss with age. Electron microscopy also showed an increased number and CSA of IFM with age, which may reveal more endurance at 12months of age. Together, mice at early stage of aging already show significant changes in gastrocnemius muscle morphology and ultrastructure that are suggestive of the onset of sarcopenia. Copyright © 2016 Elsevier Inc. All rights reserved.

Reservoir development in bryozoan bafflestone facies of the Ullin (Warsaw) Limestone (Middle Mississippian) in the Illinois basin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lasemi, Z.; Treworgy, J.D.; Norby, R.D.

1994-08-01

Recent drilling in Enfield South and Johnsonville fields in southern Illinois has encountered prolific petroleum-producing zones within the Ullin (Warsaw) Limestone. This and large cumulative production from a number of older wells in the Illinois basin indicate that the Ullin has greater reservoir potential than previously recognized. The Ullin reservoir facies is mainly a fenestrate bryozoan-dominated bafflestone developed on the flanks of Waulsortian-type mud mounds or on transported skeletal sand buildups. Subsurface geology and petrography reveal such porous bryozoan bafflestone facies (some with shows of oil) at various horizons within the Ullin. However, in part because of water problems inmore » some areas, only the upper part of the Ullin has been tested thus far and, as a result, significant reservoirs in the deeper part of the unit may have been missed. Preliminary data indicate several facies in the Ullin that vary in their aerial distribution in the basin. These facies include (1) skeletal sand-wave facies and/or bryozoan bafflestone in the upper Ullin, (2) bryozoan bafflestone with a dense Waulsortian mud mound core, (3) thick bryozoan bafflestone over a skeletal grainstone facies, and (4) thick mud mound-dominated facies with thin porous flanking bafflestone/grainstone facies. Areas with facies type 1 and 2 have the highest potential for commercial reservoir development. Facies type 3, although quite porous, is commonly wet, and the porous facies type 4 may be localized and not extensive enough to be commercial. Petrographic examination shows excellent preservation of primary intra- and interparticle porosities within the bryozoan bafflestone facies. The generally stable original mineralogy prevented extensive dissolution-reprecipitation and occlusion of porosity. Further, the stable mineralogy and minor early marine cementation prevented later compaction and burial diagenesis.« less

Intraspecific variation in an Ediacaran skeletal metazoan: Namacalathus from the Nama Group, Namibia.

PubMed

Penny, A M; Wood, R A; Zhuravlev, A Yu; Curtis, A; Bowyer, F; Tostevin, R

2017-01-01

Namacalathus hermanastes is one of the oldest known skeletal metazoans, found in carbonate settings of the terminal Ediacaran (~550-541 million years ago [Ma]). The palaeoecology of this widespread, goblet-shaped, benthic organism is poorly constrained yet critical for understanding the dynamics of the earliest metazoan communities. Analysis of in situ assemblages from the Nama Group, Namibia (~548-541 Ma), shows that Namacalathus exhibited size variation in response to differing water depths, hydrodynamic conditions and substrate types. In low-energy, inner ramp environments, Namacalathus attains the largest average sizes but grew in transient, loosely aggregating, monospecific aggregations attached to microbial mats. In high-energy mid-ramp reefs, Namacalathus spatially segregated into different palaeoecological habitats with distinct size distributions. In outer ramp environments, individuals were small and formed patchy, dense, monospecific aggregations attached to thin microbial mats. Asexual budding is common in all settings. We infer that variations in size distribution in Namacalathus reflect differences in habitat heterogeneity and stability, including the longevity of mechanically stable substrates and oxic conditions. In the Nama Group, long-lived skeletal metazoan communities developed within topographically heterogeneous mid-ramp reefs, which provided diverse mechanically stable microbial substrates in persistently oxic waters, while inner and outer ramp communities were often ephemeral, developing during fleeting episodes of either oxia and/or substrate stability. We conclude that Namacalathus, which forms a component of these communities in the Nama Group, was a generalist that adapted to various palaeoecological habitats within a heterogeneous ecosystem landscape where favourable conditions persisted, and was also able to opportunistically colonise transiently hospitable environments. These early skeletal metazoans colonised previously unoccupied substrates in thrombolitic reefs and other microbial carbonate settings, and while they experienced relatively low levels of interspecific competition, they were nonetheless adapted to the diverse environments and highly dynamic redox conditions present in the terminal Ediacaran. © 2016 John Wiley & Sons Ltd.

Discovery of a Mammalian Splice Variant of Myostatin That Stimulates Myogenesis

PubMed Central

Jeanplong, Ferenc; Falconer, Shelley J.; Oldham, Jenny M.; Thomas, Mark; Gray, Tarra S.; Hennebry, Alex; Matthews, Kenneth G.; Kemp, Frederick C.; Patel, Ketan; Berry, Carole; Nicholas, Gina; McMahon, Christopher D.

2013-01-01

Myostatin plays a fundamental role in regulating the size of skeletal muscles. To date, only a single myostatin gene and no splice variants have been identified in mammals. Here we describe the splicing of a cryptic intron that removes the coding sequence for the receptor binding moiety of sheep myostatin. The deduced polypeptide sequence of the myostatin splice variant (MSV) contains a 256 amino acid N-terminal domain, which is common to myostatin, and a unique C-terminus of 65 amino acids. Western immunoblotting demonstrated that MSV mRNA is translated into protein, which is present in skeletal muscles. To determine the biological role of MSV, we developed an MSV over-expressing C2C12 myoblast line and showed that it proliferated faster than that of the control line in association with an increased abundance of the CDK2/Cyclin E complex in the nucleus. Recombinant protein made for the novel C-terminus of MSV also stimulated myoblast proliferation and bound to myostatin with high affinity as determined by surface plasmon resonance assay. Therefore, we postulated that MSV functions as a binding protein and antagonist of myostatin. Consistent with our postulate, myostatin protein was co-immunoprecipitated from skeletal muscle extracts with an MSV-specific antibody. MSV over-expression in C2C12 myoblasts blocked myostatin-induced Smad2/3-dependent signaling, thereby confirming that MSV antagonizes the canonical myostatin pathway. Furthermore, MSV over-expression increased the abundance of MyoD, Myogenin and MRF4 proteins (P<0.05), which indicates that MSV stimulates myogenesis through the induction of myogenic regulatory factors. To help elucidate a possible role in vivo, we observed that MSV protein was more abundant during early post-natal muscle development, while myostatin remained unchanged, which suggests that MSV may promote the growth of skeletal muscles. We conclude that MSV represents a unique example of intra-genic regulation in which a splice variant directly antagonizes the biological activity of the canonical gene product. PMID:24312578

Deletion of Skeletal Muscle SOCS3 Prevents Insulin Resistance in Obesity

PubMed Central

Jorgensen, Sebastian Beck; O’Neill, Hayley M.; Sylow, Lykke; Honeyman, Jane; Hewitt, Kimberly A.; Palanivel, Rengasamy; Fullerton, Morgan D.; Öberg, Lisa; Balendran, Anudharan; Galic, Sandra; van der Poel, Chris; Trounce, Ian A.; Lynch, Gordon S.; Schertzer, Jonathan D.; Steinberg, Gregory R.

2013-01-01

Obesity is associated with chronic low-grade inflammation that contributes to defects in energy metabolism and insulin resistance. Suppressor of cytokine signaling (SOCS)-3 expression is increased in skeletal muscle of obese humans. SOCS3 inhibits leptin signaling in the hypothalamus and insulin signal transduction in adipose tissue and the liver. Skeletal muscle is an important tissue for controlling energy expenditure and whole-body insulin sensitivity; however, the physiological importance of SOCS3 in this tissue has not been examined. Therefore, we generated mice that had SOCS3 specifically deleted in skeletal muscle (SOCS MKO). The SOCS3 MKO mice had normal muscle development, body mass, adiposity, appetite, and energy expenditure compared with wild-type (WT) littermates. Despite similar degrees of obesity when fed a high-fat diet, SOCS3 MKO mice were protected against the development of hyperinsulinemia and insulin resistance because of enhanced skeletal muscle insulin receptor substrate 1 (IRS1) and Akt phosphorylation that resulted in increased skeletal muscle glucose uptake. These data indicate that skeletal muscle SOCS3 does not play a critical role in regulating muscle development or energy expenditure, but it is an important contributing factor for inhibiting insulin sensitivity in obesity. Therapies aimed at inhibiting SOCS3 in skeletal muscle may be effective in reversing obesity-related glucose intolerance and insulin resistance. PMID:22961088

Femoral Metastasis from Penile Carcinoma: Report of 2 Cases

PubMed Central

Braumann, Laura; Tsagozis, Panagiotis; Wedin, Rikard; Brosjö, Otte

2015-01-01

Purpose. Penile cancer rarely gives symptomatic skeletal metastases. Methods. We present 2 patients with squamous carcinoma of the penis who were surgically treated for metastases in the femur. Results. Both patients had pathological fractures and were operated on. In one case, the skeletal metastasis preceded any lymphatic spread of the disease, suggesting early haematogenous dissemination. Conclusions. Endoprosthetic reconstruction resulted in pain relief and restored the ambulatory capacity. Clinicians should be aware of the possibility for symptomatic bone metastases with a risk for pathological fracture in patients with penile cancer. PMID:26579327

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jones, B.; Renaut, R.W.

Skeletal crystals are hollow crystals that develop because their outer walls grow before their cores. The presence of skeletal crystals of calcite (three types--trigonal prisms, hexagonal prisms, and plates) and trona in hot (> 90 C) spring deposits in New Zealand (Waikite Springs and Ohaaki Pool) and Kenya (Lorusio hot springs) shows that they can form in natural sedimentary regimes. Analysis of samples from these deposits shows that this crystal morphology develops under disequilibrium conditions that are unrelated to a specific environmental or diagenetic setting. Skeletal crystals transform into solid crystals when subsequent precipitation fills their hollow cores. In somemore » cases, this may involve precipitation of crystalline material that has a sieve-like texture. In other examples, the skeletal crystal provides a framework upon which other materials can be precipitated. Walls in the skeletal trigonal calcite prisms from Waikite Springs are formed of subcrystals that mimic the shape of the parent crystal. Similarly, plate-like skeletal crystals from Lorusio are formed of densely packed subcrystals that are < 0.5 {micro}m long. Conversely, the walls of the skeletal hexagonal calcite crystals from Ohaaki Pool and the skeletal trona crystals from Lorusio are not formed of subcrystals. Recognition of skeletal crystals is important because they represent growth that follows the reverse pattern of normal growth. Failure to recognize that crystal growth followed the skeletal motif may lead to false interpretations concerning the growth of a crystal.« less

Methods and application of bone densitometry in clinical diagnosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wahner, H.W.; Riggs, B.L.

1986-01-01

With the awareness of osteoporosis as a major health problem for an aging population, there is great interest in early recognition and treatment of abnormal bone loss. Effective prevention of bone loss has to occur prior to the occurrence of irreparable damage. Standard radiographic procedures are not sensitive enough for the task. Therefore, a number of alternative procedures to estimate bone loss have been developed over the years, ranging from efforts to quantitate information obtained from radiographic images to sophisticated procedures such as neutron activation analysis or procedures based on the Compton scatter phenomenon. Only two procedures, photon absorptiometry andmore » computed tomography (CT), have emerged as applicable for routine clinical use. In photon absorptiometry the entire bone mineral (cortical and trabecular bone) of a specific skeletal site is measured. CT allows measuring of bone mineral of trabecular or cortical bone alone. Normally, bone mass reaches a maximum in the third decade and then continuously declines. This age-related bone loss is greater in women in whom an accelerated rate of loss occurs at the menopause. When bone density reaches a critical fracture threshold, skeletal fractures occur (spine, hip, and distal long bones). The age at which this critical fracture threshold is reached depends on the maximal bone mass achieved in early adulthood and the rate of loss with increasing age. With the exception of NaF, present-day therapeutic efforts only retard or prevent bone loss but do not significantly add bone mineral to the skeleton. Recognition of high-risk groups and early treatment are therefore required. 79 references.« less

Accentuated lines in the enamel of primary incisors from skeletal remains: A contribution to the explanation of early childhood mortality in a medieval population from Poland.

PubMed

Żądzińska, Elżbieta; Lorkiewicz, Wiesław; Kurek, Marta; Borowska-Strugińska, Beata

2015-07-01

Physiological disruptions resulting from an impoverished environment during the first years of life are of key importance for the health and biological status of individuals and populations. Studies of growth processes in archaeological populations point to the fact that the main causes of childhood mortality in the past are to be sought among extrinsic factors. Based on this assumption, one would expect random mortality of children, with the deceased individuals representing the entire subadult population. The purpose of this study is to explore whether differences in early childhood survival are reflected in differences in deciduous tooth enamel, which can provide an insight into the development of an individual during prenatal and perinatal ontogeny. Deciduous incisors were taken from 83 individuals aged 2.0-6.5 years from a medieval inhumation cemetery dated AD 1300-1600. Prenatal and postnatal enamel formation time, neonatal line width, and the number of accentuated lines were measured using an optical microscope. The significantly wider neonatal line and the higher frequency of accentuated lines in the enamel of the incisors of children who died at the age of 2-3 years suggest the occurrence of stronger or more frequent stress events in this group. These results indicate that in skeletal populations mortality was not exclusively determined by random external factors. Individuals predisposed by an unfavorable course of prenatal and perinatal growth were more likely to die in early childhood. © 2015 Wiley Periodicals, Inc.

MicroRNA-128 targets myostatin at coding domain sequence to regulate myoblasts in skeletal muscle development.

PubMed

Shi, Lei; Zhou, Bo; Li, Pinghua; Schinckel, Allan P; Liang, Tingting; Wang, Han; Li, Huizhi; Fu, Lingling; Chu, Qingpo; Huang, Ruihua

2015-09-01

MicroRNAs (miRNAs or miRs) play a critical role in skeletal muscle development. In a previous study we observed that miR-128 was highly expressed in skeletal muscle. However, its function in regulating skeletal muscle development is not clear. Our hypothesis was that miR-128 is involved in the regulation of the proliferation and differentiation of skeletal myoblasts. In this study, through bioinformatics analyses, we demonstrate that miR-128 specifically targeted mRNA of myostatin (MSTN), a critical inhibitor of skeletal myogenesis, at coding domain sequence (CDS) region, resulting in down-regulating of myostatin post-transcription. Overexpression of miR-128 inhibited proliferation of mouse C2C12 myoblast cells but promoted myotube formation; whereas knockdown of miR-128 had completely opposite effects. In addition, ectopic miR-128 regulated the expression of myogenic factor 5 (Myf5), myogenin (MyoG), paired box (Pax) 3 and 7. Furthermore, an inverse relationship was found between the expression of miR-128 and MSTN protein expression in vivo and in vitro. Taken together, these results reveal that there is a novel pathway in skeletal muscle development in which miR-128 regulates myostatin at CDS region to inhibit proliferation but promote differentiation of myoblast cells. Copyright © 2015 Elsevier Inc. All rights reserved.

In vitro Differentiation of Functional Human Skeletal Myotubes in a Defined System

PubMed Central

Guo, Xiufang; Greene, Keshel; Akanda, Nesar; Smith, Alec; Stancescu, Maria; Lambert, Stephen; Vandenburgh, Herman; Hickman, James

2013-01-01

In vitro human skeletal muscle systems are valuable tools for the study of human muscular development, disease and treatment. However, published in vitro human muscle systems have so far only demonstrated limited differentiation capacities. Advanced differentiation features such as cross-striations and contractility have only been observed in co-cultures with motoneurons. Furthermore, it is commonly regarded that cultured human myotubes do not spontaneously contract, and any contraction has been considered to originate from innervation. This study developed a serum-free culture system in which human skeletal myotubes demonstrated advanced differentiation. Characterization by immunocytochemistry, electrophysiology and analysis of contractile function revealed these major features: A) well defined sarcomeric development, as demonstrated by the presence of cross-striations. B) finely developed excitation-contraction coupling apparatus characterized by the close apposition of dihydropyridine receptors on T-tubules and Ryanodine receptors on sarcoplasmic reticulum membranes. C) spontaneous and electrically controlled contractility. This report not only demonstrates an improved level of differentiation of cultured human skeletal myotubes, but also provides the first published evidence that such myotubes are capable of spontaneous contraction. Use of this functional in vitro human skeletal muscle system would advance studies concerning human skeletal muscle development and physiology, as well as muscle-related disease and therapy. PMID:24516722

In vitro Differentiation of Functional Human Skeletal Myotubes in a Defined System.

PubMed

Guo, Xiufang; Greene, Keshel; Akanda, Nesar; Smith, Alec; Stancescu, Maria; Lambert, Stephen; Vandenburgh, Herman; Hickman, James

2014-01-01

In vitro human skeletal muscle systems are valuable tools for the study of human muscular development, disease and treatment. However, published in vitro human muscle systems have so far only demonstrated limited differentiation capacities. Advanced differentiation features such as cross-striations and contractility have only been observed in co-cultures with motoneurons. Furthermore, it is commonly regarded that cultured human myotubes do not spontaneously contract, and any contraction has been considered to originate from innervation. This study developed a serum-free culture system in which human skeletal myotubes demonstrated advanced differentiation. Characterization by immunocytochemistry, electrophysiology and analysis of contractile function revealed these major features: A) well defined sarcomeric development, as demonstrated by the presence of cross-striations. B) finely developed excitation-contraction coupling apparatus characterized by the close apposition of dihydropyridine receptors on T-tubules and Ryanodine receptors on sarcoplasmic reticulum membranes. C) spontaneous and electrically controlled contractility. This report not only demonstrates an improved level of differentiation of cultured human skeletal myotubes, but also provides the first published evidence that such myotubes are capable of spontaneous contraction. Use of this functional in vitro human skeletal muscle system would advance studies concerning human skeletal muscle development and physiology, as well as muscle-related disease and therapy.

Odontogenic Keratocysts in Gorlin-Goltz Syndrome: A Case Report.

PubMed

Chandran, Satheesh; Marudhamuthu, Karthikeyan; Riaz, R; Balasubramaniam, Saravanan

2015-01-01

Gorlin-Goltz syndrome is an autosomal dominant inherited condition comprising the principle triad of basal cell carcinomas, multiple jaw keratocysts, and skeletal anomalies. The presence of jaw cysts are the early diagnostic feature of this syndrome, and this can be incidentally identified by routine radiographs. A patient presented with signs and symptoms of Gorlin-Goltz syndrome to us in her early stages.

Effects of audiogenic hazard on fetal skeletal development in mice

NASA Astrophysics Data System (ADS)

Murata, M.; Kawade, F.; Kondo, M.; Takigawa, H.; Sakamoto, H.

1990-06-01

The effects of noise on fetal skeletal development in mice were examined. Pregnant ICR mice were exposed to a wide octave-band noise at 100 dB(C) for 6 hours a day in three ways: the first group was continuously exposed only on day 7 of pregnancy (group "N"); the second was exposed intermittently (15 min on/15 min off) only on day 7 of pregnancy (group "IN"); and the third was exposed to a continuous noise recurrently during days 7-12 of pregnancy (group "RN"). On day 18 of pregnancy, fetuses were removed and prepared as skeletons of cleared specimens stained with alizarin red S for examining skeletal development. Skeletal immaturity was observed in group "RN". The percentage of fetuses with skeletal malformations was significantly increased in group "N", as compared with the control. Significantly higher percentages of fetuses with variations in cervical vertebral arches were observed in groups "N" and "RN".

Regenerating skeletal muscle in the face of aging and disease.

PubMed

Jasuja, Ravi; LeBrasseur, Nathan K

2014-11-01

Skeletal muscle is a fundamental organ in the generation of force and movement, the regulation of whole-body metabolism, and the provision of resiliency. Indeed, physical medicine and rehabilitation is recognized for optimizing skeletal muscle health in the context of aging (sarcopenia) and disease (cachexia). Exercise is, and will remain, the cornerstone of therapies to improve skeletal muscle health. However, there are now a number of promising biologic and small molecule interventions currently under development to rejuvenate skeletal muscle, including myostatin inhibitors, selective androgen receptor modulators, and an activator of the fast skeletal muscle troponin complex. The opportunities for skeletal muscle-based regenerative therapies and a selection of emerging pharmacologic interventions are discussed in this review.

Advances in Skeletal Dysplasia Genetics

PubMed Central

Geister, Krista A.; Camper, Sally A.

2017-01-01

Skeletal dysplasias result from disruptions in normal skeletal growth and development and are a major contributor to severe short stature. They occur in approximately 1/5,000 births, and some are lethal. Since the most recent publication of the Nosology and Classification of Genetic Skeletal Disorders, genetic causes of 56 skeletal disorders have been uncovered. This remarkable rate of discovery is largely due to the expanded use of high-throughput genomic technologies. In this review, we discuss these recent discoveries and our understanding of the molecular mechanisms behind these skeletal dysplasia phenotypes. We also cover potential therapies, unusual genetic mechanisms, and novel skeletal syndromes both with and without known genetic causes. The acceleration of skeletal dysplasia genetics is truly spectacular, and these advances hold great promise for diagnostics, risk prediction, and therapeutic design. PMID:25939055

Inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ signaling mediates delayed myogenesis in Duchenne muscular dystrophy fetal muscle.

PubMed

Farini, Andrea; Sitzia, Clementina; Cassinelli, Letizia; Colleoni, Federica; Parolini, Daniele; Giovanella, Umberto; Maciotta, Simona; Colombo, Augusto; Meregalli, Mirella; Torrente, Yvan

2016-02-15

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder characterized by muscle wasting and premature death. The defective gene is dystrophin, a structural protein, absence of which causes membrane fragility and myofiber necrosis. Several lines of evidence showed that in adult DMD patients dystrophin is involved in signaling pathways that regulate calcium homeostasis and differentiation programs. However, secondary aspects of the disease, such as inflammation and fibrosis development, might represent a bias in the analysis. Because fetal muscle is not influenced by gravity and does not suffer from mechanical load and/or inflammation, we investigated 12-week-old fetal DMD skeletal muscles, highlighting for the first time early alterations in signaling pathways mediated by the absence of dystrophin itself. We found that PLC/IP3/IP3R/Ryr1/Ca(2+) signaling is widely active in fetal DMD skeletal muscles and, through the calcium-dependent PKCα protein, exerts a fundamental regulatory role in delaying myogenesis and in myofiber commitment. These data provide new insights into the origin of DMD pathology during muscle development. © 2016. Published by The Company of Biologists Ltd.

The relationship between form and function throughout the history of excitation-contraction coupling.

PubMed

Franzini-Armstrong, Clara

2018-02-05

The concept of excitation-contraction coupling is almost as old as Journal of General Physiology It was understood as early as the 1940s that a series of stereotyped events is responsible for the rapid contraction response of muscle fibers to an initial electrical event at the surface. These early developments, now lost in what seems to be the far past for most young investigators, have provided an endless source of experimental approaches. In this Milestone in Physiology, I describe in detail the experiments and concepts that introduced and established the field of excitation-contraction coupling in skeletal muscle. More recent advances are presented in an abbreviated form, as readers are likely to be familiar with recent work in the field. © 2018 Franzini-Armstrong.

Clinical Features and Risk Factors of Skeletal-Related Events in Genitourinary Cancer Patients with Bone Metastasis: A Retrospective Analysis of Prostate Cancer, Renal Cell Carcinoma, and Urothelial Carcinoma.

PubMed

Owari, Takuya; Miyake, Makito; Nakai, Yasushi; Morizawa, Yosuke; Itami, Yoshitaka; Hori, Shunta; Anai, Satoshi; Tanaka, Nobumichi; Fujimoto, Kiyohide

2018-06-06

The objective of the present study was to report the incidence of skeletal-related events (SREs) and identify risk factors for SREs in patients with genitourinary cancer with newly diagnosed bone metastasis. This retrospective study included 180 patients with bone metastasis from prostate cancer (PCa; n = 111), renal cell carcinoma (RCC; n = 43), and urothelial carcinoma (UC; n = 26). Clinical factors at the time of diagnosis of bone metastasis were evaluated with Cox proportional hazards regression analysis to identify independent risk factors for SREs. During follow-up, 29 (26%) patients with PCa, 30 (70%) with RCC, and 15 (58%) with UC developed SREs. Treatment with bone-modifying agents (BMAs) before the development of SREs and within 6 months from the diagnosis of bone metastasis significantly delayed the time to first SRE as compared to nonuse of BMAs. Multivariate analysis identified type of primary cancer (PCa vs. RCC, PCa vs. UC), performance status, and bone pain as significant independent predictive risk factors for SREs. Treatment with BMAs significantly delayed the development of first SREs. The identified predictors of SREs might be useful to select patients who would benefit most from early treatment with BMAs. © 2018 S. Karger AG, Basel.

Neural crest apoptosis and the establishment of craniofacial pattern: an honorable death.

PubMed

Graham, A; Koentges, G; Lumsden, A

1996-01-01

During development of the vertebrate head neural crest cells emigrate from the hindbrain and populate the branchial arches, giving rise to distinct skeletal elements and muscle connective tissues in each arch. The production of neural crest from the hindbrain is discontinuous and crest cells destined for different arches, carrying different positional cues, are separated by regions of apoptosis centered on rhombomeres (r) 3 and r5. This cell death program is under the interactive control of the neighboring hindbrain segments. Both r3 and r5 produce large numbers of crest cells when freed from their flanking rhombomere, but when conjoined with their neighbor the cell death program is restored. Two key components of this program are Bmp 4 and msx-2, both of which are expressed in the apoptotic foci of r3 and r5 and which are also regulated by neighbor interactions. Importantly, the addition of recombinant Bmp 4 to isolated cultures of r3 and r5 induces the expression of Bmp 4 and msx-2 and restores the cell death program. This early neural crest segregation is maintained during development and it has profound effects upon the final craniofacial pattern. Even though crest cells from different axial origins will contribute to compound skeletal elements, these distinct populations do not intermingle. Furthermore head muscle connective tissues are exclusively anchored to skeletal domains arising from neural crest from the same axial level. Thus the discontinuous production of neural crest sculpts the crest into nonmixing streams and consequently ensures the fidelity of patterning.

Effects of lead-contaminated sediment on Rana sphenocephala tadpoles.

PubMed

Sparling, Donald W; Krest, Sherry; Ortiz-Santaliestra, Manuel

2006-10-01

We exposed larval southern leopard frogs (Rana sphenocephala) to lead-contaminated sediments to determine the lethal and sublethal effects of this metal. Tadpoles were laboratory-raised from early free-swimming stage through metamorphosis at lead concentrations of 45, 75, 180, 540, 2360, 3940, 5520, and 7580 mg/kg dry weight in sediment. Corresponding pore water lead concentrations were 123, 227, 589, 1833, 8121, 13,579, 19,038, and 24,427 microg/L. Tadpoles exposed to lead concentrations in sediment of 3940 mg/kg or higher died within 2 to 5 days of exposure. At lower concentrations, mortality through metamorphosis ranged from 3.5% at 45 mg/kg lead to 37% at 2360 mg/kg lead in sediment. The LC50 value for lead in sediment was 3728 mg/kg (95% CI = 1315 to 72,847 mg/kg), which corresponded to 12,539 microg/L lead in pore water (95% CI = 4000 to 35,200 microg/L). Early growth and development were depressed at 2,360 mg/kg lead in sediment (8100 microg/L in pore water) but differences were not evident by the time of metamorphosis. The most obvious effect of lead was its pronounced influence on skeletal development. Whereas tadpoles at 45 mg/kg lead in sediment did not display permanent abnormalities, skeletal malformations increased in frequency and severity at all higher lead concentrations. By 2360 mg/kg, 100% of surviving metamorphs displayed severe spinal problems, reduced femur and humerus lengths, deformed digits, and other bone malformations. Lead concentrations in tissues correlated positively with sediment and pore water concentrations.

Effects of lead-contaminated sediment on Rana sphenocephala tadpoles

USGS Publications Warehouse

Sparling, D.W.; Krest, S.K.; Ortiz-Santaliestra, M.

2006-01-01

We exposed larval southern leopard frogs (Rana sphenocephala) to lead-contaminated sediments to determine the lethal and sublethal effects of this metal. Tadpoles were laboratory-raised from early free-swimming stage through metamorphosis at lead concentrations of 45, 75, 180, 540, 2360, 3940, 5520, and 7580 mg/kg dry weight in sediment. Corresponding pore water lead concentrations were 123, 227, 589, 1833, 8121, 13,579, 19,038, and 24,427 ug/L. Tadpoles exposed to lead concentrations in sediment of 3940 mg/kg or higher died within 2 to 5 days of exposure. At lower concentrations, mortality through metamorphosis ranged from 3.5% at 45 mg/kg lead to 37% at 2360 mg/kg lead in sediment. The LC50 value for lead in sediment was 3728 mg/kg (95% CI=1315 to 72,847 mg/kg), which corresponded to 12,539 ug/L lead in pore water (95% CI= 4000 to 35,200 ug/L). Early growth and development were depressed at 2,360 mg/kg lead in sediment (8100 ug/L in pore water) but differences were not evident by the time of metamorphosis. The most obvious effect of lead was its pronounced influence on skeletal development. Whereas tadpoles at 45 mg/kg lead in sediment did not display permanent abnormalities, skeletal malformations increased in frequency and severity at all higher lead concentrations. By 2360 mg/kg, 100% of surviving metamorphs displayed severe spinal problems, reduced femur and humerus lengths, deformed digits, and other bone malformations. Lead concentrations in tissues correlated positively with sediment and pore water concentrations.

Adipose tissue development during early life: novel insights into energy balance from small and large mammals.

PubMed

Symonds, Michael E; Pope, Mark; Budge, Helen

2012-08-01

Since the rediscovery of brown adipose tissue (BAT) in adult human subjects in 2007, there has been a dramatic resurgence in research interest in its role in heat production and energy balance. This has coincided with a reassessment of the origins of BAT and the suggestion that brown preadipocytes could share a common lineage with skeletal myoblasts. In precocial newborns, such as sheep, the onset of non-shivering thermogenesis through activation of the BAT-specific uncoupling protein 1 (UCP1) is essential for effective adaptation to the cold exposure of the extra-uterine environment. This is mediated by a combination of endocrine adaptations which accompany normal parturition at birth and further endocrine stimulation from the mother's milk. Three distinct adipose depots have been identified in all species studied to date. These contain either primarily white, primarily brown or a mix of brown and white adipocytes. The latter tissue type is present, at least, in the fetus and, thereafter, appears to take on the characteristics of white adipose tissue during postnatal development. It is becoming apparent that a range of organ-specific mechanisms can promote UCP1 expression. They include the liver, heart and skeletal muscle, and involve unique endocrine systems that are stimulated by cold exposure and/or exercise. These multiple pathways that promote BAT function vary with age and between species that may determine the potential to be manipulated in early life. Such interventions could modify, or reverse, the normal ontogenic pathway by which BAT disappears after birth, thereby facilitating BAT thermogenesis through the life cycle.

Gene expression changes controlling distinct adaptations in the heart and skeletal muscle of a hibernating mammal

PubMed Central

Vermillion, Katie L.; Anderson, Kyle J.; Hampton, Marshall

2015-01-01

Throughout the hibernation season, the thirteen-lined ground squirrel (Ictidomys tridecemlineatus) experiences extreme fluctuations in heart rate, metabolism, oxygen consumption, and body temperature, along with prolonged fasting and immobility. These conditions necessitate different functional requirements for the heart, which maintains contractile function throughout hibernation, and the skeletal muscle, which remains largely inactive. The adaptations used to maintain these contractile organs under such variable conditions serves as a natural model to study a variety of medically relevant conditions including heart failure and disuse atrophy. To better understand how two different muscle tissues maintain function throughout the extreme fluctuations of hibernation we performed Illumina HiSeq 2000 sequencing of cDNAs to compare the transcriptome of heart and skeletal muscle across the circannual cycle. This analysis resulted in the identification of 1,076 and 1,466 differentially expressed genes in heart and skeletal muscle, respectively. In both heart and skeletal muscle we identified a distinct cold-tolerant mechanism utilizing peroxisomal metabolism to make use of elevated levels of unsaturated depot fats. The skeletal muscle transcriptome also shows an early increase in oxidative capacity necessary for the altered fuel utilization and increased oxygen demand of shivering. Expression of the fetal gene expression profile is used to maintain cardiac tissue, either through increasing myocyte size or proliferation of resident cardiomyocytes, while skeletal muscle function and mass are protected through transcriptional regulation of pathways involved in protein turnover. This study provides insight into how two functionally distinct muscles maintain function under the extreme conditions of mammalian hibernation. PMID:25572546

Wnt antagonist, secreted frizzled-related protein 1, is involved in prenatal skeletal muscle development and is a target of miRNA-1/206 in pigs.

PubMed

Yang, Yalan; Sun, Wei; Wang, Ruiqi; Lei, Chuzhao; Zhou, Rong; Tang, Zhonglin; Li, Kui

2015-03-08

The Wnt signaling pathway is involved in the control of cell proliferation and differentiation during skeletal muscle development. Secreted frizzled-related proteins (SFRPs), such as SFRP1, function as inhibitors of Wnt signaling. MicroRNA-1/206(miRNA-1/206) is specifically expressed in skeletal muscle and play a critical role in myogenesis. The miRNA-mRNA profiles and bioinformatics study suggested that the SFRP1 gene was potentially regulated by miRNA-1/206 during porcine skeletal muscle development. To understand the function of SFRP1 and miRNA-1/206 in swine myogenesis, we first predicted the targets of miRNA-1/206 with the TargetScan and PicTar programs, and analyzed the molecular characterization of the porcine SFRP1 gene. We performed a temporal-spatial expression analysis of SFRP1 mRNA and miRNA-206 in Tongcheng pigs (a Chinese indigenous breed) by quantitative real-time polymerase chain reaction, and conducted the co-expression analyses of SFRP1 and miRNA-1/206. Subsequently, the interaction between SFRP1 and miRNA-1/206 was validated via dual luciferase and Western blot assays. The bioinformatics analysis predicted SFRP1 to be a target of miRNA-1/206. The expression level of the SFRP1 was highly varied across numerous pig tissues and it was down-regulated during porcine skeletal muscle development. The expression level of the SFRP1 was significantly higher in the embryonic skeletal compared with postnatal skeletal muscle, whereas miR-206 showed the inverse pattern of expression. A significant negative correlation was observed between the expression of miR-1/206 and SFRP1 during porcine skeletal muscle development (p <0.05). Dual luciferase assay and Western-blot results demonstrated that SFRP1 was a target of miR-1/206 in porcine iliac endothelial cells. Our results indicate that the SFRP1 gene is regulated by miR-1/206 and potentially affects skeletal muscle development. These findings increase understanding of the biological functions and the regulation of the SFRP1 gene in mammals.

Genes uniquely expressed in human growth plate chondrocytes uncover a distinct regulatory network.

PubMed

Li, Bing; Balasubramanian, Karthika; Krakow, Deborah; Cohn, Daniel H

2017-12-20

Chondrogenesis is the earliest stage of skeletal development and is a highly dynamic process, integrating the activities and functions of transcription factors, cell signaling molecules and extracellular matrix proteins. The molecular mechanisms underlying chondrogenesis have been extensively studied and multiple key regulators of this process have been identified. However, a genome-wide overview of the gene regulatory network in chondrogenesis has not been achieved. In this study, employing RNA sequencing, we identified 332 protein coding genes and 34 long non-coding RNA (lncRNA) genes that are highly selectively expressed in human fetal growth plate chondrocytes. Among the protein coding genes, 32 genes were associated with 62 distinct human skeletal disorders and 153 genes were associated with skeletal defects in knockout mice, confirming their essential roles in skeletal formation. These gene products formed a comprehensive physical interaction network and participated in multiple cellular processes regulating skeletal development. The data also revealed 34 transcription factors and 11,334 distal enhancers that were uniquely active in chondrocytes, functioning as transcriptional regulators for the cartilage-selective genes. Our findings revealed a complex gene regulatory network controlling skeletal development whereby transcription factors, enhancers and lncRNAs participate in chondrogenesis by transcriptional regulation of key genes. Additionally, the cartilage-selective genes represent candidate genes for unsolved human skeletal disorders.

Postinjury Exercise and Platelet-Rich Plasma Therapies Improve Skeletal Muscle Healing in Rats But Are Not Synergistic When Combined.

PubMed

Contreras-Muñoz, Paola; Torrella, Joan Ramon; Serres, Xavier; Rizo-Roca, David; De la Varga, Meritxell; Viscor, Ginés; Martínez-Ibáñez, Vicente; Peiró, José Luis; Järvinen, Tero A H; Rodas, Gil; Marotta, Mario

2017-07-01

Skeletal muscle injuries are the most common sports-related injury and a major concern in sports medicine. The effect of platelet-rich plasma (PRP) injections on muscle healing is still poorly understood, and current data are inconclusive. To evaluate the effects of an ultrasound-guided intramuscular PRP injection, administered 24 hours after injury, and/or posttraumatic daily exercise training for 2 weeks on skeletal muscle healing in a recently established rat model of skeletal muscle injury that highly mimics the muscle trauma seen in human athletes. Controlled laboratory study. A total of 40 rats were assigned to 5 groups. Injured rats (medial gastrocnemius injury) received a single PRP injection (PRP group), daily exercise training (Exer group), or a combination of a single PRP injection and daily exercise training (PRP-Exer group). Untreated and intramuscular saline-injected animals were used as controls. Muscle force was determined 2 weeks after muscle injury, and muscles were harvested and evaluated by means of histological assessment and immunofluorescence microscopy. Both PRP (exhibiting 4.8-fold higher platelet concentration than whole blood) and exercise training improved muscle strength (maximum tetanus force, TetF) in approximately 18%, 20%, and 30% of rats in the PRP, PRP-Exer, and Exer groups, respectively. Specific markers of muscle regeneration (developmental myosin heavy chain, dMHC) and scar formation (collagen I) demonstrated the beneficial effect of the tested therapies in accelerating the muscle healing process in rats. PRP and exercise treatments stimulated the growth of newly formed regenerating muscle fibers (1.5-, 2-, and 2.5-fold increase in myofiber cross-sectional area in PRP, PRP-Exer, and Exer groups, respectively) and reduced scar formation in injured skeletal muscle (20%, 34%, and 41% of reduction in PRP, PRP-Exer, and Exer groups, respectively). Exercise-treated muscles (PRP-Exer and Exer groups) had significantly reduced percentage of dMHC-positive regenerating fibers (35% and 47% decrease in dMHC expression, respectively), indicating that exercise therapies accelerated the muscle healing process witnessed by the more rapid replacement of the embryonic-developmental myosin isoform by mature muscle myosin isoforms. Intramuscular PRP injection and, especially, treadmill exercise improve histological outcome and force recovery of the injured skeletal muscle in a rat injury model that imitates sports-related muscle injuries in athletes. However, there was not a synergistic effect when both treatments were combined, suggesting that PRP does not add any beneficial effect to exercise-based therapy in the treatment of injured skeletal muscle. This study demonstrates the efficacy of an early active rehabilitation protocol or single intramuscular PRP injection on muscle recovery. The data also reveal that the outcome of the early active rehabilitation is adversely affected by the PRP injection when the two therapies are combined, and this could explain why PRP therapies have failed in randomized clinical trials where the athletes have adhered to postinjection rehabilitation protocols based on the principle of early, active mobilization.

The Impact of Fat and Obesity on Bone Microarchitecture and Strength in Children

PubMed Central

Farr, Joshua N.; Dimitri, Paul

2016-01-01

A complex interplay of genetic, environmental, hormonal, and behavioral factors affect skeletal development, several of which are associated with childhood fractures. Given the rise in obesity worldwide, it is of particular concern that excess fat accumulation during childhood appears to be a risk factor for fractures. Plausible explanations for this higher fracture risk include a greater propensity for falls, greater force generation upon fall impact, unhealthy lifestyle habits, and excessive adipose tissue that may have direct or indirect detrimental effects on skeletal development. To date, there remains little resolution or agreement about the impact of obesity and adiposity on skeletal development as well as the mechanisms underpinning these changes. Limitations of imaging modalities, short duration of follow-up in longitudinal studies, and differences among cohorts examined may all contribute to conflicting results. Nonetheless, a linear relationship between increasing adiposity and skeletal development seems unlikely. Fat mass may confer advantages to the developing cortical and trabecular bone compartments, provided that gains in fat mass are not excessive. However, when fat mass accumulation reaches excessive levels, unfavorable metabolic changes may impede skeletal development. Mechanisms underpinning these changes may relate to changes in the hormonal milieu, with adipokines potentially playing a central role, but again findings have been confounding. Changes in the relationship between fat and bone also appear to be age and sex dependent. Clearly, more work is needed to better understand the controversial impact of fat and obesity on skeletal development and fracture risk during childhood. PMID:28013362

The Impact of Fat and Obesity on Bone Microarchitecture and Strength in Children.

PubMed

Farr, Joshua N; Dimitri, Paul

2017-05-01

A complex interplay of genetic, environmental, hormonal, and behavioral factors affect skeletal development, several of which are associated with childhood fractures. Given the rise in obesity worldwide, it is of particular concern that excess fat accumulation during childhood appears to be a risk factor for fractures. Plausible explanations for this higher fracture risk include a greater propensity for falls, greater force generation upon fall impact, unhealthy lifestyle habits, and excessive adipose tissue that may have direct or indirect detrimental effects on skeletal development. To date, there remains little resolution or agreement about the impact of obesity and adiposity on skeletal development as well as the mechanisms underpinning these changes. Limitations of imaging modalities, short duration of follow-up in longitudinal studies, and differences among cohorts examined may all contribute to conflicting results. Nonetheless, a linear relationship between increasing adiposity and skeletal development seems unlikely. Fat mass may confer advantages to the developing cortical and trabecular bone compartments, provided that gains in fat mass are not excessive. However, when fat mass accumulation reaches excessive levels, unfavorable metabolic changes may impede skeletal development. Mechanisms underpinning these changes may relate to changes in the hormonal milieu, with adipokines potentially playing a central role, but again findings have been confounding. Changes in the relationship between fat and bone also appear to be age and sex dependent. Clearly, more work is needed to better understand the controversial impact of fat and obesity on skeletal development and fracture risk during childhood.

Interrelationships among invasive and non-invasive indicators of biological maturation in adolescent male soccer players.

PubMed

Malina, Robert M; Coelho E Silva, Manuel J; Figueiredo, António J; Carling, Christopher; Beunen, Gaston P

2012-01-01

The relationships among indicators of biological maturation were evaluated and concordance between classifications of maturity status in two age groups of youth soccer players examined (11-12 years, n = 87; 13-14 years, n = 93). Data included chronological age (CA), skeletal age (SA, Fels method), stage of pubic hair, predicted age at peak height velocity, and percent of predicted adult height. Players were classified as on time, late or early in maturation using the SA-CA difference, predicted age at peak height velocity, and percent of predicted mature height. Factor analyses indicated two factors in players aged 11-12 years (maturity status: percent of predicted mature height, stage of pubic hair, 59% of variance; maturity timing: SA/CA ratio, predicted age at peak height velocity, 26% of variance), and one factor in players aged 13-14 years (68% of variance). Kappa coefficients were low (0.02-0.23) and indicated poor agreement between maturity classifications. Spearman rank-order correlations between categories were low to moderate (0.16-0.50). Although the indicators were related, concordance of maturity classifications between skeletal age and predicted age at peak height velocity and percent predicted mature height was poor. Talent development programmes call for the classification of youth as early, average, and late maturing for the purpose of designing training and competition programmes. Non-invasive indicators of maturity status have limitations for this purpose.

Silicon in broiler drinking water promotes bone development in broiler chickens.

PubMed

Sgavioli, S; de Faria Domingues, C H; Castiblanco, D M C; Praes, M F F M; Andrade-Garcia, Giuliana M; Santos, E T; Baraldi-Artoni, S M; Garcia, R G; Junqueira, O M

2016-10-01

Skeletal abnormalities, bone deformities and fractures cause significant losses in broiler production during both rearing and processing. Silicon is an essential mineral for bone and connective tissue synthesis and for calcium absorption during the early stages of bone formation. Performance was not affected by the addition of silicon. However, broilers receiving silicon showed a significant increase of phosphorus, zinc, copper, manganese and ash in the tibia. In conclusion, broiler performance was not impaired by adding the tested silicon product to the drinking water. In addition, bone development improved, as demonstrated by higher mineral and ash content. Further studies are required to determine the optimal concentration of silicon, including heat stress simulations, to better understand the effects of silicon on bone development.

Alterations in Skeletal Muscle Fatty Acid Handling Predisposes Middle-Aged Mice to Diet-Induced Insulin Resistance

PubMed Central

Koonen, Debby P.Y.; Sung, Miranda M.Y.; Kao, Cindy K.C.; Dolinsky, Vernon W.; Koves, Timothy R.; Ilkayeva, Olga; Jacobs, René L.; Vance, Dennis E.; Light, Peter E.; Muoio, Deborah M.; Febbraio, Maria; Dyck, Jason R.B.

2010-01-01

OBJECTIVE Although advanced age is a risk factor for type 2 diabetes, a clear understanding of the changes that occur during middle age that contribute to the development of skeletal muscle insulin resistance is currently lacking. Therefore, we sought to investigate how middle age impacts skeletal muscle fatty acid handling and to determine how this contributes to the development of diet-induced insulin resistance. RESEARCH DESIGN AND METHODS Whole-body and skeletal muscle insulin resistance were studied in young and middle-aged wild-type and CD36 knockout (KO) mice fed either a standard or a high-fat diet for 12 weeks. Molecular signaling pathways, intramuscular triglycerides accumulation, and targeted metabolomics of in vivo mitochondrial substrate flux were also analyzed in the skeletal muscle of mice of all ages. RESULTS Middle-aged mice fed a standard diet demonstrated an increase in intramuscular triglycerides without a concomitant increase in insulin resistance. However, middle-aged mice fed a high-fat diet were more susceptible to the development of insulin resistance—a condition that could be prevented by limiting skeletal muscle fatty acid transport and excessive lipid accumulation in middle-aged CD36 KO mice. CONCLUSION Our data provide insight into the mechanisms by which aging becomes a risk factor for the development of insulin resistance. Our data also demonstrate that limiting skeletal muscle fatty acid transport is an effective approach for delaying the development of age-associated insulin resistance and metabolic disease during exposure to a high-fat diet. PMID:20299464

Relationship between Body Mass Index, Skeletal Maturation and Dental Development in 6- to 15- Year Old Orthodontic Patients in a Sample of Iranian Population.

PubMed

Hedayati, Zohreh; Khalafinejad, Fatemeh

2014-12-01

The prevalence of overweight and obesity has been increasing markedly in recent years. It may influence growth in pre pubertal children. The purpose of this study was to determine whether increased Body Mass Index (BMI) is associated with accelerated skeletal maturation and dental maturation in six to fifteen years old orthodontic patients in Shiraz, Iran. Skeletal maturation and dental development of 95 orthodontic patients (65 females and 30 males), aged 6 to 15 years, were determined. Dental development was assessed using the Demerjian method and skeletal maturation was evaluated by cervical vertebral method as presented by Bacetti. The BMI was determined for each patient. T-test was applied to compare the mean difference between chronologic and dental age among the study groups. A regression model was used to assess the relationship between BMI percentile, skeletal maturation, and dental development. 18.9% of subjects were overweight and obese. The mean differences between dental age and chronologic age were 0.73±1.3 for underweight and normal weight children and 1.8±1.08 for overweight and obese children. These results highlighted the correlation between accelerated dental maturity and increasing BMI percentile (p= 0.002). A new formula was introduced for this relationship. There was not any significant relationship between BMI percentile and skeletal maturation. Children who were overweight or obese had accelerated dental development whereas they did not have accelerated skeletal maturation significantly after being adjusted for age and gender.

The effect of age and body composition on body mass estimation of males using the stature/bi-iliac method.

PubMed

Junno, Juho-Antti; Niskanen, Markku; Maijanen, Heli; Holt, Brigitte; Sladek, Vladimir; Niinimäki, Sirpa; Berner, Margit

2018-02-01

The stature/bi-iliac breadth method provides reasonably precise, skeletal frame size (SFS) based body mass (BM) estimations across adults as a whole. In this study, we examine the potential effects of age changes in anthropometric dimensions on the estimation accuracy of SFS-based body mass estimation. We use anthropometric data from the literature and our own skeletal data from two osteological collections to study effects of age on stature, bi-iliac breadth, body mass, and body composition, as they are major components behind body size and body size estimations. We focus on males, as relevant longitudinal data are based on male study samples. As a general rule, lean body mass (LBM) increases through adolescence and early adulthood until people are aged in their 30s or 40s, and starts to decline in the late 40s or early 50s. Fat mass (FM) tends to increase until the mid-50s and declines thereafter, but in more mobile traditional societies it may decline throughout adult life. Because BM is the sum of LBM and FM, it exhibits a curvilinear age-related pattern in all societies. Skeletal frame size is based on stature and bi-iliac breadth, and both of those dimensions are affected by age. Skeletal frame size based body mass estimation tends to increase throughout adult life in both skeletal and anthropometric samples because an age-related increase in bi-iliac breadth more than compensates for an age-related stature decline commencing in the 30s or 40s. Combined with the above-mentioned curvilinear BM change, this results in curvilinear estimation bias. However, for simulations involving low to moderate percent body fat, the stature/bi-iliac method works well in predicting body mass in younger and middle-aged adults. Such conditions are likely to have applied to most human paleontological and archaeological samples. Copyright © 2017 Elsevier Ltd. All rights reserved.

Enzyme Replacement for Craniofacial Skeletal Defects and Craniosynostosis in Murine Hypophosphatasia

PubMed Central

Liu, Jin; Campbell, Cassie; Nam, Hwa Kyung; Caron, Alexandre; Yadav, Manisha C; Millán, José Luis; Hatch, Nan E.

2015-01-01

Hypophosphatasia (HPP) is an inborn-error-of-metabolism disorder characterized by deficient bone and tooth mineralization due to loss-of function mutations in the gene (Alpl) encoding tissue-nonspecific alkaline phosphatase (TNAP). Alpl−/− mice exhibit many characteristics seen in infantile HPP including long bone and tooth defects, vitamin B6 responsive seizures and craniosynostosis. Previous reports demonstrated that a mineral-targeted form of TNAP rescues long bone, verterbral and tooth mineralization defects in Alpl−/− mice. Here we report that enzyme replacement with mineral-targeted TNAP (asfotase-alfa) also prevents craniosynostosis (the premature fusion of cranial bones) and additional craniofacial skeletal abnormalities in Alpl−/− mice. Craniosynostosis, cranial bone volume and density, and craniofacial shape abnormalities were assessed by microsocopy, histology, digital caliper measurements and micro CT. We found that craniofacial shape defects, cranial bone mineralization and craniosynostosis were corrected in Alpl−/− mice injected daily subcutaneously starting at birth with recombinant enzyme. Analysis of Alpl−/− calvarial cells indicates that TNAP deficiency leads to aberrant osteoblastic gene expression and diminished proliferation. Some but not all of these cellular abnormalities were rescued by treatment with inorganic phosphate. These results confirm an essential role for TNAP in craniofacial skeletal development and demonstrate the efficacy of early postnatal mineral-targeted enzyme replacement for preventing craniofacial abnormalities including craniosynostosis in murine infantile HPP. PMID:25959417

[Development and prospect on skeletal age evaluation methods of X-ray film].

PubMed

Wang, Ya-hui; Zhu, Guang-you; Qiao, Ke; Bian, Shi-zhong; Fan, Li-hua; Cheng, Yi-bin; Ying, Chong-liang; Shen, Yan

2007-10-01

The traditional methods of skeletal age estimation mainly include Numeration, Atlas, and Counting scores. In recent years, other new methods were proposed by several scholars. Utilizing image logical characteristics of X-ray film to extrapolate skeletal age is a key means by present forensic medicine workers in evaluating skeletal age. However, there exist some variations when we present the conclusion of skeletal age as an "evidence" directly to the Justice Trial Authority. In order to enhance the accuracy of skeletal age determination, further investigation for appropriate methodology should be undertaken. After a collective study of pertinent domestic and international literatures, we present this review of the research and advancement on skeletal age evaluation methods of X-ray film.

Odontogenic Keratocysts in Gorlin–Goltz Syndrome: A Case Report

PubMed Central

Chandran, Satheesh; Marudhamuthu, Karthikeyan; Riaz, R; Balasubramaniam, Saravanan

2015-01-01

Gorlin–Goltz syndrome is an autosomal dominant inherited condition comprising the principle triad of basal cell carcinomas, multiple jaw keratocysts, and skeletal anomalies. The presence of jaw cysts are the early diagnostic feature of this syndrome, and this can be incidentally identified by routine radiographs. A patient presented with signs and symptoms of Gorlin–Goltz syndrome to us in her early stages. PMID:26225111

Cytokine Response of Cultured Skeletal Muscle Cells Stimulated with Proinflammatory Factors Depends on Differentiation Stage

PubMed Central

Podbregar, Matej; Lainscak, Mitja; Prelovsek, Oja; Mars, Tomaz

2013-01-01

Myoblast proliferation and myotube formation are critical early events in skeletal muscle regeneration. The attending inflammation and cytokine signaling are involved in regulation of skeletal muscle cell proliferation and differentiation. Secretion of muscle-derived cytokines upon exposure to inflammatory factors may depend on the differentiation stage of regenerating muscle cells. Cultured human myoblasts and myotubes were exposed to 24-hour treatment with tumor necrosis factor (TNF)-α or lipopolysaccharide (LPS). Secretion of interleukin 6 (IL-6), a major muscle-derived cytokine, and interleukin 1 (IL-1), an important regulator of inflammatory response, was measured 24 hours after termination of TNF-α or LPS treatment. Myoblasts pretreated with TNF-α or LPS displayed robustly increased IL-6 secretion during the 24-hour period after removal of treatments, while IL-1 secretion remained unaltered. IL-6 secretion was also increased in myotubes, but the response was less pronounced compared with myoblasts. In contrast to myoblasts, IL-1 secretion was markedly stimulated in LPS-pretreated myotubes. We demonstrate that preceding exposure to inflammatory factors stimulates a prolonged upregulation of muscle-derived IL-6 and/or IL-1 in cultured skeletal muscle cells. Our findings also indicate that cytokine response to inflammatory factors in regenerating skeletal muscle partially depends on the differentiation stage of myogenic cells. PMID:23509435

Solitary extra-skeletal sinonasal metastasis from a primary skeletal Ewing's sarcoma.

PubMed

Hayes, S M; Jani, T N; Rahman, S M; Jogai, S; Harries, P G; Salib, R J

2011-08-01

Ewing's sarcoma is a rare, malignant tumour predominantly affecting young adolescent males. We describe a unique case of an isolated extra-skeletal metastasis from a skeletal Ewing's sarcoma primary, arising in the right sinonasal cavity of a young man who presented with severe epistaxis and periorbital cellulitis. Histologically, the lesion comprised closely packed, slightly diffuse, atypical cells with round, hyperchromatic nuclei, scant cytoplasm and occasional mitotic figures, arranged in a sheet-like pattern. Immunohistochemical analysis showed positive staining only for cluster of differentiation 99 glycoprotein. Fluorescent in situ hybridisation identified the Ewing's sarcoma gene, confirming the diagnosis. Complete surgical resection was achieved via a minimally invasive endoscopic transnasal approach; post-operative radiotherapy. Ten months post-operatively, there were no endoscopic or radiological signs of disease. Metastatic Ewing's sarcoma within the head and neck is incredibly rare and can pose significant diagnostic and therapeutic challenges. An awareness of different clinical presentations and distinct histopathological features is important to enable early diagnosis. This case illustrates one potential management strategy, and reinforces the evolving role of endoscopic transnasal approaches in managing sinonasal cavity and anterior skull base tumours.

Hatching, growth, ion accumulation, and skeletal ossification of brook trout (Salvelinus fontinalis) alevins in acidic soft waters

USGS Publications Warehouse

Steingraeber, M.T.; Gingerich, W.H.

1991-01-01

Brook trout eyed eggs and subsequent alevins were exposed to pH 5.0, 6.5, and 7.0 in soft reconstituted water and to pH 8.2 in hard well water for up to 72 d. Hatching was delayed and hatching success reduced (p K+ > Cl- during yolk absorption and early exogenous feeding. Whole-body monovalent ion concentrations were reduced for short periods during yolk absorption in alevins exposed to pH 6.5 and throughout most of the experiment for those exposed to pH 5.0. Whole-body Mg2+ concentrations were not affected by treatment pH and remained near their median hatch level throughout the exposure. The whole-body concentration of Ca2+ was reduced in fish exposed to pH 5.0, particularly near the end of the experiment. Calcium accumulation in fish was influenced by the interaction of pH and time at pH 5.0 but not at the other pH levels. Alevins exposed to pH 5.0 experienced delayed ossification of skeletal structures associated with feeding, respiration, and locomotion that usually persisted for up to 10 d. The detection of skeletal abnormalities early in life might aid in identifying fish populations at risk in acidified waters.

Development of a transgenic zebrafish model expressing GFP in the notochord, somite and liver directed by the hfe2 gene promoter.

PubMed

Bian, Yue-Hong; Xu, Cheng; Li, Junling; Xu, Jin; Zhang, Hongwei; Du, Shao Jun

2011-08-01

Hemojuvelin, also known as RGMc, is encoded by hfe2 gene that plays an important role in iron homeostasis. hfe2 is specifically expressed in the notochord, developing somite and skeletal muscles during development. The molecular regulation of hfe2 expression is, however, not clear. We reported here the characterization of hfe2 gene expression and the regulation of its tissue-specific expression in zebrafish embryos. We demonstrated that the 6 kb 5'-flanking sequence upstream of the ATG start codon in the zebrafish hfe2 gene could direct GFP specific expression in the notochord, somites, and skeletal muscle of zebrafish embryos, recapitulating the expression pattern of the endogenous gene. However, the Tg(hfe2:gfp) transgene is also expressed in the liver of fish embryos, which did not mimic the expression of the endogenous hfe2 at the early stage. Nevertheless, the Tg(hfe2:gfp) transgenic zebrafish provides a useful model to study liver development. Treating Tg(hfe2:gfp) transgenic zebrafish embryos with valproic acid, a liver development inhibitor, significantly inhibited GFP expression in zebrafish. Together, these data indicate that the tissue specific expression of hfe2 in the notochord, somites and muscles is regulated by regulatory elements within the 6 kb 5'-flanking sequence of the hfe2 gene. Moreover, the Tg(hfe2:gfp) transgenic zebrafish line provides a useful model system for analyzing liver development in zebrafish.

Distal tibial pilon fractures (AO/OTA type B, and C) treated with the external skeletal and minimal internal fixation method.

PubMed

Milenković, Sasa; Mitković, Milorad; Micić, Ivan; Mladenović, Desimir; Najman, Stevo; Trajanović, Miroslav; Manić, Miodrag; Mitković, Milan

2013-09-01

Distal tibial pilon fractures include extra-articular fractures of the tibial metaphysis and the more severe intra-articular tibial pilon fractures. There is no universal method for treating distal tibial pilon fractures. These fractures are treated by means of open reduction, internal fixation (ORIF) and external skeletal fixation. The high rate of soft-tissue complications associated with primary ORIF of pilon fractures led to the use of external skeletal fixation, with limited internal fixation as an alternative technique for definitive management. The aim of this study was to estimate efficacy of distal tibial pilon fratures treatment using the external skeletal and minimal internal fixation method. We presented a series of 31 operated patients with tibial pilon fractures. The patients were operated on using the method of external skeletal fixation with a minimal internal fixation. According to the AO/OTA classification, 17 patients had type B fracture and 14 patients type C fractures. The rigid external skeletal fixation was transformed into a dynamic external skeletal fixation 6 weeks post-surgery. This retrospective study involved 31 patients with tibial pilon fractures, average age 41.81 (from 21 to 60) years. The average follow-up was 21.86 (from 12 to 48) months. The percentage of union was 90.32%, nonunion 3.22% and malunion 6.45%. The mean to fracture union was 14 (range 12-20) weeks. There were 4 (12.19%) infections around the pins of the external skeletal fixator and one (3.22%) deep infections. The ankle joint arthrosis as a late complication appeared in 4 (12.90%) patients. All arthroses appeared in patients who had type C fractures. The final functional results based on the AOFAS score were excellent in 51.61%, good in 32.25%, average in 12.90% and bad in 3.22% of the patients. External skeletal fixation and minimal internal fixation of distal tibial pilon fractures is a good method for treating all types of inta-articular pilon fractures. In fractures types B and C dynamic external skeletal fixation allows early mobility in the ankle joint.

Skeletal Complications in Neurofibromatosis Type 1: The Role of Neurofibromin Haploinsufficiency in Defective Skeletal Remodeling and Bone Healing in NF1

DTIC Science & Technology

2007-01-01

including scoliosis and pseudoarthrosis, which are compounded by osteoporosis and poor bone healing. Corrective orthopaedic intervention often fails...3 - Introduction: A large proportion of patients with Neurofibromatosis Type 1 display skeletal abnormalities including scoliosis and...abnormalities including alterations in bone size and shape, the presence of scoliosis , and a tendency to develop pseudoarthrosis. These skeletal

Remodeling of the skeletal muscle microcirculation increases resistance to perfusion in obese Zucker rats.

PubMed

Frisbee, Jefferson C

2003-07-01

Whereas previous studies have demonstrated that the development of syndrome X in obese Zucker rats (OZR) is associated with impaired arteriolar reactivity to vasoactive stimuli, additional results from these studies indicate that the passive diameter of skeletal muscle arterioles is reduced in OZR versus lean Zucker rats (LZR). On the basis of these prior observations, the present study evaluated structural alterations to the skeletal muscle microcirculation as potential contributors to an elevated vascular resistance. Isolated skeletal muscle resistance arterioles exhibited a reduced passive diameter at all levels of intralumenal pressure and a left-shifted stress-strain curve in OZR versus LZR, indicative of structural remodeling of individual arterioles. Histological analyses using Griffonia simplicifolia I lectin-stained sections of skeletal muscle demonstrated reduced microvessel density (rarefaction) in OZR versus LZR, suggesting remodeling of entire microvascular networks. Finally, under maximally dilated conditions, constant flow-perfused skeletal muscle of OZR exhibited significant elevations in perfusion pressure versus LZR, indicative of an increased resistance to perfusion within the microcirculation. These data suggest that developing structural alterations to the skeletal muscle microcirculation in OZR result in elevated vascular resistance, which may, acting in concert with impaired arteriolar reactivity, contribute to blunted active hyperemic responses and compromised performance of in situ skeletal muscle with elevated metabolic demand.

Structure-function relationship of skeletal muscle provides inspiration for design of new artificial muscle

NASA Astrophysics Data System (ADS)

Gao, Yingxin; Zhang, Chi

2015-03-01

A variety of actuator technologies have been developed to mimic biological skeletal muscle that generates force in a controlled manner. Force generation process of skeletal muscle involves complicated biophysical and biochemical mechanisms; therefore, it is impossible to replace biological muscle. In biological skeletal muscle tissue, the force generation of a muscle depends not only on the force generation capacity of the muscle fiber, but also on many other important factors, including muscle fiber type, motor unit recruitment, architecture, structure and morphology of skeletal muscle, all of which have significant impact on the force generation of the whole muscle or force transmission from muscle fibers to the tendon. Such factors have often been overlooked, but can be incorporated in artificial muscle design, especially with the discovery of new smart materials and the development of innovative fabrication and manufacturing technologies. A better understanding of the physiology and structure-function relationship of skeletal muscle will therefore benefit the artificial muscle design. In this paper, factors that affect muscle force generation are reviewed. Mathematical models used to model the structure-function relationship of skeletal muscle are reviewed and discussed. We hope the review will provide inspiration for the design of a new generation of artificial muscle by incorporating the structure-function relationship of skeletal muscle into the design of artificial muscle.

Skeletal muscle regeneration and impact of aging and nutrition.

PubMed

Domingues-Faria, Carla; Vasson, Marie-Paule; Goncalves-Mendes, Nicolas; Boirie, Yves; Walrand, Stephane

2016-03-01

After skeletal muscle injury a regeneration process takes place to repair muscle. Skeletal muscle recovery is a highly coordinated process involving cross-talk between immune and muscle cells. It is well known that the physiological activities of both immune cells and muscle stem cells decline with advancing age, thereby blunting the capacity of skeletal muscle to regenerate. The age-related reduction in muscle repair efficiency contributes to the development of sarcopenia, one of the most important factors of disability in elderly people. Preserving muscle regeneration capacity may slow the development of this syndrome. In this context, nutrition has drawn much attention: studies have demonstrated that nutrients such as amino acids, n-3 polyunsaturated fatty acids, polyphenols and vitamin D can improve skeletal muscle regeneration by targeting key functions of immune cells, muscle cells or both. Here we review the process of skeletal muscle regeneration with a special focus on the cross-talk between immune and muscle cells. We address the effect of aging on immune and skeletal muscle cells involved in muscle regeneration. Finally, the mechanisms of nutrient action on muscle regeneration are described, showing that quality of nutrition may help to preserve the capacity for skeletal muscle regeneration with age. Copyright © 2015 Elsevier B.V. All rights reserved.

Induction of functional tissue-engineered skeletal muscle constructs by defined electrical stimulation.

PubMed

Ito, Akira; Yamamoto, Yasunori; Sato, Masanori; Ikeda, Kazushi; Yamamoto, Masahiro; Fujita, Hideaki; Nagamori, Eiji; Kawabe, Yoshinori; Kamihira, Masamichi

2014-04-24

Electrical impulses are necessary for proper in vivo skeletal muscle development. To fabricate functional skeletal muscle tissues in vitro, recapitulation of the in vivo niche, including physical stimuli, is crucial. Here, we report a technique to engineer skeletal muscle tissues in vitro by electrical pulse stimulation (EPS). Electrically excitable tissue-engineered skeletal muscle constructs were stimulated with continuous electrical pulses of 0.3 V/mm amplitude, 4 ms width, and 1 Hz frequency, resulting in a 4.5-fold increase in force at day 14. In myogenic differentiation culture, the percentage of peak twitch force (%Pt) was determined as the load on the tissue constructs during the artificial exercise induced by continuous EPS. We optimized the stimulation protocol, wherein the tissues were first subjected to 24.5%Pt, which was increased to 50-60%Pt as the tissues developed. This technique may be a useful approach to fabricate tissue-engineered functional skeletal muscle constructs.

Fibroblast growth factor receptor signaling crosstalk in skeletogenesis.

PubMed

Miraoui, Hichem; Marie, Pierre J

2010-11-02

Fibroblast growth factors (FGFs) play important roles in the control of embryonic and postnatal skeletal development by activating signaling through FGF receptors (FGFRs). Germline gain-of-function mutations in FGFR constitutively activate FGFR signaling, causing chondrocyte and osteoblast dysfunctions that result in skeletal dysplasias. Crosstalk between the FGFR pathway and other signaling cascades controls skeletal precursor cell differentiation. Genetic analyses revealed that the interplay of WNT and FGFR1 determines the fate and differentiation of mesenchymal stem cells during mouse craniofacial skeletogenesis. Additionally, interactions between FGFR signaling and other receptor tyrosine kinase networks, such as those mediated by the epidermal growth factor receptor and platelet-derived growth factor receptor α, were associated with excessive osteoblast differentiation and bone formation in the human skeletal dysplasia called craniosynostosis, which is a disorder of skull development. We review the roles of FGFR signaling and its crosstalk with other pathways in controlling skeletal cell fate and discuss how this crosstalk could be pharmacologically targeted to correct the abnormal cell phenotype in skeletal dysplasias caused by aberrant FGFR signaling.

Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy.

PubMed

Petchey, Louisa K; Risebro, Catherine A; Vieira, Joaquim M; Roberts, Tom; Bryson, John B; Greensmith, Linda; Lythgoe, Mark F; Riley, Paul R

2014-07-01

Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiac-specific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, and myosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease.

Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy

PubMed Central

Petchey, Louisa K.; Risebro, Catherine A.; Vieira, Joaquim M.; Roberts, Tom; Bryson, John B.; Greensmith, Linda; Lythgoe, Mark F.; Riley, Paul R.

2014-01-01

Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiac-specific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, and myosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease. PMID:24938781

A Murine Model for Human ECO Syndrome Reveals a Critical Role of Intestinal Cell Kinase in Skeletal Development.

PubMed

Ding, Mengmeng; Jin, Li; Xie, Lin; Park, So Hyun; Tong, Yixin; Wu, Di; Chhabra, A Bobby; Fu, Zheng; Li, Xudong

2018-03-01

An autosomal-recessive inactivating mutation R272Q in the human intestinal cell kinase (ICK) gene caused profound multiplex developmental defects in human endocrine-cerebro-osteodysplasia (ECO) syndrome. ECO patients exhibited a wide variety of skeletal abnormalities, yet the underlying mechanisms by which ICK regulates skeletal development remained largely unknown. The goal of this study was to understand the structural and mechanistic basis underlying skeletal anomalies caused by ICK dysfunction. Ick R272Q knock-in transgenic mouse model not only recapitulated major ECO skeletal defects such as short limbs and polydactyly but also revealed a deformed spine with defective intervertebral disk. Loss of ICK function markedly reduced mineralization in the spinal column, ribs, and long bones. Ick mutants showed a significant decrease in the proliferation zone of long bones and the number of type X collagen-expressing hypertrophic chondrocytes in the spinal column and the growth plate of long bones. These results implicate that ICK plays an important role in bone and cartilage development by promoting chondrocyte proliferation and maturation. Our findings provided new mechanistic insights into the skeletal phenotype of human ECO and ECO-like syndromes.

Skeletal variation among early Holocene North American humans: implications for origins and diversity in the Americas.

PubMed

Auerbach, Benjamin M

2012-12-01

The movement of humans into the Americas remains a major topic of debate among scientific disciplines. Central to this discussion is ascertaining the timing and migratory routes of the earliest colonizers, in addition to understanding their ancestry. Molecular studies have recently argued that the colonizing population was isolated from other Asian populations for an extended period before proceeding to colonize the Americas. This research has suggested that Beringia was the location of this "incubation," though archaeological and skeletal data have not yet supported this hypothesis. This study employs the remains of the five most complete North American male early Holocene skeletons to examine patterns of human morphology at the earliest observable time period. Stature, body mass, body breadth, and limb proportions are examined in the context of male skeletal samples representing the range of morphological variation in North America in the last two millennia of the Holocene. These are also compared with a global sample. Results indicate that early Holocene males have variable postcranial morphologies, but all share the common trait of wide bodies. This trait, which is retained in more recent indigenous North American groups, is associated with adaptations to cold climates. Peoples from the Americas exhibit wider bodies than other populations sampled globally. This pattern suggests the common ancestral population of all of these indigenous American groups had reduced morphological variation in this trait. Furthermore, this provides support for a single, possibly high latitude location for the genetic isolation of ancestors of the human colonizers of the Americas. Copyright © 2012 Wiley Periodicals, Inc.

Developing bones are differentially affected by compromised skeletal muscle formation

PubMed Central

Nowlan, Niamh C.; Bourdon, Céline; Dumas, Gérard; Tajbakhsh, Shahragim; Prendergast, Patrick J.; Murphy, Paula

2010-01-01

Mechanical forces are essential for normal adult bone function and repair, but the impact of prenatal muscle contractions on bone development remains to be explored in depth in mammalian model systems. In this study, we analyze skeletogenesis in two ‘muscleless’ mouse mutant models in which the formation of skeletal muscle development is disrupted; Myf5nlacZ/nlacZ:MyoD−/− and Pax3Sp/Sp (Splotch). Ossification centers were found to be differentially affected in the muscleless limbs, with significant decreases in bone formation in the scapula, humerus, ulna and femur, but not in the tibia. In the scapula and humerus, the morphologies of ossification centers were abnormal in muscleless limbs. Histology of the humerus revealed a decreased extent of the hypertrophic zone in mutant limbs but no change in the shape of this region. The elbow joint was also found to be clearly affected with a dramatic reduction in the joint line, while no abnormalities were evident in the knee. The humeral deltoid tuberosity was significantly reduced in size in the Myf5nlacZ/nlacZ:MyoD−/− mutants while a change in shape but not in size was found in the humeral tuberosities of the Pax3Sp/Sp mutants. We also examined skeletal development in a ‘reduced muscle’ model, the Myf5nlacZ/+:MyoD−/− mutant, in which skeletal muscle forms but with reduced muscle mass. The reduced muscle phenotype appeared to have an intermediate effect on skeletal development, with reduced bone formation in the scapula and humerus compared to controls, but not in other rudiments. In summary, we have demonstrated that skeletal development is differentially affected by the lack of skeletal muscle, with certain rudiments and joints being more severely affected than others. These findings indicate that the response of skeletal progenitor cells to biophysical stimuli may depend upon their location in the embryonic limb, implying a complex interaction between mechanical forces and location-specific regulatory factors affecting bone and joint development. PMID:19948261

Estimation of skeletal movement of human locomotion from body surface shapes using dynamic spatial video camera (DSVC) and 4D human model.

PubMed

Saito, Toshikuni; Suzuki, Naoki; Hattori, Asaki; Suzuki, Shigeyuki; Hayashibe, Mitsuhiro; Otake, Yoshito

2006-01-01

We have been developing a DSVC (Dynamic Spatial Video Camera) system to measure and observe human locomotion quantitatively and freely. A 4D (four-dimensional) human model with detailed skeletal structure, joint, muscle, and motor functionality has been built. The purpose of our research was to estimate skeletal movements from body surface shapes using DSVC and the 4D human model. For this purpose, we constructed a body surface model of a subject and resized the standard 4D human model to match with geometrical features of the subject's body surface model. Software that integrates the DSVC system and the 4D human model, and allows dynamic skeletal state analysis from body surface movement data was also developed. We practically applied the developed system in dynamic skeletal state analysis of a lower limb in motion and were able to visualize the motion using geometrically resized standard 4D human model.

Homozygous EEF1A2 mutation causes dilated cardiomyopathy, failure to thrive, global developmental delay, epilepsy and early death.

PubMed

Cao, Siqi; Smith, Laura L; Padilla-Lopez, Sergio R; Guida, Brandon S; Blume, Elizabeth; Shi, Jiahai; Morton, Sarah U; Brownstein, Catherine A; Beggs, Alan H; Kruer, Michael C; Agrawal, Pankaj B

2017-09-15

Eukaryotic elongation factor 1A (EEF1A), is encoded by two distinct isoforms, EEF1A1 and EEF1A2; whereas EEF1A1 is expressed almost ubiquitously, EEF1A2 expression is limited such that it is only detectable in skeletal muscle, heart, brain and spinal cord. Currently, the role of EEF1A2 in normal cardiac development and function is unclear. There have been several reports linking de novo dominant EEF1A2 mutations to neurological issues in humans. We report a pair of siblings carrying a homozygous missense mutation p.P333L in EEF1A2 who exhibited global developmental delay, failure to thrive, dilated cardiomyopathy and epilepsy, ultimately leading to death in early childhood. A third sibling also died of a similar presentation, but DNA was unavailable to confirm the mutation. Functional genomic analysis was performed in S. cerevisiae and zebrafish. In S. cerevisiae, there was no evidence for a dominant-negative effect. Previously identified putative de novo mutations failed to complement yeast strains lacking the EEF1A ortholog showing a major growth defect. In contrast, the introduction of the mutation seen in our family led to a milder growth defect. To evaluate its function in zebrafish, we knocked down eef1a2 expression using translation blocking and splice-site interfering morpholinos. EEF1A2-deficient zebrafish had skeletal muscle weakness, cardiac failure and small heads. Human EEF1A2 wild-type mRNA successfully rescued the morphant phenotype, but mutant RNA did not. Overall, EEF1A2 appears to be critical for normal heart function in humans, and its deficiency results in clinical abnormalities in neurologic function as well as in skeletal and cardiac muscle defects. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The titin A-band rod domain is dispensable for initial thick filament assembly in zebrafish.

PubMed

Myhre, J Layne; Hills, Jordan A; Prill, Kendal; Wohlgemuth, Serene L; Pilgrim, David B

2014-03-01

The sarcomeres of skeletal and cardiac muscle are highly structured protein arrays, consisting of thick and thin filaments aligned precisely to one another and to their surrounding matrix. The contractile mechanisms of sarcomeres are generally well understood, but how the patterning of sarcomeres is initiated during early skeletal muscle and cardiac development remains uncertain. Two of the most widely accepted hypotheses for this process include the "molecular ruler" model, in which the massive protein titin defines the length of the sarcomere and provides a scaffold along which the myosin thick filament is assembled, and the "premyofibril" model, which proposes that thick filament formation does not require titin, but that a "premyofibril" consisting of non-muscle myosin, α-actinin and cytoskeletal actin is used as a template. Each model posits a different order of necessity of the various components, but these have been difficult to test in vivo. Zebrafish motility mutants with developmental defects in sarcomere patterning are useful for the elucidation of such mechanisms, and here we report the analysis of the herzschlag mutant, which shows deficits in both cardiac and skeletal muscle. The herzschlag mutant produces a truncated titin protein, lacking the C-terminal rod domain that is proposed to act as a thick filament scaffold, yet muscle patterning is still initiated, with grossly normal thick and thin filament assembly. Only after embryonic muscle contraction begins is breakdown of sarcomeric myosin patterning observed, consistent with the previously noted role of titin in maintaining the contractile integrity of mature sarcomeres. This conflicts with the "molecular ruler" model of early sarcomere patterning and supports a titin-independent model of thick filament organization during sarcomerogenesis. These findings are also consistent with the symptoms of human titin myopathies that exhibit a late onset, such as tibial muscular dystrophy. Copyright © 2013 Elsevier Inc. All rights reserved.

Tanner-Whitehouse Skeletal Ages in Male Youth Soccer Players: TW2 or TW3?

PubMed

Malina, Robert M; Coelho-E-Silva, Manuel J; Figueiredo, António J; Philippaerts, Renaat M; Hirose, Norikazu; Peña Reyes, Maria Eugenia; Gilli, Giulio; Benso, Andrea; Vaeyens, Roel; Deprez, Dieter; Guglielmo, Luiz F; Buranarugsa, Rojapon

2018-04-01

The Tanner-Whitehouse radius-ulna-short bone protocol (TW2 RUS) for the assessment of skeletal age (SA) is widely used to estimate the biological (skeletal) maturity status of children and adolescents. The scale for converting TW RUS ratings to an SA has been revised (TW3 RUS) and has implications for studies of youth athletes in age-group sports. The aim of this study was to compare TW2 and TW3 RUS SAs in an international sample of male youth soccer players and to compare distributions of players by maturity status defined by each SA protocol. SA assessments with the TW RUS method were collated for 1831 male soccer players aged 11-17 years from eight countries. RUS scores were converted to TW2 and TW3 SAs using the appropriate tables. SAs were related to chronological age (CA) in individual athletes and compared by CA groups. The difference of SA minus CA with TW2 SA and with TW3 SA was used to classify players as late, average, or early maturing with each method. Concordance of maturity classifications was evaluated with Cohen's Kappa coefficients. For the same RUS score, TW3 SAs were systematically and substantially reduced compared with TW2 SAs; mean differences by CA group ranged from - 0.97 to - 1.16 years. Kappa coefficients indicated at best fair concordance of TW2 and TW3 maturity classifications. Across the age range, 42% of players classified as average with TW2 SA were classified as late with TW3 SA, and 64% of players classified as early with TW2 SA were classified as average with TW3 SA. TW3 SAs were systematically lower than corresponding TW2 SAs in male youth soccer players. The differences between scales have major implications for the classification of players by maturity status, which is central to some talent development programs.

Adipocyte-myocyte crosstalk in skeletal muscle insulin resistance; is there a role for thyroid hormone?

PubMed

Havekes, Bas; Sauerwein, Hans P

2010-11-01

To review original research studies and reviews that present data on adipocyte-myocyte crosstalk in the development of skeletal muscle insulin resistance with a specific focus on thyroid hormone. Adipose tissue communicates with skeletal muscle not only through free fatty acids but also through secretion of various products called adipokines. Adipokines came out as governors of insulin sensitivity and are deregulated in obesity. In addition to well known leptin, adiponectin, interleukin-6 and tumor necrosis factor-alpha, newer adipokines like retinol-binding protein 4 have been associated with insulin resistance. There is mounting evidence that not only adipose tissue but also skeletal muscle produces and secretes biologically active proteins or 'myokines' that facilitate metabolic crosstalk between organ systems. In recent years, increased expression of myostatin, a secreted anabolic inhibitor of muscle growth and development, has been associated with obesity and insulin resistance. Both hypothyroidism and hyperthyroidism affect insulin sensitivity in multiple ways that might overlap adipocyte-myocyte crosstalk. Recent studies have provided new insights in effects of processing of the parent hormone T4 to the active T3 at the level of the skeletal muscle. Adipocyte-myocyte crosstalk is an important modulator in the development of skeletal muscle insulin resistance. Thyroid disorders are very common and may have detrimental effects on skeletal muscle insulin resistance, potentially by interacting with adipocyte-myocyte crosstalk.

Disease-Induced Skeletal Muscle Atrophy and Fatigue

PubMed Central

Powers, Scott K.; Lynch, Gordon S.; Murphy, Kate T.; Reid, Michael B.; Zijdewind, Inge

2016-01-01

Numerous health problems including acute critical illness, cancer, diseases associated with chronic inflammation, and neurological disorders often result in skeletal muscle weakness and fatigue. Disease-related muscle atrophy and fatigue is an important clinical problem because acquired skeletal muscle weakness can increase the duration of hospitalization, result in exercise limitation, and contribute to a poor quality of life. Importantly, skeletal muscle atrophy is also associated with increased morbidity and mortality of patients. Therefore, improving our understanding of the mechanism(s) responsible for skeletal muscle weakness and fatigue in patients is a required first step to develop clinical protocols to prevent these skeletal muscle problems. This review will highlight the consequences and potential mechanisms responsible for skeletal muscle atrophy and fatigue in patients suffering from acute critical illness, cancer, chronic inflammatory diseases, and neurological disorders. PMID:27128663

Influence of racial origin and skeletal muscle properties on disease prevalence and physical performance.

PubMed

Suminski, Richard R; Mattern, Craig O; Devor, Steven T

2002-01-01

Skeletal muscle properties are related to disease (e.g. obesity) and physical performance. For example, a predominance of type I muscle fibres is associated with better performance in endurance sports and a lower risk of obesity. Disease and physical performance also differ among certain racial groups. African Americans are more likely than Caucasians to develop obesity, diabetes mellitus and hypertension. Empirical studies indicate that aerobic capacity is lower in African Americans than Caucasians. Because genetics is a partial determinant of skeletal muscle properties, it is reasonable to assume that skeletal muscle properties vary as a function of race. As such, genetically determined and race-specific skeletal muscle properties may partially explain racial disparities in disease and physical performance. However, additional research is needed in this area to enable the development of more definitive conclusions.

External skeletal robusticity of children and adolescents - European references from birth to adulthood and international comparisons.

PubMed

Mumm, Rebekka; Godina, Elena; Koziel, Slawomir; Musalek, Martin; Sedlak, Petr; Wittwer-Backofen, Ursula; Hesse, Volker; Dasgupta, Parasmani; Henneberg, Maciej; Scheffler, Christiane

2018-06-11

Background: In our modern world, the way of life in nutritional and activity behaviour has changed. As a consequence, parallel trends of an epidemic of overweight and a decline in external skeletal robusticity are observed in children and adolescents. Aim: We aim to develop reference centiles for external skeletal robusticity of European girls and boys aged 0 to 18 years using the Frame Index as an indicator and identify population specific age-related patterns. Methods: We analysed cross-sectional & longitudinal data on body height and elbow breadth of boys and girls from Europe (0-18 years, n = 41.679), India (7-18 years, n = 3.297) and South Africa (3-18 years, n = 4.346). As an indicator of external skeletal robusticity Frame Index after Frisancho (1990) was used. We developed centiles for boys and girls using the LMS-method and its extension. Results: Boys have greater external skeletal robusticity than girls. Whereas in girls Frame Index decreases continuously during growth, an increase of Frame Index from 12 to 16 years in European boys can be observed. Indian and South African boys are almost similar in Frame Index to European boys. In girls, the pattern is slightly different. Whereas South African girls are similar to European girls, Indian girls show a lesser external skeletal robusticity. Conclusion: Accurate references for external skeletal robusticity are needed to evaluate if skeletal development is adequate per age. They should be used to monitor effects of changes in way of life and physical activity levels in children and adolescents to avoid negative health outcomes like osteoporosis and arthrosis.

Skeletal development in Pan paniscus with comparisons to Pan troglodytes.

PubMed

Bolter, Debra R; Zihlman, Adrienne L

2012-04-01

Fusion of skeletal elements provides markers for timing of growth and is one component of a chimpanzee's physical development. Epiphyseal closure defines bone growth and signals a mature skeleton. Most of what we know about timing of development in chimpanzees derives from dental studies on Pan troglodytes. Much less is known about the sister species, Pan paniscus, with few in captivity and a wild range restricted to central Africa. Here, we report on the timing of skeletal fusion for female captive P. paniscus (n = 5) whose known ages range from 0.83 to age 11.68 years. Observations on the skeletons were made after the individuals were dissected and bones cleaned. Comparisons with 10 female captive P. troglodytes confirm a generally uniform pattern in the sequence of skeletal fusion in the two captive species. We also compared the P. paniscus to a sample of three unknown-aged female wild P. paniscus, and 10 female wild P. troglodytes of known age from the Taï National Park, Côte d'Ivoire. The sequence of teeth emergence to bone fusion is generally consistent between the two species, with slight variations in late juvenile and subadult stages. The direct-age comparisons show that skeletal growth in captive P. paniscus is accelerated compared with both captive and wild P. troglodytes populations. The skeletal data combined with dental stages have implications for estimating the life stage of immature skeletal materials of wild P. paniscus and for more broadly comparing the skeletal growth rates among captive and wild chimpanzees (Pan), Homo sapiens, and fossil hominins. Copyright © 2012 Wiley Periodicals, Inc.

Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations

PubMed Central

Gkourogianni, Alexandra; Andrew, Melissa; Tyzinski, Leah; Crocker, Melissa; Douglas, Jessica; Dunbar, Nancy; Fairchild, Jan; Funari, Mariana F. A.; Heath, Karen E.; Jorge, Alexander A. L.; Kurtzman, Tracey; LaFranchi, Stephen; Lalani, Seema; Lebl, Jan; Lin, Yuezhen; Los, Evan; Newbern, Dorothee; Nowak, Catherine; Olson, Micah; Popovic, Jadranka; Průhová, Štěpánka; Elblova, Lenka; Quintos, Jose Bernardo; Segerlund, Emma; Sentchordi, Lucia; Shinawi, Marwan; Stattin, Eva-Lena; Swartz, Jonathan; del Angel, Ariadna González; Cuéllar, Sinhué Diaz; Hosono, Hidekazu; Sanchez-Lara, Pedro A.; Hwa, Vivian; Baron, Jeffrey; Dauber, Andrew

2017-01-01

Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, −2.8 standard deviation score (SDS); range, −5.9 to −0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype–phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, −2.0 SDS; range, −4.2 to −0.6). Most children with ACAN mutations had advanced bone age (bone age − chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients. PMID:27870580

Paternal low protein diet programs preimplantation embryo gene expression, fetal growth and skeletal development in mice.

PubMed

Watkins, Adam J; Sirovica, Slobodan; Stokes, Ben; Isaacs, Mark; Addison, Owen; Martin, Richard A

2017-06-01

Defining the mechanisms underlying the programming of early life growth is fundamental for improving adult health and wellbeing. While the association between maternal diet, offspring growth and adult disease risk is well-established, the effect of father's diet on offspring development is largely unknown. Therefore, we fed male mice an imbalanced low protein diet (LPD) to determine the impact on post-fertilisation development and fetal growth. We observed that in preimplantation embryos derived from LPD fed males, expression of multiple genes within the central metabolic AMPK pathway was reduced. In late gestation, paternal LPD programmed increased fetal weight, however, placental weight was reduced, resulting in an elevated fetal:placental weight ratio. Analysis of gene expression patterns revealed increased levels of transporters for calcium, amino acids and glucose within LPD placentas. Furthermore, placental expression of the epigenetic regulators Dnmt1 and Dnmt3L were increased also, coinciding with altered patterns of maternal and paternal imprinted genes. More strikingly, we observed fetal skeletal development was perturbed in response to paternal LPD. Here, while offspring of LPD fed males possessed larger skeletons, their bones comprised lower volumes of high mineral density in combination with reduced maturity of bone apatite. These data offer new insight in the underlying programming mechanisms linking poor paternal diet at the time of conception with the development and growth of his offspring. Copyright © 2017 Elsevier B.V. All rights reserved.

Hitherto unknown detailed muscle anatomy in an 8-week-old embryo.

PubMed

Warmbrunn, Moritz V; de Bakker, Bernadette S; Hagoort, Jaco; Alefs-de Bakker, Pauline B; Oostra, Roelof-Jan

2018-05-03

Congenital muscle diseases, such as myopathies or dystrophies, occur relatively frequently, with estimated incidences of up to 4.7 per 100 000 newborns. To diagnose congenital diseases in the early stages of pregnancy, and to interpret the results of increasingly advanced in utero imaging techniques, a profound knowledge of normal human morphological development of the locomotor system and the nervous system is necessary. Muscular development, however, is an often neglected topic or is only described in a general way in embryology textbooks and papers. To provide the required detailed and updated comprehensive picture of embryologic muscular anatomy, three-dimensional (3D) reconstructions were created based on serial histological sections of a human embryo at Carnegie stage 23 (8 weeks of development, crown-rump length of 23.8 mm), using Amira reconstruction software. Reconstructed muscles, tendons, bones and nerves were exported in a 3D-PDF file to permit interactive viewing. Almost all adult skeletal muscles of the trunk and limbs could be individually identified in their relative adult position. The pectoralis major muscle was divided in three separate muscle heads. The reconstructions showed remarkable highly developed extraocular, infrahyoid and suprahyoid muscles at this age but surprisingly also absence of the facial muscles that have been described to be present at this stage of development. The overall stage of muscle development suggests heterochrony of skeletal muscle development. Several individual muscle groups were found to be developed earlier and in more detail than described in current literature. © 2018 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.

A Study on Generic Representation of Skeletal Remains Replication of Prehistoric Burial

NASA Astrophysics Data System (ADS)

Shao, C.-W.; Chiu, H.-L.; Chang, S.-K.

2015-08-01

Generic representation of skeletal remains from burials consists of three dimensions which include physical anthropologists, replication technicians, and promotional educators. For the reason that archaeological excavation is irreversible and disruptive, detail documentation and replication technologies are surely needed for many purposes. Unearthed bones during the process of 3D digital scanning need to go through reverse procedure, 3D scanning, digital model superimposition, rapid prototyping, mould making, and the integrated errors generated from the presentation of colours and textures are important issues for the presentation of replicate skeleton remains among professional decisions conducted by physical anthropologists, subjective determination of makers, and the expectations of viewers. This study presents several cases and examines current issues on display and replication technologies for human skeletal remains of prehistoric burials. This study documented detail colour changes of human skeleton over time for the reference of reproduction. The tolerance errors of quantification and required technical qualification is acquired according to the precision of 3D scanning, the specification requirement of rapid prototyping machine, and the mould making process should following the professional requirement for physical anthropological study. Additionally, the colorimeter is adopted to record and analyse the "colour change" of the human skeletal remains from wet to dry condition. Then, the "colure change" is used to evaluate the "real" surface texture and colour presentation of human skeletal remains, and to limit the artistic presentation among the human skeletal remains reproduction. The"Lingdao man No.1", is a well preserved burial of early Neolithic period (8300 B.P.) excavated from Liangdao-Daowei site, Matsu, Taiwan , as the replicating object for this study. In this study, we examined the reproduction procedures step by step for ensuring the surface texture and colour of the replica matches the real human skeletal remains when discovered. The "colour change" of the skeleton documented and quantified in this study could be the reference for the future study and educational exhibition of human skeletal remain reproduction.

Muscle interleukin-6 and fasting-induced PDH regulation in mouse skeletal muscle.

PubMed

Gudiksen, Anders; Bertholdt, Laerke; Vingborg, Mikkel Birkkjaer; Hansen, Henriette Watson; Ringholm, Stine; Pilegaard, Henriette

2017-03-01

Fasting prompts a metabolic shift in substrate utilization from carbohydrate to predominant fat oxidation in skeletal muscle, and pyruvate dehydrogenase (PDH) is seen as a controlling link between the competitive oxidation of carbohydrate and fat during metabolic challenges like fasting. Interleukin (IL)-6 has been proposed to be released from muscle with concomitant effects on both glucose and fat utilization. The aim was to test the hypothesis that muscle IL-6 has a regulatory impact on fasting-induced suppression of skeletal muscle PDH. Skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice and floxed littermate controls (control) were either fed or fasted for 6 or 18 h. Lack of muscle IL-6 elevated the respiratory exchange ratio in the fed and early fasting state, but not with prolonged fasting. Activity of PDH in the active form (PDHa) was higher in fed and fasted IL-6 MKO than in control mice at 18 h, but not at 6 h, whereas lack of muscle IL-6 did not prevent downregulation of PDHa activity in skeletal muscle or changes in plasma and muscle substrate levels in response to 18 h of fasting. Phosphorylation of three of four sites on PDH-E1α increased with 18 h of fasting, but was lower in IL-6 MKO mice than in control. In addition, both PDK4 mRNA and protein increased with 6 and 18 h of fasting in both genotypes, but PDK4 protein was lower in IL-6 MKO than in control. In conclusion, skeletal muscle IL-6 seems to regulate whole body substrate utilization in the fed, but not fasted, state and influence skeletal muscle PDHa activity in a circadian manner. However, skeletal muscle IL-6 is not required for maintaining metabolic flexibility in response to fasting. Copyright © 2017 the American Physiological Society.

Three members of the iodothyronine deiodinase family, dio1, dio2 and dio3, are expressed in spatially and temporally specific patterns during metamorphosis of the flounder, Paralichthys olivaceus.

PubMed

Itoh, Kae; Watanabe, Kohei; Wu, Xiaoming; Suzuki, Tohru

2010-07-01

Flounder metamorphosis, marked by eye migration, lateralized pigmentation, and tissue differentiation in the stomach and skeletal muscle, is stimulated by thyroid hormone (TH). It is known that tri-iodothyronine (T3) produced by iodothyronine deiodinase type-1 (Dio1) from thyroxine (T4) enters the blood, whereas T3 produced by Dio2 penetrates into the nucleus of the Dio2-expressing cells, and then Dio3 inactivates both T4 and T3. To better understand the distinct functions of these three deiodinases in T3 regulation during flounder metamorphosis, we examined the tissue expression patterns of dio1, dio2, and dio3 in larvae of the Japanese flounder, Paralichthys olivaceus, by section in situ hybridization (SISH). We found that each deiodinase is expressed in a spatially and temporally specific pattern. dio1 is expressed in liver parenchymal cells from pro-metamorphosis to early climax, while dio2 is expressed in limited regions of the eyes, tectum, and skeletal muscles from pro-metamorphosis to post-climax. Considering these findings together with reports on other vertebrates, we predict that the liver cells expressing dio1 supply T3 to the blood, and that this systemic T3 synchronizes metamorphosis of differentiating tissues throughout the larval body, whereas the eyes, tectum, and skeletal muscles autonomously produce additional T3 for local tissue differentiation. Finally, dio3 expression is detected in skeletal muscle and gastric gland blastemas, which both undergo marked tissue differentiation at metamorphic climax. We hypothesize that dio3 expression protects these tissues from basal T3 levels early in metamorphosis, ensuring, together with the T3 surge from the liver, the synchronization of tissue differentiation at metamorphic climax.

Defective mitochondrial dynamics is an early event in skeletal muscle of an amyotrophic lateral sclerosis mouse model.

PubMed

Luo, Guo; Yi, Jianxun; Ma, Changling; Xiao, Yajuan; Yi, Frank; Yu, Tian; Zhou, Jingsong

2013-01-01

Mitochondria are dynamic organelles that constantly undergo fusion and fission to maintain their normal functionality. Impairment of mitochondrial dynamics is implicated in various neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is an adult-onset neuromuscular degenerative disorder characterized by motor neuron death and muscle atrophy. ALS onset and progression clearly involve motor neuron degeneration but accumulating evidence suggests primary muscle pathology may also be involved. Here, we examined mitochondrial dynamics in live skeletal muscle of an ALS mouse model (G93A) harboring a superoxide dismutase mutation (SOD1(G93A)). Using confocal microscopy combined with overexpression of mitochondria-targeted photoactivatable fluorescent proteins, we discovered abnormal mitochondrial dynamics in skeletal muscle of young G93A mice before disease onset. We further demonstrated that similar abnormalities in mitochondrial dynamics were induced by overexpression of mutant SOD1(G93A) in skeletal muscle of normal mice, indicating the SOD1 mutation drives ALS-like muscle pathology in the absence of motor neuron degeneration. Mutant SOD1(G93A) forms aggregates inside muscle mitochondria and leads to fragmentation of the mitochondrial network as well as mitochondrial depolarization. Partial depolarization of mitochondrial membrane potential in normal muscle by carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) caused abnormalities in mitochondrial dynamics similar to that in the SOD1(G93A) model muscle. A specific mitochondrial fission inhibitor (Mdivi-1) reversed the SOD1(G93A) action on mitochondrial dynamics, indicating SOD1(G93A) likely promotes mitochondrial fission process. Our results suggest that accumulation of mutant SOD1(G93A) inside mitochondria, depolarization of mitochondrial membrane potential and abnormal mitochondrial dynamics are causally linked and cause intrinsic muscle pathology, which occurs early in the course of ALS and may actively promote ALS progression.

Effects of seawater acidification on the early development of sea urchin Glyptocidaris crenularis

NASA Astrophysics Data System (ADS)

Zhan, Yaoyao; Hu, Wanbin; Duan, Lizhu; Liu, Minbo; Zhang, Weijie; Chang, Yaqing; Li, Cong

2017-10-01

In this study, we evaluated the effects of CO2-induced seawater acidification on fertilization, embryogenesis and early larval development in the sea urchin Glyptocidaris crenularis, that inhabits subtidal coastal areas in northern China. The range in seawater pH used in experiments was based on the projections of the Intergovernmental Panel on Climate Change (IPCC), to the year 2100. A natural seawater treatment (pHnbs=7.98±0.03) and three laboratory-controlled acidified treatments (OA1, ΔpHnbs=-0.3 units; OA2, ΔpHnbs=-0.4 units; OA3, ΔpHnbs=-0.5 units) were used in experiments. Results show that: (1) there was a negative effect of seawater acidification on fertilization and on the percentage of abnormal fertilized eggs; (2) the size of early cleavage stage embryos decreased in a dose-dependent manner with decreasing pH; (3) both the hatching rate of blastulae and the survival rate of four-armed pluteus larvae decreased as pH declined; (4) larval abnormalities including asymmetrical development, changes in the length of skeletal elements, and corroded spicules were observed in all seawater acidified-treatments compared with the control. These data indicate that seawater acidification has a negative impact on the early development of G. crenularis, and supports the hypothesis that the response of echinoderms to ocean acidification (OA) varies among species. Further research is required to clarify the specific cellular mechanisms involved.

Congenital axis dysmorphism in a medieval skeleton : …secunda a vertendo epistropheus….

PubMed

Travan, Luciana; Saccheri, Paola; Toso, Francesco; Crivellato, Enrico

2013-05-01

We describe here the axis dysmorphism that we observed in the skeletal remains of a human child dug up from a fifteenth century cemetery located in north-eastern Italy. This bone defect is discussed in the light of pertinent literature. We performed macroscopical examination and CT scan analysis of the axis. Axis structure was remarkably asymmetric. Whilst the left half exhibited normal morphology, the right one was smaller than normal, and its lateral articular surface showed horizontal orientation. In addition, the odontoid process appeared leftward deviated and displayed a supplementary articular-like facet situated on the right side of its surface. These findings suggest a diagnosis of unilateral irregular segmentation of atlas and axis, a rare dysmorphism dependent upon disturbances of notochordal development in early embryonic life. Likewise other malformations of the craniovertebral junction, this axis defect may alter the delicate mechanisms of upper neck movements and cause a complex series of clinical symptoms. This is an emblematic case whereby human skeletal remains may provide valuable information on the anatomical defects of craniovertebral junction.

The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts

DOE PAGES

Kim, Hyunsoo; Walsh, Matthew C.; Takegahara, Noriko; ...

2017-03-15

Excessive bone resorption by osteoclasts (OCs) can result in serious clinical outcomes, including bone loss that may weaken skeletal or periodontal strength. Proper bone homeostasis and skeletal strength are maintained by balancing OC function with the bone-forming function of osteoblasts. Unfortunately, current treatments that broadly inhibit OC differentiation or function may also interfere with coupled bone formation. We therefore identified a factor, the purinergic receptor P2X5 that is highly expressed during the OC maturation phase, and which we show here plays no apparent role in early bone development and homeostasis, but which is required for osteoclast-mediated inflammatory bone loss andmore » hyper-multinucleation of OCs. We further demonstrate that P2X5 is required for ATP-mediated inflammasome activation and IL-1β production by OCs, and that P2X5-deficient OC maturation is rescued in vitro by addition of exogenous IL-1β. These findings identify a mechanism by which OCs react to inflammatory stimuli, and may identify purinergic signaling as a therapeutic target for bone loss related inflammatory conditions.« less

The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Hyunsoo; Walsh, Matthew C.; Takegahara, Noriko

Excessive bone resorption by osteoclasts (OCs) can result in serious clinical outcomes, including bone loss that may weaken skeletal or periodontal strength. Proper bone homeostasis and skeletal strength are maintained by balancing OC function with the bone-forming function of osteoblasts. Unfortunately, current treatments that broadly inhibit OC differentiation or function may also interfere with coupled bone formation. We therefore identified a factor, the purinergic receptor P2X5 that is highly expressed during the OC maturation phase, and which we show here plays no apparent role in early bone development and homeostasis, but which is required for osteoclast-mediated inflammatory bone loss andmore » hyper-multinucleation of OCs. We further demonstrate that P2X5 is required for ATP-mediated inflammasome activation and IL-1β production by OCs, and that P2X5-deficient OC maturation is rescued in vitro by addition of exogenous IL-1β. These findings identify a mechanism by which OCs react to inflammatory stimuli, and may identify purinergic signaling as a therapeutic target for bone loss related inflammatory conditions.« less

SoxB2 in sea urchin development: implications in neurogenesis, ciliogenesis and skeletal patterning.

PubMed

Anishchenko, Evgeniya; Arnone, Maria Ina; D'Aniello, Salvatore

2018-01-01

Current studies in evolutionary developmental biology are focused on the reconstruction of gene regulatory networks in target animal species. From decades, the scientific interest on genetic mechanisms orchestrating embryos development has been increasing in consequence to the fact that common features shared by evolutionarily distant phyla are being clarified. In 2011, a study across eumetazoan species showed for the first time the existence of a highly conserved non-coding element controlling the SoxB2 gene, which is involved in the early specification of the nervous system. This discovery raised several questions about SoxB2 function and regulation in deuterostomes from an evolutionary point of view. Due to the relevant phylogenetic position within deuterostomes, the sea urchin Strongylocentrotus purpuratus represents an advantageous animal model in the field of evolutionary developmental biology. Herein, we show a comprehensive study of SoxB2 functions in sea urchins, in particular its expression pattern in a wide range of developmental stages, and its co-localization with other neurogenic markers, as SoxB1 , SoxC and Elav . Moreover, this work provides a detailed description of the phenotype of sea urchin SoxB2 knocked-down embryos, confirming its key function in neurogenesis and revealing, for the first time, its additional roles in oral and aboral ectoderm cilia and skeletal rod morphology. We concluded that SoxB2 in sea urchins has a neurogenic function; however, this gene could have multiple roles in sea urchin embryogenesis, expanding its expression in non-neurogenic cells. We showed that SoxB2 is functionally conserved among deuterostomes and suggested that in S. purpuratus this gene acquired additional functions, being involved in ciliogenesis and skeletal patterning.

Long-Term Clinical Outcome and Carrier Phenotype in Autosomal Recessive Hypophosphatemia Caused by a Novel DMP1 Mutation

PubMed Central

Mäkitie, Outi; Pereira, Renata C; Kaitila, Ilkka; Turan, Serap; Bastepe, Murat; Laine, Tero; Kröger, Heikki; Cole, William G; Jüppner, Harald

2010-01-01

Homozygous inactivating mutations in DMP1 (dentin matrix protein 1), the gene encoding a noncollagenous bone matrix protein expressed in osteoblasts and osteocytes, cause autosomal recessive hypophosphatemia (ARHP). Herein we describe a family with ARHP owing to a novel homozygous DMP1 mutation and provide a detailed description of the associated skeletal dysplasia and carrier phenotype. The two adult patients with ARHP, a 78-year-old man and his 66-year-old sister, have suffered from bone pain and lower extremity varus deformities since early childhood. With increasing age, both patients developed severe joint pain, contractures, and complete immobilization of the spine. Radiographs showed short and deformed long bones, significant cranial hyperostosis, enthesopathies, and calcifications of the paraspinal ligaments. Biochemistries were consistent with hypophosphatemia owing to renal phosphate wasting; markers of bone turnover and serum fibroblast growth factor 23 (FGF-23) levels were increased significantly. Nucleotide sequence analysis of DMP1 revealed a novel homozygous mutation at the splice acceptor junction of exon 6 (IVS5-1G > A). Two heterozygous carriers of the mutation also showed mild hypophosphatemia, and bone biopsy in one of these individuals showed focal areas of osteomalacia. In bone, DMP1 expression was absent in the homozygote but normal in the heterozygote, whereas FGF-23 expression was increased in both subjects but higher in the ARHP patient. The clinical and laboratory observations in this family confirm that DMP1 has an important role in normal skeletal development and mineral homeostasis. The skeletal phenotype in ARHP may be significantly more severe than in other forms of hypophosphatemic rickets. © 2010 American Society for Bone and Mineral Research. PMID:20499351

Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.

PubMed

Mäkitie, Outi; Pereira, Renata C; Kaitila, Ilkka; Turan, Serap; Bastepe, Murat; Laine, Tero; Kröger, Heikki; Cole, William G; Jüppner, Harald

2010-10-01

Homozygous inactivating mutations in DMP1 (dentin matrix protein 1), the gene encoding a noncollagenous bone matrix protein expressed in osteoblasts and osteocytes, cause autosomal recessive hypophosphatemia (ARHP). Herein we describe a family with ARHP owing to a novel homozygous DMP1 mutation and provide a detailed description of the associated skeletal dysplasia and carrier phenotype. The two adult patients with ARHP, a 78-year-old man and his 66-year-old sister, have suffered from bone pain and lower extremity varus deformities since early childhood. With increasing age, both patients developed severe joint pain, contractures, and complete immobilization of the spine. Radiographs showed short and deformed long bones, significant cranial hyperostosis, enthesopathies, and calcifications of the paraspinal ligaments. Biochemistries were consistent with hypophosphatemia owing to renal phosphate wasting; markers of bone turnover and serum fibroblast growth factor 23 (FGF-23) levels were increased significantly. Nucleotide sequence analysis of DMP1 revealed a novel homozygous mutation at the splice acceptor junction of exon 6 (IVS5-1G > A). Two heterozygous carriers of the mutation also showed mild hypophosphatemia, and bone biopsy in one of these individuals showed focal areas of osteomalacia. In bone, DMP1 expression was absent in the homozygote but normal in the heterozygote, whereas FGF-23 expression was increased in both subjects but higher in the ARHP patient. The clinical and laboratory observations in this family confirm that DMP1 has an important role in normal skeletal development and mineral homeostasis. The skeletal phenotype in ARHP may be significantly more severe than in other forms of hypophosphatemic rickets.

Dietary effects on body composition, glucose metabolism, and longevity are modulated by skeletal muscle mitochondrial uncoupling in mice

PubMed Central

Keipert, Susanne; Voigt, Anja; Klaus, Susanne

2011-01-01

Little is known about how diet and energy metabolism interact in determination of lifespan under ad libitum feeding. From 12 weeks of age until death, male and female wild-type (WT) and transgenic (TG) mice with increased skeletal muscle mitochondrial uncoupling (HSA-mUCP1 mice) were fed one of three different semisynthetic diets differing in macronutrient ratio: control (high-carbohydrate/low-fat-HCLF) and two high-fat diets: high-carbohydrate/high-fat (HCHF), and low-carbohydrate/high-fat (LCHF). Compared to control and LCHF, HCHF feeding rapidly and significantly increased body fat content in WT. Median lifespan of WT was decreased by 33% (HCHF) and 7% (LCHF) compared to HCLF. HCHF significantly increased insulin resistance (HOMA) of WT from 24 weeks on compared to control. TG mice had lower lean body mass and increased energy expenditure, insulin sensitivity, and maximum lifespan (+10%) compared to WT. They showed a delayed development of obesity on HCHF but reached similar maximum adiposity as WT. TG median lifespan was only slightly reduced by HCHF (−7%) and unaffected by LCHF compared to control. Correlation analyses showed that decreased longevity was more strongly linked to a high rate of fat gain than to adiposity itself. Furthermore, insulin resistance was negatively and weight-specific energy expenditure was positively correlated with longevity. We conclude that (i) dietary macronutrient ratios strongly affected obesity development, glucose homeostasis, and longevity, (ii) that skeletal muscle mitochondrial uncoupling alleviated the detrimental effects of high-fat diets, and (iii) that early imbalances in energy homeostasis leading to increased insulin resistance are predictive for a decreased lifespan. PMID:21070590

Dietary effects on body composition, glucose metabolism, and longevity are modulated by skeletal muscle mitochondrial uncoupling in mice.

PubMed

Keipert, Susanne; Voigt, Anja; Klaus, Susanne

2011-02-01

Little is known about how diet and energy metabolism interact in determination of lifespan under ad libitum feeding. From 12 weeks of age until death, male and female wild-type (WT) and transgenic (TG) mice with increased skeletal muscle mitochondrial uncoupling (HSA-mUCP1 mice) were fed one of three different semisynthetic diets differing in macronutrient ratio: control (high-carbohydrate/low-fat-HCLF) and two high-fat diets: high-carbohydrate/high-fat (HCHF), and low-carbohydrate/high-fat (LCHF). Compared to control and LCHF, HCHF feeding rapidly and significantly increased body fat content in WT. Median lifespan of WT was decreased by 33% (HCHF) and 7% (LCHF) compared to HCLF. HCHF significantly increased insulin resistance (HOMA) of WT from 24 weeks on compared to control. TG mice had lower lean body mass and increased energy expenditure, insulin sensitivity, and maximum lifespan (+10%) compared to WT. They showed a delayed development of obesity on HCHF but reached similar maximum adiposity as WT. TG median lifespan was only slightly reduced by HCHF (-7%) and unaffected by LCHF compared to control. Correlation analyses showed that decreased longevity was more strongly linked to a high rate of fat gain than to adiposity itself. Furthermore, insulin resistance was negatively and weight-specific energy expenditure was positively correlated with longevity. We conclude that (i) dietary macronutrient ratios strongly affected obesity development, glucose homeostasis, and longevity, (ii) that skeletal muscle mitochondrial uncoupling alleviated the detrimental effects of high-fat diets, and (iii) that early imbalances in energy homeostasis leading to increased insulin resistance are predictive for a decreased lifespan.

Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice.

PubMed

Jackson, Kathryn C; Wohlers, Lindsay M; Lovering, Richard M; Schuh, Rosemary A; Maher, Amy C; Bonen, Arend; Koves, Timothy R; Ilkayeva, Olga; Thomson, David M; Muoio, Deborah M; Spangenburg, Espen E

2013-02-01

Disruptions of ovarian function in women are associated with increased risk of metabolic disease due to dysregulation of peripheral glucose homeostasis in skeletal muscle. Our previous evidence suggests that alterations in skeletal muscle lipid metabolism coupled with altered mitochondrial function may also develop. The objective of this study was to use an integrative metabolic approach to identify potential areas of dysfunction that develop in skeletal muscle from ovariectomized (OVX) female mice compared with age-matched ovary-intact adult female mice (sham). The OVX mice exhibited significant increases in body weight, visceral, and inguinal fat mass compared with sham mice. OVX mice also had significant increases in skeletal muscle intramyocellular lipids (IMCL) compared with the sham animals, which corresponded to significant increases in the protein content of the fatty acid transporters CD36/FAT and FABPpm. A targeted metabolic profiling approach identified significantly lower levels of specific acyl carnitine species and various amino acids in skeletal muscle from OVX mice compared with the sham animals, suggesting a potential dysfunction in lipid and amino acid metabolism, respectively. Basal and maximal mitochondrial oxygen consumption rates were significantly impaired in skeletal muscle fibers from OVX mice compared with sham animals. Collectively, these data indicate that loss of ovarian function results in increased IMCL storage that is coupled with alterations in mitochondrial function and changes in the skeletal muscle metabolic profile.

Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice

PubMed Central

Jackson, Kathryn C.; Wohlers, Lindsay M.; Lovering, Richard M.; Schuh, Rosemary A.; Maher, Amy C.; Bonen, Arend; Koves, Timothy R.; Ilkayeva, Olga; Thomson, David M.; Muoio, Deborah M.

2013-01-01

Disruptions of ovarian function in women are associated with increased risk of metabolic disease due to dysregulation of peripheral glucose homeostasis in skeletal muscle. Our previous evidence suggests that alterations in skeletal muscle lipid metabolism coupled with altered mitochondrial function may also develop. The objective of this study was to use an integrative metabolic approach to identify potential areas of dysfunction that develop in skeletal muscle from ovariectomized (OVX) female mice compared with age-matched ovary-intact adult female mice (sham). The OVX mice exhibited significant increases in body weight, visceral, and inguinal fat mass compared with sham mice. OVX mice also had significant increases in skeletal muscle intramyocellular lipids (IMCL) compared with the sham animals, which corresponded to significant increases in the protein content of the fatty acid transporters CD36/FAT and FABPpm. A targeted metabolic profiling approach identified significantly lower levels of specific acyl carnitine species and various amino acids in skeletal muscle from OVX mice compared with the sham animals, suggesting a potential dysfunction in lipid and amino acid metabolism, respectively. Basal and maximal mitochondrial oxygen consumption rates were significantly impaired in skeletal muscle fibers from OVX mice compared with sham animals. Collectively, these data indicate that loss of ovarian function results in increased IMCL storage that is coupled with alterations in mitochondrial function and changes in the skeletal muscle metabolic profile. PMID:23193112

Early-life programming of susceptibility to dysregulation of glucose metabolism and the development of Type 2 diabetes mellitus.

PubMed Central

Holness, M J; Langdown, M L; Sugden, M C

2000-01-01

There is increasing epidemiological evidence in humans which associates low birthweight with later metabolic disorders, including insulin resistance and glucose intolerance. There is evidence that nutritional and hormonal factors (e.g. maternal protein restriction, exposure to excess maternal glucocorticoids) markedly influence intra-uterine growth and development. A picture is also emerging of the biochemical and physiological mechanisms that may underlie these effects. This review focuses on recent research directed towards understanding the molecular basis of the relationship between indices of poor early growth and the subsequent development of glucose intolerance and Type 2 diabetes mellitus using animal models that attempt to recreate the process of programming via an adverse intra-uterine or neonatal environment. Emphasis is on the chain of events and potential mechanisms by which adverse adaptations affect pancreatic-beta-cell insulin secretion and the sensitivity to insulin of key metabolic processes, including hepatic glucose production, skeletal-muscle glucose disposal and adipose-tissue lipolysis. Unravelling the molecular details involved in metabolic programming may provide new insights into the pathogenesis of impaired glucoregulation and Type 2 diabetes. PMID:10903125

Dried Plum Protects From Radiation-Induced Bone Loss by Attenuating Pro-Osteoclastic and Oxidative Stress Responses

NASA Technical Reports Server (NTRS)

Globus, Ruth

2015-01-01

Future space explorations beyond the earths magnetosphere will increase human exposure to space radiation and associated risks to skeletal health. We hypothesize that oxidative stress resulting from radiation exposure plays a major role in progressive bone loss and dysfunction in associated tissue. In animal studies, increased free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. Our long-term goals are to define the mechanisms and risk of bone loss in the spaceflight environment and to facilitate the development of effective countermeasures. We had previously reported that exposure to low or high-LET radiation correlates with an acute increase in the expression of pro-osteoclastic and oxidative stress genes in bone during the early response to radiation followed by pathological changes in skeletal structure. We then conducted systematic screening for potential countermeasures against bone loss where we tested the ability of various antioxidants to mitigate the radiation-induced increase in expression of these markers. For the screen, 16-week old C57Bl6J mice were treated with a dietary antioxidant cocktail, injectable DHLA or a dried plum-enriched diet (DP). Mice were then exposed to 2Gy 137Cs radiation and one day later, marrow cells were collected and the relevant genes analyzed for expression levels. Among the candidate countermeasures tested, DP was most effective in reducing the expression of genes associated with bone loss. Furthermore, analysis of skeletal structure by microcomputed tomography (microCT) revealed that DP also prevents the radiation-induced deterioration in skeletal microarchitecture as indicated by parameters such as percent bone volume (BVTV), trabecular spacing and trabecular number. We also found that DP has similar protective effects on skeletal structure in a follow-up study using 1 Gy of sequential proton and iron, radiation species relevant to spaceflight. When cultured ex vivo under osteogenic conditions, bone marrow-derived cells from DP-fed animals exhibited increased colony numbers compared to control diet-fed animals. These findings suggest that DP exerts pro-osteogenic effects apart from its previously demonstrated anti-resorptive action, which may be one of the mechanisms underlying its radioprotective effect on bone. In conclusion, a diet enriched in certain types of antioxidants may be useful as an intervention for radiation-induced bone loss.

Skeletal Mechanism Generation of Surrogate Jet Fuels for Aeropropulsion Modeling

NASA Astrophysics Data System (ADS)

Sung, Chih-Jen; Niemeyer, Kyle E.

2010-05-01

A novel implementation for the skeletal reduction of large detailed reaction mechanisms using the directed relation graph with error propagation and sensitivity analysis (DRGEPSA) is developed and presented with skeletal reductions of two important hydrocarbon components, n-heptane and n-decane, relevant to surrogate jet fuel development. DRGEPSA integrates two previously developed methods, directed relation graph-aided sensitivity analysis (DRGASA) and directed relation graph with error propagation (DRGEP), by first applying DRGEP to efficiently remove many unimportant species prior to sensitivity analysis to further remove unimportant species, producing an optimally small skeletal mechanism for a given error limit. It is illustrated that the combination of the DRGEP and DRGASA methods allows the DRGEPSA approach to overcome the weaknesses of each previous method, specifically that DRGEP cannot identify all unimportant species and that DRGASA shields unimportant species from removal.

Transcriptome analysis reveals long intergenic non-coding RNAs involved in skeletal muscle growth and development in pig.

PubMed

Zou, Cheng; Li, Jingxuan; Luo, Wenzhe; Li, Long; Hu, An; Fu, Yuhua; Hou, Ye; Li, Changchun

2017-08-18

Long intergenic non-coding RNAs (lincRNAs) play essential roles in numerous biological processes and are widely studied. The skeletal muscle is an important tissue that plays an essential role in individual movement ability. However, lincRNAs in pig skeletal muscles are largely undiscovered and their biological functions remain elusive. In this study, we assembled transcriptomes using RNA-seq data published in previous studies of our laboratory group and identified 323 lincRNAs in porcine leg muscle. We found that these lincRNAs have shorter transcript length, fewer exons and lower expression level than protein-coding genes. Gene ontology and pathway analyses indicated that many potential target genes (PTGs) of lincRNAs were involved in skeletal-muscle-related processes, such as muscle contraction and muscle system process. Combined our previous studies, we found a potential regulatory mechanism in which the promoter methylation of lincRNAs can negatively regulate lincRNA expression and then positively regulate PTG expression, which can finally result in abnormal phenotypes of cloned piglets through a certain unknown pathway. This work detailed a number of lincRNAs and their target genes involved in skeletal muscle growth and development and can facilitate future studies on their roles in skeletal muscle growth and development.

The Not-so-Dark Ages: ecology for human growth in medieval and early twentieth century Portugal as inferred from skeletal growth profiles.

PubMed

Cardoso, Hugo F V; Garcia, Susana

2009-02-01

This study attempts to address the issue of relative living standards in Portuguese medieval and early 20th century periods. Since the growth of children provides a good measure of environmental quality for the overall population, the skeletal growth profiles of medieval Leiria and early 20th century Lisbon were compared. Results show that growth in femur length of medieval children did not differ significantly from that of early 20th century children, but after puberty medieval adolescents seem to have recovered, as they have significantly longer femora as adults. This is suggestive of greater potential for catch-up growth in medieval adolescents. We suggest that this results from distinct child labor practices, which impact differentially on the growth of Leiria and Lisbon adolescents. Work for medieval children and adolescents were related to family activities, and care and attention were provided by family members. Conversely, in early 20th century Lisbon children were more often sent to factories at around 12 years of age as an extra source of family income, where they were exploited for their labor. Since medieval and early 20th century children were stunted at an early age, greater potential for catch-up growth in medieval adolescents results from exhausting work being added to modern adolescent's burdens of disease and poor diet, when they entered the labor market. Although early 20th century Lisbon did not differ in overall unfavorable living conditions from medieval Leiria, after puberty different child labor practices may have placed modern adolescents at greater risk of undernutrition and poor growth. 2008 Wiley-Liss, Inc.

Computer-aided mechanogenesis of skeletal muscle organs from single cells in vitro

NASA Technical Reports Server (NTRS)

Vanderburgh, Herman H.; Swasdison, Somporn; Karlisch, Patricia

1991-01-01

Complex mechanical forces generated in the growing embryo play an important role in organogenesis. Computerized application of similar forces to differentiating skeletal muscle myoblasts in vitro generate three dimensional artificial muscle organs. These organs contain parallel networks of long unbranched myofibers organized into fascicle-like structures. Tendon development is initiated and the muscles are capable of performing directed, functional work. Kinetically engineered organs provide a new method for studying the growth and development of normal and diseased skeletal muscle.

Computer aided mechanogenesis of skeletal muscle organs from single cells in vitro

NASA Technical Reports Server (NTRS)

Vandenburgh, Herman H.; Swasdison, Somporn; Karlisch, Patricia

1990-01-01

Complex mechanical forces generated in the growing embryo play an important role in organogenesis. Computerized application of similar forces to differentiating skeletal muscle myoblasts in vitro generate three dimensional artificial muscle organs. These organs contain parallel networks of long unbranched myofibers organized into fascicle-like structures. Tendon development is initiated and the muscles are capable of performing directed, functional work. Kinetically engineered organs provide a new method for studying the growth and development of normal and diseased skeletal muscle.

Growth factor involvement in tension-induced skeletal muscle growth

NASA Technical Reports Server (NTRS)

Vandenburgh, H. H.

1987-01-01

Muscle tissue culture techniques were developed to grow skeletal myofibers which differentiate into more adult-like myofibers. Mechanical simulation studies of these muscle cells in a newly developed mechanical cell simulator can now be performed to study growth processes in skeletal muscle. Conditions in the mechanical cell simulator were defined where mechanical activity can either prevent muscle wasting or stimulate muscle growth. The role of endogenous and exogenous growth factors in tension-induced muscle growth is being investigated under the defined conditions of tissue culture.

Margaret Buckingham, discoveries in skeletal and cardiac muscle development, elected to the National Academy of Science.

PubMed

Rudnicki, Michael A

2012-06-07

Margaret Buckingham was presented as a newly elected member to the National Academy of Sciences on 28 April 2012. Over the course of her career, Dr Buckingham made many seminal contributions to the understanding of skeletal muscle and cardiac development. Her studies on cardiac progenitor populations has provided insight into understanding heart malformations, while her work on skeletal muscle progenitors has elucidated their embryonic origins and the transcriptional hierarchies controlling their developmental progression.

Estimation of skeletal muscle mass from body creatine content

NASA Technical Reports Server (NTRS)

Pace, N.; Rahlmann, D. F.

1982-01-01

Procedures have been developed for studying the effect of changes in gravitational loading on skeletal muscle mass through measurements of the body creatine content. These procedures were developed for studies of gravitational scale effects in a four-species model, comprising the hamster, rat, guinea pig, and rabbit, which provides a sufficient range of body size for assessment of allometric parameters. Since intracellular muscle creatine concentration varies among species, and with age within a given species, the concentration values for metabolically mature individuals of these four species were established. The creatine content of the carcass, skin, viscera, smooth muscle, and skeletal muscle was determined for each species. In addition, the skeletal muscle mass of the major body components was determined, as well as the total and fat-free masses of the body and carcass, and the percent skeletal muscle in each. It is concluded that these procedures are particularly useful for studying the effect of gravitational loading on the skeletal muscle content of the animal carcass, which is the principal weight-bearing organ of the body.

Early activation of mTORC1 signalling in response to mechanical overload is independent of phosphoinositide 3-kinase/Akt signalling

PubMed Central

Miyazaki, Mitsunori; McCarthy, John J; Fedele, Mark J; Esser, Karyn A

2011-01-01

Abstract The mammalian target of rapamycin complex 1 (mTORC1) functions as a central integrator of a wide range of signals that modulate protein metabolism and cell growth. However, the contributions of individual pathways regulating mTORC1 activity in skeletal muscle are poorly defined. The purpose of this study was to determine the regulatory mechanisms that contribute to mTORC1 activation during mechanical overload-induced skeletal muscle hypertrophy. Consistent with previous studies, mechanical overload induced progressive hypertrophy of the plantaris muscle which was associated with significant increases in total RNA content and protein metabolism. mTORC1 was activated after a single day of overload as indicated by a significant increase in S6K1 phosphorylation at T389 and T421/S424. In contrast, Akt activity, as assessed by Akt phosphorylation status (T308 and S473), phosphorylation of direct downstream targets (glycogen synthase kinase 3 β, proline-rich Akt substrate 40 kDa and tuberous sclerosis 2 (TSC2)) and a kinase assay, was not significantly increased until 2–3 days of overload. Inhibition of phosphoinositide 3-kinase (PI3K) activity by wortmannin was sufficient to block insulin-dependent signalling but did not prevent the early activation of mTORC1 in response to overload. We identified that the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)-dependent pathway was activated at day 1 after overload. In addition, a target of MEK/ERK signalling, phosphorylation of TSC2 at S664, was also increased at this early time point. These observations demonstrate that in vivo, mTORC1 activation at the early phase of mechanical overload in skeletal muscle occurs independently of PI3K/Akt signalling and provide evidence that the MEK/ERK pathway may contribute to mTORC1 activation through phosphorylation of TSC2. PMID:21300751

Taxonomy of rare genetic metabolic bone disorders.

PubMed

Masi, L; Agnusdei, D; Bilezikian, J; Chappard, D; Chapurlat, R; Cianferotti, L; Devolgelaer, J-P; El Maghraoui, A; Ferrari, S; Javaid, M K; Kaufman, J-M; Liberman, U A; Lyritis, G; Miller, P; Napoli, N; Roldan, E; Papapoulos, S; Watts, N B; Brandi, M L

2015-10-01

This article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes. Rare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients. IOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis. This taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity. This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.

Skeletal mechanism generation for surrogate fuels using directed relation graph with error propagation and sensitivity analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Niemeyer, Kyle E.; Sung, Chih-Jen; Raju, Mandhapati P.

2010-09-15

A novel implementation for the skeletal reduction of large detailed reaction mechanisms using the directed relation graph with error propagation and sensitivity analysis (DRGEPSA) is developed and presented with examples for three hydrocarbon components, n-heptane, iso-octane, and n-decane, relevant to surrogate fuel development. DRGEPSA integrates two previously developed methods, directed relation graph-aided sensitivity analysis (DRGASA) and directed relation graph with error propagation (DRGEP), by first applying DRGEP to efficiently remove many unimportant species prior to sensitivity analysis to further remove unimportant species, producing an optimally small skeletal mechanism for a given error limit. It is illustrated that the combination ofmore » the DRGEP and DRGASA methods allows the DRGEPSA approach to overcome the weaknesses of each, specifically that DRGEP cannot identify all unimportant species and that DRGASA shields unimportant species from removal. Skeletal mechanisms for n-heptane and iso-octane generated using the DRGEP, DRGASA, and DRGEPSA methods are presented and compared to illustrate the improvement of DRGEPSA. From a detailed reaction mechanism for n-alkanes covering n-octane to n-hexadecane with 2115 species and 8157 reactions, two skeletal mechanisms for n-decane generated using DRGEPSA, one covering a comprehensive range of temperature, pressure, and equivalence ratio conditions for autoignition and the other limited to high temperatures, are presented and validated. The comprehensive skeletal mechanism consists of 202 species and 846 reactions and the high-temperature skeletal mechanism consists of 51 species and 256 reactions. Both mechanisms are further demonstrated to well reproduce the results of the detailed mechanism in perfectly-stirred reactor and laminar flame simulations over a wide range of conditions. The comprehensive and high-temperature n-decane skeletal mechanisms are included as supplementary material with this article. (author)« less

Skeletal Muscle Tissue Engineering: Methods to Form Skeletal Myotubes and Their Applications

PubMed Central

Ostrovidov, Serge; Hosseini, Vahid; Ahadian, Samad; Fujie, Toshinori; Parthiban, Selvakumar Prakash; Ramalingam, Murugan; Bae, Hojae; Kaji, Hirokazu

2014-01-01

Skeletal muscle tissue engineering (SMTE) aims to repair or regenerate defective skeletal muscle tissue lost by traumatic injury, tumor ablation, or muscular disease. However, two decades after the introduction of SMTE, the engineering of functional skeletal muscle in the laboratory still remains a great challenge, and numerous techniques for growing functional muscle tissues are constantly being developed. This article reviews the recent findings regarding the methodology and various technical aspects of SMTE, including cell alignment and differentiation. We describe the structure and organization of muscle and discuss the methods for myoblast alignment cultured in vitro. To better understand muscle formation and to enhance the engineering of skeletal muscle, we also address the molecular basics of myogenesis and discuss different methods to induce myoblast differentiation into myotubes. We then provide an overview of different coculture systems involving skeletal muscle cells, and highlight major applications of engineered skeletal muscle tissues. Finally, potential challenges and future research directions for SMTE are outlined. PMID:24320971

Resorbable bone fixation alloys, forming, and post-fabrication treatments.

PubMed

Ibrahim, Hamdy; Esfahani, Sajedeh Nasr; Poorganji, Behrang; Dean, David; Elahinia, Mohammad

2017-01-01

Metallic alloys have been introduced as biodegradable metals for various biomedical applications over the last decade owing to their gradual corrosion in the body, biocompatibility and superior strength compared to biodegradable polymers. Mg alloys possess advantageous properties that make them the most extensively studied biodegradable metallic material for orthopedic applications such as their low density, modulus of elasticity, close to that of the bone, and resorbability. Early resorption (i.e., <3months) and relatively inadequate strength are the main challenges that hinder the use of Mg alloys for bone fixation applications. The development of resorbable Mg-based bone fixation hardware with superior mechanical and corrosion performance requires a thorough understanding of the physical and mechanical properties of Mg alloys. This paper discusses the characteristics of successful Mg-based skeletal fixation hardware and the possible ways to improve its properties using different methods such as mechanical and heat treatment processes. We also review the most recent work pertaining to Mg alloys and surface coatings. To this end, this paper covers (i) the properties and development of Mg alloys and coatings with an emphasis on the Mg-Zn-Ca-based alloys; (ii) Mg alloys fabrication techniques; and (iii) strategies towards achieving Mg-based, resorbable, skeletal fixation devices. Copyright © 2016 Elsevier B.V. All rights reserved.

Clinical trials update: highlights of the scientific sessions of the American Heart Association year 2000: Val HeFT, COPERNICUS, MERIT, CIBIS-II, BEST, AMIOVIRT, V-MAC, BREATHE, HEAT, MIRACL, FLORIDA, VIVA and the first human cardiac skeletal muscle myoblast transfer for heart failure.

PubMed

Thackray, S D; Witte, K K; Khand, A; Dunn, A; Clark, A L; Cleland, J G

2001-01-01

This article continues a series of reports summarising recent research developments pertinent to the topic of heart failure. This is a summary of presentations made at scientific sessions of the American Heart Association in November 2000. Clinical studies of particular interest to people caring for patients with heart failure include Val-HeFT, AMIOVIRT and V-MAC. New data from beta-blockers trials are reviewed, highlights from some important developments in post-infarction care, including MIRACL and FLORIDA, discussed and results of some early studies of gene therapy reported.

Histological image data of limb skeletal tissue from larval and adult Ambystoma mexicanum.

PubMed

McCusker, Catherine D; Diaz-Castillo, Carlos; Sosnik, Julian; Phan, Anne; Gardiner, David M

2016-09-01

The data presented in this article are related to the article entitled "Cartilage and bone cells do not participate in skeletal regeneration in Ambystoma mexicanum limbs" [1]. Here we present image data of the post-embryonic development of the forelimb skeletal tissue of Ambystoma Mexicanum. Histological staining was performed on sections from the intact limbs of young (6.5 cm) and old (25 cm) animals, and on dissected skeletal tissues (cartilage, bone, and periosteum) from these animals.

Skeletal muscle performance and ageing

PubMed Central

Trouwborst, Inez; Clark, Brian C.

2017-01-01

Abstract The world population is ageing rapidly. As society ages, the incidence of physical limitations is dramatically increasing, which reduces the quality of life and increases healthcare expenditures. In western society, ~30% of the population over 55 years is confronted with moderate or severe physical limitations. These physical limitations increase the risk of falls, institutionalization, co‐morbidity, and premature death. An important cause of physical limitations is the age‐related loss of skeletal muscle mass, also referred to as sarcopenia. Emerging evidence, however, clearly shows that the decline in skeletal muscle mass is not the sole contributor to the decline in physical performance. For instance, the loss of muscle strength is also a strong contributor to reduced physical performance in the elderly. In addition, there is ample data to suggest that motor coordination, excitation–contraction coupling, skeletal integrity, and other factors related to the nervous, muscular, and skeletal systems are critically important for physical performance in the elderly. To better understand the loss of skeletal muscle performance with ageing, we aim to provide a broad overview on the underlying mechanisms associated with elderly skeletal muscle performance. We start with a system level discussion and continue with a discussion on the influence of lifestyle, biological, and psychosocial factors on elderly skeletal muscle performance. Developing a broad understanding of the many factors affecting elderly skeletal muscle performance has major implications for scientists, clinicians, and health professionals who are developing therapeutic interventions aiming to enhance muscle function and/or prevent mobility and physical limitations and, as such, support healthy ageing. PMID:29151281

A short-term statin treatment changes the contractile properties of fast-twitch skeletal muscles.

PubMed

Piette, Antoine Boulanger; Dufresne, Sébastien S; Frenette, Jérôme

2016-10-28

Cumulative evidence indicates that statins induce myotoxicity. However, the lack of understanding of how statins affect skeletal muscles at the structural, functional, and physiological levels hampers proper healthcare management. The purpose of the present study was to investigate the early after-effects of lovastatin on the slow-twitch soleus (Sol) and fast-twitch extensor digitorum longus (EDL) muscles. Adult C57BL/6 mice were orally administrated with placebo or lovastatin [50 mg/kg/d] for 28 days. At the end of the treatment, the isometric ex vivo contractile properties of the Sol and EDL muscles were measured. Subtetanic and tetanic contractions were assessed and contraction kinetics were recorded. The muscles were then frozen for immunohistochemical analyses. Data were analyzed by two-way ANOVA followed by an a posteriori Tukey's test. The short-term lovastatin treatment did not induce muscle mass loss, muscle fiber atrophy, or creatine kinase (CK) release. It had no functional impact on slow-twitch Sol muscles. However, subtetanic stimulations at 10 Hz provoked greater force production in fast-twitch EDL muscles. The treatment also decreased the maximal rate of force development (dP/dT) of twitch contractions and prolonged the half relaxation time (1/2RT) of tetanic contractions of EDL muscles. An early short-term statin treatment induced subtle but significant changes in some parameters of the contractile profile of EDL muscles, providing new insights into the selective initiation of statin-induced myopathy in fast-twitch muscles.

Possible role of TIEG1 as a feedback regulator of myostatin and TGF-{beta} in myoblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miyake, Masato; Hayashi, Shinichiro; Iwasaki, Shunsuke

2010-03-19

Myostatin and TGF-{beta} negatively regulate skeletal muscle development and growth. Both factors signal through the Smad2/3 pathway. However, the regulatory mechanism of myostatin and TGF-{beta} signaling remains unclear. TGF-{beta} inducible early gene (TIEG) 1 is highly expressed in skeletal muscle and has been implicated in the modulation of TGF-{beta} signaling. These findings prompted us to investigate the effect of TIEG1 on myostatin and TGF-{beta} signaling using C2C12 myoblasts. Myostatin and TGF-{beta} induced the expression of TIEG1 and Smad7 mRNAs, but not TIEG2 mRNA, in proliferating C2C12 cells. When differentiating C2C12 myoblasts were stimulated by myostatin, TIEG1 mRNA was up-regulated atmore » a late stage of differentiation. In contrast, TGF-{beta} enhanced TIEG1 expression at an early stage. Overexpression of TIEG1 prevented the transcriptional activation of Smad by myostatin and TGF-{beta} in both proliferating or differentiating C2C12 cells, but the expression of Smad2 and Smad7 mRNAs was not affected. Forced expression of TIEG1 inhibited myogenic differentiation but did not cause more inhibition than the empty vector in the presence of myostatin or TGF-{beta}. These results demonstrate that TIEG1 is one possible feedback regulator of myostatin and TGF-{beta} that prevents excess action in myoblasts.« less

Diagenetic comparisons between non-tropical Cenozoic limestones of New Zealand and tropical Mississippian limestones from Indiana, USA: Is the non-tropical model better than the tropical model?

NASA Astrophysics Data System (ADS)

Dodd, J. Robert; Nelson, Campbell S.

1998-10-01

Mississippian limestones exposed in Indiana, U.S.A., were deposited in a shallow tropical ocean. However, many properties of these limestones are more like those of modern and Cenozoic non-tropical limestones such as those found in New Zealand. The dominant skeletal grains in the Indiana limestones are calcitic echinoderms, bryozoans, and brachiopods. The dominant skeletal grains in most Cenozoic limestones of New Zealand are calcitic bryozoans, echinoderms, bivalve molluscs, and foraminifera. In contrast, modern and Cenozoic tropical limestones contain an abundance of aragonitic green algae, corals, and molluscs. Early in diagenesis the metastable aragonite dissolves and reprecipitates as calcite, causing early cementation of the sediments. Originally aragonitic fossils that have dissolved can be identified as molds that are commonly filled with secondary calcite. Because they contained little aragonite, most of the Indiana and New Zealand limestones did not have an abundant source of early cement. Except for local cases in which grains were cemented in contact with carbonate supersaturated seawater, grainstones were relatively deeply buried with little cement between the grains. This resulted in mechanical and chemical compaction of skeletal grains, producing a `fitted fabric' with greatly reduced pore space, either open or filled with cement between the grains. Cement in these aragonite-poor grainstones comes largely from pressure dissolution between grains and along stylolitic seams in the rock, features that are common only after burial beyond a few hundred meters. The final product of deeply buried (up to 2000 m) Cenozoic New Zealand grainstones is similar to the Mississippian grainstones of Indiana. In the Indiana limestones we have only the final product of this extensive burial diagenesis. However, the New Zealand sediments and rocks reveal all steps of formation of the final deeply buried limestone. The reason for the scarcity of originally aragonitic fossil grains in Paleozoic rocks worldwide is unknown. Organisms with aragonitic skeletons such as some molluscan groups and calcareous green algae were present, but seldom in much abundance. The aragonitic scleractinian corals had not yet evolved. Previous researchers have noted that non-skeletal precipitates such as ooids and cements have at times during the Paleozoic been predominantly aragonite and at other times calcite. They have attributed this difference to secular variation in seawater chemistry (icehouse vs. greenhouse seas). Abundance of aragonitic and calcitic skeletal grains does not follow this pattern.

Influence of performance on gene expression in skeletal muscle: effects of forced inactivity

NASA Technical Reports Server (NTRS)

Thomason, D. B.; Booth, F. W.

1989-01-01

Joint immobilization and hindlimb suspension are used to examine muscle protein expression and mRNA quantities in rats. A decrease in protein synthesis was not associated with alteration in alpha-actin mRNA, cytochrome c mRNA, or beta-myosin heavy chain mRNA early in treatment. Percentage declines after seven days are compared with early treatment quantities to determine acute and chronic response to muscular atrophy.

Pediatric Sports Medicine Injuries: Common Problems and Solutions.

PubMed

Huleatt, Joel B; Nissen, Carl W; Milewski, Matthew D

2018-04-01

The treatment of sports injuries in the skeletally immature has a unique set of complications. Growth deformity may occur after anterior cruciate ligament reconstruction; therefore, skeletal age is used to help guide the choice between physeal sparing and transphyseal techniques. Arthrofibrosis after tibial spine fracture fixation can be reduced by initiating immediate range of motion, and should be treated early and cautiously to avoid iatrogenic fracture. Nonunions of medial epicondyle elbow fractures are more common with nonoperative treatment, but seldom lead to clinical problems outside of certain athletes. Risks of OCD fixation are specific to the material of screw used. Copyright © 2017 Elsevier Inc. All rights reserved.

Different exercise modalities have distinct effects on the integrin-linked kinase (ILK) and Ca2+ signaling pathways in the male rat bone

PubMed Central

Sontam, Dharani M; Firth, Elwyn C; Tsai, Peter; Vickers, Mark H; O’Sullivan, Justin M

2015-01-01

Mechanical loading is essential to maintain optimal skeletal health. Despite the fact that early-life exercise has positive, long-lasting effects on the musculo-skeletal system, the response of the musculo-skeletal system to spontaneous low-impact exercise has been poorly studied. Previously, we identified subtle morphological changes in the femoral diaphysis of exercised animals compared to nonexercised controls. We hypothesized that significant changes in gene expression of cells should precede significant measurable phenotypic changes in the tissues of which they are part. Here, we employed RNA-Seq to analyse the transcriptome of the cortical bone from the femoral mid-diaphysis of prepubertal male Sprague-Dawley rats that were assigned to control (CON); bipedal stance (BPS); or wheel exercise (WEX) groups for 15 days. We identified 808 and 324 differentially expressed transcripts in the BPS and WEX animals respectively. While a number of transcripts change their levels in an exercise-specific manner, we identified 191 transcripts that were differentially expressed in both BPS and WEX. Importantly, we observed that the exercise mode had diametrically opposite effects on transcripts for multiple genes within the integrin-linked kinase (ILK) and Ca2+ signaling pathways such that they were up-regulated in BPS and down-regulated in WEX. The findings are important for our understanding of possible ways in which different exercise regimens might affect bone when normal activities apply mechanical stimuli during postnatal growth and development. PMID:26471755

Skeletal manifestations of hydatid disease in Serbia: demographic distribution, site involvement, radiological findings, and complications.

PubMed

Bracanovic, Djurdja; Djuric, Marija; Sopta, Jelena; Djonic, Danijela; Lujic, Nenad

2013-08-01

Although Serbia is recognized as an endemic country for echinococcosis, no information about precise incidence in humans has been available. The aim of this study was to investigate the skeletal manifestations of hydatid disease in Serbia. This retrospective study was conducted by reviewing the medical database of Institute for Pathology (Faculty of Medicine in Belgrade), a reference institution for bone pathology in Serbia. We reported a total of 41 patients with bone cystic echinococcosis (CE) during the study period. The mean age of 41 patients was 40.9±18.8 years. In 39% of patients, the fracture line was the only visible radiological sign, followed by cyst and tumefaction. The spine was the most commonly involved skeletal site (55.8%), followed by the femur (18.6%), pelvis (13.9%), humerus (7.0%), rib (2.3%), and tibia (2.3%). Pain was the symptom in 41.5% of patients, while some patients demonstrated complications such as paraplegia (22.0%), pathologic fracture (48.8%), and scoliosis (9.8%). The pathological fracture most frequently affected the spine (75.0%) followed by the femur (20.0%) and tibia (5.0%). However, 19.5% of patients didn't develop any complication or symptom. In this study, we showed that bone CE is not uncommon in Serbian population. As reported in the literature, therapy of bone CE is controversial and its results are poor. In order to improve the therapy outcome, early diagnosis, before symptoms and complications occur, can be contributive.

Skeletal Manifestations of Hydatid Disease in Serbia: Demographic Distribution, Site Involvement, Radiological Findings, and Complications

PubMed Central

Bracanovic, Djurdja; Sopta, Jelena; Djonic, Danijela; Lujic, Nenad

2013-01-01

Although Serbia is recognized as an endemic country for echinococcosis, no information about precise incidence in humans has been available. The aim of this study was to investigate the skeletal manifestations of hydatid disease in Serbia. This retrospective study was conducted by reviewing the medical database of Institute for Pathology (Faculty of Medicine in Belgrade), a reference institution for bone pathology in Serbia. We reported a total of 41 patients with bone cystic echinococcosis (CE) during the study period. The mean age of 41 patients was 40.9±18.8 years. In 39% of patients, the fracture line was the only visible radiological sign, followed by cyst and tumefaction. The spine was the most commonly involved skeletal site (55.8%), followed by the femur (18.6%), pelvis (13.9%), humerus (7.0%), rib (2.3%), and tibia (2.3%). Pain was the symptom in 41.5% of patients, while some patients demonstrated complications such as paraplegia (22.0%), pathologic fracture (48.8%), and scoliosis (9.8%). The pathological fracture most frequently affected the spine (75.0%) followed by the femur (20.0%) and tibia (5.0%). However, 19.5% of patients didn't develop any complication or symptom. In this study, we showed that bone CE is not uncommon in Serbian population. As reported in the literature, therapy of bone CE is controversial and its results are poor. In order to improve the therapy outcome, early diagnosis, before symptoms and complications occur, can be contributive. PMID:24039289

LINE-1 Mediated Insertion into Poc1a (Protein of Centriole 1 A) Causes Growth Insufficiency and Male Infertility in Mice

PubMed Central

Geister, Krista A.; Brinkmeier, Michelle L.; Cheung, Leonard Y.; Wendt, Jennifer; Oatley, Melissa J.; Burgess, Daniel L.; Kozloff, Kenneth M.; Cavalcoli, James D.; Oatley, Jon M.; Camper, Sally A.

2015-01-01

Skeletal dysplasias are a common, genetically heterogeneous cause of short stature that can result from disruptions in many cellular processes. We report the identification of the lesion responsible for skeletal dysplasia and male infertility in the spontaneous, recessive mouse mutant chagun. We determined that Poc1a, encoding protein of the centriole 1a, is disrupted by the insertion of a processed Cenpw cDNA, which is flanked by target site duplications, suggestive of a LINE-1 retrotransposon-mediated event. Mutant fibroblasts have impaired cilia formation and multipolar spindles. Male infertility is caused by defective spermatogenesis early in meiosis and progressive germ cell loss. Spermatogonial stem cell transplantation studies revealed that Poc1a is essential for normal function of both Sertoli cells and germ cells. The proliferative zone of the growth plate is small and disorganized because chondrocytes fail to re-align after cell division and undergo increased apoptosis. Poc1a and several other genes associated with centrosome function can affect the skeleton and lead to skeletal dysplasias and primordial dwarfisms. This mouse mutant reveals how centrosome dysfunction contributes to defects in skeletal growth and male infertility. PMID:26496357

Diagnostic strategies using myoglobin measurement in myocardial infarction.

PubMed

Plebani, M; Zaninotto, M

1998-04-06

Myoglobin, a low molecular-weight heme protein (17800 D) present in both cardiac and skeletal muscle, is an old test with new perspectives. Advantages and disadvantages of myoglobin determination are well known. Myoglobin is the earliest known, commercially available, biochemical marker of acute myocardial infarction (AMI) and its rapid kinetics make it an early, good marker of reperfusion. However, since myoglobin is present in both skeletal and cardiac muscle, any damage to these muscle types results in its release into blood. Serum myoglobin levels are falsely elevated in conditions unrelated to AMI as skeletal muscle and neuromuscular disorders, renal failure, intramuscular injection, strenuous exercise, and after several toxins and drugs intake. New strategies for myoglobin measurement may resolve this limitation. These strategies include both the combined measurement of myoglobin and a skeletal specific marker (carbonic anhydrase III) or a cardiac specific marker (troponin I), as well as the myoglobin evaluation on serial samples. In particular, the diagnostic algorithm based on the combined measurement of myoglobin and troponin I, assuring a satisfactory analytical turnaround time, significantly improves the diagnostic efficiency of laboratory assessment of suspected AMI patients, allowing the successive monitoring of coronary reperfusion.

LINE-1 Mediated Insertion into Poc1a (Protein of Centriole 1 A) Causes Growth Insufficiency and Male Infertility in Mice.

PubMed

Geister, Krista A; Brinkmeier, Michelle L; Cheung, Leonard Y; Wendt, Jennifer; Oatley, Melissa J; Burgess, Daniel L; Kozloff, Kenneth M; Cavalcoli, James D; Oatley, Jon M; Camper, Sally A

2015-10-01

Skeletal dysplasias are a common, genetically heterogeneous cause of short stature that can result from disruptions in many cellular processes. We report the identification of the lesion responsible for skeletal dysplasia and male infertility in the spontaneous, recessive mouse mutant chagun. We determined that Poc1a, encoding protein of the centriole 1a, is disrupted by the insertion of a processed Cenpw cDNA, which is flanked by target site duplications, suggestive of a LINE-1 retrotransposon-mediated event. Mutant fibroblasts have impaired cilia formation and multipolar spindles. Male infertility is caused by defective spermatogenesis early in meiosis and progressive germ cell loss. Spermatogonial stem cell transplantation studies revealed that Poc1a is essential for normal function of both Sertoli cells and germ cells. The proliferative zone of the growth plate is small and disorganized because chondrocytes fail to re-align after cell division and undergo increased apoptosis. Poc1a and several other genes associated with centrosome function can affect the skeleton and lead to skeletal dysplasias and primordial dwarfisms. This mouse mutant reveals how centrosome dysfunction contributes to defects in skeletal growth and male infertility.

Bone development in laboratory mammals used in developmental toxicity studies.

PubMed

DeSesso, John M; Scialli, Anthony R

2018-06-19

Evaluation of the skeleton in laboratory animals is a standard component of developmental toxicology testing. Standard methods of performing the evaluation have been established, and modification of the evaluation using imaging technologies is under development. The embryology of the rodent, rabbit, and primate skeleton has been characterized in detail and summarized herein. The rich literature on variations and malformations in skeletal development that can occur in the offspring of normal animals and animals exposed to test articles in toxicology studies is reviewed. These perturbations of skeletal development include ossification delays, alterations in number, shape, and size of ossification centers, and alterations in numbers of ribs and vertebrae. Because the skeleton is undergoing developmental changes at the time fetuses are evaluated in most study designs, transient delays in development can produce apparent findings of abnormal skeletal structure. The determination of whether a finding represents a permanent change in embryo development with adverse consequences for the organism is important in study interpretation. Knowledge of embryological processes and schedules can assist in interpretation of skeletal findings. © 2018 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.

Laminin and Matrix metalloproteinase 11 regulate Fibronectin levels in the zebrafish myotendinous junction.

PubMed

Jenkins, Molly H; Alrowaished, Sarah S; Goody, Michelle F; Crawford, Bryan D; Henry, Clarissa A

2016-01-01

Remodeling of the extracellular matrix (ECM) regulates cell adhesion as well as signaling between cells and their microenvironment. Despite the importance of tightly regulated ECM remodeling for normal muscle development and function, mechanisms underlying ECM remodeling in vivo remain elusive. One excellent paradigm in which to study ECM remodeling in vivo is morphogenesis of the myotendinous junction (MTJ) during zebrafish skeletal muscle development. During MTJ development, there are dramatic shifts in the primary components comprising the MTJ matrix. One such shift involves the replacement of Fibronectin (Fn)-rich matrix, which is essential for both somite and early muscle development, with laminin-rich matrix essential for normal function of the myotome. Here, we investigate the mechanism underlying this transition. We show that laminin polymerization indirectly promotes Fn downregulation at the MTJ, via a matrix metalloproteinase 11 (Mmp11)-dependent mechanism. Laminin deposition and organization is required for localization of Mmp11 to the MTJ, where Mmp11 is both necessary and sufficient for Fn downregulation in vivo. Furthermore, reduction of residual Mmp11 in laminin mutants promotes a Fn-rich MTJ that partially rescues skeletal muscle architecture. These results identify a mechanism for Fn downregulation at the MTJ, highlight crosstalk between laminin and Fn, and identify a new in vivo function for Mmp11. Taken together, our data demonstrate a novel signaling pathway mediating Fn downregulation. Our data revealing new regulatory mechanisms that guide ECM remodeling during morphogenesis in vivo may inform pathological conditions in which Fn is dysregulated.

Analysis of the causes of discrepancies in troponin I concentrations as measured by ARCHITECT High-Sensitive Troponin I ST and STACIA CLEIA cTnI.

PubMed

Kondo, Takashi; Kobayashi, Daisuke; Mochizuki, Maki; Asanuma, Kouichi; Takahashi, Satoshi

2017-01-01

Background Recently developed reagents for the highly sensitive measurement of cardiac troponin I are useful for early diagnosis of acute coronary syndrome. However, differences in measured values between these new reagents and previously used reagents have not been well studied. In this study, we aimed to compare the values between ARCHITECT High-Sensitive Troponin I ST (newly developed reagents), ARCHITECT Troponin I ST and STACIA CLEIA cardiac troponin I (two previously developed reagent kits). Methods Gel filtration high-performance liquid chromatography was used to analyse the causes of differences in measured values. Results The measured values differed between ARCHITECT High-Sensitive Troponin I ST and STACIA CLEIA cardiac troponin I reagents (r = 0.82). Cross-reactivity tests using plasma with added skeletal-muscle troponin I resulted in higher reactivity (2.17-3.03%) for the STACIA CLEIA cardiac troponin I reagents compared with that for the ARCHITECT High-Sensitive Troponin I ST reagents (less than 0.014%). In addition, analysis of three representative samples using gel filtration high-performance liquid chromatography revealed reagent-specific differences in the reactivity against each cardiac troponin I complex; this could explain the differences in values observed for some of the samples. Conclusion The newly developed ARCHITECT High-Sensitive Troponin I ST reagents were not affected by the presence of skeletal-muscle troponin I in the blood and may be useful for routine examinations.

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

PubMed Central

Maupin, Kevin A.; Droscha, Casey J.; Williams, Bart O.

2013-01-01

The Wnt signaling pathway plays key roles in differentiation and development and alterations in this signaling pathway are causally associated with numerous human diseases. While several laboratories were examining roles for Wnt signaling in skeletal development during the 1990s, interest in the pathway rose exponentially when three key papers were published in 2001–2002. One report found that loss of the Wnt co-receptor, Low-density lipoprotein related protein-5 (LRP5), was the underlying genetic cause of the syndrome Osteoporosis pseudoglioma (OPPG). OPPG is characterized by early-onset osteoporosis causing increased susceptibility to debilitating fractures. Shortly thereafter, two groups reported that individuals carrying a specific point mutation in LRP5 (G171V) develop high-bone mass. Subsequent to this, the causative mechanisms for these observations heightened the need to understand the mechanisms by which Wnt signaling controlled bone development and homeostasis and encouraged significant investment from biotechnology and pharmaceutical companies to develop methods to activate Wnt signaling to increase bone mass to treat osteoporosis and other bone disease. In this review, we will briefly summarize the cellular mechanisms underlying Wnt signaling and discuss the observations related to OPPG and the high-bone mass disorders that heightened the appreciation of the role of Wnt signaling in normal bone development and homeostasis. We will then present a comprehensive overview of the core components of the pathway with an emphasis on the phenotypes associated with mice carrying genetically engineered mutations in these genes and clinical observations that further link alterations in the pathway to changes in human bone. PMID:26273492

Development and external validation of nomograms to predict the risk of skeletal metastasis at the time of diagnosis and skeletal metastasis-free survival in nasopharyngeal carcinoma.

PubMed

Yang, Lin; Xia, Liangping; Wang, Yan; He, Shasha; Chen, Haiyang; Liang, Shaobo; Peng, Peijian; Hong, Shaodong; Chen, Yong

2017-09-06

The skeletal system is the most common site of distant metastasis in nasopharyngeal carcinoma (NPC); various prognostic factors have been reported for skeletal metastasis, though most studies have focused on a single factor. We aimed to establish nomograms to effectively predict skeletal metastasis at initial diagnosis (SMAD) and skeletal metastasis-free survival (SMFS) in NPC. A total of 2685 patients with NPC who received bone scintigraphy (BS) and/or 18F-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and 2496 patients without skeletal metastasis were retrospectively assessed to develop individual nomograms for SMAD and SMFS. The models were validated externally using separate cohorts of 1329 and 1231 patients treated at two other institutions. Five independent prognostic factors were included in each nomogram. The SMAD nomogram had a significantly higher c-index than the TNM staging system (training cohort, P = 0.005; validation cohort, P < 0.001). The SMFS nomogram had significantly higher c-index values in the training and validation sets than the TNM staging system (P < 0.001 and P = 0.005, respectively). Three proposed risk stratification groups were created using the nomograms, and enabled significant discrimination of SMFS for each risk group. The prognostic nomograms established in this study enable accurate stratification of distinct risk groups for skeletal metastasis, which may improve counseling and facilitate individualized management of patients with NPC.

Biomimetic Scaffolds for Regeneration of Volumetric Muscle Loss in Skeletal Muscle Injuries

PubMed Central

Grasman, Jonathan M.; Zayas, Michelle J.; Page, Ray; Pins, George D.

2015-01-01

Skeletal muscle injuries typically result from traumatic incidents such as combat injuries where soft-tissue extremity injuries are present in one of four cases. Further, about 4.5 million reconstructive surgical procedures are performed annually as a result of car accidents, cancer ablation, or cosmetic procedures. These combat- and trauma-induced skeletal muscle injuries are characterized by volumetric muscle loss (VML), which significantly reduces the functionality of the injured muscle. While skeletal muscle has an innate repair mechanism, it is unable to compensate for VML injuries because large amounts of tissue including connective tissue and basement membrane are removed or destroyed. This results in in a significant need to develop off-the-shelf biomimetic scaffolds to direct skeletal muscle regeneration. Here, the structure and organization of native skeletal muscle tissue is described in order to reveal clear design parameters that are necessary for scaffolds to mimic in order to successfully regenerate muscular tissue. We review the literature with respect to the materials and methodologies used to develop scaffolds for skeletal muscle tissue regeneration as well as the limitations of these materials. We further discuss the variety of cell sources and different injury models to provide some context for the multiple approaches used to evaluate these scaffold materials. Recent findings are highlighted to address the state of the field and directions are outlined for future strategies, both in scaffold design and in the use of different injury models to evaluate these materials, for regenerating functional skeletal muscle. PMID:26219862

Evidence of fatal skeletal injuries on Malapa Hominins 1 and 2

PubMed Central

L’Abbé, Ericka N.; Symes, Steven A.; Pokines, James T.; Cabo, Luis L.; Stull, Kyra E.; Kuo, Sharon; Raymond, David E.; Randolph-Quinney, Patrick S.; Berger, Lee R.

2015-01-01

Malapa is one of the richest early hominin sites in Africa and the discovery site of the hominin species, Australopithecus sediba. The holotype and paratype (Malapa Hominin 1 and 2, or MH1 and MH2, respectively) skeletons are among the most complete in the early hominin record. Dating to approximately two million years BP, MH1 and MH2 are hypothesized to have fallen into a natural pit trap. All fractures evident on MH1 and MH2 skeletons were evaluated and separated based on wet and dry bone fracture morphology/characteristics. Most observed fractures are post-depositional, but those in the right upper limb of the adult hominin strongly indicate active resistance to an impact, while those in the juvenile hominin mandible are consistent with a blow to the face. The presence of skeletal trauma independently supports the falling hypothesis and supplies the first evidence for the manner of death of an australopith in the fossil record that is not attributed to predation or natural death. PMID:26459912

Tumor Necrosis Factor Alpha and Insulin-Like Growth Factor 1 Induced Modifications of the Gene Expression Kinetics of Differentiating Skeletal Muscle Cells

PubMed Central

Meyer, Swanhild U.; Krebs, Stefan; Thirion, Christian; Blum, Helmut; Krause, Sabine; Pfaffl, Michael W.

2015-01-01

Introduction TNF-α levels are increased during muscle wasting and chronic muscle degeneration and regeneration processes, which are characteristic for primary muscle disorders. Pathologically increased TNF-α levels have a negative effect on muscle cell differentiation efficiency, while IGF1 can have a positive effect; therefore, we intended to elucidate the impact of TNF-α and IGF1 on gene expression during the early stages of skeletal muscle cell differentiation. Methodology/Principal Findings This study presents gene expression data of the murine skeletal muscle cells PMI28 during myogenic differentiation or differentiation with TNF-α or IGF1 exposure at 0 h, 4 h, 12 h, 24 h, and 72 h after induction. Our study detected significant coregulation of gene sets involved in myoblast differentiation or in the response to TNF-α. Gene expression data revealed a time- and treatment-dependent regulation of signaling pathways, which are prominent in myogenic differentiation. We identified enrichment of pathways, which have not been specifically linked to myoblast differentiation such as doublecortin-like kinase pathway associations as well as enrichment of specific semaphorin isoforms. Moreover to the best of our knowledge, this is the first description of a specific inverse regulation of the following genes in myoblast differentiation and response to TNF-α: Aknad1, Cmbl, Sepp1, Ndst4, Tecrl, Unc13c, Spats2l, Lix1, Csdc2, Cpa1, Parm1, Serpinb2, Aspn, Fibin, Slc40a1, Nrk, and Mybpc1. We identified a gene subset (Nfkbia, Nfkb2, Mmp9, Mef2c, Gpx, and Pgam2), which is robustly regulated by TNF-α across independent myogenic differentiation studies. Conclusions This is the largest dataset revealing the impact of TNF-α or IGF1 treatment on gene expression kinetics of early in vitro skeletal myoblast differentiation. We identified novel mRNAs, which have not yet been associated with skeletal muscle differentiation or response to TNF-α. Results of this study may facilitate the understanding of transcriptomic networks underlying inhibited muscle differentiation in inflammatory diseases. PMID:26447881

An FGF-driven feed-forward circuit patterns the cardiopharyngeal mesoderm in space and time

PubMed Central

Razy-Krajka, Florian; Gravez, Basile; Kaplan, Nicole; Racioppi, Claudia; Wang, Wei

2018-01-01

In embryos, multipotent progenitors divide to produce distinct progeny and express their full potential. In vertebrates, multipotent cardiopharyngeal progenitors produce second-heart-field-derived cardiomyocytes, and branchiomeric skeletal head muscles. However, the mechanisms underlying these early fate choices remain largely elusive. The tunicate Ciona emerged as an attractive model to study early cardiopharyngeal development at high resolution: through two asymmetric and oriented divisions, defined cardiopharyngeal progenitors produce distinct first and second heart precursors, and pharyngeal muscle (aka atrial siphon muscle, ASM) precursors. Here, we demonstrate that differential FGF-MAPK signaling distinguishes between heart and ASM precursors. We characterize a feed-forward circuit that promotes the successive activations of essential ASM determinants, Hand-related, Tbx1/10 and Ebf. Finally, we show that coupling FGF-MAPK restriction and cardiopharyngeal network deployment with cell divisions defines the timing of gene expression and permits the emergence of diverse cell types from multipotent progenitors. PMID:29431097

Conditional inactivation of Has2 reveals a crucial role for hyaluronan in skeletal growth, patterning, chondrocyte maturation and joint formation in the developing limb.

PubMed

Matsumoto, Kazu; Li, Yingcui; Jakuba, Caroline; Sugiyama, Yoshinori; Sayo, Tetsuya; Okuno, Misako; Dealy, Caroline N; Toole, Bryan P; Takeda, Junji; Yamaguchi, Yu; Kosher, Robert A

2009-08-01

The glycosaminoglycan hyaluronan (HA) is a structural component of extracellular matrices and also interacts with cell surface receptors to directly influence cell behavior. To explore functions of HA in limb skeletal development, we conditionally inactivated the gene for HA synthase 2, Has2, in limb bud mesoderm using mice that harbor a floxed allele of Has2 and mice carrying a limb mesoderm-specific Prx1-Cre transgene. The skeletal elements of Has2-deficient limbs are severely shortened, indicating that HA is essential for normal longitudinal growth of all limb skeletal elements. Proximal phalanges are duplicated in Has2 mutant limbs indicating an involvement of HA in patterning specific portions of the digits. The growth plates of Has2-deficient skeletal elements are severely abnormal and disorganized, with a decrease in the deposition of aggrecan in the matrix and a disruption in normal columnar cellular relationships. Furthermore, there is a striking reduction in the number of hypertrophic chondrocytes and in the expression domains of markers of hypertrophic differentiation in the mutant growth plates, indicating that HA is necessary for the normal progression of chondrocyte maturation. In addition, secondary ossification centers do not form in the central regions of Has2 mutant growth plates owing to a failure of hypertrophic differentiation. In addition to skeletal defects, the formation of synovial joint cavities is defective in Has2-deficient limbs. Taken together, our results demonstrate that HA has a crucial role in skeletal growth, patterning, chondrocyte maturation and synovial joint formation in the developing limb.

[Skeletal Mass Depletion Is a Negative Prognostic Factor in Gastrointestinal Cancer Patients in the Terminal Stage].

PubMed

Takahashi, Goro; Yamada, Takeshi; Kan, Hayato; Koizumi, Michihiro; Shinji, Seiichi; Yokoyama, Yasuyuki; Iwai, Takuma; Uchida, Eiji

2015-10-01

Skeletal mass depletion has been reported to be a prognostic factor for cancer patients. However, special and expensive devices are required to measure skeletal mass, and this is a major reason why skeletal mass is not used extensively for prognostic marker in clinical settings. We developed a new method to measure skeletal mass for use as a prognostic marker using CT images without special and expensive devices. In this study, we evaluated the usefulness of skeletal mass as measured by this new method as a prognostic marker for gastrointestinal cancer patients. Patients who died from gastrointestinal cancer between March 2010 and October 2013 were included. We measured the right-sided maximum psoas muscle cross sectional area (MPCA) by using CT images before surgery and after the patients developed a terminal condition. The maximum psoas muscle cross sectional area ratio (MPCA-R) was defined as follows: MPCA-R=MPCA before surgery/MPCA after developing a terminal condition. We evaluated the correlation between MPCA-R and survival. Fifty-nine patients were included. The median survival was 44 days, and MPCA-R was significantly correlated with survival (p=0.001). On receiver operating characteristic (ROC) analysis, the area under the curve (AUC) to predict 30-day and 90-day survival was 0.710 and 0.748, respectively. MPCA-R is a new and novel prognostic marker for gastrointestinal cancer patients in terminal condition.

Runx2 is required for early stages of endochondral bone formation but delays final stages of bone repair in Axin2-deficient mice

PubMed Central

McGee-Lawrence, Meghan E.; Carpio, Lomeli R.; Bradley, Elizabeth W.; Dudakovic, Amel; Lian, Jane B.; van Wijnen, Andre J.; Kakar, Sanjeev; Hsu, Wei; Westendorf, Jennifer J.

2014-01-01

Runx2 and Axin2 regulate skeletal development. We recently determined that Axin2 and Runx2 molecularly interact in differentiating osteoblasts to regulate intramembranous bone formation, but the relationship between these factors in endochondral bone formation was unresolved. To address this, we examined the effects of Axin2 deficiency on the cleidocranial dysplasia (CCD) phenotype of Runx2+/− mice, focusing on skeletal defects attributed to improper endochondral bone formation. Axin2 deficiency unexpectedly exacerbated calvarial components of the CCD phenotype in the Runx2+/− mice; the endocranial layer of the frontal suture, which develops by endochondral bone formation, failed to mineralize in the Axin2−/−:Runx2+/− mice, resulting in a cartilaginous, fibrotic and larger fontanel than observed in Runx2+/− mice. Transcripts associated with cartilage development (e.g., Acan, miR140) were expressed at higher levels, whereas blood vessel morphogenesis transcripts (e.g., Slit2) were suppressed in Axin2−/−:Runx2+/− calvaria. Cartilage maturation was impaired, as primary chondrocytes from double mutant mice demonstrated delayed differentiation and produced less calcified matrix in vitro. The genetic dominance of Runx2 was also reflected during endochondral fracture repair, as both Runx2+/− and double mutant Axin2−/−:Runx2+/− mice had enlarged fracture calluses at early stages of healing. However, by the end stages of fracture healing, double mutant animals diverged from the Runx2+/− mice, showing smaller calluses and increased torsional strength indicative of more rapid end stage bone formation as seen in the Axin2−/− mice. Taken together, our data demonstrate a dominant role for Runx2 in chondrocyte maturation, but implicate Axin2 as an important modulator of the terminal stages of endochondral bone formation. PMID:24973690

Development of a Novel Synthetic Drug for Osteoporosis and Fracture Healing

DTIC Science & Technology

2012-09-01

application to chondrosarcoma , and preparation for bone fracture study. Body Aim 1: Development of salubrinal formulations and determination of...development of bone marrow derived cells, osteoclasts, osteoblasts, and chondrocytes. Application to chondrosarcoma : Besides osteoporosis and...osteoarthritis, we considered a potential application of salubrinal to skeletal malignancies. Approximately one-third of skeletal cancers form chondrosarcoma

Skeletal muscle performance and ageing.

PubMed

Tieland, Michael; Trouwborst, Inez; Clark, Brian C

2018-02-01

The world population is ageing rapidly. As society ages, the incidence of physical limitations is dramatically increasing, which reduces the quality of life and increases healthcare expenditures. In western society, ~30% of the population over 55 years is confronted with moderate or severe physical limitations. These physical limitations increase the risk of falls, institutionalization, co-morbidity, and premature death. An important cause of physical limitations is the age-related loss of skeletal muscle mass, also referred to as sarcopenia. Emerging evidence, however, clearly shows that the decline in skeletal muscle mass is not the sole contributor to the decline in physical performance. For instance, the loss of muscle strength is also a strong contributor to reduced physical performance in the elderly. In addition, there is ample data to suggest that motor coordination, excitation-contraction coupling, skeletal integrity, and other factors related to the nervous, muscular, and skeletal systems are critically important for physical performance in the elderly. To better understand the loss of skeletal muscle performance with ageing, we aim to provide a broad overview on the underlying mechanisms associated with elderly skeletal muscle performance. We start with a system level discussion and continue with a discussion on the influence of lifestyle, biological, and psychosocial factors on elderly skeletal muscle performance. Developing a broad understanding of the many factors affecting elderly skeletal muscle performance has major implications for scientists, clinicians, and health professionals who are developing therapeutic interventions aiming to enhance muscle function and/or prevent mobility and physical limitations and, as such, support healthy ageing. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Space travel directly induces skeletal muscle atrophy

NASA Technical Reports Server (NTRS)

Vandenburgh, H.; Chromiak, J.; Shansky, J.; Del Tatto, M.; Lemaire, J.

1999-01-01

Space travel causes rapid and pronounced skeletal muscle wasting in humans that reduces their long-term flight capabilities. To develop effective countermeasures, the basis of this atrophy needs to be better understood. Space travel may cause muscle atrophy indirectly by altering circulating levels of factors such as growth hormone, glucocorticoids, and anabolic steroids and/or by a direct effect on the muscle fibers themselves. To determine whether skeletal muscle cells are directly affected by space travel, tissue-cultured avian skeletal muscle cells were tissue engineered into bioartificial muscles and flown in perfusion bioreactors for 9 to 10 days aboard the Space Transportation System (STS, i.e., Space Shuttle). Significant muscle fiber atrophy occurred due to a decrease in protein synthesis rates without alterations in protein degradation. Return of the muscle cells to Earth stimulated protein synthesis rates of both muscle-specific and extracellular matrix proteins relative to ground controls. These results show for the first time that skeletal muscle fibers are directly responsive to space travel and should be a target for countermeasure development.

Bone and Skeletal Muscle: Key Players in Mechanotransduction and Potential Overlapping Mechanisms

PubMed Central

Goodman, Craig A.; Hornberger, Troy A.; Robling, Alexander G.

2015-01-01

The development and maintenance of skeletal muscle and bone mass is critical for movement, health and issues associated with the quality of life. Skeletal muscle and bone mass are regulated by a variety of factors that include changes in mechanical loading. Moreover, bone mass is, in large part, regulated by muscle-derived mechanical forces and thus by changes in muscle mass/strength. A thorough understanding of the cellular mechanism(s) responsible for mechanotransduction in bone and skeletal muscle is essential for the development of effective exercise and pharmaceutical strategies aimed at increasing, and/or preventing the loss of, mass in these tissues. Thus, in this review we will attempt to summarize the current evidence for the major molecular mechanisms involved in mechanotransduction in skeletal muscle and bone. By examining the differences and similarities in mechanotransduction between these two tissues, it is hoped that this review will stimulate new insights and ideas for future research and promote collaboration between bone and muscle biologists. PMID:26453495

Dietary supplementation with vitamin k affects transcriptome and proteome of Senegalese sole, improving larval performance and quality.

PubMed

Richard, Nadège; Fernández, Ignacio; Wulff, Tune; Hamre, Kristin; Cancela, Leonor; Conceição, Luis E C; Gavaia, Paulo J

2014-10-01

Nutritional factors strongly influence fish larval development and skeletogenesis, and may induce skeletal deformities. Vitamin K (VK) has been largely disregarded in aquaculture nutrition, despite its important roles in bone metabolism, in γ-carboxylation of Gla proteins, and in regulating gene expression through the pregnane X receptor (Pxr). Since the mechanisms mediating VK effects over skeletal development are poorly known, we investigated the effects of VK-supplementation on skeletal development in Senegalese sole larvae, aiming to identify molecular pathways involved. Larvae were fed live preys enriched with graded levels of phylloquinone (PK) (0, 50, and 250 mg kg(-1)) and survival rate, growth, VK contents, calcium content and incidence of skeletal deformities were determined, revealing an improvement of larval performance and decreasing the incidence of deformities in VK-supplemented groups. Comparative proteome analysis revealed a number of differentially expressed proteins between Control and Diet 250 associated with key biological processes including skin, muscle, and bone development. Expression analysis showed that genes encoding proteins related to the VK cycle (ggcx, vkor), VK nuclear receptor (pxr), and VK-dependent proteins (VKDPs; oc1 and grp), were differentially expressed. This study highlights the potential benefits of increasing dietary VK levels in larval diets, and brings new insights on the mechanisms mediating the positive effects observed on larval performance and skeletal development.

Integrative Analysis of Porcine microRNAome during Skeletal Muscle Development

PubMed Central

Qin, Lijun; Chen, Yaosheng; Liu, Xiaohong; Ye, Sanxing; Yu, Kaifan; Huang, Zheng; Yu, Jingwei; Zhou, Xingyu; Chen, Hu; Mo, Delin

2013-01-01

Pig is an important agricultural animal for meat production and provides a valuable model for many human diseases. Functional studies have demonstrated that microRNAs (miRNAs) play critical roles in almost all aspects of skeletal muscle development and disease pathogenesis. To investigate the miRNAs involved in regulating different periods of skeletal muscle development, we herein performed a comprehensive research for porcine microRNAome (miRNAome) during 10 skeletal muscle developmental stages including 35, 49, 63, 77, 91 dpc (days post coitum) and 2, 28, 90, 120, 180 dpn (days postnatal) using Solexa sequencing technology. Our results extend the repertoire of pig miRNAome to 247 known miRNAs processed from 210 pre-miRNAs and 297 candidate novel miRNAs through comparison with known miRNAs in the miRBase. Expression analysis of the 15 most abundant miRNAs in every library indicated that functional miRNAome may be smaller and tend to be highly expressed. A series of muscle-related miRNAs summarized in our study present different patterns between myofibers formation phase and muscle maturation phase, providing valuable reference for investigation of functional miRNAs during skeletal muscle development. Analysis of temporal profiles of miRNA expression identifies 18 novel candidate myogenic miRNAs in pig, which might provide new insight into regulation mechanism mediated by miRNAs underlying muscle development. PMID:24039761

Deciphering skeletal patterning: clues from the limb.

PubMed

Mariani, Francesca V; Martin, Gail R

2003-05-15

Even young children can distinguish a Tyrannosaurus rex from a Brontosaurus by observing differences in bone size, shape, number and arrangement, that is, skeletal pattern. But despite our extensive knowledge about cartilage and bone formation per se, it is still largely a mystery how skeletal pattern is established. Much of what we do know has been learned from studying limb development in chicken and mouse embryos. Based on the data from such studies, models for how limb skeletal pattern is established have been proposed and continue to be hotly debated.

Shades of Gray: Skeletal Analysis and the Repatriation Process

ERIC Educational Resources Information Center

Mayes, Arion T.

2010-01-01

Negotiations over archaeological human remains have been complicated interactions spanning centuries of attempts to resolve differences of opinion with regard to the investigation, ownership, and disposition of early American Indian burials. Guilt, fear, power, politics, legitimacy, science, religion, and denial--all of these elements commonly…

Synergistic effects of TGFβ2, WNT9a, and FGFR4 signals attenuate satellite cell differentiation during skeletal muscle development.

PubMed

Zhang, Weiya; Xu, Yueyuan; Zhang, Lu; Wang, Sheng; Yin, Binxu; Zhao, Shuhong; Li, Xinyun

2018-06-04

Satellite cells play a key role in the aging, generation, and damage repair of skeletal muscle. The molecular mechanism of satellite cells in these processes remains largely unknown. This study systematically investigated for the first time the characteristics of mouse satellite cells at ten different ages. Results indicated that the number and differentiation capacity of satellite cells decreased with age during skeletal muscle development. Transcriptome analysis revealed that 2,907 genes were differentially expressed at six time points at postnatal stage. WGCNA and GO analysis indicated that 1,739 of the 2,907 DEGs were mainly involved in skeletal muscle development processes. Moreover, the results of WGCNA and protein interaction analysis demonstrated that Tgfβ2, Wnt9a, and Fgfr4 were the key genes responsible for the differentiation of satellite cells. Functional analysis showed that TGFβ2 and WNT9a inhibited, whereas FGFR4 promoted the differentiation of satellite cells. Furthermore, each two of them had a regulatory relationship at the protein level. In vivo study also confirmed that TGFβ2 could regulate the regeneration of skeletal muscle, as well as the expression of WNT9a and FGFR4. Therefore, we concluded that the synergistic effects of TGFβ2, WNT9a, and FGFR4 were responsible for attenuating of the differentiation of aging satellite cells during skeletal muscle development. This study provided new insights into the molecular mechanism of satellite cell development. The target genes and signaling pathways investigated in this study would be useful for improving the muscle growth of livestock or treating muscle diseases in clinical settings. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

[Regulatory mechanism for lncRNAs in skeletal muscle development and progress on its research in domestic animals].

PubMed

Zhou, Rui; Wang, Yi Xin; Long, Ke Ren; Jiang, An An; Jin, Long

2018-04-20

Skeletal muscle is an essential tissue to maintain the normal functions of an organism. It is also closely associated with important economic performance, such as carcass weight, of domestic animals. In recent years, studies using high-throughput sequencing techniques have identified numerous long non-coding RNAs (lncRNAs) with myogenic functions involved in regulation of gene expression at multiple levels, including epigenetic, transcriptional and post-transcriptional regulation. These lncRNAs target myogenic factors, which participate in all processes of skeletal muscle development, including proliferation, migration and differentiation of skeletal muscle stem cells, proliferation, differentiation and fusion of myocytes, muscle hypertrophy and conversion of muscle fiber types. In this review, we summarize the functional roles of lncRNAs in regulation of myogenesis in humans and mice, describe the methods for the analysis of lncRNA function, discuss the progress of lncRNA research in domestic animals, and highlight the current problems and challenges in lncRNA research on livestock production. We hope to provide a useful reference for research on lncRNA in domestic animals, thereby further identifying the molecular regulatory mechanisms in skeletal muscle growth and development.

Development of Bone Targeting Drugs.

PubMed

Stapleton, Molly; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J; Mackenzie, William G; Mason, Robert W; Orii, Tadao; Tomatsu, Shunji

2017-06-23

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca 2+ . The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments.

Development of Bone Targeting Drugs

PubMed Central

Stapleton, Molly; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J.; Mackenzie, William G.; Mason, Robert W.; Orii, Tadao; Tomatsu, Shunji

2017-01-01

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca2+. The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments. PMID:28644392

Maturity aggravates sepsis-associated skeletal muscle catabolism in growing pigs

USDA-ARS?s Scientific Manuscript database

Synthesis and accretion of muscle protein is elevated in neonates and decreases with development. During sepsis, muscle protein synthesis is reduced, but the effect of development on the metabolic response to sepsis in skeletal muscle is not well understood. Fasted 7- and 26-d-old pigs were infused ...

EFFECTS OF HYPERTHERMIA AND BORIC ACID ON SKELETAL DEVELOPMENT IN RAT EMBRYOS

EPA Science Inventory

BACKGROUND: The individual effects of boric acid (BA) and hyperthermia on the development of the axial skeleton have previously been reported. Both cause an increased incidence of axial skeletal defects including a decrease in the total number of ribs and vertebrae. Because of th...

Transient gestational and neonatal hypothyroidism-induced specific changes in androgen receptor expression in skeletal and cardiac muscles of adult rat.

PubMed

Annapoorna, K; Anbalagan, J; Neelamohan, R; Vengatesh, G; Stanley, J; Amudha, G; Aruldhas, M M

2013-03-01

The present study aims to identify the association between androgen status and metabolic activity in skeletal and cardiac muscles of adult rats with transient gestational/neonatal-onset hypothyroidism. Pregnant and lactating rats were made hypothyroid by exposing to 0.05% methimazole in drinking water; gestational exposure was from embryonic day 9-14 (group II) or 21 (group III), lactational exposure was from postnatal day 1-14 (group IV) or 29 (group V). Serum was collected for hormone assay. Androgen receptor status, Glu-4 expression, and enzyme activities were assessed in the skeletal and cardiac muscles. Serum testosterone and estradiol levels decreased in adult rats of groups II and III, whereas testosterone remained normal but estradiol increased in group IV and V, when compared to coeval control. Androgen receptor ligand binding activity increased in both muscle phenotypes with a consistent increase in the expression level of its mRNA and protein expressions except in the forelimb of adult rats with transient hypothyroidism (group II-V). Glut-4 expression remained normal in skeletal and cardiac muscle of experimental rats. Specific activity of hexokinase and lactate dehydrogenase increased in both muscle phenotypes whereas, creatine kinase activity increased in skeletal muscles alone. It is concluded that transient gestational/lactational exposure to methimazole results in hypothyroidism during prepuberal life whereas it increases AR status and glycolytic activity in skeletal and cardiac muscles even at adulthood. Thus, the present study suggests that euthyroid status during prenatal and early postnatal life is essential to have optimal AR status and metabolic activity at adulthood. © Georg Thieme Verlag KG Stuttgart · New York.

Mitochondrial and performance adaptations to exercise training in mice lacking skeletal muscle LKB1

PubMed Central

Tanner, Colby B.; Madsen, Steven R.; Hallowell, David M.; Goring, Darren M. J.; Moore, Timothy M.; Hardman, Shalene E.; Heninger, Megan R.; Atwood, Daniel R.

2013-01-01

LKB1 and its downstream targets of the AMP-activated protein kinase family are important regulators of many aspects of skeletal muscle cell function, including control of mitochondrial content and capillarity. LKB1 deficiency in skeletal and cardiac muscle (mLKB1-KO) greatly impairs exercise capacity. However, cardiac dysfunction in that genetic model prevents a clear assessment of the role of skeletal muscle LKB1 in the observed effects. Our purposes here were to determine whether skeletal muscle-specific knockout of LKB1 (skmLKB1-KO) decreases exercise capacity and mitochondrial protein content, impairs accretion of mitochondrial proteins after exercise training, and attenuates improvement in running performance after exercise training. We found that treadmill and voluntary wheel running capacity was reduced in skmLKB1-KO vs. control (CON) mice. Citrate synthase activity, succinate dehydrogenase activity, and pyruvate dehydrogenase kinase content were lower in KO vs. CON muscles. Three weeks of treadmill training resulted in significantly increased treadmill running performance in both CON and skmLKB1-KO mice. Citrate synthase activity increased significantly with training in both genotypes, but protein content and activity for components of the mitochondrial electron transport chain increased only in CON mice. Capillarity and VEGF protein was lower in skmLKB1-KO vs. CON muscles, but VEGF increased with training only in skmLKB1-KO. Three hours after an acute bout of muscle contractions, PGC-1α, cytochrome c, and VEGF gene expression all increased in CON but not skmLKB1-KO muscles. Our findings indicate that skeletal muscle LKB1 is required for accretion of some mitochondrial proteins but not for early exercise capacity improvements with exercise training. PMID:23982155

Effect of experimental hyperthyroidism on protein turnover in skeletal and cardiac muscle.

PubMed

Carter, W J; Van Der Weijden Benjamin, W S; Faas, F H

1980-10-01

Since experimental hyperthyroidism reduces skeletal muscle mass while simultaneously increasing cardiac muscle mass, the effect of hyperthyroidism on muscle protein degradation was compared in skeletal and cardiac muscle. Pulse-labeling studies using (3H) leucine and (14C) carboxyl labeled aspartate and glutamate were carried out. Hyperthyroidism caused a 25%-29% increase in protein breakdown in both sarcoplasmic and myofibrillar fractions of skeletal muscle. Increased muscle protein degradation may be a major factor in the development of skeletal muscle wasting and weakness in hyperthyroidism. In contrast, protein breakdown appeared to be reduced 22% in the sarcoplasmic fraction of hyperthyroid heart muscle and was unchanged in the myofibrillar fraction. Possible reasons for the contrasting effects of hyperthyroidism on skeletal and cardiac muscle include increased sensitivity of the hyperthyroid heart to catecholamines, increased cardiac work caused by the hemodynamic effects of hyperthyroidism, and a different direct effect of thyroid hormone at the nuclear level in cardiac as opposed to skeletal muscle.

Aberrant and alternative splicing in skeletal system disease.

PubMed

Fan, Xin; Tang, Liling

2013-10-01

The main function of skeletal system is to support the body and help movement. A variety of factors can lead to skeletal system disease, including age, exercise, and of course genetic makeup and expression. Pre-mRNA splicing plays a crucial role in gene expression, by creating multiple protein variants with different biological functions. The recent studies show that several skeletal system diseases are related to pre-mRNA splicing. This review focuses on the relationship between pre-mRNA splicing and skeletal system disease. On the one hand, splice site mutation that leads to aberrant splicing often causes genetic skeletal system disease, like COL1A1, SEDL and LRP5. On the other hand, alternative splicing without genomic mutation may generate some marker protein isoforms, for example, FN, VEGF and CD44. Therefore, understanding the relationship between pre-mRNA splicing and skeletal system disease will aid in uncovering the mechanism of disease and contribute to the future development of gene therapy. © 2013 Elsevier B.V. All rights reserved.

Bone scan in metabolic bone diseases. Review.

PubMed

Abdelrazek, Saeid; Szumowski, Piotr; Rogowski, Franciszek; Kociura-Sawicka, Agnieszka; Mojsak, Małgorzata; Szorc, Małgorzata

2012-08-25

Metabolic bone disease encompasses a number of disorders that tend to present a generalized involvement of the whole skeleton. The disorders are mostly related to increased bone turnover and increased uptake of radiolabelled diphosphonate. Skeletal uptake of 99mTc-labelled diphosphonate depends primarily upon osteoblastic activity, and to a lesser extent, skeletal vascularity. A bone scan image therefore presents a functional display of total skeletal metabolism and has valuable role to play in the assessment of patients with metabolic bone disorders. However, the bone scan appearances in metabolic bone disease are often non-specific, and their recognition depends on increased tracer uptake throughout the whole skeleton. It is the presence of local lesions, as in metastatic disease, that makes a bone scan appearance obviously abnormal. In the early stages, there will be difficulty in evaluating the bone scans from many patients with metabolic bone disease. However, in the more severe cases scan appearances can be quite striking and virtually diagnostic.

A Zebrafish Embryo Culture System Defines Factors that Promote Vertebrate Myogenesis across Species

PubMed Central

Ciarlo, Christie; Liu, Jingxia; Castiglioni, Alessandra; Price, Emily; Liu, Min; Barton, Elisabeth R.; Kahn, C. Ronald; Wagers, Amy J.; Zon, Leonard I.

2013-01-01

SUMMARY Ex vivo expansion of satellite cells and directed differentiation of pluripotent cells to mature skeletal muscle have proved difficult challenges for regenerative biology. Using a zebrafish embryo culture system with reporters of early and late skeletal muscle differentiation, we examined the influence of 2,400 chemicals on myogenesis and identified six that expanded muscle progenitors, including three GSK3β inhibitors, two calpain inhibitors and one adenylyl cyclase activator, forskolin. Forskolin also enhanced proliferation of mouse satellite cells in culture and maintained their ability to engraft muscle in vivo. A combination of bFGF, forskolin and the GSK3β inhibitor BIO induced skeletal muscle differentiation in human induced pluripotent stem cells (iPSCs) and produced engraftable myogenic progenitors that contributed to muscle repair in vivo. In summary, these studies reveal functionally conserved pathways regulating myogenesis across species and identify chemical compounds that expand mouse satellite cells and differentiate human iPSCs into engraftable muscle. PMID:24209627

Bone age in children with obstetrical brachial plexus palsy: effect of peripheral nerve injury on skeletal maturation.

PubMed

Oktay, Fügen; Cömert, Didem; Gökkaya, Nilüfer Kutay Ordu; Ozbudak, Sibel Demir; Uysal, Hilmi

2014-02-01

The purpose of this retrospective study was to analyze the effect of peripheral nerve injury on the skeletal maturation process. The bone ages of the affected and unaffected hand-wrists of 42 children with obstetrical brachial palsy were determined according to the Greulich and Pyle atlas. In 23 patients, the bone ages of the both sides were identical (bone-age-symmetrical group), in 19 patients the bone age of the affected side was delayed (bone-age-delayed group). The mean bone age of the affected side was delayed 0.48 ± 0.25 years that of the unaffected side (P = .000), and the delay of bone age was inversely correlated with chronological age (R (2) = .45, P < .02) in the bone-age-delayed group. Skeletal retardation can be recognized after appearance of ossification centers by plain radiography, dating from the third month of life, in early infancy. Thus, bone age determination method might be helpful for predicting potential future limb shortness.

Bone Metabolism after Bariatric Surgery

PubMed Central

Yu, Elaine W.

2014-01-01

Bariatric surgery is a popular and effective treatment for severe obesity, but may have negative effects on the skeleton. This review summarizes changes in bone density and bone metabolism from animal and clinical studies of bariatric surgery, with specific attention to Roux-en-Y gastric bypass (RYGB), adjustable gastric banding (AGB), and sleeve gastrectomy (SG). Skeletal imaging artifacts from obesity and weight loss are also considered. Despite challenges in bone density imaging, the preponderance of evidence suggests that bariatric surgery procedures have negative skeletal effects that persist beyond the first year of surgery, and that these effects vary by surgical type. The long-term clinical implications and current clinical recommendations are presented. Further study is required to determine mechanisms of bone loss after bariatric surgery. Although early studies focused on calcium/vitamin D metabolism and mechanical unloading of the skeleton, it seems likely that surgically-induced changes in the hormonal and metabolic profile may be responsible for the skeletal phenotypes observed after bariatric surgery. PMID:24677277

Do Secular Trends in Skeletal Maturity Occur Equally in Both Sexes?

PubMed

Duren, Dana L; Nahhas, Ramzi W; Sherwood, Richard J

2015-08-01

Skeletal maturity assessment provides information on a child's physical development and expectations based on chronological age. Given recently recognized trends for earlier maturity in a variety of systems, most notably puberty, examination of sex-specific secular trends in skeletal maturation is important. For the orthopaedist, recent trends and changes in developmental timing can affect clinical management (eg, treatment timing) if they are currently based on outdated sources. (1) Has the male or female pediatric skeleton experienced a secular trend for earlier maturation over the past 80 years? (2) Do all indicators of maturity trend in the same direction (earlier versus later)? In this retrospective study, a total of 1240 children were examined longitudinally through hand-wrist radiographs for skeletal maturity based on the Fels method. All subjects participate in the Fels Longitudinal Study based in Ohio and were born between 1930 and 1964 for the "early" cohort and between 1965 and 2001 for the "recent" cohort. Sex-specific secular trends were estimated for (1) mean relative skeletal maturity through linear mixed models; and (2) median age of maturation for individual maturity indicators through logistic regression and generalized estimating equations. Overall relative skeletal maturity was significantly advanced in the recent cohort (maximum difference of 5 months at age 13 years for girls, 4 months at age 15 years for boys). For individual maturity indicators, the direction and magnitude of secular trends varied by indicator type and sex. The following statistically significant secular trends were found: (1) earlier maturation of indicators of fusion in both sexes (4 months for girls, 3 months for boys); (2) later maturation of indicators of projection in long bones in both sexes (3 months for girls, 2 months for boys); (3) earlier maturation of indicators of density (4 months) and projection (3 months) in carpals and density in long bones (6 months), for girls only; and (4) later maturation of indicators of long bone shape (3 months) for boys only. A secular trend has occurred in the tempo of maturation of individual components of the pediatric skeleton, and it has occurred in a sex-specific manner. The mosaic nature of this trend, with both earlier and later maturation of individual components of the skeletal age phenotype, calls for greater attention to specific aspects of maturation in addition to the overall skeletal age estimate. The Fels method is currently the most robust method for capturing these components, and future work by our group will deliver an updated, user-friendly version of the Fels assessment tool. Appreciation of sex-specific secular changes in maturation is important for clinical management, including treatment timing, of orthopaedic patients, because children today exhibit a different pattern of maturation than children on whom original maturity assessments were based (including Fels and Greulich-Pyle).

Engineered skeletal muscle tissue for soft robotics: fabrication strategies, current applications, and future challenges.

PubMed

Duffy, Rebecca M; Feinberg, Adam W

2014-01-01

Skeletal muscle is a scalable actuator system used throughout nature from the millimeter to meter length scales and over a wide range of frequencies and force regimes. This adaptability has spurred interest in using engineered skeletal muscle to power soft robotics devices and in biotechnology and medical applications. However, the challenges to doing this are similar to those facing the tissue engineering and regenerative medicine fields; specifically, how do we translate our understanding of myogenesis in vivo to the engineering of muscle constructs in vitro to achieve functional integration with devices. To do this researchers are developing a number of ways to engineer the cellular microenvironment to guide skeletal muscle tissue formation. This includes understanding the role of substrate stiffness and the mechanical environment, engineering the spatial organization of biochemical and physical cues to guide muscle alignment, and developing bioreactors for mechanical and electrical conditioning. Examples of engineered skeletal muscle that can potentially be used in soft robotics include 2D cantilever-based skeletal muscle actuators and 3D skeletal muscle tissues engineered using scaffolds or directed self-organization. Integration into devices has led to basic muscle-powered devices such as grippers and pumps as well as more sophisticated muscle-powered soft robots that walk and swim. Looking forward, current, and future challenges include identifying the best source of muscle precursor cells to expand and differentiate into myotubes, replacing cardiomyocytes with skeletal muscle tissue as the bio-actuator of choice for soft robots, and vascularization and innervation to enable control and nourishment of larger muscle tissue constructs. © 2013 Wiley Periodicals, Inc.

Digital radiographic evaluation of hand-wrist bone maturation and prediction of age in South Indian adolescents.

PubMed

Mohammed, Rezwana Begum; Reddy, M Asha Lata; Jain, Megha; Singh, Johar Rajvinder; Sanghvi, Praveen; Thetay, Anshuj Ajay Rao

2014-09-01

In the growing years, indicators of the level of maturational development of the individual provide the best means for evaluating biologic age and the associated timing of skeletal growth. The relative stage of maturity of a child may be determined by comparing the child's hand-wrist radiograph to the known standards of skeletal development. In this study, we assessed various levels of skeletal maturation and also identified the relationship between chronological age (CA) and maturation stage using the hand-wrist radiographs in adolescents of Indian origin. Three hundred and thirty hand-wrist digital radiographs of individuals aged 8 to 18 years were evaluated for skeletal maturity levels using Fishman's method. The data was analysed using the SPSS software package (version 12, SPSS Inc., Chicago, IL, USA). Regression analysis was performed for calculating bone age of both males and females. Spearman's rank-order correlation coefficients were estimated separately for males and females to assess the relation between CA and maturation level. An association between skeletal maturation indicator stages and CA (r = 0.82) was significant. Interestingly, female subjects were observed to be advanced in skeletal maturity compared to males. Regression equations were derived to calculate bone age in males, females and the whole sample. The results of this study showed significant association between hand-wrist skeletal maturation levels and CA. Digital radiographic assessment of hand-wrist skeletal maturation can be used as a better choice for predicting average bone age of an individual because of its simplicity, reliability and lesser radiation exposure.

Animal and robot experiments to discover principles behind the evolution of a minimal locomotor apparatus for robust legged locomotion

NASA Astrophysics Data System (ADS)

McInroe, Benjamin; Astley, Henry; Kawano, Sandy; Blob, Richard; Goldman, Daniel I.

2015-03-01

In the evolutionary transition from an aquatic to a terrestrial environment, early walkers adapted to the challenges of locomotion on complex, flowable substrates (e.g. sand and mud). Our previous biological and robotic studies have demonstrated that locomotion on such substrates is sensitive to both limb morphology and kinematics. Although reconstructions of early vertebrate skeletal morphologies exist, the kinematic strategies required for successful locomotion by these organisms have not yet been explored. To gain insight into how early walkers contended with complex substrates, we developed a robotic model with appendage morphology inspired by a model analog organism, the mudskipper. We tested mudskippers and the robot on different substrates, including rigid ground and dry granular media, varying incline angle. The mudskippers moved effectively on all level substrates using a fin-driven gait. But as incline angle increased, the animals used their tails in concert with their fins to generate propulsion. Adding an actuated tail to the robot improved robustness, making possible locomotion on otherwise inaccessible inclines. With these discoveries, we are elucidating a minimal template that may have allowed the early walkers to adapt to locomotion on land. This work was supported by NSF PoLS.

Declining Coral Skeletal Extension for Forereef Colonies of Siderastrea siderea on the Mesoamerican Barrier Reef System, Southern Belize

PubMed Central

Castillo, Karl D.; Ries, Justin B.; Weiss, Jack M.

2011-01-01

Background Natural and anthropogenic stressors are predicted to have increasingly negative impacts on coral reefs. Understanding how these environmental stressors have impacted coral skeletal growth should improve our ability to predict how they may affect coral reefs in the future. We investigated century-scale variations in skeletal extension for the slow-growing massive scleractinian coral Siderastrea siderea inhabiting the forereef, backreef, and nearshore reefs of the Mesoamerican Barrier Reef System (MBRS) in the western Caribbean Sea. Methodology/Principal Findings Thirteen S. siderea cores were extracted, slabbed, and X-rayed. Annual skeletal extension was estimated from adjacent low- and high-density growth bands. Since the early 1900s, forereef S. siderea colonies have shifted from exhibiting the fastest to the slowest average annual skeletal extension, while values for backreef and nearshore colonies have remained relatively constant. The rates of change in annual skeletal extension were −0.020±0.005, 0.011±0.006, and −0.008±0.006 mm yr−1 per year [mean±SE] for forereef, backreef, and nearshore colonies respectively. These values for forereef and nearshore S. siderea were significantly lower by 0.031±0.008 and by 0.019±0.009 mm yr−1 per year, respectively, than for backreef colonies. However, only forereef S. siderea exhibited a statistically significant decline in annual skeletal extension over the last century. Conclusions/Significance Our results suggest that forereef S. siderea colonies are more susceptible to environmental stress than backreef and nearshore counterparts, which may have historically been exposed to higher natural baseline stressors. Alternatively, sediment plumes, nutrients, and pollution originating from watersheds of Guatemala and Honduras may disproportionately impact the forereef environment of the MBRS. We are presently reconstructing the history of environmental stressors that have impacted the MBRS to constrain the cause(s) of the observed reductions in coral skeletal growth. This should improve our ability to predict and potentially mitigate the effects of future environmental stressors on coral reef ecosystems. PMID:21359203

Induction of Sirt1 by Mechanical Stretch of Skeletal Muscle through the Early Response Factor EGR1 Triggers an Antioxidative Response*

PubMed Central

Pardo, Patricia S.; Mohamed, Junaith S.; Lopez, Michael A.; Boriek, Aladin M.

2011-01-01

Mechanical loading of muscles by intrinsic muscle activity or passive stretch leads to an increase in the production of reactive oxygen species (1, 2). The NAD-dependent protein deacetylase SIRT1 is involved in the protection against oxidative stress by enhancing FOXO-driven Sod2 transcription (3–5). In this report, we unravel a mechanism triggered by mechanical stretch of skeletal muscle cells that leads to an EGR1-dependent transcriptional activation of the Sirt1 gene. The resulting transient increase in SIRT1 expression generates an antioxidative response that contributes to reactive oxygen species scavenging. PMID:20971845

Conditional inactivation of Has2 reveals a crucial role for hyaluronan in skeletal growth, patterning, chondrocyte maturation and joint formation in the developing limb

PubMed Central

Matsumoto, Kazu; Li, Yingcui; Jakuba, Caroline; Sugiyama, Yoshinori; Sayo, Tetsuya; Okuno, Misako; Dealy, Caroline N.; Toole, Bryan P.; Takeda, Junji; Yamaguchi, Yu; Kosher, Robert A.

2009-01-01

Summary The glycosaminoglycan hyaluronan (HA) is a structural component of extracellular matrices and also interacts with cell surface receptors to directly influence cell behavior. To explore functions of HA in limb skeletal development, we conditionally inactivated the gene for HA synthase 2, Has2, in limb bud mesoderm using mice that harbor a floxed allele of Has2 and mice carrying a limb mesoderm-specific Prx1-Cre transgene. The skeletal elements of Has2-deficient limbs are severely shortened, indicating that HA is essential for normal longitudinal growth of all limb skeletal elements. Proximal phalanges are duplicated in Has2 mutant limbs indicating an involvement of HA in patterning specific portions of the digits. The growth plates of Has2-deficient skeletal elements are severely abnormal and disorganized, with a decrease in the deposition of aggrecan in the matrix and a disruption in normal columnar cellular relationships. Furthermore, there is a striking reduction in the number of hypertrophic chondrocytes and in the expression domains of markers of hypertrophic differentiation in the mutant growth plates, indicating that HA is necessary for the normal progression of chondrocyte maturation. In addition, secondary ossification centers do not form in the central regions of Has2 mutant growth plates owing to a failure of hypertrophic differentiation. In addition to skeletal defects, the formation of synovial joint cavities is defective in Has2-deficient limbs. Taken together, our results demonstrate that HA has a crucial role in skeletal growth, patterning, chondrocyte maturation and synovial joint formation in the developing limb. PMID:19633173

FXIIIA and TGF-beta over-expression produces normal musculo-skeletal phenotype in TG2-/- mice.

PubMed

Tarantino, U; Oliva, F; Taurisano, G; Orlandi, A; Pietroni, V; Candi, E; Melino, G; Maffulli, N

2009-04-01

Transglutaminase (TGs) enzymes and proteins crosslinking have for long time been implicated in the formation of hard tissue development, matrix maturation and mineralization. Among the TGs family members, in the context of connective tissue formation, TG2 and Factor XIII are expressed in cartilage by hypertrophic chondrocytes. Here, we analyse the morphological consequences of TG2 deficiency, during the development of skeletal elements. When TG2 is absent, there are not gross abnormalities in the development of the skeletal system, probably from compensatory mechanisms resulting in increased expression of FXIIIA and TGF-beta 1. In vivo other TGs may be involved in promoting chondrocytes and osteoblast differentiation and matrix mineralisation.

Analysis of cervical ribs in a series of human fetuses

PubMed Central

Bots, Jessica; Wijnaendts, Liliane C D; Delen, Sofie; Van Dongen, Stefan; Heikinheimo, Kristiina; Galis, Frietson

2011-01-01

In humans, an increasing body of evidence has linked the frequency of cervical ribs to stillbirths, other malformations and early childhood cancers. However, the frequency of cervical ribs in a putatively healthy fetal population is not sufficiently known to assess the actual medical risks of these prenatal findings. We therefore analyzed the presence of skeletal anomalies in a series of 199 electively aborted fetuses, which were whole-mount stained with alizarin red specific for skeletal tissues. Results show that approximately 40% of the fetuses had cervical ribs, even though external congenital abnormalities such as craniofacial and limb defects were absent. A literature overview indicates that the observed frequency of cervical ribs is comparable to results previously obtained for deceased fetuses with no or minor congenital anomalies, and higher than expected for healthy fetuses. This unexpected result can probably in part be explained by a higher detection rate of small cervical ribs when using alizarin red staining instead of radiographs. Additionally, studies in the literature suggest that the size of a cervical rib may indicate the severity of abnormalities, but this possibility requires further research. Anomalies of the axial skeleton are known to be caused by a disturbance of early development, which alters Hox gene expression, but in this study the origin of the stress could not be verified as maternal medical data were not available. The co-occurrence of rudimentary or absent 12th ribs in 23.6% of the cases with cervical ribs indicates that in approximately 8% of the fetuses a homeotic shift occurred over a larger part of the vertebral column. This suggests that the expression of multiple Hox genes may have been affected in these fetuses. Together, the high incidence of cervical ribs and also their co-occurrence with rudimentary or absent 12th ribs suggests that there may have been a disturbance of early development such that the studied fetuses are probably not informative about the general population. Future studies determining the frequency of cervical ribs in a more healthy fetal population are therefore needed to evaluate their potential as an indicator of medical risks. PMID:21689099

Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting

PubMed Central

Breitbart, Astrid; Auger-Messier, Mannix; Molkentin, Jeffery D.

2011-01-01

A significant proportion of heart failure patients develop skeletal muscle wasting and cardiac cachexia, which is associated with a very poor prognosis. Recently, myostatin, a cytokine from the transforming growth factor-β (TGF-β) family and a known strong inhibitor of skeletal muscle growth, has been identified as a direct mediator of skeletal muscle atrophy in mice with heart failure. Myostatin is mainly expressed in skeletal muscle, although basal expression is also detectable in heart and adipose tissue. During pathological loading of the heart, the myocardium produces and secretes myostatin into the circulation where it inhibits skeletal muscle growth. Thus, genetic elimination of myostatin from the heart reduces skeletal muscle atrophy in mice with heart failure, whereas transgenic overexpression of myostatin in the heart is capable of inducing muscle wasting. In addition to its endocrine action on skeletal muscle, cardiac myostatin production also modestly inhibits cardiomyocyte growth under certain circumstances, as well as induces cardiac fibrosis and alterations in ventricular function. Interestingly, heart failure patients show elevated myostatin levels in their serum. To therapeutically influence skeletal muscle wasting, direct inhibition of myostatin was shown to positively impact skeletal muscle mass in heart failure, suggesting a promising strategy for the treatment of cardiac cachexia in the future. PMID:21421824

Muscle-specific deletion of Prkaa1 enhances skeletal muscle lipid accumulation in mice fed a high-fat diet.

PubMed

Wu, Weiche; Xu, Ziye; Zhang, Ling; Liu, Jiaqi; Feng, Jie; Wang, Xinxia; Shan, Tizhong; Wang, Yizhen

2018-05-01

Excessive intramyocellular triacylglycerols (IMTGs, muscle lipids) are associated with the abnormal energy metabolism and insulin resistance of skeletal muscle. AMP-activated protein kinase (AMPK), a crucial cellular energy sensor, consists of α, β and γ subunits. Researchers have not clearly determined whether Prkaa1 (also known as AMPKα1) affects IMTG accumulation in skeletal muscle. Here, we show an important role of Prkaa1 in skeletal muscle lipid metabolism. Deletion of muscle Prkaa1 leads to the delayed development of skeletal muscles but does not affect glucose tolerance or insulin sensitivity in animals fed a normal diet. Notably, when animals are fed a high-fat diet, the skeletal muscle of muscle-specific Prkaa1 knockout mice accumulates more lipids than the skeletal muscle of wild-type (WT) mice, with concomitant upregulation of adipogenic gene expressions and downregulation of the expression of genes associated with mitochondrial oxidation. Muscle-specific Prkaa1 ablation also results in hyperlipidemia, which may contribute to the increased IMTG levels. Furthermore, Prkaa1 deletion activates skeletal muscle mTOR signalling, which has a central role in lipid metabolism and mitochondrial oxidation. Collectively, our study provides new insights into the role of Prkaa1 in skeletal muscle. This knowledge may contribute to the treatment of related metabolic diseases.

Skeletal maturation, fundamental motor skills and motor coordination in children 7-10 years.

PubMed

Freitas, Duarte L; Lausen, Berthold; Maia, José António; Lefevre, Johan; Gouveia, Élvio Rúbio; Thomis, Martine; Antunes, António Manuel; Claessens, Albrecht L; Beunen, Gaston; Malina, Robert M

2015-01-01

Relationships between skeletal maturation and fundamental motor skills and gross motor coordination were evaluated in 429 children (213 boys and 216 girls) 7-10 years. Skeletal age was assessed (Tanner-Whitehouse 2 method), and stature, body mass, motor coordination (Körperkoordinations Test für Kinder, KTK) and fundamental motor skills (Test of Gross Motor Development, TGMD-2) were measured. Relationships among chronological age, skeletal age (expressed as the standardised residual of skeletal age on chronological age) and body size and fundamental motor skills and motor coordination were analysed with hierarchical multiple regression. Standardised residual of skeletal age on chronological age interacting with stature and body mass explained a maximum of 7.0% of the variance in fundamental motor skills and motor coordination over that attributed to body size per se. Standardised residual of skeletal age on chronological age alone accounted for a maximum of 9.0% of variance in fundamental motor skills, and motor coordination over that attributed to body size per se and interactions between standardised residual of skeletal age on chronological age and body size. In conclusion, skeletal age alone or interacting with body size has a negligible influence on fundamental motor skills and motor coordination in children 7-10 years.

Cervical vertebral maturation and dental age in coeliac patients.

PubMed

Costacurta, M; Condò, R; Sicuro, L; Perugia, C; Docimo, R

2011-07-01

The aim of the study was to evaluate the cervical vertebral maturation and dental age, in group of patients with coelic disease (CD), in comparison with a control group of healthy subjects. At the Paediatric Dentistry Unit of PTV Hospital, "Tor Vergata" University of Rome, 120 female patients, age range 12.0-12.9 years were recruited. Among them, 60 subjects (Group 1) were affected by CD, while the control group (Group 2) consisted of 60 healthy subjects, sex and age-matched. The Group 1 was subdivided, according to the period of CD diagnosis, in Group A (early diagnosis) and Group B (late diagnosis). The skeletal age was determined by assessing the cervical vertebral maturation, while the dental age has been determined using the method codified by Demirjiyan. STATISTICS.: The analyses were performed using the SPSS software (version 16; SPSS Inc., Chicago IL, USA). In all the assessments a significant level of alpha = 0.05 was considered. There are no statistically significant differences between Group 1 and Group 2 as for chronological age (p=0.122). Instead, from the assessment of skeletal-dental age, there are statistically significant differences between Group 1 - Group 2 (p<0.001) and Group A - Group B (p<0.001). The statistical analysis carried out to assess the differences between chronological and skeletal-dental age within the single groups, show a statistically significant difference in Group 1 (p<0.001) and in Group B (p<0.001), while there are no statistically significant differences in Group 2 (p=0.538) and in Group A (p=0.475). A correlation between skeletal and dental age was registered; for Groups 1-2 and for Groups A-B the Pearson coefficient was respectively equal to 0.967 and 0.969, with p<0.001. Through the analysis of data it is possible to assess that the percentage of subjects with skeletal and dental age delay corresponds to 20% in healthy subjects, 56.7% in coeliac subjects, 23% in coeliac subjects with early diagnosis and 90% in coeliac subjects with late diagnosis. From the comparison between Group 2 and Group A there are no statistically significant differences (p=0.951). Conclusions. The skeletal age and dental age delay may be two predictive indexes for a CD diagnosis. The dental age and cervical vertebral maturity can be assessed with a low cost, non invasive, easy to perform exam carried out through the routine radiographic examinations such as orthopanoramic and lateral teleradiography.

Early and middle(?) Cambrian metazoan and protistan fossils from West Africa

USGS Publications Warehouse

Culver, S.J.; Repetski, J.E.; Pojeta, J.; Hunt, D.

1996-01-01

Supposed Upper Proterozoic strata in the southwest Taoudeni Basin, Guinea and Senegal, and from the Mauritanide fold belt, Mauritania, have yielded mostly poorly preserved small skeletal fossils of metazoan and protistan origin. Problematic, but possible echinoderm material and spicules of the heteractinid sponge Eiffelia dominate the Taoudeni Basin assemblage. The age of the material is not certain but the paleontologic data suggest an Early Cambrian age for the stratigraphically lowest faunas, and a Middle Cambrian age is possible for the stratigraphically highest collections.

A gravid lizard from the Cretaceous of China and the early history of squamate viviparity

NASA Astrophysics Data System (ADS)

Wang, Yuan; Evans, Susan E.

2011-09-01

Although viviparity is most often associated with mammals, roughly one fifth of extant squamate reptiles give birth to live young. Phylogenetic analyses indicate that the trait evolved more than 100 times within Squamata, a frequency greater than that of all other vertebrate clades combined. However, there is debate as to the antiquity of the trait and, until now, the only direct fossil evidence of squamate viviparity was in Late Cretaceous mosasauroids, specialised marine lizards without modern equivalents. Here, we document viviparity in a specimen of a more generalised lizard, Yabeinosaurus, from the Early Cretaceous of China. The gravid female contains more than 15 young at a level of skeletal development corresponding to that of late embryos of living viviparous lizards. This specimen documents the first occurrence of viviparity in a fossil reptile that was largely terrestrial in life, and extends the temporal distribution of the trait in squamates by at least 30 Ma. As Yabeinosaurus occupies a relatively basal position within crown-group squamates, it suggests that the anatomical and physiological preconditions for viviparity arose early within Squamata.

Stem Cells in Skeletal Tissue Engineering: Technologies and Models

PubMed Central

Langhans, Mark T.; Yu, Shuting; Tuan, Rocky S.

2017-01-01

This review surveys the use of pluripotent and multipotent stem cells in skeletal tissue engineering. Specific emphasis is focused on evaluating the function and activities of these cells in the context of development in vivo, and how technologies and methods of stem cell-based tissue engineering for stem cells must draw inspiration from developmental biology. Information on the embryonic origin and in vivo differentiation of skeletal tissues is first reviewed, to shed light on the persistence and activities of adult stem cells that remain in skeletal tissues after embryogenesis. Next, the development and differentiation of pluripotent stem cells is discussed, and some of their advantages and disadvantages in the context of tissue engineering is presented. The final section highlights current use of multipotent adult mesenchymal stem cells, reviewing their origin, differentiation capacity, and potential applications to tissue engineering. PMID:26423296

A compact skeletal mechanism for n -dodecane with optimized semi-global low-temperature chemistry for diesel engine simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yao, Tong; Pei, Yuanjiang; Zhong, Bei-Jing

A skeletal mechanism with 54 species and 269 reactions was developed to predict pyrolysis and oxidation of n-dodecane as a diesel fuel surrogate involving both high-temperature (high-T) and low-temperature (low-T) conditions. The skeletal mechanism was developed from a semi-detailed mechanism developed at the University of Southern California (USC). Species and reactions for high-T pyrolysis and oxidation of C5-C12 were reduced by using reaction flow analysis (RFA), isomer lumping, and then merged into a skeletal C0-C4 core to form a high-T sub-mechanism. Species and lumped semi-global reactions for low-T chemistry were then added to the high-T sub-mechanism and a 54-species skeletalmore » mechanism is obtained. The rate parameters of the low-T reactions were tuned against a detailed mechanism by the Lawrence Livermore National Laboratory (LLNL), as well as the Spray A flame experimental data, to improve the prediction of ignition delay at low-T conditions, while the high-T chemistry remained unchanged. The skeletal mechanism was validated for auto-ignition, perfectly stirred reactors (PSR), flow reactors and laminar premixed flames over a wide range of flame conditions. The skeletal mechanism was then employed to simulate three-dimensional turbulent spray flames at compression ignition engine conditions and validated against experimental data from the Engine Combustion Network (ECN).« less

Orthopedic surgery and bone fracture pain are both significantly attenuated by sustained blockade of nerve growth factor

PubMed Central

Majuta, Lisa A.; Longo, Geraldine; Fealk, Michelle N.; McCaffrey, Gwen; Mantyh, Patrick W.

2015-01-01

The number of patients suffering from postoperative pain due to orthopedic surgery and bone fracture is projected to dramatically increase because the human life span, weight, and involvement in high-activity sports continue to rise worldwide. Joint replacement or bone fracture frequently results in skeletal pain that needs to be adequately controlled for the patient to fully participate in needed physical rehabilitation. Currently, the 2 major therapies used to control skeletal pain are nonsteroidal anti-inflammatory drugs and opiates, both of which have significant unwanted side effects. To assess the efficacy of novel therapies, mouse models of orthopedic and fracture pain were developed and evaluated here. These models, orthopedic surgery pain and bone fracture pain, resulted in skeletal pain–related behaviors that lasted 3 weeks and 8 to 10 weeks, respectively. These skeletal pain behaviors included spontaneous and palpation-induced nocifensive behaviors, dynamic weight bearing, limb use, and voluntary mechanical loading of the injured hind limb. Administration of anti–nerve growth factor before orthopedic surgery or after bone fracture attenuated skeletal pain behaviors by 40% to 70% depending on the end point being assessed. These data suggest that nerve growth factor is involved in driving pain due to orthopedic surgery or bone fracture. These animal models may be useful in developing an understanding of the mechanisms that drive postoperative orthopedic and bone fracture pain and the development of novel therapies to treat these skeletal pains. PMID:25599311

Lowered extracellular pH is involved in the pathogenesis of skeletal muscle insulin resistance.

PubMed

Hayata, Hiroki; Miyazaki, Hiroaki; Niisato, Naomi; Yokoyama, Noriko; Marunaka, Yoshinori

2014-02-28

Insulin resistance in the skeletal muscle is manifested by diminished insulin-stimulated glucose uptake and is a core factor in the pathogenesis of type 2 diabetes mellitus (DM), but the mechanism causing insulin resistance is still unknown. Our recent study has shown that pH of interstitial fluids was lowered in early developmental stage of insulin resistance in OLETF rats, a model of type 2 DM. Therefore, in the present study, we confirmed effects of the extracellular pH on the insulin signaling pathway in a rat skeletal muscle-derived cell line, L6 cell. The phosphorylation level (activation) of the insulin receptor was significantly diminished in low pH media. The phosphorylation level of Akt, which is a downstream target of the insulin signaling pathway, also decreased in low pH media. Moreover, the insulin binding to its receptor was reduced by lowering extracellular pH, while the expression of insulin receptors on the plasma membrane was not affected by the extracellular pH. Finally, insulin-stimulated 2-deoxyglucose uptake in L6 cells was diminished in low pH media. Our present study suggests that lowered extracellular pH conditions may produce the pathogenesis of insulin resistance in skeletal muscle cells. Copyright © 2014. Published by Elsevier Inc.

Scenes from the past: radiologic evidence of anthropogenic mummification in the Capuchin Catacombs of Palermo, Sicily.

PubMed

Panzer, Stephanie; Zink, Albert R; Piombino-Mascali, Dario

2010-01-01

The purpose of this study was to use paleoradiologic analyses to investigate a sample of the mummies in the Capuchin Catacombs in Palermo, Sicily, in order to assess skeletal abnormalities and the state of preservation, especially the condition of the internal organs, and to determine radiologic evidence of anthropogenic mummification. Ten 19th and early 20th century mummies with good external preservation were investigated by using a portable direct radiography unit inside the Capuchin Catacombs. The radiographs clearly demonstrated signs of anthropogenic mummification in nine of the 10 mummies investigated. The embalming methods that had been used included (a) evisceration and arterial injection; (b) the placement of foreign materials into the orbits and the nasal and oral cavities; and (c) filling of the thoracic, abdominal, and rectal cavities with foreign materials. Organ preservation varied greatly among the mummies, although brain tissue was found in all of the mummies. Analyses of the skeletal material of the mummies showed evidence of healed vertebral fractures, age-related degenerative changes, and, in one of the child mummies, a remarkable skeletal pathologic condition. The radiographs clearly illustrated different methods of anthropogenic mummification in the catacomb mummies of Palermo, allowed assessment of the preservation of the mummies, and demonstrated skeletal abnormalities.

Edentulism, beaks, and biomechanical innovations in the evolution of theropod dinosaurs.

PubMed

Lautenschlager, Stephan; Witmer, Lawrence M; Altangerel, Perle; Rayfield, Emily J

2013-12-17

Maniraptoriformes, the speciose group of derived theropod dinosaurs that ultimately gave rise to modern birds, display a diverse and remarkable suite of skeletal adaptations. Apart from the evolution of flight, a large-scale change in dietary behavior appears to have been one of the main triggers for specializations in the bauplan of these derived theropods. Among the different skeletal specializations, partial or even complete edentulism and the development of keratinous beaks form a recurring and persistent trend in from the evolution of derived nonavian dinosaurs. Therizinosauria is an enigmatic maniraptoriform clade, whose members display these and other osteological characters thought to be correlated with the shift from carnivory to herbivory. This makes therizinosaurians prime candidates to assess the functional significance of these morphological characters. Based on a highly detailed biomechanical model of Erlikosaurus andrewsi, a therizinosaurid from the Upper Cretaceous of Mongolia, different morphological configurations incorporating soft-tissue structures, such as a keratinous rhamphotheca, are evaluated for their biomechanical performance. Our results indicate that the development of beaks and the presence of a keratinous rhamphotheca would have helped to dissipate stress and strain, making the rostral part of the skull less susceptible to bending and displacement, and this benefit may extend to other vertebrate clades that possess rhamphothecae. Keratinous beaks, paralleled by edentulism, thus represent an evolutionary innovation developed early in derived theropods to enhance cranial stability, distinct to postulated mass-saving benefits associated with the origin of flight.

Edentulism, beaks, and biomechanical innovations in the evolution of theropod dinosaurs

PubMed Central

Lautenschlager, Stephan; Witmer, Lawrence M.; Altangerel, Perle; Rayfield, Emily J.

2013-01-01

Maniraptoriformes, the speciose group of derived theropod dinosaurs that ultimately gave rise to modern birds, display a diverse and remarkable suite of skeletal adaptations. Apart from the evolution of flight, a large-scale change in dietary behavior appears to have been one of the main triggers for specializations in the bauplan of these derived theropods. Among the different skeletal specializations, partial or even complete edentulism and the development of keratinous beaks form a recurring and persistent trend in from the evolution of derived nonavian dinosaurs. Therizinosauria is an enigmatic maniraptoriform clade, whose members display these and other osteological characters thought to be correlated with the shift from carnivory to herbivory. This makes therizinosaurians prime candidates to assess the functional significance of these morphological characters. Based on a highly detailed biomechanical model of Erlikosaurus andrewsi, a therizinosaurid from the Upper Cretaceous of Mongolia, different morphological configurations incorporating soft-tissue structures, such as a keratinous rhamphotheca, are evaluated for their biomechanical performance. Our results indicate that the development of beaks and the presence of a keratinous rhamphotheca would have helped to dissipate stress and strain, making the rostral part of the skull less susceptible to bending and displacement, and this benefit may extend to other vertebrate clades that possess rhamphothecae. Keratinous beaks, paralleled by edentulism, thus represent an evolutionary innovation developed early in derived theropods to enhance cranial stability, distinct to postulated mass-saving benefits associated with the origin of flight. PMID:24297877

Activity Dependent Signal Transduction in Skeletal Muscle

NASA Technical Reports Server (NTRS)

Hamilton, Susan L.

1999-01-01

The overall goals of this project are: 1) to define the initial signal transduction events whereby the removal of gravitational load from antigravity muscles, such as the soleus, triggers muscle atrophy, and 2) to develop countermeasures to prevent this from happening. Our rationale for this approach is that, if countermeasures can be developed to regulate these early events, we could avoid having to deal with the multiple cascades of events that occur downstream from the initial event. One of our major findings is that hind limb suspension causes an early and sustained increase in intracellular Ca(2+) concentration ([Ca (2+)](sub i)). In most cells the consequences of changes in ([Ca (2+)](sub i))depend on the amplitude, frequency and duration of the Ca(2+) signal and on other factors in the intracellular environment. We propose that muscle remodeling in microgravity represents a change in the balance among several CA(2+) regulated signal transduction pathways, in particular those involving the transcription factors NFAT and NFkB and the pro-apoptotic protein BAD. Other Ca(2+) sensitive pathways involving PKC, ras, rac, and CaM kinase II may also contribute to muscle remodeling.

Polyurethane acrylates as effective substrates for sustained in vitro culture of human myotubes.

PubMed

Andriani, Yosephine; Chua, Jason Min-Wen; Chua, Benjamin Yan-Jiang; Phang, In Yee; Shyh-Chang, Ng; Tan, Wui Siew

2017-07-15

Muscular disease has debilitating effects with severe damage leading to death. Our knowledge of muscle biology, disease and treatment is largely derived from non-human cell models, even though non-human cells are known to differ from human cells in their biochemical responses. Attempts to develop highly sought after in vitro human cell models have been plagued by early cell delamination and difficulties in achieving human myotube culture in vitro. In this work, we developed polyurethane acrylate (PUA) materials to support long-term in vitro culture of human skeletal muscle tissue. Using a constant base with modulated crosslink density we were able to vary the material modulus while keeping surface chemistry and roughness constant. While previous studies have focused on materials that mimic soft muscle tissue with stiffness ca. 12kPa, we investigated materials with tendon-like surface moduli in the higher 150MPa to 2.4GPa range, which has remained unexplored. We found that PUA of an optimal modulus within this range can support human myoblast proliferation, terminal differentiation and sustenance beyond 35days, without use of any extracellular protein coating. Results show that PUA materials can serve as effective substrates for successful development of human skeletal muscle cell models and are suitable for long-term in vitro studies. We developed polyurethane acrylates (PUA) to modulate the human skeletal muscle cell growth and maturation in vitro by controlling surface chemistry, morphology and tuning material's stiffness. PUA was able to maintain muscle cell viability for over a month without any detectable signs of material degradation. The best performing PUA prevented premature cell detachment from the substrate which often hampered long-term muscle cell studies. It also supported muscle cell maturation up to the late stages of differentiation. The significance of these findings lies in the possibility to advance studies on muscle cell biology, disease and therapy by using human muscle cells instead of relying on the widely used animal-based in vitro models. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Cardiac Niche Influences the Direct Reprogramming of Canine Fibroblasts into Cardiomyocyte-Like Cells

PubMed Central

Palazzolo, Giacomo; Quattrocelli, Mattia; Toelen, Jaan; Dominici, Roberto; Tettamenti, Guido; Barthelemy, Inès; Blot, Stephane; Gijsbers, Rik; Cassano, Marco

2016-01-01

The Duchenne and Becker muscular dystrophies are caused by mutation of dystrophin gene and primarily affect skeletal and cardiac muscles. Cardiac involvement in dystrophic GRMD dogs has been demonstrated by electrocardiographic studies with the onset of a progressive cardiomyopathy similar to the cardiac disease in DMD patients. In this respect, GRMD is a useful model to explore cardiac and skeletal muscle pathogenesis and for developing new therapeutic protocols. Here we describe a protocol to convert GRMD canine fibroblasts isolated from heart and skin into induced cardiac-like myocytes (ciCLMs). We used a mix of transcription factors (GATA4, HAND2, TBX5, and MEF2C), known to be able to differentiate mouse and human somatic cells into ciCLMs. Exogenous gene expression was obtained using four lentiviral vectors carrying transcription factor genes and different resistance genes. Our data demonstrate a direct switch from fibroblast into ciCLMs with no activation of early cardiac genes. ciCLMs were unable to contract spontaneously, suggesting, differently from mouse and human cells, an incomplete differentiation process. However, when transplanted in neonatal hearts of SCID/Beige mice, ciCLMs participate in cardiac myogenesis. PMID:26681949

Cardiac Niche Influences the Direct Reprogramming of Canine Fibroblasts into Cardiomyocyte-Like Cells.

PubMed

Palazzolo, Giacomo; Quattrocelli, Mattia; Toelen, Jaan; Dominici, Roberto; Anastasia, Luigi; Tettamenti, Guido; Barthelemy, Inès; Blot, Stephane; Gijsbers, Rik; Cassano, Marco; Sampaolesi, Maurilio

2016-01-01

The Duchenne and Becker muscular dystrophies are caused by mutation of dystrophin gene and primarily affect skeletal and cardiac muscles. Cardiac involvement in dystrophic GRMD dogs has been demonstrated by electrocardiographic studies with the onset of a progressive cardiomyopathy similar to the cardiac disease in DMD patients. In this respect, GRMD is a useful model to explore cardiac and skeletal muscle pathogenesis and for developing new therapeutic protocols. Here we describe a protocol to convert GRMD canine fibroblasts isolated from heart and skin into induced cardiac-like myocytes (ciCLMs). We used a mix of transcription factors (GATA4, HAND2, TBX5, and MEF2C), known to be able to differentiate mouse and human somatic cells into ciCLMs. Exogenous gene expression was obtained using four lentiviral vectors carrying transcription factor genes and different resistance genes. Our data demonstrate a direct switch from fibroblast into ciCLMs with no activation of early cardiac genes. ciCLMs were unable to contract spontaneously, suggesting, differently from mouse and human cells, an incomplete differentiation process. However, when transplanted in neonatal hearts of SCID/Beige mice, ciCLMs participate in cardiac myogenesis.

The Skeletal Muscle Environment and Its Role in Immunity and Tolerance to AAV Vector-Mediated Gene Transfer

PubMed Central

Boisgérault, Florence; Mingozzi, Federico

2015-01-01

Since the early days of gene therapy, muscle has been one the most studied tissue targets for the correction of enzyme deficiencies and myopathies. Several preclinical and clinical studies have been conducted using adeno-associated virus (AAV) vectors. Exciting progress has been made in the gene delivery technologies, from the identification of novel AAV serotypes to the development of novel vector delivery techniques. In parallel, significant knowledge has been generated on the host immune system and its interaction with both the vector and the transgene at the muscle level. In particular, the role of underlying muscle inflammation, characteristic of several diseases affecting the muscle, has been defined in terms of its potential detrimental impact on gene transfer with AAV vectors. At the same time, feedback immunomodulatory mechanisms peculiar of skeletal muscle involving resident regulatory T cells have been identified, which seem to play an important role in maintaining, at least to some extent, muscle homeostasis during inflammation and regenerative processes. Devising strategies to tip this balance towards unresponsiveness may represent an avenue to improve the safety and efficacy of muscle gene transfer with AAV vectors. PMID:26122097

Craniofacial structures' development in prenatal period: An MRI study.

PubMed

Begnoni, G; Serrao, G; Musto, F; Pellegrini, G; Triulzi, F M; Dellavia, C

2018-05-01

The development of skeletal structures (cranial base, upper and lower) and upper airways spaces (oropharyngeal and nasopharyngeal) of the skull has always been an issue of great interest in orthodontics. Foetal MRI images obtained as screening exam during pregnancy can help to understand the development of these structures using a sample cephalometric analysis. A total of 28 MRI images in sagittal section of foetuses from 20th to 32th weeks of gestation were obtained to dispel doubts about the presence of skeletal malformations. Cephalometric measurements were performed on MRI T2-dependent images acquired with a 1.5 T scanner. The Software Osirix 5 permits to study sagittal and vertical dimensions of the skull analysing linear measurements, angles and areas of the skeletal structures. Vertical and sagittal dimension of cranial base, maxilla and mandible grow significantly (P < .01) between the second and third trimester of gestational period as well as nasopharyngeal and oropharyngeal spaces (P < .05). High correlation between the development of anterior cranial base and functional areas devoted to speech and swallow is demonstrated (r: .97). The development of craniofacial structures during foetal period seems to show a close correlation between skeletal features and functional spaces with a peak between the second and third trimester of gestation. MRI images result helpful for the clinician to detect with a sample cephalometric analysis anomalies of skeletal and functional structures during prenatal period. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A Novel Heterozygous Mutation in the T-box Protein 4 Gene in an Adult Case of Small Patella Syndrome.

PubMed

Oda, Tomoyuki; Matsushita, Masaki; Ono, Yohei; Kitoh, Hiroshi; Sakai, Tadahiro

2018-01-01

Small patella syndrome (SPS) is a rare skeletal dysplasia relating to the T-box protein 4 (TBX4) gene, which regulates the development of lower extremities. Patients typically present with recurrent patellar dislocation (RPD) in childhood or adolescence, leading to a diagnosis of SPS and subsequent treatment to improve activity levels. However, those with mild symptoms may not be diagnosed when young and present later after skeletal maturation, which might compromise treatment options. Further understanding of genetic mutations of SPS could possibly help early diagnosis and following adequate surgical treatment. In this case report, we present a surgically treated adult female case of RPD associated with SPS, carrying a novel heterozygous mutation in the TBX4 gene. A 19-year-old female presented with persistent right knee pain after an atraumatic episode ofpatellar dislocation during walking. The patient had a history of recurrent patella instability of the right knee with an onset at the age of 8 years due to a minor trauma. Patellar apprehension sign was positive bilaterally. There was radiological evidence of bilateral small patellae, hypoplastic femoral trochlea, and tibial tuberosity. A direct sequencing of the coding regions in the TBX4 gene had confirmed the diagnosis of SPS. A novel heterozygous mutation (p.L39PfsX35) was found in the patient and her father. Surgical treatment was indicated and the patient underwent an isolated medial patellofemoral ligament (MPFL) reconstruction while no distal realignment osteotomy was performed due to hypoplastic tibial tuberosity. Excellent subjective and objective outcomes were obtained at 1 year postoperatively. To the best of our knowledge, this is the first reported SPS case with a novel mutation in the TBX4 gene in an Asian population. While a satisfying short-term outcome was obtained by an isolated MPFL reconstruction, early genetic diagnosis in childhood with adequate surgical treatment (e.g., Roux-Goldthwait procedure) would be ideal considering the limited treatment options in skeletally matured patients. The reported case has added one mutation variant of the TBX4 gene, which may help prevent delays in diagnosis of SPS.

Cinnamon extract prevents the insulin resistance induced by a high-fructose diet.

PubMed

Qin, B; Nagasaki, M; Ren, M; Bajotto, G; Oshida, Y; Sato, Y

2004-02-01

The aim of this study was to determine whether cinnamon extract (CE) would improve the glucose utilization in normal male Wistar rats fed a high-fructose diet (HFD) for three weeks with or without CE added to the drinking water (300 mg/kg/day). In vivo glucose utilization was measured by the euglycemic clamp technique. Further analyses on the possible changes in insulin signaling occurring in skeletal muscle were performed afterwards by Western blotting. At 3 mU/kg/min insulin infusions, the decreased glucose infusion rate (GIR) in HFD-fed rats (60 % of controls, p < 0.01) was improved by CE administration to the same level of controls (normal chow diet) and the improving effect of CE on the GIR of HFD-fed rats was blocked by approximately 50 % by N-monometyl-L-arginine. The same tendency was found during the 30 mU/kg/min insulin infusions. There were no differences in skeletal muscle insulin receptor (IR)-beta, IR substrate (IRS)-1, or phosphatidylinositol (PI) 3-kinase protein content in any groups. However, the muscular insulin-stimulated IR-beta and IRS-1 tyrosine phosphorylation levels and IRS-1 associated with PI 3-kinase in HFD-fed rats were only 70 +/- 9 %, 76 +/- 5 %, and 72 +/- 6 % of controls (p < 0.05), respectively, and these decreases were significantly improved by CE treatment. These results suggest that early CE administration to HFD-fed rats would prevent the development of insulin resistance at least in part by enhancing insulin signaling and possibly via the NO pathway in skeletal muscle.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cross, S.L.; Lighty, R.G.

Coral-rudist reefs of the Lower Cretaceous Mural limestone, southeastern Arizona, show a pronounced relationship between specific reef facies, primary porosity, and early submarine diagenesis. These large open-shelf reefs differ from the well-studied low-relief rudist buildups, and provide an alternate analog for many Cretaceous reef reservoirs. Arizona buildups have diverse corals, high depositional relief, and a well-developed facies zonation from fore reef to back reef: skeletal grainstone talus, muddy fore reef with branching and lamellar corals, massive reef crest with abundant lamellar corals and sandy matrix, protected thickets of delicate branching corals and large rudist mounds, and a wide sediment apronmore » of well-washed coral, rudist, and benthic foraminiferal sands. These well-exposed outcrops permit a detailed facies comparison of primary interparticle porosity. Porosity as high as 40% in grainstones was occluded by later subsurface cements. Reef-framework interparticle porosity was negligible because fore-reef coral and back-reef rudist facies were infilled by muds, and high-energy reef-crest frameworks were filled by peloidal submarine cement crusts and muddy skeletal sands. These thick crusts coated lamellar corals in cryptic and open reef-crest areas, and are laminated with ripple and draped bed forms that suggest current influence. Similar peloidal crusts and laminated textures are common magnesium-calcite submarine cement features in modern reefs. By documenting specific facies control on early cementation and textural variability, patterns of late-stage subsurface diagenesis and secondary porosity may be more easily explained for Cretaceous reef reservoirs. Significant primary porosity might be retained between sands in back-reef facies and within coral skeletons.« less

Skeletal muscle protease activities in the early growth and development of wild Atlantic salmon (Salmo salar L.).

PubMed

Lysenko, Liudmila A; Kantserova, Nadezda P; Kaivarainen, Elena I; Krupnova, Marina Yu; Nemova, Nina N

2017-09-01

Growth-related dynamics of intracellular protease activities in four year classes of the Atlantic salmon (Salmo salar L. 1758) parr and smolts inhabiting salmon rivers of northwestern Russia (the White Sea basin) were studied. Cathepsin B, cathepsin D, proteasome, and calpain activities in the skeletal muscles of salmon were assessed to investigate their relative contribution to the total protein degradation as well as to young fish growth process. It was confirmed that calpain activity dominates in salmon muscles while proteasome plays a minor role, in contrast to terrestrial vertebrates. Calpain and proteasome activities were maximal at the early post-larval stage (in parrs 0+) and declined with age (parrs 1+ through 2+) dropping to the lowest level in salmon smolts. Annual growth increments and proteolytic activities of calpains and proteasome in the muscles of salmon juveniles changed with age in an orchestrated manner, while lysosomal cathepsin activities increased with age. Comparing protease activities and growth increments in salmon parr and smolts we suggested that the partial suppression of the protein degradation could be a mechanism stimulating efficient growth in smoltifying salmon. Growth and smoltification-related dynamics of protease activities was quite similar in salmon populations from studied spawning rivers, such as Varzuga and Indera; however, some habitat-related differences were observed. Growth increments and protease activities varied in salmon parr 0+ (but not on later ages) inhabiting either main rivers or small tributaries apparently due to habitat difference on the resources for fish growth. Copyright © 2017 Elsevier Inc. All rights reserved.

Proliferation Rates of Bovine Primary Muscle Cells Relate to Liveweight and Carcase Weight in Cattle

PubMed Central

Coles, Chantal A.; Wadeson, Jenny; Leyton, Carolina P.; Siddell, Jason P.; Greenwood, Paul L.; White, Jason D.; McDonagh, Matthew B.

2015-01-01

Muscling in cattle is largely influenced by genetic background, ultimately affecting beef yield and is of major interest to the beef industry. This investigation aimed to determine whether primary skeletal muscle cells isolated from different breeds of cattle with a varying genetic potential for muscling differ in their myogenic proliferative capacity. Primary skeletal muscle cells were isolated and cultured from the Longissimus muscle (LM) of 6 month old Angus, Hereford and Wagyu X Angus cattle. Cells were assessed for rate of proliferation and gene expression of PAX7, MYOD, MYF5, and MYOG. Proliferation rates were found to differ between breeds of cattle whereby myoblasts from Angus cattle were found to proliferate at a greater rate than those of Hereford and Wagyu X Angus during early stages of growth (5–20 hours in culture) in vitro (P < 0.05). The proliferation rates of myoblasts during early stages of culture in vitro were also found to be positively related to the liveweight and carcase weight of cattle (P < 0.05). Gene expression of MYF5 was also found to be significantly down-regulated in WagyuX compared with Angus cattle (P < 0.05). These findings suggest that early events during myogenesis are important for determining liveweight and caracase weights in cattle. PMID:25875203

Global microbial carbonate proliferation after the end-Devonian mass extinction: Mainly controlled by demise of skeletal bioconstructors

PubMed Central

Yao, Le; Aretz, Markus; Chen, Jitao; Webb, Gregory E.; Wang, Xiangdong

2016-01-01

Microbial carbonates commonly flourished following mass extinction events. The end-Devonian (Hangenberg) mass extinction event is a first-order mass extinction on the scale of the ‘Big Five’ extinctions. However, to date, it is still unclear whether global microbial carbonate proliferation occurred after the Hangenberg event. The earliest known Carboniferous stromatolites on tidal flats are described from intertidal environments of the lowermost Tournaisian (Qianheishan Formation) in northwestern China. With other early Tournaisian microbe-dominated bioconstructions extensively distributed on shelves, the Qianheishan stromatolites support microbial carbonate proliferation after the Hangenberg extinction. Additional support comes from quantitative analysis of the abundance of microbe-dominated bioconstructions through the Famennian and early Tournaisian, which shows that they were globally distributed (between 40° latitude on both sides of the palaeoequator) and that their abundance increased distinctly in the early Tournaisian compared to the latest Devonian (Strunian). Comparison of variations in the relative abundance of skeleton- versus microbe-dominated bioconstructions across the Hangenberg and ‘Big Five’ extinctions suggests that changes in abundance of skeletal bioconstructors may play a first-order control on microbial carbonate proliferation during extinction transitions but that microbial proliferation is not a general necessary feature after mass extinctions. PMID:28009013

Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development.

PubMed

Bonilla-Claudio, Margarita; Wang, Jun; Bai, Yan; Klysik, Elzbieta; Selever, Jennifer; Martin, James F

2012-02-01

We performed an in depth analysis of Bmp4, a critical regulator of development, disease, and evolution, in cranial neural crest (CNC). Conditional Bmp4 overexpression, using a tetracycline-regulated Bmp4 gain-of-function allele, resulted in facial skeletal changes that were most dramatic after an E10.5 Bmp4 induction. Expression profiling uncovered a signature of Bmp4-induced genes (BIG) composed predominantly of transcriptional regulators that control self-renewal, osteoblast differentiation and negative Bmp autoregulation. The complimentary experiment, CNC inactivation of Bmp2, Bmp4 and Bmp7, resulted in complete or partial loss of multiple CNC-derived skeletal elements, revealing a crucial requirement for Bmp signaling in membranous bone and cartilage development. Importantly, the BIG signature was reduced in Bmp loss-of-function mutants, indicating Bmp-regulated target genes are modulated by Bmp dose. Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation. These data support the hypothesis that Bmp signaling regulates craniofacial skeletal development by balancing self-renewal and differentiation pathways in CNC progenitors.

Molecular cloning and expression analysis of the retinoid X receptor (RXR) gene in golden pompano Trachinotus ovatus fed Artemia nauplii with different enrichments.

PubMed

Yang, Qibin; Zheng, Panlong; Ma, Zhenhua; Li, Tao; Jiang, Shigui; Qin, Jian G

2015-12-01

The retinoid X receptors (RXRs) are involved in the skeletal development and other biological process such as blood vessel formation and metabolism. Partial sequences of RXRα and β genes were obtained, and their expressions were quantified on golden pompano Trachinotus ovatus at 28 days post hatching (DPH) to explore the molecular response to nutritional manipulation in fish larvae. As live food, Artemia nauplii were separately enriched with Nannochloropsis and Algamac 3080 and non-enriched Artemia nauplii (control) for fish feeding. The expressions of RXRs were detected in the embryos and fish larvae at early stages, suggesting that the skeletal development in golden pompano initiated before yolk re-sorption completion. Fish fed non-enriched Artemia nauplii ended up with higher jaw malformation. The highest specific growth rate was obtained when fish were fed with the Artemia nauplii enriched with Algamac 3080, and the lowest growth rate was observed when fish were fed with unenriched Artemia nauplii. The highest survival was obtained when fish were fed with non-enriched or Nannochloropsis-enriched Artemia nauplii. This study indicates that the use of enriched formula for Artemia nauplii can significantly affect the expression levels of RXRs and jaw malformation of golden pompano larvae, but there is no clear correlation between RXRs expressions and malformation rates when fish are subjected to nutrient challenge.

Enzyme Replacement Therapy Prevents Dental Defects in a Model of Hypophosphatasia

PubMed Central

McKee, M.D.; Nakano, Y.; Masica, D.L.; Gray, J.J.; Lemire, I.; Heft, R.; Whyte, M.P.; Crine, P.; Millán, J.L.

2011-01-01

Hypophosphatasia (HPP) occurs from loss-of-function mutation in the tissue-non-specific alkaline phosphatase (TNALP) gene, resulting in extracellular pyrophosphate accumulation that inhibits skeletal and dental mineralization. TNALP-null mice (Akp2-/-) phenocopy human infantile hypophosphatasia; they develop rickets at 1 week of age, and die before being weaned, having severe skeletal and dental hypomineralization and episodes of apnea and vitamin B6-responsive seizures. Delay and defects in dentin mineralization, together with a deficiency in acellular cementum, are characteristic. We report the prevention of these dental abnormalities in Akp2-/- mice receiving treatment from birth with daily injections of a mineral-targeting, human TNALP (sALP-FcD10). sALP-FcD10 prevented hypomineralization of alveolar bone, dentin, and cementum as assessed by micro-computed tomography and histology. Osteopontin – a marker of acellular cementum – was immuno-localized along root surfaces, confirming that acellular cementum, typically missing or reduced in Akp2-/- mice, formed normally. Our findings provide insight concerning how acellular cementum is formed on tooth surfaces to effect periodontal ligament attachment to retain teeth in their osseous alveolar sockets. Furthermore, they provide evidence that this enzyme-replacement therapy, applied early in post-natal life – where the majority of tooth root development occurs, including acellular cementum formation – could prevent the accelerated tooth loss seen in individuals with HPP. PMID:21212313

Enzyme replacement therapy prevents dental defects in a model of hypophosphatasia.

PubMed

McKee, M D; Nakano, Y; Masica, D L; Gray, J J; Lemire, I; Heft, R; Whyte, M P; Crine, P; Millán, J L

2011-04-01

Hypophosphatasia (HPP) occurs from loss-of-function mutation in the tissue-non-specific alkaline phosphatase (TNALP) gene, resulting in extracellular pyrophosphate accumulation that inhibits skeletal and dental mineralization. TNALP-null mice (Akp2(-/-)) phenocopy human infantile hypophosphatasia; they develop rickets at 1 week of age, and die before being weaned, having severe skeletal and dental hypomineralization and episodes of apnea and vitamin B(6)-responsive seizures. Delay and defects in dentin mineralization, together with a deficiency in acellular cementum, are characteristic. We report the prevention of these dental abnormalities in Akp2(-/-) mice receiving treatment from birth with daily injections of a mineral-targeting, human TNALP (sALP-FcD(10)). sALP-FcD(10) prevented hypomineralization of alveolar bone, dentin, and cementum as assessed by micro-computed tomography and histology. Osteopontin--a marker of acellular cementum--was immuno-localized along root surfaces, confirming that acellular cementum, typically missing or reduced in Akp2(-/-) mice, formed normally. Our findings provide insight concerning how acellular cementum is formed on tooth surfaces to effect periodontal ligament attachment to retain teeth in their osseous alveolar sockets. Furthermore, they provide evidence that this enzyme-replacement therapy, applied early in post-natal life--where the majority of tooth root development occurs, including acellular cementum formation--could prevent the accelerated tooth loss seen in individuals with HPP.

NOTCH signaling in skeletal progenitors is critical for fracture repair

PubMed Central

Wang, Cuicui; Inzana, Jason A.; Mirando, Anthony J.; Liu, Zhaoyang; Shen, Jie; O’Keefe, Regis J.; Awad, Hani A.; Hilton, Matthew J.

2016-01-01

Fracture nonunions develop in 10%–20% of patients with fractures, resulting in prolonged disability. Current data suggest that bone union during fracture repair is achieved via proliferation and differentiation of skeletal progenitors within periosteal and soft tissues surrounding bone, while bone marrow stromal/stem cells (BMSCs) and other skeletal progenitors may also contribute. The NOTCH signaling pathway is a critical maintenance factor for BMSCs during skeletal development, although the precise role for NOTCH and the requisite nature of BMSCs following fracture is unknown. Here, we evaluated whether NOTCH and/or BMSCs are required for fracture repair by performing nonstabilized and stabilized fractures on NOTCH-deficient mice with targeted deletion of RBPjk in skeletal progenitors, maturing osteoblasts, and committed chondrocytes. We determined that removal of NOTCH signaling in BMSCs and subsequent depletion of this population result in fracture nonunion, as the fracture repair process was normal in animals harboring either osteoblast- or chondrocyte-specific deletion of RBPjk. Together, this work provides a genetic model of a fracture nonunion and demonstrates the requirement for NOTCH and BMSCs in fracture repair, irrespective of fracture stability and vascularity. PMID:26950423

Brief communication: a proposed method for the assessment of pubertal stage in human skeletal remains using cervical vertebrae maturation.

PubMed

Shapland, Fiona; Lewis, Mary E

2014-01-01

The assessment of age-at-death in non-adult skeletal remains is under constant review. However, in many past societies an individual's physical maturation may have been more important in social terms than their exact age, particularly during the period of adolescence. In a recent article (Shapland and Lewis: Am J Phys Anthropol 151 (2013) 302-310) highlighted a set of dental and skeletal indicators that may be useful in mapping the progress of the pubertal growth spurt. This article presents a further skeletal indicator of adolescent development commonly used by modern clinicians: cervical vertebrae maturation (CVM). This method is applied to a collection of 594 adolescents from the medieval cemetery of St. Mary Spital, London. Analysis reveals a potential delay in ages of attainment of the later CVM stages compared with modern adolescents, presumably reflecting negative environmental conditions for growth and development. The data gathered on CVM is compared to other skeletal indicators of pubertal maturity and long bone growth from this site to ascertain the usefulness of this method on archaeological collections. Copyright © 2013 Wiley Periodicals, Inc.

Troponin T3 regulates nuclear localization of the calcium channel Ca{sub v}β{sub 1a} subunit in skeletal muscle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Tan; Taylor, Jackson; Jiang, Yang

The voltage-gated calcium channel (Ca{sub v}) β{sub 1a} subunit (Ca{sub v}β{sub 1a}) plays an important role in excitation–contraction coupling (ECC), a process in the myoplasm that leads to muscle-force generation. Recently, we discovered that the Ca{sub v}β{sub 1a} subunit travels to the nucleus of skeletal muscle cells where it helps to regulate gene transcription. To determine how it travels to the nucleus, we performed a yeast two-hybrid screening of the mouse fast skeletal muscle cDNA library and identified an interaction with troponin T3 (TnT3), which we subsequently confirmed by co-immunoprecipitation and co-localization assays in mouse skeletal muscle in vivo andmore » in cultured C2C12 muscle cells. Interacting domains were mapped to the leucine zipper domain in TnT3 COOH-terminus (160–244 aa) and Ca{sub v}β{sub 1a} NH{sub 2}-terminus (1–99 aa), respectively. The double fluorescence assay in C2C12 cells co-expressing TnT3/DsRed and Ca{sub v}β{sub 1a}/YFP shows that TnT3 facilitates Ca{sub v}β{sub 1a} nuclear recruitment, suggesting that the two proteins play a heretofore unknown role during early muscle differentiation in addition to their classical role in ECC regulation. - Highlights: • Previously, we demonstrated that Ca{sub v}β{sub 1a} is a gene transcription regulator. • Here, we show that TnT3 interacts with Ca{sub v}β{sub 1a}. • We mapped TnT3 and Ca{sub v}β{sub 1a} interaction domain. • TnT3 facilitates Ca{sub v}β{sub 1a} nuclear enrichment. • The two proteins play a heretofore unknown role during early muscle differentiation.« less

Vitamin K2 improves proliferation and migration of bovine skeletal muscle cells in vitro.

PubMed

Rønning, Sissel Beate; Pedersen, Mona Elisabeth; Berg, Ragnhild Stenberg; Kirkhus, Bente; Rødbotten, Rune

2018-01-01

Skeletal muscle function is highly dependent on the ability to regenerate, however, during ageing or disease, the proliferative capacity is reduced, leading to loss of muscle function. We have previously demonstrated the presence of vitamin K2 in bovine skeletal muscles, but whether vitamin K has a role in muscle regulation and function is unknown. In this study, we used primary bovine skeletal muscle cells, cultured in monolayers in vitro, to assess a potential effect of vitamin K2 (MK-4) during myogenesis of muscle cells. Cell viability experiments demonstrate that the amount of ATP produced by the cells was unchanged when MK-4 was added, indicating viable cells. Cytotoxicity analysis show that MK-4 reduced the lactate dehydrogenase (LDH) released into the media, suggesting that MK-4 was beneficial to the muscle cells. Cell migration, proliferation and differentiation was characterised after MK-4 incubation using wound scratch analysis, immunocytochemistry and real-time PCR analysis. Adding MK-4 to the cells led to an increased muscle proliferation, increased gene expression of the myogenic transcription factor myod as well as increased cell migration. In addition, we observed a reduction in the fusion index and relative gene expression of muscle differentiation markers, with fewer complex myotubes formed in MK-4 stimulated cells compared to control cells, indicating that the MK-4 plays a significant role during the early phases of muscle proliferation. Likewise, we see the same pattern for the relative gene expression of collagen 1A, showing increased gene expression in proliferating cells, and reduced expression in differentiating cells. Our results also suggest that MK-4 incubation affect low density lipoprotein receptor-related protein 1 (LRP1) and the low-density lipoprotein receptor (LDLR) with a peak in gene expression after 45 min of MK-4 incubation. Altogether, our experiments show that MK-4 has a positive effect on muscle cell migration and proliferation, which are two important steps during early myogenesis.

Early adiposity rebound is associated with metabolic risk in 7-year-old children.

PubMed

González, L; Corvalán, C; Pereira, A; Kain, J; Garmendia, M L; Uauy, R

2014-10-01

Early adiposity rebound (AR <5 years) has been consistently associated with increased obesity risk, but its relationship with metabolic markers is less clear; in addition, the biologic mechanisms involved in these associations have not been established. The objective of this study was to assess the association between timing of AR and metabolic status at age 7 years, evaluating the potential role of adiposity, adipose functionality and skeletal maturation in this association. We estimated the age of AR from the body mass index (BMI) trajectories from 0 to 7 years in 910 children from the Growth and Obesity Chilean Cohort Study (GOCS). At 7 years, we measured waist circumference (WC) and blood glucose, insulin, triglycerides and high-density lipoprotein-cholesterol levels and constructed a metabolic risk score. We also measured percent fat mass (adiposity), plasma concentrations of leptin and adiponectin (adipose functionality) and bone age using wrist ultrasound (skeletal maturation). We found that 44% of the children had an AR <5 years. Earlier AR was associated with larger WC (β: 5.10 (95% confidence interval (CI): 4.29-5.91)), higher glucose (β: 1.02 (1.00-1.03)), insulin resistance (β Homeostatic Model Assessment: 1.06 (1.03-1.09)), triglycerides (β: 10.37 (4.01-6.73)) and adverse metabolic score (β: 0.30 (0.02-0.37)). Associations decreased significantly if adiposity was added to the models (i.e. β WC: 0.85 (0.33-1.38)) and, to a lesser extent, when adipokines (i.e. β WC: 0.73 (0.14-1.32)) and skeletal maturation (i.e. β WC: 0.65 (0.10-1.20)) were added. In GOCS children, AR at a younger age predicts higher metabolic risk at 7 years; these associations are mostly explained by increased adiposity, but adipose dysfunction and accelerated skeletal maturation also have a role.

Quantification of skeletal fraction volume of a soil pit by means of photogrammetry

NASA Astrophysics Data System (ADS)

Baruck, Jasmin; Zieher, Thomas; Bremer, Magnus; Rutzinger, Martin; Geitner, Clemens

2015-04-01

The grain size distribution of a soil is a key parameter determining soil water behaviour, soil fertility and land use potential. It plays an important role in soil classification and allows drawing conclusions on landscape development as well as soil formation processes. However, fine soil material (i.e. particle diameter ≤2 mm) is usually documented more thoroughly than the skeletal fraction (i.e. particle diameter >2 mm). While fine soil material is commonly analysed in the laboratory in order to determine the soil type, the skeletal fraction is typically estimated in the field at the profile. For a more precise determination of the skeletal fraction other methods can be applied and combined. These methods can be volume-related (sampling rings, percussion coring tubes) or non-volume-related (sieve of spade excavation). In this study we present a framework for the quantification of skeletal fraction volumes of a soil pit by means of photogrammetry. As a first step 3D point clouds of both soil pit and skeletal grains were generated. Therefore all skeletal grains of the pit were spread out onto a plane, clean plastic sheet in the field and numerous digital photos were taken using a reflex camera. With the help of the open source tool VisualSFM (structure from motion) two scaled 3D point clouds were derived. As a second step the skeletal fraction point cloud was segmented by radiometric attributes in order to determine volumes of single skeletal grains. The comparison of the total skeletal fraction volume with the volume of the pit (closed by spline interpolation) yields an estimate of the volumetric proportion of skeletal grains. The presented framework therefore provides an objective reference value of skeletal fraction for the support of qualitative field records.

Inferring the Skeletal Muscle Developmental Changes of Grazing and Barn-Fed Goats from Gene Expression Data.

PubMed

Huang, Jinyu; Jiao, Jinzhen; Tan, Zhi-Liang; He, Zhixiong; Beauchemin, Karen A; Forster, Robert; Han, Xue-Feng; Tang, Shao-Xun; Kang, Jinghe; Zhou, Chuanshe

2016-09-14

Thirty-six Xiangdong black goats were used to investigate age-related mRNA and protein expression levels of some genes related to skeletal muscle structural proteins, MRFs and MEF2 family, and skeletal muscle fiber type and composition during skeletal muscle growth under grazing (G) and barn-fed (BF) feeding systems. Goats were slaughtered at six time points selected to reflect developmental changes of skeletal muscle during nonrumination (days 0, 7, and 14), transition (day 42), and rumination phases (days 56 and 70). It was observed that the number of type IIx in the longissimus dorsi was increased quickly while numbers of type IIa and IIb decreased slightly, indicating that these genes were coordinated during the rapid growth and development stages of skeletal muscle. No gene expression was affected (P > 0.05) by feeding system except Myf5 and Myf6. Protein expressions of MYOZ3 and MEF2C were affected (P < 0.05) by age, whereas PGC-1α was linearly decreased in the G group, and only MYOZ3 protein was affected (P < 0.001) by feeding system. Moreover, it was found that PGC-1α and MEF2C proteins may interact with each other in promoting muscle growth. The current results indicate that (1) skeletal muscle growth during days 0-70 after birth is mainly myofiber hypertrophy and differentiation, (2) weaning affects the expression of relevant genes of skeletal muscle structural proteins, skeletal muscle growth, and skeletal muscle fiber type and composition, and (3) nutrition or feeding regimen mainly influences the expression of skeletal muscle growth genes.

Characterization of disuse skeletal muscle atrophy and the efficacy of a novel muscle atrophy countermeasure during spaceflight and simulated microgravity

NASA Astrophysics Data System (ADS)

Hanson, Andrea Marie

Humans are an integral part of the engineered systems that will enable return to the Moon and eventually travel to Mars. Major advancements in countermeasure development addressing deleterious effects of microgravity and reduced gravity on the musculoskeletal system need to be made to ensure mission safety and success. The primary objectives of this dissertation are to advance the knowledge and understanding of skeletal muscle atrophy, and support development of novel countermeasures for disuse atrophy to enable healthy long-duration human spaceflight. Models simulating microgravity and actual spaceflight were used to examine the musculoskeletal adaptations during periods of unloading. Myostatin inhibition, a novel anti-atrophy drug therapy, and exercise were examined as a means of preventing and recovering from disuse atrophy. A combination of assays was used to quantify adaptation responses to unloading and examine efficacy of the countermeasures. Body and muscle masses were collected to analyze systemic changes due to treatments. Hindlimb strength and individual muscle forces were measured to demonstrate functional adaptations to treatments. Muscle fiber morphology and myosin heavy chain (MHC) expression was examined to identify adaptations at the cellular level. Protein synthesis signals insulin-like growth factor-1 (IGF-1), Akt, and p70s6 kinase; and the degradation signals Atrogin-1 and MuRF-1 were examined to identify adaptations at the molecular level that ultimately lead to muscle hypertrophy and atrophy. A time course study provided a thorough characterization of the adaptation of skeletal muscle during unloading in C57BL/6 mice, and baseline data for comparison to and evaluation of subsequent studies. Time points defining the on-set and endpoints of disuse muscle atrophy were identified to enable characterization of rapid vs. long-term responses of skeletal muscle to hindlimb suspension. Unloading-induced atrophy primarily resulted from increased protein degradation at early time points that predominantly affected slow-twitch muscle fibers. A second study examined the use of exercise as a means of recovery from disuse atrophy. Contrary to previous reports, a short duration of exercise following disuse provided a functional benefit to contractile mechanisms and increased resistance to fatigue---possibly due to increased expression of fast-twitch fibers. Two additional studies examined the efficacy of a myostatin inhibitor in combination with hindlimb unloading and in spaceflight. Myostatin inhibition increased expression of markers within the muscle synthesis pathway in both models. The myostatin inhibitors were potent enough for the skeletal muscles to overcome the atrophying effects of musculoskeletal unloading as demonstrated by increased mass and strength. Myostatin inhibition is demonstrated to be a very promising and effective treatment for disuse muscle atrophy that may benefit astronauts and patients with muscle wasting diseases. This dissertation provides the first analyses of an unloading model in combination with a myostatin inhibitor as a countermeasure for skeletal muscle disuse atrophy while exploring the specific roles of muscle function, morphology, and translational signaling pathways.

Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering.

PubMed

Maffioletti, Sara Martina; Sarcar, Shilpita; Henderson, Alexander B H; Mannhardt, Ingra; Pinton, Luca; Moyle, Louise Anne; Steele-Stallard, Heather; Cappellari, Ornella; Wells, Kim E; Ferrari, Giulia; Mitchell, Jamie S; Tyzack, Giulia E; Kotiadis, Vassilios N; Khedr, Moustafa; Ragazzi, Martina; Wang, Weixin; Duchen, Michael R; Patani, Rickie; Zammit, Peter S; Wells, Dominic J; Eschenhagen, Thomas; Tedesco, Francesco Saverio

2018-04-17

Generating human skeletal muscle models is instrumental for investigating muscle pathology and therapy. Here, we report the generation of three-dimensional (3D) artificial skeletal muscle tissue from human pluripotent stem cells, including induced pluripotent stem cells (iPSCs) from patients with Duchenne, limb-girdle, and congenital muscular dystrophies. 3D skeletal myogenic differentiation of pluripotent cells was induced within hydrogels under tension to provide myofiber alignment. Artificial muscles recapitulated characteristics of human skeletal muscle tissue and could be implanted into immunodeficient mice. Pathological cellular hallmarks of incurable forms of severe muscular dystrophy could be modeled with high fidelity using this 3D platform. Finally, we show generation of fully human iPSC-derived, complex, multilineage muscle models containing key isogenic cellular constituents of skeletal muscle, including vascular endothelial cells, pericytes, and motor neurons. These results lay the foundation for a human skeletal muscle organoid-like platform for disease modeling, regenerative medicine, and therapy development. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Gorlin-Goltz syndrome and neoplasms: a case study.

PubMed

Lopes, Nilza N F; Caran, Eliana M; Lee, Maria Lucia; Silva, Nasjla Saba; Rocha, André Caroli; Macedo, Carla R D

2010-01-01

Gorlin syndrome is a rare autosomal dominant disorder exhibiting high penetrance and variable expressivity. It is characterized by facial dysmorphism, skeletal anomalies, multiple basal cell carcinomas, odontogenic keratocysts (OKC), palmar and plantar pits, bifid ribs, vertebral anomalies and a variety of other malformations. Various neoplasms, such as medulloblastomas, meningiomas, ovarian and cardiac fibromas are also found in this syndrome. To describe a twelve-year-old patient with Gorlin-Goltz syndrome, with basal cell carcinomas and promyelocytic leukemia developed after receiving craniospinal radiation for a medulloblastoma. Bifid ribs as well as mandibular and maxillar OKC were also diagnosed Conclusion: The patient with Gorlin-Goltz syndrome should receive close follow-up for early detection of malformations nd malignant neoplasias.

Ichthyosis linearis circumflexa with bamboo hair: challenges in the diagnosis and management.

PubMed

Dev, Tanvi; Raman Kumar, Marwaha; Sethuraman, Gomathy

2017-05-28

A 15-year-old boy had persistent and refractory erythroderma since early childhood. His parents noticed polycyclic skin lesions and hair fragility around the age of 5 years. He was treated by a local untrained practitioner for more than 3 years without any significant improvement, and he developed weight gain, thinning of skin, muscle weakness and growth retardation. He was evaluated in 2015 and found to have iatrogenic Cushing's disease with severe skeletal complications and pituitary-adrenal-gonadal suppression, which persisted despite gradual withdrawal of steroids. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Effects of increased pCO2 and geographic origin on purple sea urchin (Strongylocentrotus purpuratus) calcite elemental composition

NASA Astrophysics Data System (ADS)

LaVigne, M.; Hill, T. M.; Sanford, E.; Gaylord, B.; Russell, A. D.; Lenz, E. A.; Hosfelt, J. D.; Young, M. K.

2012-12-01

Ocean acidification will likely have negative impacts on invertebrates producing skeletons composed of calcium carbonate. Skeletal solubility is partly controlled by the incorporation of "foreign" ions (such as Mg and Sr) into the crystal lattice of these skeletal structures, a process that is sensitive to a variety of biological and environmental factors. Here we explore the effects of life stage, oceanographic region of origin, and changes in the partial pressure of carbon dioxide in seawater (pCO2) on trace elemental composition in the purple sea urchin (Strongylocentrotus purpuratus). We show that, similar to other urchin taxa, adult purple sea urchins have the ability to precipitate skeleton composed of a range of biominerals spanning low to high magnesium calcites. Mg/Ca and Sr/Ca ratios were substantially lower in adult spines compared to adult tests. On the other hand, trace elemental composition was invariant among adults collected from four oceanographically distinct regions along the US west coast (Oregon, Northern California, Central California, and Southern California). Skeletons of newly settled juvenile urchins that originated from adults from the four regions exhibited intermediate Mg/Ca and Sr/Ca between adult spine and test endmembers, indicating that skeleton precipitated during early life stages is more soluble than adult spines and less soluble than adult tests. Mean skeletal Mg/Ca or Sr/Ca of juvenile skeleton did not vary with source region when larvae were reared under present-day, global-average seawater carbonate conditions (400 ppm; pH = 8.02 ± 0.03 1 SD; Ωcalcite = 3.3 ± 0.2 1 SD). However, when reared under elevated CO2 (900 ppm; pH = 7.72 ± 0.03; Ωcalcite = 1.8 ± 0.1), skeletal Sr/Ca in juveniles exhibited increased variance across the four regions. Although larvae from the northern populations (Oregon, Northern California, Central California) did not exhibit differences in Mg or Sr incorporation under elevated CO2 (Sr/Ca = 2.09 ± 0.06 mmol mol-1; Mg/Ca = 66.9 ± 4.1 mmol mol-1), juveniles of Southern California origin partitioned ∼ 8% more Sr into their skeletons when exposed to higher CO2 (Sr/Ca = 2.26 ± 0.05 vs. 2.10 ± 0.03 mmol mol-1 1 SD). Together these results suggest that the diversity of carbonate minerologies present across different skeletal structures and life stages in purple sea urchins does not translate into an equivalent plasticity of response associated with geographic variation or temporal shifts in seawater properties. Rather, composition of S. purpuratus skeleton precipitated during both early and adult life history stages appears relatively robust to spatial gradients and predicted changes in seawater carbonate chemistry for 2100. An exception to this trend may arise during early life stages, where certain populations of purple sea urchins may alter skeletal mineral precipitation rates and composition beyond a given CO2 threshold. The degree to which this latter geochemical plasticity might affect mineral stability and solubility in a future, altered ocean requires additional study.

Exercise, age, and bones.

PubMed

Thomas, W C

1994-05-01

Skeletal development in average healthy individuals is maximal at age 25 in women and at age 30 to 35 in men. However, there are significant racial differences, skeletal mass being greater in black than in white individuals. This difference appears best accounted for by increased muscle mass in blacks. Bed rest, immobilization, weightlessness (as in space flights), and aging induce a decrease in skeletal mass. The degree of osteopenia in the elderly depends partly on skeletal development during formative years and can be prevented from becoming severe by maintaining good nutritional status (calcium, vitamin D, protein) and physical activity. Maintenance or actual increase in muscle mass is a desired effect of appropriate physical activity, but excessive physical exercise may induce estrogen deficiency and menstrual irregularities in premenopausal women. In addition to diet and exercise, pharmacologic therapy (estrogens, androgens, diphosphonates, or calcitonin) is indicated in patients with significant osteoporosis.

Myosin Heavy Chain Gene Expression in Developing Neonatal Skeletal Muscle: Involvement of the Nerve, Gravity, and Thyroid State

NASA Technical Reports Server (NTRS)

Baldwin, K. M.; Adams, G.; Haddad, F.; Zeng, M.; Qin, A.; Qin, L.; McCue, S.; Bodell, P.

1999-01-01

The myosin heavy chain (MHC) gene family encodes at least six MHC proteins (herein designated as neonatal, embryonic, slow type I (beta), and fast IIa, IIx, and IIb) that are expressed in skeletal muscle in a muscle-specific and developmentally-regulated fashion. At birth, both antigravity (e.g. soleus) and locomotor (e.g., plantaris) skeletal muscles are undifferentiated relative to the adult MHC phenotype such that the neonatal and embryonic MHC isoforms account for 80 - 90% of the MHC pool in a fast locomotor muscle; whereas, the embryonic and slow, type I isoforms account for approx. 90% of the pool in a typical antigravity muscle. The goal of this study was to investigate the role of an intact nerve, gravity and thyroid hormone (T3), as well as certain interactions of these interventions, on MHC gene expression in developing neonatal skeletal muscles of rodents.

Treatment of hypophosphatemic rickets in generalized arterial calcification of infancy (GACI) without worsening of vascular calcification.

PubMed

Ferreira, Carlos R; Ziegler, Shira G; Gupta, Ashutosh; Groden, Catherine; Hsu, Kevin S; Gahl, William A

2016-05-01

Patients with generalized arterial calcification of infancy (GACI) develop vascular calcifications early in life. About half of them die within the first 6 months despite optimal medical care. A subset of those who survive eventually develop hypophosphatemic rickets. Since hypophosphatemia and hyperphosphaturia have been previously associated with increased survival in GACI patients, physicians often avoid phosphate repletion as treatment for rickets. As a consequence, GACI patients develop severe rachitic complications such as short stature and skeletal deformities. It appears that the recognition of hypophosphatemia later in life in some GACI patients is a consequence of having survived the first few months of life, and not the cause of their survival per se. Here, we report the long-term follow-up of a GACI patient who was phosphate-repleted for his rickets for more than 7 years without worsening of vascular calcification. © 2016 Wiley Periodicals, Inc.

A new modified tandem appliance for management of developing Class III malocclusion.

PubMed

Sukh, Ram; Singh, Gyan P; Tandon, Pradeep

2013-10-01

Most developing Class III patients display a retruded maxilla. Early intervention in mixed dentition is associated with better patient compliance and possibly a better orthopedic response, which can produce favorable results. The aim of this article is to present the fabrication of the new modified tandem appliance and its use in management of developing Class III malocclusion. The therapeutic results of a new modified tandem appliance are presented in an 8 year-old male patient with anterior cross bite and retrognathic maxilla at the mixed dentition stage. Anterior cross bite was corrected in 3 months and the positive overjet of 4 mm after continued use of the appliance for 1 year. There was a significant improvement in profile of the patient. The use of this appliance in this type of malocclusion enabled the correction of malocclusion in a few months and encouraging favorable skeletal growth in the future.

Advances in treating exposed fractures.

PubMed

Nogueira Giglio, Pedro; Fogaça Cristante, Alexandre; Ricardo Pécora, José; Partezani Helito, Camilo; Lei Munhoz Lima, Ana Lucia; Dos Santos Silva, Jorge

2015-01-01

The management of exposed fractures has been discussed since ancient times and remains of great interest to present-day orthopedics and traumatology. These injuries are still a challenge. Infection and nonunion are feared complications. Aspects of the diagnosis, classification and initial management are discussed here. Early administration of antibiotics, surgical cleaning and meticulous debridement are essential. The systemic conditions of patients with multiple trauma and the local conditions of the limb affected need to be taken into consideration. Early skeletal stabilization is necessary. Definitive fixation should be considered when possible and provisional fixation methods should be used when necessary. Early closure should be the aim, and flaps can be used for this purpose.

Effect of Dystrophin Deficiency on Selected Intrinsic Laryngeal Muscles of the "mdx" Mouse

ERIC Educational Resources Information Center

Fry, Lisa T.; Stemple, Joseph C.; Andreatta, Richard D.; Harrison, Anne L.; Andrade, Francisco H.

2010-01-01

Background: Intrinsic laryngeal muscles (ILM) show biological differences from the broader class of skeletal muscles. Yet most research regarding ILM specialization has been completed on a few muscles, most notably the thyroarytenoid and posterior cricoarytenoid. Little information exists regarding the biology of other ILM. Early evidence suggests…

Translating insights from development into regenerative medicine: the function of Wnts in bone biology.

PubMed

Leucht, P; Minear, S; Ten Berge, D; Nusse, R; Helms, J A

2008-10-01

The Wnt pathway constitutes one of the most attractive candidates for modulating skeletal tissue regeneration based on its functions during skeletal development and homeostasis. Wnts participate in every stage of skeletogenesis, from the self-renewal and proliferation of skeletal stem cells to the specification of osteochondroprogenitor cells and the maturation of chondrocytes and osteoblasts. We propose that the function of Wnts depend upon a skeletogenic cell's state of differentiation. In this review we summarize recent data with a focus on the roles of Wnt signaling in mesenchymal stem cell fate, osteoprogenitor cell differentiation, chondrocyte maturation, bone remodeling, and bone regeneration.

Metabolic inflexibility in skeletal muscle: a prelude to the cardiometabolic syndrome?

PubMed

Thyfault, John P; Rector, R Scott; Noland, Robert C

2006-01-01

Peripheral insulin resistance, which is largely dependent on skeletal muscle, is closely linked to the development of the cardiometabolic syndrome. Metabolic flexibility is the capacity for skeletal muscle to acutely shift its reliance between lipids or glucose during fasting or postprandial conditions. Obese and insulin-resistant individuals display elevated intramuscular lipids, impaired vasculature function, decreased fatty add oxidation during fasting, and reduced postprandial glucose metabolism. Impairments in metabolic flexibility are linked to physical inactivity, excess energy intake and obesity, and genetic predisposition. Each of these factors precludes the development of insulin resistance and the cardiometabolic syndrome by mechanistic links that are not fully understood.

Myogenic Maturation by Optical-Training in Cultured Skeletal Muscle Cells.

PubMed

Asano, Toshifumi; Ishizuka, Toru; Yawo, Hiromu

2017-01-01

Optogenetic techniques are powerful tools for manipulating biological processes in identified cells using light under high temporal and spatial resolutions. Here, we describe an optogenetic training strategy to promote morphological maturation and functional development of skeletal muscle cells in vitro. Optical stimulation with a rhythmical frequency facilitates specific structural alignment of sarcomeric proteins. Optical stimulation also depolarizes the membrane potential, and induces contractile responses in synchrony with the given pattern of light pulses. These results suggest that optogenetic techniques can be employed to manipulate activity-dependent processes during myogenic development and control contraction of photosensitive skeletal muscle cells with high temporal and special precision.

The Effects of Maxillary Protraction with or without Rapid Maxillary Expansion and Age Factors in Treating Class III Malocclusion: A Meta-Analysis

PubMed Central

Zhang, Wei; Qu, Hong-Chen; Yu, Mo; Zhang, Yang

2015-01-01

We conducted a comprehensive meta-analysis of 12 studies to examine whether maxillary protraction face mask associated with rapid maxillary expansion (FM/RME) could be an effective treatment for Class III malocclusion and to evaluate the effect of timing on treatment response. Patients with a maxillary deficiency who were treated with FM with or without RME were compared with those who had an untreated Class III malocclusion. In both treatment groups, forward displacement of the maxilla and skeletal changes were found to be statistically significant. In addition, posterior rotation of the mandible and increased facial height were more evident in the FM group compared with the control group. However, no significant differences were observed between the early treatment groups and late treatment groups. The results indicated that both FM/RME and FM therapy produced favorable skeletal changes for correcting anterior crossbite, and the curative time was not affected by the presence of deciduous teeth, early mixed dentition or late mixed dentition in the patient. PMID:26068221

Sorting receptor Rer1 controls surface expression of muscle acetylcholine receptors by ER retention of unassembled alpha-subunits.

PubMed

Valkova, Christina; Albrizio, Marina; Röder, Ira V; Schwake, Michael; Betto, Romeo; Rudolf, Rüdiger; Kaether, Christoph

2011-01-11

The nicotinic acetylcholine receptor of skeletal muscle is composed of five subunits that are assembled in a stepwise manner. Quality control mechanisms ensure that only fully assembled receptors reach the cell surface. Here, we show that Rer1, a putative Golgi-ER retrieval receptor, is involved in the biogenesis of acetylcholine receptors. Rer1 is expressed in the early secretory pathway in the myoblast line C2C12 and in mouse skeletal muscle, and up-regulated during myogenesis. Upon down-regulation of Rer1 in C2C12 cells, unassembled acetylcholine receptor α-subunits escape from the ER and are transported to the plasma membrane and lysosomes, where they are degraded. As a result, the amount of fully assembled receptor at the cell surface is reduced. In vivo Rer1 knockdown and genetic inactivation of one Rer1 allele lead to significantly smaller neuromuscular junctions in mice. Our data show that Rer1 is a functionally important unique factor that controls surface expression of muscle acetylcholine receptors by localizing unassembled α-subunits to the early secretory pathway.

Mississippian subadults from the Middle Cumberland and Eastern regions of Tennessee: Biological indicators of population interaction.

PubMed

Scopa Kelso, Rebecca

2018-06-01

Human subadult skeletal remains can provide a unique perspective into biosocial aspects of Mississippian period population interactions within and between the Middle Cumberland (MCR) and Eastern Tennessee Regions (ETR). The majority of previous studies have concentrated on adult skeletal remains, leaving out a large and extremely important population segment. Skeletal indicators of disease, growth, body proportions, and metabolic stress were collected from subadult remains from five archaeological sites over several temporal periods. Crucial to overcoming limitations associated with the osteological paradox, the biological results were placed into an archaeological context based on prior studies as well as paleoclimatological data. Results reveal homogeneity both within and between regions for most skeletal indicators. However, MCR individuals exhibit a higher frequency of pathology than those from ETC, while stature is significantly lower in younger subadults from the MCR. Within the ETR, there is no evidence for biological differences between Early Dallas and subsequent Late Dallas and Mouse Creek cultural phases. Despite presumed signs of increased conflict at the Dallas site, frequencies and types of skeletal pathology and growth disruptions are comparable to other regional sites. These findings suggest that despite cultural differences between the ETR and MCR, there was no large-scale intrusion from an outside population into the ETR during the Late Mississippian Period, or if one occurred, it is biologically invisible. Combined with climatic and archaeobotanical data, results suggest the MCR subadults were under increased stress in their earlier years. This may have been associated with increased interpersonal violence and dependence on few food sources occurring with greater scarcity. © 2018 Wiley Periodicals, Inc.

Exercise Promotes Healthy Aging of Skeletal Muscle

PubMed Central

Cartee, Gregory D.; Hepple, Russell T.; Bamman, Marcas M.; Zierath, Juleen R.

2016-01-01

Primary aging is the progressive and inevitable process of bodily deterioration during adulthood. In skeletal muscle, primary aging causes defective mitochondrial energetics, and reduced muscle mass. Secondary aging refers to additional deleterious structural and functional age-related changes caused by diseases and lifestyle factors. Secondary aging can exacerbate deficits in mitochondrial function and muscle mass, concomitant with the development of skeletal muscle insulin resistance. Exercise opposes deleterious effects of secondary aging by preventing the decline in mitochondrial respiration, mitigating aging-related loss of muscle mass and enhancing insulin sensitivity. This review focuses on mechanisms by which exercise promotes “healthy aging” by inducing modifications in skeletal muscle. PMID:27304505

Skeletal and body composition evaluation

NASA Technical Reports Server (NTRS)

Mazess, R. B.

1983-01-01

Research on radiation detectors for absorptiometry; analysis of errors affective single photon absorptiometry and development of instrumentation; analysis of errors affecting dual photon absorptiometry and development of instrumentation; comparison of skeletal measurements with other techniques; cooperation with NASA projects for skeletal evaluation in spaceflight (Experiment MO-78) and in laboratory studies with immobilized animals; studies of postmenopausal osteoporosis; organization of scientific meetings and workshops on absorptiometric measurement; and development of instrumentation for measurement of fluid shifts in the human body were performed. Instrumentation was developed that allows accurate and precise (2% error) measurements of mineral content in compact and trabecular bone and of the total skeleton. Instrumentation was also developed to measure fluid shifts in the extremities. Radiation exposure with those procedures is low (2-10 MREM). One hundred seventy three technical reports and one hundred and four published papers of studies from the University of Wisconsin Bone Mineral Lab are listed.

Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy.

PubMed

Burns, David T; Donkervoort, Sandra; Müller, Juliane S; Knierim, Ellen; Bharucha-Goebel, Diana; Faqeih, Eissa Ali; Bell, Stephanie K; AlFaifi, Abdullah Y; Monies, Dorota; Millan, Francisca; Retterer, Kyle; Dyack, Sarah; MacKay, Sara; Morales-Gonzalez, Susanne; Giunta, Michele; Munro, Benjamin; Hudson, Gavin; Scavina, Mena; Baker, Laura; Massini, Tara C; Lek, Monkol; Hu, Ying; Ezzo, Daniel; AlKuraya, Fowzan S; Kang, Peter B; Griffin, Helen; Foley, A Reghan; Schuelke, Markus; Horvath, Rita; Bönnemann, Carsten G

2018-05-03

The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3, EXOSC8, and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in vitro in affected individuals' fibroblasts and skeletal muscle and in vivo in zebrafish. The clinical presentation was severe, early-onset, progressive SMA-like motor neuronopathy, cerebellar atrophy, and in one affected individual, congenital fractures of the long bones. Three affected individuals of different ethnicity carried the homozygous c.41T>C (p.Leu14Pro) variant, whereas one affected individual was compound heterozygous for c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161 ∗ ). We detected reduced EXOSC9 in fibroblasts and skeletal muscle and observed a reduction of the whole multi-subunit exosome complex on blue-native polyacrylamide gel electrophoresis. RNA sequencing of fibroblasts and skeletal muscle detected significant >2-fold changes in genes involved in neuronal development and cerebellar and motor neuron degeneration, demonstrating the widespread effect of the variants. Morpholino oligonucleotide knockdown and CRISPR/Cas9-mediated mutagenesis of exosc9 in zebrafish recapitulated aspects of the human phenotype, as they have in other zebrafish models of exosomal disease. Specifically, portions of the cerebellum and hindbrain were absent, and motor neurons failed to develop and migrate properly. In summary, we show that variants in EXOSC9 result in a neurological syndrome combining cerebellar atrophy and spinal motoneuronopathy, thus expanding the list of human exosomopathies. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Heart and skeletal muscle inflammation (HSMI) disease diagnosed on a British Columbia salmon farm through a longitudinal farm study

PubMed Central

Ferguson, Hugh W.; Schulze, Angela D.; Kaukinen, Karia H.; Li, Shaorong; Vanderstichel, Raphaël; Wessel, Øystein; Rimstad, Espen; Gardner, Ian A.; Hammell, K. Larry; Miller, Kristina M.

2017-01-01

Heart and skeletal muscle inflammation (HSMI) is an emerging disease of marine-farmed Atlantic Salmon (Salmo salar), first recognized in 1999 in Norway, and later also reported in Scotland and Chile. We undertook a longitudinal study involving health evaluation over an entire marine production cycle on one salmon farm in British Columbia (Canada). In previous production cycles at this farm site and others in the vicinity, cardiac lesions not linked to a specific infectious agent or disease were identified. Histologic assessments of both live and moribund fish samples collected at the farm during the longitudinal study documented at the population level the development, peak, and recovery phases of HSMI. The fish underwent histopathological evaluation of all tissues, Twort’s Gram staining, immunohistochemistry, and molecular quantification in heart tissue of 44 agents known or suspected to cause disease in salmon. Our analysis showed evidence of HSMI histopathological lesions over an 11-month timespan, with the prevalence of lesions peaking at 80–100% in sampled fish, despite mild clinical signs with no associated elevation in mortalities reported at the farm level. Diffuse mononuclear inflammation and myodegeneration, consistent with HSMI, was the predominant histologic observation in affected heart and skeletal muscle. Infective agent monitoring identified three agents at high prevalence in salmon heart tissue, including Piscine orthoreovirus (PRV), and parasites Paranucleospora theridion and Kudoa thyrsites. However, PRV alone was statistically correlated with the occurrence and severity of histopathological lesions in the heart. Immunohistochemical staining further localized PRV throughout HSMI development, with the virus found mainly within red blood cells in early cases, moving into the cardiomyocytes within or, more often, on the periphery of the inflammatory reaction during the peak disease, and reducing to low or undetectable levels later in the production cycle. This study represents the first longitudinal assessment of HSMI in a salmon farm in British Columbia, providing new insights on the pathogenesis of the disease. PMID:28225783

Desmin Is Essential for the Tensile Strength and Integrity of Myofibrils but Not for Myogenic Commitment, Differentiation, and Fusion of Skeletal Muscle

PubMed Central

Li, Zhenlin; Mericskay, Mathias; Agbulut, Onnik; Butler-Browne, Gillian; Carlsson, Lena; Thornell, Lars-Eric; Babinet, Charles; Paulin, Denise

1997-01-01

A null mutation was introduced into the mouse desmin gene by homologous recombination. The desmin knockout mice (Des −/−) develop normally and are fertile. However, defects were observed after birth in skeletal, smooth, and cardiac muscles (Li, Z., E. Colucci-Guyon, M. Pincon-Raymond, M. Mericskay, S. Pournin, D. Paulin, and C. Babinet. 1996. Dev. Biol. 175:362–366; Milner, D.J., G. Weitzer, D. Tran, A. Bradley, and Y. Capetanaki. 1996. J. Cell Biol. 134:1255– 1270). In the present study we have carried out a detailed analysis of somitogenesis, muscle formation, maturation, degeneration, and regeneration in Des −/− mice. Our results demonstrate that all early stages of muscle differentiation and cell fusion occur normally. However, after birth, modifications were observed essentially in weight-bearing muscles such as the soleus or continually used muscles such as the diaphragm and the heart. In the absence of desmin, mice were weaker and fatigued more easily. The lack of desmin renders these fibers more susceptible to damage during contraction. We observed a process of degeneration of myofibers, accompanied by macrophage infiltration, and followed by a process of regeneration. These cycles of degeneration and regeneration resulted in a relative increase in slow myosin heavy chain (MHC) and decrease in fast MHC. Interestingly, this second wave of myofibrillogenesis during regeneration was often aberrant and showed signs of disorganization. Subsarcolemmal accumulation of mitochondria were also observed in these muscles. The lack of desmin was not compensated by an upregulation of vimentin in these mice either during development or regeneration. Absence of desmin filaments within the sarcomere does not interfere with primary muscle formation or regeneration. However, myofibrillogenesis in regenerating fibers is often abortive, indicating that desmin may be implicated in this repair process. The results presented here show that desmin is essential to maintain the structural integrity of highly solicited skeletal muscle. PMID:9314534

In Vivo Rodent Models of Skeletal Muscle Adaptation to Decreased Use.

PubMed

Cho, Su Han; Kim, Jang Hoe; Song, Wook

2016-03-01

Skeletal muscle possesses plasticity and adaptability to external and internal physiological changes. Due to these characteristics, skeletal muscle shows dramatic changes depending on its response to stimuli such as physical activity, nutritional changes, disease status, and environmental changes. Modulation of the rate of protein synthesis/degradation plays an important role in atrophic responses. The purpose of this review is to describe different features of skeletal muscle adaptation with various models of deceased use. In this review, four models were addressed: immobilization, spinal cord transection, hindlimb unloading, and aging. Immobilization is a form of decreased use in which skeletal muscle shows electrical activity, tension development, and motion. These results differ by muscle group. Spinal cord transection was selected to simulate spinal cord injury. Similar to the immobilization model, dramatic atrophy occurs in addition to fiber type conversion in this model. Despite the fact that electromyography shows unremarkable changes in muscle after hindlimb unloading, decreased muscle mass and contractile force are observed. Lastly, aging significantly decreases the numbers of muscle fibers and motor units. Skeletal muscle responses to decreased use include decreased strength, decreased fiber numbers, and fiber type transformation. These four models demonstrated different changes in the skeletal muscle. This review elucidates the different skeletal muscle adaptations in these four decreased use animal models and encourages further studies.

AMPK in skeletal muscle function and metabolism

PubMed Central

Kjøbsted, Rasmus; Hingst, Janne R.; Fentz, Joachim; Foretz, Marc; Sanz, Maria-Nieves; Pehmøller, Christian; Shum, Michael; Marette, André; Mounier, Remi; Treebak, Jonas T.; Wojtaszewski, Jørgen F. P.; Viollet, Benoit; Lantier, Louise

2018-01-01

Skeletal muscle possesses a remarkable ability to adapt to various physiologic conditions. AMPK is a sensor of intracellular energy status that maintains energy stores by fine-tuning anabolic and catabolic pathways. AMPK’s role as an energy sensor is particularly critical in tissues displaying highly changeable energy turnover. Due to the drastic changes in energy demand that occur between the resting and exercising state, skeletal muscle is one such tissue. Here, we review the complex regulation of AMPK in skeletal muscle and its consequences on metabolism (e.g., substrate uptake, oxidation, and storage as well as mitochondrial function of skeletal muscle fibers). We focus on the role of AMPK in skeletal muscle during exercise and in exercise recovery. We also address adaptations to exercise training, including skeletal muscle plasticity, highlighting novel concepts and future perspectives that need to be investigated. Furthermore, we discuss the possible role of AMPK as a therapeutic target as well as different AMPK activators and their potential for future drug development.—Kjøbsted, R., Hingst, J. R., Fentz, J., Foretz, M., Sanz, M.-N., Pehmøller, C., Shum, M., Marette, A., Mounier, R., Treebak, J. T., Wojtaszewski, J. F. P., Viollet, B., Lantier, L. AMPK in skeletal muscle function and metabolism. PMID:29242278

Proteomics of Skeletal Muscle: Focus on Insulin Resistance and Exercise Biology

PubMed Central

Deshmukh, Atul S.

2016-01-01

Skeletal muscle is the largest tissue in the human body and plays an important role in locomotion and whole body metabolism. It accounts for ~80% of insulin stimulated glucose disposal. Skeletal muscle insulin resistance, a primary feature of Type 2 diabetes, is caused by a decreased ability of muscle to respond to circulating insulin. Physical exercise improves insulin sensitivity and whole body metabolism and remains one of the most promising interventions for the prevention of Type 2 diabetes. Insulin resistance and exercise adaptations in skeletal muscle might be a cause, or consequence, of altered protein expressions profiles and/or their posttranslational modifications (PTMs). Mass spectrometry (MS)-based proteomics offer enormous promise for investigating the molecular mechanisms underlying skeletal muscle insulin resistance and exercise-induced adaptation; however, skeletal muscle proteomics are challenging. This review describes the technical limitations of skeletal muscle proteomics as well as emerging developments in proteomics workflow with respect to samples preparation, liquid chromatography (LC), MS and computational analysis. These technologies have not yet been fully exploited in the field of skeletal muscle proteomics. Future studies that involve state-of-the-art proteomics technology will broaden our understanding of exercise-induced adaptations as well as molecular pathogenesis of insulin resistance. This could lead to the identification of new therapeutic targets. PMID:28248217

Early life factors in the pathogenesis of osteoporosis.

PubMed

Winsloe, Chivon; Earl, Susie; Dennison, Elaine M; Cooper, Cyrus; Harvey, Nicholas C

2009-12-01

Osteoporosis is a major public health burden through associated fragility fractures. Bone mass, a composite of bone size and volumetric density, increases through early life and childhood to a peak in early adulthood. The peak bone mass attained is a strong predictor of future risk of osteoporosis. Evidence is accruing that environmental factors in utero and in early infancy may permanently modify the postnatal pattern of skeletal growth to peak and thus influence risk of osteoporosis in later life. This article describes the latest data in this exciting area of research, including novel epigenetic and translation work, which should help to elucidate the underlying mechanisms and give rise to potential public health interventions to reduce the burden of osteoporotic fracture in future generations.

Association between growth stunting with dental development and skeletal maturation stage.

PubMed

Flores-Mir, Carlos; Mauricio, Franco Raul; Orellana, Maria Fernanda; Major, Paul William

2005-11-01

The aim of this study was to determine the influence of growth stunting on the maturation stage of the medium phalanx of the third finger (MP3) and the dental development of the left mandibular canine in 280 high school children (140 stunted and 140 normal controls; equally distributed by sex) between 9.5 and 16.5 years of age, from a representative Peruvian school. Periapical radiographs of the MP3 from the left hand were used to determine the skeletal maturity stage, according to an adaptation of the Hägg and Taranger method. Panoramic radiographs were used to determine the dental maturity stage of the lower left canine, according to Demirjian method. Stunting was determined by relating height and age, according to the World Health Organization recommendations. There was no statistically significant difference in the skeletal maturation stage (P = .134) and the dental development stage (P = .497) according to nutritional status, even when considering different age groups (P > .183). A high correlation (r = 0.85) was found between both maturity indicators regardless of the nutritional status (growth stunted, r = 0.855 and normal controls, r = 0.863) or sex (boys, r = 0.809 and girls, r = 0.892). When skeletal level was considered, correlations values were similar between advanced (r = 0.903) and average (r = 0.895) maturers but lower (r = 0.751) for delayed maturers. Growth stunting was not associated with dental development and skeletal maturity stages in Peruvian school children.

Diffusion tensor imaging and T2 mapping in early denervated skeletal muscle in rats.

PubMed

Ha, Dong-Ho; Choi, Sunseob; Kang, Eun-Ju; Park, Hwan Tae

2015-09-01

To evaluate the temporal changes of diffusion tensor imaging (DTI) indices, T2 values, and visual signal intensity on various fat suppression techniques in the early state of denervated skeletal muscle in a rat model. Institutional Animal Care and Use Committee approval was obtained. Sciatic nerves of eight rats were transected for irreversible neurotmesis model. We examined normal lower leg and denervated muscles at 3 days, 1 week, and 2 weeks on a 3 Tesla MR. fractional anisotropy (FA), mean apparent diffusion coefficient (mADC), and T2 values were measured by using DTI and T2 mapping scan. We subjectively classified the signal intensity change on various fat suppression images into the following three grades: negative, suspicious, and definite change. Wilcoxon-sign rank test and Kruskal-Wallis test were used for the comparison of FA, mADC, T2 values. McNemar's test was used for comparing signal intensity change among fat suppression techniques. FA values of denervated muscles at 3 days (0.35 ± 0.06), 1 week (0.29 ± 0.04), and 2 weeks (0.34 ± 0.05) were significantly (P < 0.05) lower than that in the control group (0.54 ± 0.17). mADC of denervated muscles decreased without statistically significant (P > 0.05) change. T2 values were significantly increased at 1 week (38.11 ± 6.42 ms, P = 0.017) and markedly increased at 2 weeks (46.53 ± 5.17 ms, P = 0.012). The grade of visual signal intensity change on chemical shift selective fat saturation, STIR and IDEAL images were identical in all cases (P = 1.000). FA and T2 values can demonstrate the early temporal changes in denervated rat skeletal muscle. © 2014 Wiley Periodicals, Inc.

Identification of disease specific pathways using in vivo SILAC proteomics in dystrophin deficient mdx mouse.

PubMed

Rayavarapu, Sree; Coley, William; Cakir, Erdinc; Jahnke, Vanessa; Takeda, Shin'ichi; Aoki, Yoshitsugu; Grodish-Dressman, Heather; Jaiswal, Jyoti K; Hoffman, Eric P; Brown, Kristy J; Hathout, Yetrib; Nagaraju, Kanneboyina

2013-05-01

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder caused by a mutation in the dystrophin gene. DMD is characterized by progressive weakness of skeletal, cardiac, and respiratory muscles. The molecular mechanisms underlying dystrophy-associated muscle weakness and damage are not well understood. Quantitative proteomics techniques could help to identify disease-specific pathways. Recent advances in the in vivo labeling strategies such as stable isotope labeling in mouse (SILAC mouse) with (13)C6-lysine or stable isotope labeling in mammals (SILAM) with (15)N have enabled accurate quantitative analysis of the proteomes of whole organs and tissues as a function of disease. Here we describe the use of the SILAC mouse strategy to define the underlying pathological mechanisms in dystrophin-deficient skeletal muscle. Differential SILAC proteome profiling was performed on the gastrocnemius muscles of 3-week-old (early stage) dystrophin-deficient mdx mice and wild-type (normal) mice. The generated data were further confirmed in an independent set of mdx and normal mice using a SILAC spike-in strategy. A total of 789 proteins were quantified; of these, 73 were found to be significantly altered between mdx and normal mice (p < 0.05). Bioinformatics analyses using Ingenuity Pathway software established that the integrin-linked kinase pathway, actin cytoskeleton signaling, mitochondrial energy metabolism, and calcium homeostasis are the pathways initially affected in dystrophin-deficient muscle at early stages of pathogenesis. The key proteins involved in these pathways were validated by means of immunoblotting and immunohistochemistry in independent sets of mdx mice and in human DMD muscle biopsies. The specific involvement of these molecular networks early in dystrophic pathology makes them potential therapeutic targets. In sum, our findings indicate that SILAC mouse strategy has uncovered previously unidentified pathological pathways in mouse models of human skeletal muscle disease.

Identification of Disease Specific Pathways Using in Vivo SILAC Proteomics in Dystrophin Deficient mdx Mouse*

PubMed Central

Rayavarapu, Sree; Coley, William; Cakir, Erdinc; Jahnke, Vanessa; Takeda, Shin'ichi; Aoki, Yoshitsugu; Grodish-Dressman, Heather; Jaiswal, Jyoti K.; Hoffman, Eric P.; Brown, Kristy J.; Hathout, Yetrib; Nagaraju, Kanneboyina

2013-01-01

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder caused by a mutation in the dystrophin gene. DMD is characterized by progressive weakness of skeletal, cardiac, and respiratory muscles. The molecular mechanisms underlying dystrophy-associated muscle weakness and damage are not well understood. Quantitative proteomics techniques could help to identify disease-specific pathways. Recent advances in the in vivo labeling strategies such as stable isotope labeling in mouse (SILAC mouse) with 13C6-lysine or stable isotope labeling in mammals (SILAM) with 15N have enabled accurate quantitative analysis of the proteomes of whole organs and tissues as a function of disease. Here we describe the use of the SILAC mouse strategy to define the underlying pathological mechanisms in dystrophin-deficient skeletal muscle. Differential SILAC proteome profiling was performed on the gastrocnemius muscles of 3-week-old (early stage) dystrophin-deficient mdx mice and wild-type (normal) mice. The generated data were further confirmed in an independent set of mdx and normal mice using a SILAC spike-in strategy. A total of 789 proteins were quantified; of these, 73 were found to be significantly altered between mdx and normal mice (p < 0.05). Bioinformatics analyses using Ingenuity Pathway software established that the integrin-linked kinase pathway, actin cytoskeleton signaling, mitochondrial energy metabolism, and calcium homeostasis are the pathways initially affected in dystrophin-deficient muscle at early stages of pathogenesis. The key proteins involved in these pathways were validated by means of immunoblotting and immunohistochemistry in independent sets of mdx mice and in human DMD muscle biopsies. The specific involvement of these molecular networks early in dystrophic pathology makes them potential therapeutic targets. In sum, our findings indicate that SILAC mouse strategy has uncovered previously unidentified pathological pathways in mouse models of human skeletal muscle disease. PMID:23297347

Short Stature, Accelerated Bone Maturation, and Early Growth Cessation Due to Heterozygous Aggrecan Mutations

PubMed Central

Nilsson, Ola; Guo, Michael H.; Dunbar, Nancy; Popovic, Jadranka; Flynn, Daniel; Jacobsen, Christina; Lui, Julian C.; Hirschhorn, Joel N.; Baron, Jeffrey

2014-01-01

Context: Many children with idiopathic short stature have a delayed bone age. Idiopathic short stature with advanced bone age is far less common. Objective: The aim was to identify underlying genetic causes of short stature with advanced bone age. Setting and Design: We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation. Results: Affected individuals presented with short stature [adult heights −2.3 to −4.2 standard deviation scores (SDS)] with histories of early growth cessation or childhood short stature (height SDS −1.9 to −3.5 SDS), advancement of bone age, and normal endocrine evaluations. Whole-exome sequencing identified novel heterozygous variants in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The variants were present in all affected, but in no unaffected, family members. In Family 1, a novel frameshift mutation in exon 3 (c.272delA) was identified, which is predicted to cause early truncation of the aggrecan protein. In Family 2, a base-pair substitution was found in a highly conserved location within a splice donor site (c.2026+1G>A), which is also likely to alter the amino acid sequence of a large portion of the protein. In Family 3, a missense variant (c.7064T>C) in exon 14 affects a highly conserved residue (L2355P) and is strongly predicted to perturb protein function. Conclusions: Our study demonstrates that heterozygous mutations in ACAN can cause a mild skeletal dysplasia, which presents clinically as short stature with advanced bone age. The accelerating effect on skeletal maturation has not previously been noted in the few prior reports of human ACAN mutations. Our findings thus expand the spectrum of ACAN defects and provide a new molecular genetic etiology for the unusual child who presents with short stature and accelerated skeletal maturation. PMID:24762113

Myf5 and Myogenin in the development of thymic myoid cells - Implications for a murine in vivo model of myasthenia gravis.

PubMed

Hu, Bo; Simon-Keller, Katja; Küffer, Stefan; Ströbel, Philipp; Braun, Thomas; Marx, Alexander; Porubsky, Stefan

2016-03-01

Myasthenia gravis (MG) is caused by autoantibodies against the neuromuscular junction of striated muscle. Most MG patients have autoreactive T- and B-cells directed to the acetylcholine receptor (AChR). To achieve immunologic tolerance, developing thymocytes are normally eliminated after recognition of self-antigen-derived peptides. Presentation of muscle-specific antigens is likely achieved through two pathways: on medullary thymic epithelial cells and on medullary dendritic cells cross-presenting peptides derived from a unique population of thymic myoid cells (TMC). Decades ago, it has been hypothesized that TMC play a key role in the induction of immunological tolerance towards skeletal muscle antigens. However, an experimental model to address this postulate has not been available. To generate such a model, we tested the hypothesis that the development of TMC depends on myogenic regulatory factors. To this end, we utilized Myf5-deficient mice, which lack the first wave of muscle cells but form normal skeletal muscles later during development, and Myogenin-deficient mice, which fail to form differentiated myofibers. We demonstrate for the first time that Myf5- and Myogenin-deficient mice showed a partial or complete, respectively, loss of TMC in an otherwise regularly structured thymus. To overcome early postnatal lethality of muscle-deficient, Myogenin-knockout mice we transplanted Myogenin-deficient fetal thymuses into Foxn1(nu/nu) mice that lack their own thymus anlage. We found that the transplants are functional but lack TMC. In combination with established immunization strategies (utilizing AChR or Titin), this model should enable us in the future testing the hypothesis that TMC play an indispensable role in the development of central tolerance towards striated muscle antigens. Copyright © 2015 Elsevier Inc. All rights reserved.

Influence of complex childhood diseases on variation in growth and skeletal development.

PubMed

Zemel, Babette S

2017-03-01

The study of human growth and skeletal development by human biologists is framed by the larger theoretical concerns regarding the underpinnings of population variation and human evolution. This unique perspective is directly relevant to the assessment of child health and well-being at the individual and group level, as well as the construction of growth charts. Environmental, behavioral (nutrition and physical activity), and disease-related factors can prevent attainment of full genetic potential for growth. Undernutrition is most often the cause of growth faltering and poor skeletal development. Disease related factors, such as malabsorption, inflammation, and immobility also have profound effects. These effects will be illustrated with examples from diseases such as cystic fibrosis, inflammatory bowel disease, and Down syndrome. The need for separate growth charts for children with genetic disorders is often controversial because of potential medical and/or nutritional complications associated with some disorders. Children with Alagille syndrome and Down syndrome will be used to illustrate the advantages and limitations of syndrome-specific charts. This overview of health and disease effects on growth and skeletal development provides insights into the plasticity of human growth and its sensitivity to overall health and well-being. © 2017 Wiley Periodicals, Inc.

The dynamic response and shock-recovery of porcine skeletal muscle tissue

NASA Astrophysics Data System (ADS)

Wilgeroth, James Michael; Hazell, Paul; Appleby-Thomas, Gareth James

2012-03-01

A soft-capture system allowing for one-dimensional shock loading and release of soft tissues via the plate-impact technique has been developed. In addition, we present the numerical simulation of a shock-recovery experiment involving porcine skeletal muscle and further investigate the effects of the transient wave on the structure of the tissue via transmission electron microscope (TEM). This paper forms part of an ongoing research programme on the dynamic behaviour of skeletal muscle tissue.

Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor alpha1 or beta.

PubMed

O'Shea, Patrick J; Bassett, J H Duncan; Sriskantharajah, Srividya; Ying, Hao; Cheng, Sheue-yann; Williams, Graham R

2005-12-01

Thyroid hormone (T(3)) regulates bone turnover and mineralization in adults and is essential for skeletal development. Surprisingly, we identified a phenotype of skeletal thyrotoxicosis in T(3) receptor beta(PV) (TRbeta(PV)) mice in which a targeted frameshift mutation in TRbeta results in resistance to thyroid hormone. To characterize mechanisms underlying thyroid hormone action in bone, we analyzed skeletal development in TRalpha1(PV) mice in which the same PV mutation was targeted to TRalpha1. In contrast to TRbeta(PV) mice, TRalpha1(PV) mutants exhibited skeletal hypothyroidism with delayed endochondral and intramembranous ossification, severe postnatal growth retardation, diminished trabecular bone mineralization, reduced cortical bone deposition, and delayed closure of the skull sutures. Skeletal hypothyroidism in TRalpha1(PV) mutants was accompanied by impaired GH receptor and IGF-I receptor expression and signaling in the growth plate, whereas GH receptor and IGF-I receptor expression and signaling were increased in TRbeta(PV) mice. These data indicate that GH receptor and IGF-I receptor are physiological targets for T(3) action in bone in vivo. The divergent phenotypes observed in TRalpha1(PV) and TRbeta(PV) mice arise because the pituitary gland is a TRbeta-responsive tissue, whereas bone is TRalpha responsive. These studies provide a new understanding of the complex relationship between central and peripheral thyroid status.

Transcriptional dynamics of immune, growth and stress related genes in skeletal muscle of the fine flounder (Paralichthys adpersus) during different nutritional statuses.

PubMed

Valenzuela, Cristián A; Escobar, Daniela; Perez, Lorena; Zuloaga, Rodrigo; Estrada, Juan Manuel; Mercado, Luis; Valdés, Juan Antonio; Molina, Alfredo

2015-11-01

The effects of stress on immune activity and growth in early vertebrates have not been studied in detail. The present study used fine flounder (Paralichthys adspersus) skeletal muscle as a model to evaluate molecules involved in the stress response, including the glucocorticoid receptors, foxo1/3, and the target genes of these. Additionally, immune markers (il-1β and tnfα) and effector molecules of atrophy (bnip3, caspase-3, and lc3) were assessed. These molecules were analyzed during periods of long-term fasting and refeeding. During fasting, gene expression related to the stress response and atrophy increased; whereas immune markers were down-regulated. During refeeding, atrophy- and stress-related gene expression significantly decreased. In contrast, immune markers were up-regulated. These results provide novel insight on the control of growth in the skeletal muscle of a non-mammalian species under a stressful condition, suggesting that growth, stress, and immune activity in muscle are closely related and coordinated by orchestrated transcriptional dynamics. Copyright © 2015 Elsevier Ltd. All rights reserved.

Osteoarchaeological evidence for leprosy from western Central Asia.

PubMed

Blau, Soren; Yagodin, Vadim

2005-02-01

Published reports of palaeopathological analyses of skeletal collections from Central Asia are, to date, scarce. During the macroscopic examination of skeletal remains dating to the early first millennium AD from the Ustyurt Plateau, Uzbekistan, diagnostic features suggestive of leprosy were found on one individual from Devkesken 6. This adult female exhibited rhinomaxillary changes indicative of leprosy: resorption of the anterior nasal spine, rounding and widening of the nasal aperture, erosion of the alveolar margin, loss of a maxillary incisor, and inflammatory changes in the hard palate. While it is unclear whether the bones of the hands and the feet from this individual were absent as a result of collection strategy or poor preservation, lesions affecting the tibia and fibula were recorded, and the ways in which they may be related to a diagnosis of leprosy are discussed. This is the first skeletal evidence of leprosy from Central Asia and raises questions not only about the spread of the disease in the past, but also about the living conditions of what traditionally were thought of as nomadic peoples. 2004 Wiley-Liss, Inc.

A novel mutation in PNPLA2 causes neutral lipid storage disease with myopathy and triglyceride deposit cardiomyovasculopathy: a case report and literature review.

PubMed

Kaneko, Kimihiko; Kuroda, Hiroshi; Izumi, Rumiko; Tateyama, Maki; Kato, Masaaki; Sugimura, Koichiro; Sakata, Yasuhiko; Ikeda, Yoshihiko; Hirano, Ken-Ichi; Aoki, Masashi

2014-07-01

Mutations in PNPLA2 cause neutral lipid storage disease with myopathy (NLSDM) or triglyceride deposit cardiomyovasculopathy (TGCV). We report a 59-year-old patient with NLSDM/TGCV presenting marked asymmetric skeletal myopathy and cardiomyovasculopathy. Skeletal muscle and endomyocardial biopsies showed cytoplasmic vacuoles containing neutral lipid. Gene analysis revealed a novel homozygous mutation (c.576delC) in PNPLA2. We reviewed 37 genetically-proven NLSDM/TGCV cases; median age was 30 years; distribution of myopathy was proximal (69%) and distal predominant (16%); asymmetric myopathy (right>left) was reported in 41% of the patients. Frequently-affected muscles were posterior compartment of leg (75%), shoulder girdle to upper arm (50%), and paraspinal (33%). Skeletal muscle biopsies showed lipid accumulation in 100% and rimmed vacuoles in 22%. Frequent comorbidities were cardiomyopathy (44%), hyperlipidemia (23%), diabetes mellitus (24%), and pancreatitis (14%). PNPLA2 mutations concentrated in Exon 4-7 without apparent genotype-phenotype correlations. To know the characteristic features is essential for the early diagnosis of NLSDM/TGCV. Copyright © 2014 Elsevier B.V. All rights reserved.

Cholesterol depletion by methyl-beta-cyclodextrin enhances myoblast fusion and induces the formation of myotubes with disorganized nuclei.

PubMed

Mermelstein, Cláudia S; Portilho, Débora M; Medeiros, Rommel B; Matos, Aline R; Einicker-Lamas, Marcelo; Tortelote, Giovane G; Vieyra, Adalberto; Costa, Manoel L

2005-02-01

The formation of a skeletal muscle fiber begins with the withdrawal of committed mononucleated precursors from the cell cycle. These myoblasts elongate while aligning with each other, guided by recognition between their membranes. This step is followed by cell fusion and the formation of long striated multinucleated myotubes. We used methyl-beta-cyclodextrin (MCD) in primary cultured chick skeletal muscle cells to deplete membrane cholesterol and investigate its role during myogenesis. MCD promoted a significant increase in the expression of troponin T, enhanced myoblast fusion, and induced the formation of large multinucleated myotubes with nuclei being clustered centrally and not aligned at the cell periphery. MCD myotubes were striated, as indicated by sarcomeric alpha-actinin staining, and microtubule and desmin filament distribution was not altered. Pre-fusion MCD-treated myoblasts formed large aggregates, with cadherin and beta-catenin being accumulated in cell adhesion contacts. We also found that the membrane microdomain marker GM1 was not present as clusters in the membrane of MCD-treated myoblasts. Our data demonstrate that cholesterol is involved in the early steps of skeletal muscle differentiation.

FISH SKELETAL ANOMALIES IN THE GULF OF MEXICO

EPA Science Inventory

Measurement of skeletal deformities in fish has been proposed as a means of monitoring pollution effects in marine environments. Effects of organic and inorganic contaminants on bone integrity are similar in that vertebral anomalies are produced, although they may develop through...

Skeletal Growth Dysregulation in Australian Male Infants and Toddlers With Autism Spectrum Disorder.

PubMed

Green, Cherie C; Dissanayake, Cheryl; Loesch, Danuta Z; Bui, Minh; Barbaro, Josephine

2018-06-01

Recent findings suggest that children with Autism Spectrum Disorder (ASD) are larger in size for head circumference (HC), height, and weight compared to typically developing (TD) children; however, little is known about their rate of growth, especially in height and weight. The current study aimed to: (a) confirm and extend upon previous findings of early generalized overgrowth in ASD; and (b) determine if there were any differences in the rate of growth between infants and toddlers with ASD compared to their TD peers. Measurements of HC, height, and weight were available for 135 boys with ASD and 74 TD boys, from birth through 3 years of age. Size and growth rate in HC, height, and weight were analyzed using a linear mixed-effects model. Infants with ASD were significantly smaller in size at birth for HC, body length, and weight compared to TD infants (all P < 0.05); however, they grew at a significantly faster rate in HC and height in comparison to the TD children (P < 0.001); there was no significant difference between the groups in growth rate for weight (P > 0.05). The results confirmed that male infants and toddlers with ASD exhibit skeletal growth dysregulation early in life. Autism Res 2018, 11: 846-856. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. Recent findings suggest that infants with Autism Spectrum Disorder (ASD) are smaller in size at birth compared to typically developing infants but grow larger than their peers during the first year. Little is known about their rate of growth, especially for height and weight. Our findings confirmed that infants with ASD are smaller in size at birth for head circumference (HC), height, and weight, but grow at a faster rate in HC and height than their peers from birth to 3 years. © 2018 International Society for Autism Research, Wiley Periodicals, Inc.

Radiographic correlation of dental and skeletal age: Third molar, an age indicator.

PubMed

Suma, Gn; Rao, Balaji B; Annigeri, Rajeshwari G; Rao, Dayashankara Jk; Goel, Sumit

2011-01-01

Age estimation plays a great role in forensic investigations, orthodontic and surgical treatment planning, and tooth transplantation. Teeth offer an excellent material for age determination by stages of development below the age of 25 years and by secondary changes after the age of 25 years. Third molar is often not included for this purpose due to its notorious developmental patterns. The aim of this study was to evaluate the development of third molar anlage in relation to skeletal maturities and the chronological age. One hundred and fifty-six young individuals, 78 males and 78 females, were selected. The stages of development of all the third molars in every individual were determined from panoramic radiographs. The skeletal development was assessed using hand wrist radiographs. Data were analyzed statistically for mean value, standard deviation and the relationship between the recorded characteristics. A STRONG CORRELATION WAS FOUND BETWEEN THIRD MOLAR DEVELOPMENT AND SKELETAL MATURITY (IN MALES: r=0.88, P<0.001; in females: r=0.77 for maxillary third molar and 0.89 for mandibular third molar, P<0.001). Hence, it is concluded that a strong correlation exists between chronological age, developmental stages of third molars and maturation of epiphyses of hand. Any of the three parameters could be used for the assessment of other maturities.

A Novel Protocol for Directed Differentiation of C9orf72-Associated Human Induced Pluripotent Stem Cells Into Contractile Skeletal Myotubes.

PubMed

Swartz, Elliot W; Baek, Jaeyun; Pribadi, Mochtar; Wojta, Kevin J; Almeida, Sandra; Karydas, Anna; Gao, Fen-Biao; Miller, Bruce L; Coppola, Giovanni

2016-11-01

: Induced pluripotent stem cells (iPSCs) offer an unlimited resource of cells to be used for the study of underlying molecular biology of disease, therapeutic drug screening, and transplant-based regenerative medicine. However, methods for the directed differentiation of skeletal muscle for these purposes remain scarce and incomplete. Here, we present a novel, small molecule-based protocol for the generation of multinucleated skeletal myotubes using eight independent iPSC lines. Through combinatorial inhibition of phosphoinositide 3-kinase (PI3K) and glycogen synthase kinase 3β (GSK3β) with addition of bone morphogenic protein 4 (BMP4) and fibroblast growth factor 2 (FGF2), we report up to 64% conversion of iPSCs into the myogenic program by day 36 as indicated by MYOG + cell populations. These cells began to exhibit spontaneous contractions as early as 34 days in vitro in the presence of a serum-free medium formulation. We used this protocol to obtain iPSC-derived muscle cells from frontotemporal dementia (FTD) patients harboring C9orf72 hexanucleotide repeat expansions (rGGGGCC), sporadic FTD, and unaffected controls. iPSCs derived from rGGGGCC carriers contained RNA foci but did not vary in differentiation efficiency when compared to unaffected controls nor display mislocalized TDP-43 after as many as 120 days in vitro. This study presents a rapid, efficient, and transgene-free method for generating multinucleated skeletal myotubes from iPSCs and a resource for further modeling the role of skeletal muscle in amyotrophic lateral sclerosis and other motor neuron diseases. Protocols to produce skeletal myotubes for disease modeling or therapy are scarce and incomplete. The present study efficiently generates functional skeletal myotubes from human induced pluripotent stem cells using a small molecule-based approach. Using this strategy, terminal myogenic induction of up to 64% in 36 days and spontaneously contractile myotubes within 34 days were achieved. Myotubes derived from patients carrying the C9orf72 repeat expansion show no change in differentiation efficiency and normal TDP-43 localization after as many as 120 days in vitro when compared to unaffected controls. This study provides an efficient, novel protocol for the generation of skeletal myotubes from human induced pluripotent stem cells that may serve as a valuable tool in drug discovery and modeling of musculoskeletal and neuromuscular diseases. ©AlphaMed Press.

In Vitro Tissue-Engineered Skeletal Muscle Models for Studying Muscle Physiology and Disease.

PubMed

Khodabukus, Alastair; Prabhu, Neel; Wang, Jason; Bursac, Nenad

2018-04-25

Healthy skeletal muscle possesses the extraordinary ability to regenerate in response to small-scale injuries; however, this self-repair capacity becomes overwhelmed with aging, genetic myopathies, and large muscle loss. The failure of small animal models to accurately replicate human muscle disease, injury and to predict clinically-relevant drug responses has driven the development of high fidelity in vitro skeletal muscle models. Herein, the progress made and challenges ahead in engineering biomimetic human skeletal muscle tissues that can recapitulate muscle development, genetic diseases, regeneration, and drug response is discussed. Bioengineering approaches used to improve engineered muscle structure and function as well as the functionality of satellite cells to allow modeling muscle regeneration in vitro are also highlighted. Next, a historical overview on the generation of skeletal muscle cells and tissues from human pluripotent stem cells, and a discussion on the potential of these approaches to model and treat genetic diseases such as Duchenne muscular dystrophy, is provided. Finally, the need to integrate multiorgan microphysiological systems to generate improved drug discovery technologies with the potential to complement or supersede current preclinical animal models of muscle disease is described. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cavin4b/Murcb Is Required for Skeletal Muscle Development and Function in Zebrafish.

PubMed

Housley, Michael P; Njaine, Brian; Ricciardi, Filomena; Stone, Oliver A; Hölper, Soraya; Krüger, Marcus; Kostin, Sawa; Stainier, Didier Y R

2016-06-01

Skeletal muscles provide metazoans with the ability to feed, reproduce and avoid predators. In humans, a heterogeneous group of genetic diseases, termed muscular dystrophies (MD), lead to skeletal muscle dysfunction. Mutations in the gene encoding Caveolin-3, a principal component of the membrane micro-domains known as caveolae, cause defects in muscle maintenance and function; however it remains unclear how caveolae dysfunction underlies MD pathology. The Cavin family of caveolar proteins can form membrane remodeling oligomers and thus may also impact skeletal muscle function. Changes in the distribution and function of Cavin4/Murc, which is predominantly expressed in striated muscles, have been reported to alter caveolae structure through interaction with Caveolin-3. Here, we report the generation and phenotypic analysis of murcb mutant zebrafish, which display impaired swimming capacity, skeletal muscle fibrosis and T-tubule abnormalities during development. To understand the mechanistic importance of Murc loss of function, we assessed Caveolin-1 and 3 localization and found it to be abnormal. We further identified an in vivo function for Murc in Erk signaling. These data link Murc with developmental defects in T-tubule formation and progressive muscle dysfunction, thereby providing a new candidate for the etiology of muscular dystrophy.

Synergy in free radical generation is blunted by high-fat diet induced alterations in skeletal muscle mitochondrial metabolism.

PubMed

Li, Yanjun; Periwal, Vipul

2013-03-05

Due to their role in cellular energetics and metabolism, skeletal muscle mitochondria appear to play a key role in the development of insulin resistance and type II diabetes. High-fat diet can induce higher levels of reactive oxygen species (ROS), evidenced by hydrogen peroxide (H2O2) emission from mitochondria, which may be causal for insulin resistance in skeletal muscle. The underlying mechanisms are unclear. Recent published data on single substrate (pyruvate, succinate, fat) metabolism in both normal diet (CON) and high-fat diet (HFD) states of skeletal muscle allowed us to develop an integrated mathematical model of skeletal muscle mitochondrial metabolism. Model simulations suggested that long-term HFD may affect specific metabolic reaction/pathways by altering enzyme activities. Our model allows us to predict oxygen consumption and ROS generation for any combination of substrates. In particular, we predict a synergy between (iso-membrane potential) combinations of pyruvate and fat in ROS production compared to the sum of ROS production with each substrate singly in both CON and HFD states. This synergy is blunted in the HFD state. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

An Automated System for Skeletal Maturity Assessment by Extreme Learning Machines

PubMed Central

Mansourvar, Marjan; Shamshirband, Shahaboddin; Raj, Ram Gopal; Gunalan, Roshan; Mazinani, Iman

2015-01-01

Assessing skeletal age is a subjective and tedious examination process. Hence, automated assessment methods have been developed to replace manual evaluation in medical applications. In this study, a new fully automated method based on content-based image retrieval and using extreme learning machines (ELM) is designed and adapted to assess skeletal maturity. The main novelty of this approach is it overcomes the segmentation problem as suffered by existing systems. The estimation results of ELM models are compared with those of genetic programming (GP) and artificial neural networks (ANNs) models. The experimental results signify improvement in assessment accuracy over GP and ANN, while generalization capability is possible with the ELM approach. Moreover, the results are indicated that the ELM model developed can be used confidently in further work on formulating novel models of skeletal age assessment strategies. According to the experimental results, the new presented method has the capacity to learn many hundreds of times faster than traditional learning methods and it has sufficient overall performance in many aspects. It has conclusively been found that applying ELM is particularly promising as an alternative method for evaluating skeletal age. PMID:26402795

Skeletal Muscle Pathophysiology: The Emerging Role of Spermine Oxidase and Spermidine.

PubMed

Cervelli, Manuela; Leonetti, Alessia; Duranti, Guglielmo; Sabatini, Stefania; Ceci, Roberta; Mariottini, Paolo

2018-02-14

Skeletal muscle comprises approximately 40% of the total body mass. Preserving muscle health and function is essential for the entire body in order to counteract chronic diseases such as type II diabetes, cardiovascular diseases, and cancer. Prolonged physical inactivity, particularly among the elderly, causes muscle atrophy, a pathological state with adverse outcomes such as poor quality of life, physical disability, and high mortality. In murine skeletal muscle C2C12 cells, increased expression of the spermine oxidase (SMOX) enzyme has been found during cell differentiation. Notably, SMOX overexpression increases muscle fiber size, while SMOX reduction was enough to induce muscle atrophy in multiple murine models. Of note, the SMOX reaction product spermidine appears to be involved in skeletal muscle atrophy/hypertrophy. It is effective in reactivating autophagy, ameliorating the myopathic defects of collagen VI-null mice. Moreover, spermidine treatment, if combined with exercise, can affect D-gal-induced aging-related skeletal muscle atrophy. This review hypothesizes a role for SMOX during skeletal muscle differentiation and outlines its role and that of spermidine in muscle atrophy. The identification of new molecular pathways involved in the maintenance of skeletal muscle health could be beneficial in developing novel therapeutic lead compounds to treat muscle atrophy.

DOE Office of Scientific and Technical Information (OSTI.GOV)

LeJemtel, T.H.; Scortichini, D.; Katz, S.

In patients with chronic congestive heart failure (CHF), skeletal muscle blood flow can be measured directly by the continuous thermodilution technique and by the xenon-133 clearance method. The continuous thermodilution technique requires retrograde catheterization of the femoral vein and, thus, cannot be repeated conveniently in patients during evaluation of pharmacologic interventions. The xenon-133 clearance, which requires only an intramuscular injection, allows repeated determination of skeletal muscle blood flow. In patients with severe CHF, a fixed capacity of the skeletal muscle vasculature to dilate appears to limit maximal exercise performance. Moreover, the changes in peak skeletal muscle blood flow noted duringmore » long-term administration of captopril, an angiotensin-converting enzyme inhibitor, appears to correlate with the changes in aerobic capacity. In patients with CHF, resting supine deep femoral vein oxygen content can be used as an indirect measurement of resting skeletal muscle blood flow. The absence of a steady state complicates the determination of peak skeletal muscle blood flow reached during graded bicycle or treadmill exercise in patients with chronic CHF. Indirect assessments of skeletal muscle blood flow and metabolism during exercise performed at submaximal work loads are currently developed in patients with chronic CHF.« less

Skeletal manifestations of juvenile hypothyroidism and the impact of treatment on skeletal system.

PubMed

Gutch, Manish; Philip, Rajeev; Philip, Renjit; Toms, Ajit; Saran, Sanjay; Gupta, K K

2013-10-01

Thyroid hormone mediates growth and development of the skeleton through its direct effects and through its permissive effects on growth hormone. The effect of hypothyroidism on bone is well described in congenital hypothyroidism, but the impact of thyroid hormone deficiency on a growing skeleton, as it happens with juvenile hypothyroidism, is less defined. In addition, the extent to which the skeletal defects of juvenile hypothyroidism revert on the replacement of thyroid hormone is not known. A study was undertaken in 29 juvenile autoimmune hypothyroid patients to study the skeletal manifestations of juvenile hypothyroidism and the impact of treatment of hypothyroidism on the skeletal system of juvenile patients. Hypothyroidism has a profound impact on the skeletal system and delayed bone age, dwarfism, and thickened bands at the metaphyseal ends being the most common findings. Post treatment, skeletal findings like delayed bone age and dwarfism improved significantly, but there were no significant changes in enlargement of sella, presence of wormian bones, epihyseal dysgenesis, vertebral changes and thickened band at the metaphyseal ends. With the treatment of hypothyroidism, there is an exuberant advancement of bone age, the catch up of bone age being approximately double of the chronological age advancement.

GSK-3β Function in Bone Regulates Skeletal Development, Whole-Body Metabolism, and Male Life Span

PubMed Central

Gillespie, J. R.; Bush, J. R.; Bell, G. I.; Aubrey, L. A.; Dupuis, H.; Ferron, M.; Kream, B.; DiMattia, G.; Patel, S.; Woodgett, J. R.; Karsenty, G.; Hess, D. A.; Beier, F.

2016-01-01

Glycogen synthase kinase 3 β (GSK-3β) is an essential negative regulator or “brake” on many anabolic-signaling pathways including Wnt and insulin. Global deletion of GSK-3β results in peri-natal lethality and various skeletal defects. The goal of our research was to determine GSK-3β cell-autonomous effects and postnatal roles in the skeleton. We used the 3.6-kb Col1a1 promoter to inactivate the Gsk3b gene (Col1a1-Gsk3b knockout) in skeletal cells. Mutant mice exhibit decreased body fat and postnatal bone growth, as well as delayed development of several skeletal elements. Surprisingly, the mutant mice display decreased circulating glucose and insulin levels despite normal expression of GSK-3β in metabolic tissues. We showed that these effects are due to an increase in global insulin sensitivity. Most of the male mutant mice died after weaning. Prior to death, blood glucose changed from low to high, suggesting a possible switch from insulin sensitivity to resistance. These male mice die with extremely large bladders that are preceded by damage to the urogenital tract, defects that are also seen type 2 diabetes. Our data suggest that skeletal-specific deletion of GSK-3β affects global metabolism and sensitizes male mice to developing type 2 diabetes. PMID:23904355

An advanced shape-fitting algorithm applied to quadrupedal mammals: improving volumetric mass estimates

PubMed Central

Brassey, Charlotte A.; Gardiner, James D.

2015-01-01

Body mass is a fundamental physical property of an individual and has enormous bearing upon ecology and physiology. Generating reliable estimates for body mass is therefore a necessary step in many palaeontological studies. Whilst early reconstructions of mass in extinct species relied upon isolated skeletal elements, volumetric techniques are increasingly applied to fossils when skeletal completeness allows. We apply a new ‘alpha shapes’ (α-shapes) algorithm to volumetric mass estimation in quadrupedal mammals. α-shapes are defined by: (i) the underlying skeletal structure to which they are fitted; and (ii) the value α, determining the refinement of fit. For a given skeleton, a range of α-shapes may be fitted around the individual, spanning from very coarse to very fine. We fit α-shapes to three-dimensional models of extant mammals and calculate volumes, which are regressed against mass to generate predictive equations. Our optimal model is characterized by a high correlation coefficient and mean square error (r2=0.975, m.s.e.=0.025). When applied to the woolly mammoth (Mammuthus primigenius) and giant ground sloth (Megatherium americanum), we reconstruct masses of 3635 and 3706 kg, respectively. We consider α-shapes an improvement upon previous techniques as resulting volumes are less sensitive to uncertainties in skeletal reconstructions, and do not require manual separation of body segments from skeletons. PMID:26361559

Fad24, a Positive Regulator of Adipogenesis, Is Required for S Phase Re-entry of C2C12 Myoblasts Arrested in G0 Phase and Involved in p27(Kip1) Expression at the Protein Level.

PubMed

Ochiai, Natsuki; Nishizuka, Makoto; Osada, Shigehiro; Imagawa, Masayoshi

2016-05-01

Factor for adipocyte differentiation 24 (fad24) is a positive regulator of adipogenesis. We previously found that human fad24 is abundantly expressed in skeletal muscle. However, the function of fad24 in skeletal muscle remains largely unknown. Because skeletal muscle is a highly regenerative tissue, we focused on the function of fad24 in skeletal muscle regeneration. In this paper, we investigated the role of fad24 in the cell cycle re-entry of quiescent C2C12 myoblasts-mimicked satellite cells. The expression levels of fad24 and histone acetyltransferase binding to ORC1 (hbo1), a FAD24-interacting factor, were elevated at the early phase of the regeneration process in response to cardiotoxin-induced muscle injury. The knockdown of fad24 inhibited the proliferation of quiescent myoblasts, whereas fad24 knockdown did not affect differentiation. S phase entry following serum activation is abrogated by fad24 knockdown in quiescent cells. Furthermore, fad24 knockdown cells show a marked accumulation of p27(Kip1) protein. These results suggest that fad24 may have an important role in the S phase re-entry of quiescent C2C12 cells through the regulation of p27(Kip1) at the protein level.

Inefficient skeletal muscle oxidative function flanks impaired motor neuron recruitment in Amyotrophic Lateral Sclerosis during exercise.

PubMed

Lanfranconi, F; Ferri, A; Corna, G; Bonazzi, R; Lunetta, C; Silani, V; Riva, N; Rigamonti, A; Maggiani, A; Ferrarese, C; Tremolizzo, L

2017-06-07

This study aimed to evaluate muscle oxidative function during exercise in amyotrophic lateral sclerosis patients (pALS) with non-invasive methods in order to assess if determinants of reduced exercise tolerance might match ALS clinical heterogeneity. 17 pALS, who were followed for 4 months, were compared with 13 healthy controls (CTRL). Exercise tolerance was assessed by an incremental exercise test on cycle ergometer measuring peak O 2 uptake ([Formula: see text]O 2peak ), vastus lateralis oxidative function by near infrared spectroscopy (NIRS) and breathing pattern ([Formula: see text]E peak ). pALS displayed: (1) 44% lower [Formula: see text]O 2peak vs. CTRL (p < 0.0001), paralleled by a 43% decreased peak skeletal muscle oxidative function (p < 0.01), with a linear regression between these two variables (r 2  = 0.64, p < 0.0001); (2) 46% reduced [Formula: see text]E peak vs. CTRL (p < 0.0001), achieved by using an inefficient breathing pattern (increasing respiratory frequency) from the onset until the end of exercise. Inefficient skeletal muscle O 2 function, when flanking the impaired motor units recruitment, is a major determinant of pALS clinical heterogeneity and working capacity exercise tolerance. CPET and NIRS are useful tools for detecting early stages of oxidative deficiency in skeletal muscles, disclosing individual impairments in the O 2 transport and utilization chain.

Characterization of human skeletal stem and bone cell populations using dielectrophoresis.

PubMed

Ismail, A; Hughes, M P; Mulhall, H J; Oreffo, R O C; Labeed, F H

2015-02-01

Dielectrophoresis (DEP) is a non-invasive cell analysis method that uses differences in electrical properties between particles and surrounding medium to determine a unique set of cellular properties that can be used as a basis for cell separation. Cell-based therapies using skeletal stem cells are currently one of the most promising areas for treating a variety of skeletal and muscular disorders. However, identifying and sorting these cells remains a challenge in the absence of unique skeletal stem cell markers. DEP provides an ideal method for identifying subsets of cells without the need for markers by using their dielectric properties. This study used a 3D dielectrophoretic well chip device to determine the dielectric characteristics of two osteosarcoma cell lines (MG-63 and SAOS-2) and an immunoselected enriched skeletal stem cell fraction (STRO-1 positive cell) of human bone marrow. Skeletal cells were exposed to a series of different frequencies to induce dielectrophoretic cell movement, and a model was developed to generate the membrane and cytoplasmic properties of the cell populations. Differences were observed in the dielectric properties of MG-63, SAOS-2 and STRO-1 enriched skeletal populations, which could potentially be used to sort cells in mixed populations. This study provide evidence of the ability to characterize different human skeletal stem and mature cell populations, and acts as a proof-of-concept that dielectrophoresis can be exploited to detect, isolate and separate skeletal cell populations from heterogeneous bone marrow cell populations. Copyright © 2012 John Wiley & Sons, Ltd.

Carbon isotopic evidence for photosynthesis in Early Cambrian oceans

NASA Astrophysics Data System (ADS)

Surge, Donna M.; Savarese, Michael; Dodd, J. Robert; Lohmann, Kyger C.

1997-06-01

Were the first metazoan reefs ecologically similar to modern tropical reefs, enabling them to persist under oligotrophic conditions? We tested the hypothesis of ecological similarity by employing a geochemical approach. Petrography, cathodoluminescence, trace elements, and stable isotope analyses of primary precipitates of the Lower Cambrian Ajax Limestone, South Australia, indicate preservation of original C isotopic composition. All primary carbonate components exhibit C isotopic values similar to the composition of inorganically precipitated fibrous marine cements, suggesting that archaeocyaths and the calcimicrobe Epiphyton precipitated skeletal carbonate in equilibrium with ambient seawater in the absence of vital effects. Such data do not support the contention that archaeocyaths possessed photosymbionts. However, a +0.55‰ shift in δ13C occurs in reefs developed under shallower-water conditions relative to deeper reefs. This shift suggests the stratification of primary production in Early Cambrian oceans. The pattern is similar to that seen in the modern ocean, whereby significant photosynthesis modulates the C isotopic composition of the photic zone.

Exercise Promotes Healthy Aging of Skeletal Muscle.

PubMed

Cartee, Gregory D; Hepple, Russell T; Bamman, Marcas M; Zierath, Juleen R

2016-06-14

Primary aging is the progressive and inevitable process of bodily deterioration during adulthood. In skeletal muscle, primary aging causes defective mitochondrial energetics and reduced muscle mass. Secondary aging refers to additional deleterious structural and functional age-related changes caused by diseases and lifestyle factors. Secondary aging can exacerbate deficits in mitochondrial function and muscle mass, concomitant with the development of skeletal muscle insulin resistance. Exercise opposes deleterious effects of secondary aging by preventing the decline in mitochondrial respiration, mitigating aging-related loss of muscle mass and enhancing insulin sensitivity. This review focuses on mechanisms by which exercise promotes "healthy aging" by inducing modifications in skeletal muscle. Copyright © 2016 Elsevier Inc. All rights reserved.

An Assessment of Correlation between Dermatoglyphic Patterns and Sagittal Skeletal Discrepancies

PubMed Central

Philip, Biju; Madathody, Deepika; Mathew, Manu; Paul, Jose; Dlima, Johnson Prakash

2017-01-01

Introduction Investigators over years have been fascinated by dermatoglyphic patterns which has led to the development of dermatoglyphics as a science with numerous applications in various fields other than being the best and most widely used method for personal identification. Aim To assess the correlation between dermatoglyphic patterns and sagittal skeletal discrepancies. Materials and Methods A total of 180 patients, aged 18-40 years, were selected from those who attended the outpatient clinic of the Deparment of Orthodontics and Dentofacial Orthopedics, Mar Baselios Dental College, Kothamangalam, Kerala, India. The fingerprints of both hands were taken by ink and stamp method after proper hand washing. The patterns of arches, loops and whorls in fingerprints were assessed. The total ridge count was also evaluated. Data was also sent to the fingerprint experts for expert evaluation. The sagittal jaw relation was determined from the patient’s lateral cephalogram. The collected data was then statistically analyzed using Chi-square tests, ANOVA and Post-hoc tests and a Multinomial regression prediction was also done. Results A significant association was observed between the dermatoglyphic pattern exhibited by eight fingers and the sagittal skeletal discrepancies (p<0.05). An increased distribution of whorl pattern was observed in the skeletal Class II with maxillary excess group and skeletal Class II with mandibular deficiency group while an increased distribution of loop pattern was seen in the skeletal Class III with mandibular excess group and skeletal Class III with maxillary deficiency group. Higher mean of total ridge count was also seen in the groups of skeletal Class II with maxillary excess and skeletal Class II with mandibular deficiency. Multinomial regression predicting skeletal pattern with respect to the fingerprint pattern showed that the left thumb impression fits the best model for predicting the skeletal pattern. Conclusion There was a significant association between dermatoglyphic patterns and sagittal skeletal discrepancies. Dermatoglyphics could serve as a cost effective screening tool of these craniofacial problems. PMID:28511506

Improved Cell Culture Method for Growing Contracting Skeletal Muscle Models

NASA Technical Reports Server (NTRS)

Marquette, Michele L.; Sognier, Marguerite A.

2013-01-01

An improved method for culturing immature muscle cells (myoblasts) into a mature skeletal muscle overcomes some of the notable limitations of prior culture methods. The development of the method is a major advance in tissue engineering in that, for the first time, a cell-based model spontaneously fuses and differentiates into masses of highly aligned, contracting myotubes. This method enables (1) the construction of improved two-dimensional (monolayer) skeletal muscle test beds; (2) development of contracting three-dimensional tissue models; and (3) improved transplantable tissues for biomedical and regenerative medicine applications. With adaptation, this method also offers potential application for production of other tissue types (i.e., bone and cardiac) from corresponding precursor cells.

Development of Sensory Receptors in Skeletal Muscle

NASA Technical Reports Server (NTRS)

DeSantis, Mark

2000-01-01

The two major goals for this project is to (1) examine the hindlimb walking pattern of offspring from the Flight dams as compared with offspring of the ground control groups from initiation of walking up to two months thereafter; and (2) examine skeletal muscle.

Insights into skeletal muscle development and applications in regenerative medicine.

PubMed

Tran, T; Andersen, R; Sherman, S P; Pyle, A D

2013-01-01

Embryonic and postnatal development of skeletal muscle entails highly regulated processes whose complexity continues to be deconstructed. One key stage of development is the satellite cell, whose niche is composed of multiple cell types that eventually contribute to terminally differentiated myotubes. Understanding these developmental processes will ultimately facilitate treatments of myopathies such as Duchenne muscular dystrophy (DMD), a disease characterized by compromised cell membrane structure, resulting in severe muscle wasting. One theoretical approach is to use pluripotent stem cells in a therapeutic setting to help replace degenerated muscle tissue. This chapter discusses key myogenic developmental stages and their regulatory pathways; artificial myogenic induction in pluripotent stem cells; advantages and disadvantages of DMD animal models; and therapeutic approaches targeting DMD. Furthermore, skeletal muscle serves as an excellent paradigm for understanding general cell fate decisions throughout development. Copyright © 2013 Elsevier Inc. All rights reserved.

Evaluation of skeletal maturation by comparing the hand wrist radiograph and cervical vertebrae as seen in lateral cephalogram.

PubMed

Mahajan, Shally

2011-01-01

Aim of this study was to determine the validity of cervical vertebrae radiographic assessment to predict skeletal maturation. Left-hand wrist and lateral cephalometric radiographs of 100 Bangalore children aged 8-18 years, divided into 10 groups of 10 subjects each with equal distribution of males and females, were measured. On left-hand wrist radiograph, the classification of Fishman was used to assess skeletal maturation. Cervical vertebrae maturation was evaluated with lateral cephalometric radiograph, using the stages developed by Hassel and Farman. The changes in hand wrist and cervical vertebrae were correlated. Significant association was observed between skeletal maturation indicator stages and cervical vertebrae maturation indicator stages. Correlation coefficient was found to be significant (P<0.0001). The results of the study indicated that the cervical vertebrae maturation and hand wrist skeletal maturation was significantly related.

Multiscale skeletal representation of images via Voronoi diagrams

NASA Astrophysics Data System (ADS)

Marston, R. E.; Shih, Jian C.

1995-08-01

Polygonal approximations to skeletal or stroke-based representations of 2D objects may consume less storage and be sufficient to describe their shape for many applications. Multi- scale descriptions of object outlines are well established but corresponding methods for skeletal descriptions have been slower to develop. In this paper we offer a method of generating scale-based skeletal representation via the Voronoi diagram. The method has the advantages of less time complexity, a closer relationship between the skeletons at each scale and better control over simplification of the skeleton at lower scales. This is because the algorithm starts by generating the skeleton at the coarsest scale first, then it produces each finer scale, in an iterative manner, directly from the level below. The skeletal approximations produced by the algorithm also benefit from a strong relationship with the object outline, due to the structure of the Voronoi diagram.

Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy.

PubMed

Osaki, Yoshinori; Nakagawa, Yoshimi; Miyahara, Shoko; Iwasaki, Hitoshi; Ishii, Akiko; Matsuzaka, Takashi; Kobayashi, Kazuto; Yatoh, Shigeru; Takahashi, Akimitsu; Yahagi, Naoya; Suzuki, Hiroaki; Sone, Hirohito; Ohashi, Ken; Ishibashi, Shun; Yamada, Nobuhiro; Shimano, Hitoshi

2015-10-23

HMG-CoA reductase (HMGCR) catalyzes the conversion of HMG-CoA to mevalonic acid (MVA); this is the rate-limiting enzyme of the mevalonate pathway that synthesizes cholesterol. Statins, HMGCR inhibitors, are widely used as cholesterol-reducing drugs. However, statin-induced myopathy is the most adverse side effect of statins. To eludicate the mechanisms underlying statin the myotoxicity and HMGCR function in the skeletal muscle, we developed the skeletal muscle-specific HMGCR knockout mice. Knockout mice exhibited postnatal myopathy with elevated serum creatine kinase levels and necrosis. Myopathy in knockout mice was completely rescued by the oral administration of MVA. These results suggest that skeletal muscle toxicity caused by statins is dependent on the deficiencies of HMGCR enzyme activity and downstream metabolites of the mevalonate pathway in skeletal muscles rather than the liver or other organs. Copyright © 2015 Elsevier Inc. All rights reserved.

Functional conservation between rodents and chicken of regulatory sequences driving skeletal muscle gene expression in transgenic chickens

PubMed Central

2010-01-01

Background Regulatory elements that control expression of specific genes during development have been shown in many cases to contain functionally-conserved modules that can be transferred between species and direct gene expression in a comparable developmental pattern. An example of such a module has been identified at the rat myosin light chain (MLC) 1/3 locus, which has been well characterised in transgenic mouse studies. This locus contains two promoters encoding two alternatively spliced isoforms of alkali myosin light chain. These promoters are differentially regulated during development through the activity of two enhancer elements. The MLC3 promoter alone has been shown to confer expression of a reporter gene in skeletal and cardiac muscle in transgenic mice and the addition of the downstream MLC enhancer increased expression levels in skeletal muscle. We asked whether this regulatory module, sufficient for striated muscle gene expression in the mouse, would drive expression in similar domains in the chicken. Results We have observed that a conserved downstream MLC enhancer is present in the chicken MLC locus. We found that the rat MLC1/3 regulatory elements were transcriptionally active in chick skeletal muscle primary cultures. We observed that a single copy lentiviral insert containing this regulatory cassette was able to drive expression of a lacZ reporter gene in the fast-fibres of skeletal muscle in chicken in three independent transgenic chicken lines in a pattern similar to the endogenous MLC locus. Reporter gene expression in cardiac muscle tissues was not observed for any of these lines. Conclusions From these results we conclude that skeletal expression from this regulatory module is conserved in a genomic context between rodents and chickens. This transgenic module will be useful in future investigations of muscle development in avian species. PMID:20184756

Effects of ovariectomy and intrinsic aerobic capacity on tissue-specific insulin sensitivity

PubMed Central

Park, Young-Min; Rector, R. Scott; Thyfault, John P.; Zidon, Terese M.; Padilla, Jaume; Welly, Rebecca J.; Meers, Grace M.; Morris, Matthew E.; Britton, Steven L.; Koch, Lauren G.; Booth, Frank W.; Kanaley, Jill A.

2015-01-01

High-capacity running (HCR) rats are protected against the early (i.e., ∼11 wk postsurgery) development of ovariectomy (OVX)-induced insulin resistance (IR) compared with low-capacity running (LCR) rats. The purpose of this study was to utilize the hyperinsulinemic euglycemic clamp to determine whether 1) HCR rats remain protected from OVX-induced IR when the time following OVX is extended to 27 wk and 2) tissue-specific glucose uptake differences are responsible for the protection in HCR rats under sedentary conditions. Female HCR and LCR rats (n = 40; aged ∼22 wk) randomly received either OVX or sham (SHM) surgeries and then underwent the clamp 27 wk following surgeries. [3-3H]glucose was used to determine glucose clearance, whereas 2-[14C]deoxyglucose (2-DG) was used to assess glucose uptake in skeletal muscle, brown adipose tissue (BAT), subcutaneous white adipose tissue (WAT), and visceral WAT. OVX decreased the glucose infusion rate and glucose clearance in both lines, but HCR had better insulin sensitivity than LCR (P < 0.05). In both lines, OVX significantly reduced glucose uptake in soleus and gastrocnemius muscles; however, HCR showed ∼40% greater gastrocnemius glucose uptake compared with LCR (P < 0.05). HCR also exhibited greater glucose uptake in BAT and visceral WAT compared with LCR (P < 0.05), yet these tissues were not affected by OVX in either line. In conclusion, OVX impairs insulin sensitivity in both HCR and LCR rats, likely driven by impairments in insulin-mediated skeletal muscle glucose uptake. HCR rats have greater skeletal muscle, BAT, and WAT insulin-mediated glucose uptake, which may aid in protection against OVX-associated insulin resistance. PMID:26646101

A test of Hartnett's revisions to the pubic symphysis and fourth rib methods on a modern sample.

PubMed

Merritt, Catherine E

2014-05-01

Estimating age at death is one of the most important aspects of creating a biological profile. Most adult age estimation methods were developed on North American skeletal collections from the early to mid-20th century, and their applicability to modern populations has been questioned. In 2010, Hartnett used a modern skeletal collection from the Maricopia County Forensic Science Centre to revise the Suchey-Brooks pubic symphysis method and the İşcan et al. fourth rib methods. The current study tests Hartnett's revised methods as well as the original Suchey-Brooks and İşcan et al. methods on a modern sample from the William Bass Skeletal Collection (N = 313, mean age = 58.5, range 19-92). Results show that the Suchey-Brooks and İşcan et al. methods assign individuals to the correct phase 70.8% and 57.5% of the time compared with Hartnett's revised methods at 58.1% and 29.7%, respectively, with correctness scores based on one standard deviation of the mean rather than the entire age range. Accuracy and bias scores are significantly improved for Hartnett's revised pubic symphysis method and marginally better for Hartnett's revised fourth rib method, suggesting that the revised mean ages at death of Hartnett's phases better reflect this modern population. Overall, both Hartnett's revised methods are reliable age estimation methods. For the pubic symphysis, there are significant improvements in accuracy and bias scores, especially for older individuals; however, for the fourth rib, the results are comparable to the original İşcan et al. methods, with some improvement for older individuals. © 2014 American Academy of Forensic Sciences.

Myostatin-deficiency in mice increases global gene expression at the Dlk1-Dio3 locus in the skeletal muscle

PubMed Central

Hitachi, Keisuke; Tsuchida, Kunihiro

2017-01-01

Myostatin, a member of the transforming growth factor-beta superfamily, is a negative regulator of skeletal muscle growth and development. Myostatin inhibition leads to increased skeletal muscle mass in mammals; hence, myostatin is considered a potential therapeutic target for skeletal muscle wasting. However, downstream molecules of myostatin in the skeletal muscle have not been fully elucidated. Here, we identified the Dlk1-Dio3 locus at the mouse chromosome 12qF1, also called as the callipyge locus in sheep, as a novel downstream target of myostatin. In skeletal muscle of myostatin knockout mice, the expression of mature miRNAs at the Dlk1-Dio3 locus was significantly increased. The increased miRNA levels are caused by the transcriptional activation of the Dlk1-Dio3 locus, because a significant increase in the primary miRNA transcript was observed in myostatin knockout mice. In addition, we found increased expression of coding and non-coding genes (Dlk1, Gtl2, Rtl1/Rtl1as, and Rian) at the Dlk1-Dio3 locus in myostatin-deficient skeletal muscle. Moreover, epigenetic changes, associated with the regulation of the Dlk1-Dio3 locus, were observed in myostatin knockout mice. Taken together, this is the first report demonstrating the role of myostatin in regulating the Dlk1-Dio3 (the callipyge) locus in the skeletal muscle. PMID:27992376

Myostatin-deficiency in mice increases global gene expression at the Dlk1-Dio3 locus in the skeletal muscle.

PubMed

Hitachi, Keisuke; Tsuchida, Kunihiro

2017-01-24

Myostatin, a member of the transforming growth factor-beta superfamily, is a negative regulator of skeletal muscle growth and development. Myostatin inhibition leads to increased skeletal muscle mass in mammals; hence, myostatin is considered a potential therapeutic target for skeletal muscle wasting. However, downstream molecules of myostatin in the skeletal muscle have not been fully elucidated. Here, we identified the Dlk1-Dio3 locus at the mouse chromosome 12qF1, also called as the callipyge locus in sheep, as a novel downstream target of myostatin. In skeletal muscle of myostatin knockout mice, the expression of mature miRNAs at the Dlk1-Dio3 locus was significantly increased. The increased miRNA levels are caused by the transcriptional activation of the Dlk1-Dio3 locus, because a significant increase in the primary miRNA transcript was observed in myostatin knockout mice. In addition, we found increased expression of coding and non-coding genes (Dlk1, Gtl2, Rtl1/Rtl1as, and Rian) at the Dlk1-Dio3 locus in myostatin-deficient skeletal muscle. Moreover, epigenetic changes, associated with the regulation of the Dlk1-Dio3 locus, were observed in myostatin knockout mice. Taken together, this is the first report demonstrating the role of myostatin in regulating the Dlk1-Dio3 (the callipyge) locus in the skeletal muscle.

Redox Control of Skeletal Muscle Regeneration.

PubMed

Le Moal, Emmeran; Pialoux, Vincent; Juban, Gaëtan; Groussard, Carole; Zouhal, Hassane; Chazaud, Bénédicte; Mounier, Rémi

2017-08-10

Skeletal muscle shows high plasticity in response to external demand. Moreover, adult skeletal muscle is capable of complete regeneration after injury, due to the properties of muscle stem cells (MuSCs), the satellite cells, which follow a tightly regulated myogenic program to generate both new myofibers and new MuSCs for further needs. Although reactive oxygen species (ROS) and reactive nitrogen species (RNS) have long been associated with skeletal muscle physiology, their implication in the cell and molecular processes at work during muscle regeneration is more recent. This review focuses on redox regulation during skeletal muscle regeneration. An overview of the basics of ROS/RNS and antioxidant chemistry and biology occurring in skeletal muscle is first provided. Then, the comprehensive knowledge on redox regulation of MuSCs and their surrounding cell partners (macrophages, endothelial cells) during skeletal muscle regeneration is presented in normal muscle and in specific physiological (exercise-induced muscle damage, aging) and pathological (muscular dystrophies) contexts. Recent advances in the comprehension of these processes has led to the development of therapeutic assays using antioxidant supplementation, which result in inconsistent efficiency, underlying the need for new tools that are aimed at precisely deciphering and targeting ROS networks. This review should provide an overall insight of the redox regulation of skeletal muscle regeneration while highlighting the limits of the use of nonspecific antioxidants to improve muscle function. Antioxid. Redox Signal. 27, 276-310.

Selenium regulates gene expression of selenoprotein W in chicken skeletal muscle system.

PubMed

Ruan, Hongfeng; Zhang, Ziwei; Wu, Qiong; Yao, Haidong; Li, Jinlong; Li, Shu; Xu, Shiwen

2012-01-01

Selenoprotein W (SelW) is abundantly expressed in skeletal muscles of mammals and necessary for the metabolism of skeletal muscles. However, its expression pattern in skeletal muscle system of birds is still uncovered. Herein, to investigate the distribution of SelW mRNA in chicken skeletal muscle system and its response to different selenium (Se) status, 1-day-old chickens were exposed to various concentrations of Se as sodium selenite in the feed for 35 days. In addition, myoblasts were treated with different concentrations of Se in the medium for 72 h. Then the levels of SelW mRNA in skeletal muscles (wing muscle, pectoral muscle, thigh muscle) and myoblasts were determined on days 1, 15, 25, and 35 and at 0, 24, 48, and 72 h, respectively. The results showed that SelW was detected in all these muscle components and it increased both along with the growth of organism and the differentiation process of myoblasts. The thigh muscle is more responsive to Se intake than the other two skeletal muscle tissues while the optimal Se supplementation for SelW mRNA expression in chicken myoblasts was 10(-7) M. In summary, Se plays important roles in the development of chicken skeletal muscles. To effect optimal SelW gene expression, Se must be provided in the diet and the media in adequate amounts and neither at excessive nor deficient levels.

Redox Control of Skeletal Muscle Regeneration

PubMed Central

Le Moal, Emmeran; Pialoux, Vincent; Juban, Gaëtan; Groussard, Carole; Zouhal, Hassane

2017-01-01

Abstract Skeletal muscle shows high plasticity in response to external demand. Moreover, adult skeletal muscle is capable of complete regeneration after injury, due to the properties of muscle stem cells (MuSCs), the satellite cells, which follow a tightly regulated myogenic program to generate both new myofibers and new MuSCs for further needs. Although reactive oxygen species (ROS) and reactive nitrogen species (RNS) have long been associated with skeletal muscle physiology, their implication in the cell and molecular processes at work during muscle regeneration is more recent. This review focuses on redox regulation during skeletal muscle regeneration. An overview of the basics of ROS/RNS and antioxidant chemistry and biology occurring in skeletal muscle is first provided. Then, the comprehensive knowledge on redox regulation of MuSCs and their surrounding cell partners (macrophages, endothelial cells) during skeletal muscle regeneration is presented in normal muscle and in specific physiological (exercise-induced muscle damage, aging) and pathological (muscular dystrophies) contexts. Recent advances in the comprehension of these processes has led to the development of therapeutic assays using antioxidant supplementation, which result in inconsistent efficiency, underlying the need for new tools that are aimed at precisely deciphering and targeting ROS networks. This review should provide an overall insight of the redox regulation of skeletal muscle regeneration while highlighting the limits of the use of nonspecific antioxidants to improve muscle function. Antioxid. Redox Signal. 27, 276–310. PMID:28027662

Biomarker evaluation of skeletal muscle toxicity following clofibrate administration in rats.

PubMed

Bodié, Karen; Buck, Wayne R; Pieh, Julia; Liguori, Michael J; Popp, Andreas

2016-05-01

The use of sensitive biomarkers to monitor skeletal muscle toxicity in preclinical toxicity studies is important for the risk assessment in humans during the development of a novel compound. Skeletal muscle toxicity in Sprague Dawley Rats was induced with clofibrate at different dose levels for 7 days to compare standard clinical pathology assays with novel skeletal muscle and cardiac muscle biomarkers, gene expression and histopathological changes. The standard clinical pathology assays aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) enzyme activity were compared to novel biomarkers fatty acid binding protein 3 (Fabp3), myosin light chain 3 (Myl3), muscular isoform of CK immunoreactivity (three isoforms CKBB, CKMM, CKMB), parvalbumin (Prv), skeletal troponin I (sTnI), cardiac troponin T (cTnT), cardiac troponin I (cTnI), CKMM, and myoglobin (Myo). The biomarker elevations were correlated to histopathological findings detected in several muscles and gene expression changes. Clofibrate predominantly induced skeletal muscle toxicity of type I fibers of low magnitude. Useful biomarkers for skeletal muscle toxicity were AST, Fabp3, Myl3, (CKMB) and sTnI. Measurements of CK enzyme activity by a standard clinical assay were not useful for monitoring clofibrate-induced skeletal muscle toxicity in the rat at the doses used in this study. Copyright © 2016 The Authors. Published by Elsevier GmbH.. All rights reserved.

Parasite distribution and early-stage encephalitis in Sarcocystis calchasi infections in domestic pigeons (Columba livia f. domestica).

PubMed

Maier, Kristina; Olias, Philipp; Enderlein, Dirk; Klopfleisch, Robert; Mayr, Sylvia L; Gruber, Achim D; Lierz, Michael

2015-01-01

Pigeon protozoal encephalitis is a biphasic, neurologic disease of domestic pigeons (Columba livia f. domestica) caused by the apicomplexan parasite Sarcocystis calchasi. Despite severe inflammatory lesions of the brain, associated parasitic stages have only rarely been identified and the cause of the lesions is still unclear. The aim of this study was therefore to characterize the tissue distribution of S. calchasi within pigeons between the two clinical phases and during the occurrence of neurological signs. For this purpose, a semi-quantitative real-time polymerase chain reaction (PCR) was developed. Forty-five domestic pigeons were infected orally (via a cannula into the crop) with 200 S. calchasi sporocysts and euthanized in groups of three pigeons at intervals of 2 to 10 days over a period of 61 days. Tissue samples including brain and skeletal muscle were examined by histology, immunohistochemistry, and PCR. Schizonts were detected in the liver of one pigeon at day 10 post infection. A mild encephalitis was detected at day 20 post infection, around 4 weeks before the onset of neurological signs. At the same time, immature sarcocysts were present in the skeletal muscle. In seven pigeons a few sarcocysts were identified in the brain, but not associated with any lesion. These results suggest that the encephalitis is induced at a very early stage of the S. calchasi lifecycle rather than in the chronic phase of pigeon protozoal encephalitis. Despite the increasing severity of lesions in the central nervous system, the amount of sarcocysts did not increase. This supports the hypothesis of a delayed-type hypersensitivity response as the cause of the encephalitis. The study also demonstrated that S. calchasi DNA is detectable in tissues negative by histological methods, indicating a higher sensitivity of the real-time PCR.

Whole transcriptome analysis of the coral Acropora millepora reveals complex responses to CO₂-driven acidification during the initiation of calcification.

PubMed

Moya, A; Huisman, L; Ball, E E; Hayward, D C; Grasso, L C; Chua, C M; Woo, H N; Gattuso, J-P; Forêt, S; Miller, D J

2012-05-01

The impact of ocean acidification (OA) on coral calcification, a subject of intense current interest, is poorly understood in part because of the presence of symbionts in adult corals. Early life history stages of Acropora spp. provide an opportunity to study the effects of elevated CO(2) on coral calcification without the complication of symbiont metabolism. Therefore, we used the Illumina RNAseq approach to study the effects of acute exposure to elevated CO(2) on gene expression in primary polyps of Acropora millepora, using as reference a novel comprehensive transcriptome assembly developed for this study. Gene ontology analysis of this whole transcriptome data set indicated that CO(2) -driven acidification strongly suppressed metabolism but enhanced extracellular organic matrix synthesis, whereas targeted analyses revealed complex effects on genes implicated in calcification. Unexpectedly, expression of most ion transport proteins was unaffected, while many membrane-associated or secreted carbonic anhydrases were expressed at lower levels. The most dramatic effect of CO(2) -driven acidification, however, was on genes encoding candidate and known components of the skeletal organic matrix that controls CaCO(3) deposition. The skeletal organic matrix effects included elevated expression of adult-type galaxins and some secreted acidic proteins, but down-regulation of other galaxins, secreted acidic proteins, SCRiPs and other coral-specific genes, suggesting specialized roles for the members of these protein families and complex impacts of OA on mineral deposition. This study is the first exhaustive exploration of the transcriptomic response of a scleractinian coral to acidification and provides an unbiased perspective on its effects during the early stages of calcification. © 2012 Blackwell Publishing Ltd.

* Tissue-Specific Extracellular Matrix Enhances Skeletal Muscle Precursor Cell Expansion and Differentiation for Potential Application in Cell Therapy.

PubMed

Zhang, Deying; Zhang, Yong; Zhang, Yuanyuan; Yi, Hualin; Wang, Zhan; Wu, Rongpei; He, Dawei; Wei, Guanghui; Wei, Shicheng; Hu, Yun; Deng, Junhong; Criswell, Tracy; Yoo, James; Zhou, Yu; Atala, Anthony

2017-08-01

Skeletal muscle precursor cells (MPCs) are considered a key candidate for cell therapy in the treatment of skeletal muscle dysfunction due to injury, disease, or age. However, expansion of a sufficient number of functional skeletal muscle cells in vitro from a small tissue biopsy has been challenging due to changes in phenotypic expression of these cells under traditional culture conditions. Thus, the aim of the study was to develop a better culture system for the expansion and myo-differentiation of MPCs that could further be used for therapy. For this purpose, we developed an ideal method of tissue decellularization and compared the ability of different matrices to support MPC growth and differentiation. Porcine-derived skeletal muscle and liver and kidney extracellular matrix (ECM) were generated by decellularization methods consisting of distilled water, 0.2 mg/mL DNase, or 5% fetal bovine serum. Acellular matrices were further homogenized, dissolved, and combined with a hyaluronic acid-based hydrogel decorated with heparin (ECM-HA-HP). The cell proliferation and myogenic differentiation capacity of human MPCs were assessed when grown on gel alone, ECM, or each ECM-HA-HP substrate. Human MPC proliferation was significantly enhanced when cultured on the ECM-HA-HP substrates compared to the other substrates tested, with the greatest proliferation on the muscle ECM-HA-HP (mECM-HA-HP) substrate. The number of differentiated myotubes was significantly increased on the mECM-HA-HP substrate compared to the other gel-ECM substrates, as well as the numbers of MPCs expressing specific myogenic cell markers (i.e., myosin, desmin, myoD, and myf5). In conclusion, skeletal mECM-HA-HP as a culture substrate provided an optimal culture microenvironment potentially due to its similarity to the in vivo environment. These data suggest a potential use of skeletal muscle-derived ECM gel for the expansion and differentiation of human MPCs for cell-based therapy for skeletal muscle dysfunction.

Skeletal muscle tissue transcriptome differences in lean and obese female beagle dogs.

PubMed

Grant, R W; Vester Boler, B M; Ridge, T K; Graves, T K; Swanson, K S

2013-08-01

Skeletal muscle is a large and insulin-sensitive tissue that is an important contributor to metabolic homeostasis and energy expenditure. Many metabolic processes are altered with obesity, but the contribution of muscle tissue in this regard is unclear. A limited number of studies have compared skeletal muscle gene expression of lean and obese dogs. Using microarray technology, our objective was to identify genes and functional classes differentially expressed in skeletal muscle of obese (14.6 kg; 8.2 body condition score; 44.5% body fat) vs. lean (8.6 kg; 4.1 body condition score; 22.9% body fat) female beagle adult dogs. Alterations in 77 transcripts was observed in genes pertaining to the functional classes of signaling, transport, protein catabolism and proteolysis, protein modification, development, transcription and apoptosis, cell cycle and differentiation. Genes differentially expressed in obese vs. lean dog skeletal muscle indicate oxidative stress and altered skeletal muscle cell differentiation. Many genes traditionally associated with lipid, protein and carbohydrate metabolism were not altered in obese vs. lean dogs, but genes pertaining to endocannabinoid metabolism, insulin signaling, type II diabetes mellitus and carnitine transport were differentially expressed. The relatively small response of skeletal muscle could indicate that changes are occurring at a post-transcriptional level, that other tissues (e.g., adipose tissue) were buffering skeletal muscle from metabolic dysfunction or that obesity-induced changes in skeletal muscle require a longer period of time and that the length of our study was not sufficient to detect them. Although only a limited number of differentially expressed genes were detected, these results highlight genes and functional classes that may be important in determining the etiology of obesity-induced derangement of skeletal muscle function. © 2013 The Authors, Animal Genetics © 2013 Stichting International Foundation for Animal Genetics.

The Vicious Cycle of Myostatin Signaling in Sarcopenic Obesity: Myostatin Role in Skeletal Muscle Growth, Insulin Signaling and Implications for Clinical Trials.

PubMed

Consitt, L A; Clark, B C

2018-01-01

The age-related loss of skeletal muscle (sarcopenia) is a major health concern as it is associated with physical disability, metabolic impairments, and increased mortality. The coexistence of sarcopenia with obesity, termed 'sarcopenic obesity', contributes to skeletal muscle insulin resistance and the development of type 2 diabetes, a disease prevalent with advancing age. Despite this knowledge, the mechanisms contributing to sarcopenic obesity remain poorly understood, preventing the development of targeted therapeutics. This article will discuss the clinical and physiological consequences of sarcopenic obesity and propose myostatin as a potential candidate contributing to this condition. A special emphasis will be placed on examining the role of myostatin signaling in impairing both skeletal muscle growth and insulin signaling. In addition, the role of myostatin in regulating muscle-to fat cross talk, further exacerbating metabolic dysfunction in the elderly, will be highlighted. Lastly, we discuss how this knowledge has implications for the design of myostatin-inhibitor clinical trials.

A contemporary Colombian skeletal reference collection: A resource for the development of population specific standards.

PubMed

Sanabria-Medina, Cesar; González-Colmenares, Gretel; Restrepo, Hadaluz Osorio; Rodríguez, Juan Manuel Guerrero

2016-09-01

Several authors who have discussed human variability and its impact on the forensic identification of bodies pose the need for regional studies documenting the global variation of the attributes analyzed osteological characteristics that aid in establishing biological profile (sex, ancestry, biological age and height). This is primarily accomplished by studying documented human skeletal collections in order to investigate secular trends in skeletal development and aging, among others in the Colombian population. The purpose of this paper is to disclose the details of the new "Contemporary Colombian Skeletal Reference Collection" that currently comprises 600 identified skeletons of both sexes, who died between 2005 and 2008; and which contain information about their cause of death. This collection has infinite potential for research, open to the national and international community, and still has pending opportunities to address a variety of topics such as studies on osteopathology, bone trauma and taphonomic studies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

From Nutrient to MicroRNA: a Novel Insight into Cell Signaling Involved in Skeletal Muscle Development and Disease

PubMed Central

Zhang, Yong; Yu, Bing; He, Jun; Chen, Daiwen

2016-01-01

Skeletal muscle is a remarkably complicated organ comprising many different cell types, and it plays an important role in lifelong metabolic health. Nutrients, as an external regulator, potently regulate skeletal muscle development through various internal regulatory factors, such as mammalian target of rapamycin (mTOR) and microRNAs (miRNAs). As a nutrient sensor, mTOR, integrates nutrient availability to regulate myogenesis and directly or indirectly influences microRNA expression. MiRNAs, a class of small non-coding RNAs mediating gene silencing, are implicated in myogenesis and muscle-related diseases. Meanwhile, growing evidence has emerged supporting the notion that the expression of myogenic miRNAs could be regulated by nutrients in an epigenetic mechanism. Therefore, this review presents a novel insight into the cell signaling network underlying nutrient-mTOR-miRNA pathway regulation of skeletal myogenesis and summarizes the epigenetic modifications in myogenic differentiation, which will provide valuable information for potential therapeutic intervention. PMID:27766039

Assessing skeletal maturity by using blood spot insulin-like growth factor I (IGF-I) testing.

PubMed

Masoud, Mohamed; Masoud, Ibrahim; Kent, Ralph L; Gowharji, Nour; Cohen, Laurie E

2008-08-01

Accurate determination of skeletal maturity and remaining growth is crucial to many orthodontic, orthognathic, and dental-implant timing decisions. Cervical vertebral stages and hand-wrist radiographs are currently used to identify peak mandibular bone growth. These are highly subjective techniques that not only involve radiographic exposure but also lack the ability to determine the intensity of the growth spurt and the end of growth. Insulin-like growth factor I (IGF-I) is a circulating growth hormone-dependent factor whose level correlates with sexual maturity; it is used to diagnose growth hormone deficiency and excess. We hypothesized that IGF-I levels would also correlate with cervical skeletal maturity and would be highest at the cervical stages that correspond to the greatest amount of facial growth. We measured mean blood spot IGF-I levels in a cross-sectional study of 83 patients (44 female, 39 male) on recall to begin orthodontic treatment, in active treatment, or in posttreatment follow-up. Mean blood spot IGF-I levels were significantly higher in the late pubertal stages than in the prepubertal, early pubertal, and postpubertal stages. Linear correlation showed that IGF-I levels had a significant positive correlation with cervical skeletal maturity from the prepubertal to the late pubertal stages, and a significant negative correlation from the late pubertal to the postpubertal stages. In the postpubertal stage, IGF-I levels had a negative linear correlation with increasing time since the onset of puberty and with chronological age. Blood spot IGF-I could be used as a skeletal maturity indicator and might be useful in detecting residual mandibular growth in young adults.

Electrical stimulation induces IL-6 in skeletal muscle through extracellular ATP by activating Ca(2+) signals and an IL-6 autocrine loop.

PubMed

Bustamante, Mario; Fernández-Verdejo, Rodrigo; Jaimovich, Enrique; Buvinic, Sonja

2014-04-15

Interleukin-6 (IL-6) is an important myokine that is highly expressed in skeletal muscle cells upon exercise. We assessed IL-6 expression in response to electrical stimulation (ES) or extracellular ATP as a known mediator of the excitation-transcription mechanism in skeletal muscle. We examined whether the canonical signaling cascade downstream of IL-6 (IL-6/JAK2/STAT3) also responds to muscle cell excitation, concluding that IL-6 influences its own expression through a positive loop. Either ES or exogenous ATP (100 μM) increased both IL-6 expression and p-STAT3 levels in rat myotubes, a process inhibited by 100 μM suramin and 2 U/ml apyrase. ATP also evoked IL-6 expression in both isolated skeletal fibers and extracts derived from whole FDB muscles. ATP increased IL-6 release up to 10-fold. STAT3 activation evoked by ATP was abolished by the JAK2 inhibitor HBC. Blockade of secreted IL-6 with a neutralizing antibody or preincubation with the STAT3 inhibitor VIII reduced STAT3 activation evoked by extracellular ATP by 70%. Inhibitor VIII also reduced by 70% IL-6 expression evoked by ATP, suggesting a positive IL-6 loop. In addition, ATP increased up to 60% the protein levels of SOCS3, a negative regulator of the IL-6 signaling pathway. On the other hand, intracellular calcium chelation or blockade of IP3-dependent calcium signals abolished STAT3 phosphorylation evoked by either extracellular ATP or ES. These results suggest that expression of IL-6 in stimulated skeletal muscle cells is mediated by extracellular ATP and nucleotide receptors, involving IP3-dependent calcium signals as an early step that triggers a positive IL-6 autocrine loop.

Ancient skeletal evidence for leprosy in India (2000 B.C.).

PubMed

Robbins, Gwen; Tripathy, V Mushrif; Misra, V N; Mohanty, R K; Shinde, V S; Gray, Kelsey M; Schug, Malcolm D

2009-05-27

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that affects almost 250,000 people worldwide. The timing of first infection, geographic origin, and pattern of transmission of the disease are still under investigation. Comparative genomics research has suggested M. leprae evolved either in East Africa or South Asia during the Late Pleistocene before spreading to Europe and the rest of the World. The earliest widely accepted evidence for leprosy is in Asian texts dated to 600 B.C. We report an analysis of pathological conditions in skeletal remains from the second millennium B.C. in India. A middle aged adult male skeleton demonstrates pathological changes in the rhinomaxillary region, degenerative joint disease, infectious involvement of the tibia (periostitis), and injury to the peripheral skeleton. The presence and patterning of lesions was subject to a process of differential diagnosis for leprosy including treponemal disease, leishmaniasis, tuberculosis, osteomyelitis, and non-specific infection. Results indicate that lepromatous leprosy was present in India by 2000 B.C. This evidence represents the oldest documented skeletal evidence for the disease. Our results indicate that Vedic burial traditions in cases of leprosy were present in northwest India prior to the first millennium B.C. Our results also support translations of early Vedic scriptures as the first textual reference to leprosy. The presence of leprosy in skeletal material dated to the post-urban phase of the Indus Age suggests that if M. leprae evolved in Africa, the disease migrated to India before the Late Holocene, possibly during the third millennium B.C. at a time when there was substantial interaction among the Indus Civilization, Mesopotamia, and Egypt. This evidence should be impetus to look for additional skeletal and molecular evidence of leprosy in India and Africa to confirm the African origin of the disease.

Invited review: mesenchymal progenitor cells in intramuscular connective tissue development.

PubMed

Miao, Z G; Zhang, L P; Fu, X; Yang, Q Y; Zhu, M J; Dodson, M V; Du, M

2016-01-01

The abundance and cross-linking of intramuscular connective tissue contributes to the background toughness of meat, and is thus undesirable. Connective tissue is mainly synthesized by intramuscular fibroblasts. Myocytes, adipocytes and fibroblasts are derived from a common pool of progenitor cells during the early embryonic development. It appears that multipotent mesenchymal stem cells first diverge into either myogenic or non-myogenic lineages; non-myogenic mesenchymal progenitors then develop into the stromal-vascular fraction of skeletal muscle wherein adipocytes, fibroblasts and derived mesenchymal progenitors reside. Because non-myogenic mesenchymal progenitors mainly undergo adipogenic or fibrogenic differentiation during muscle development, strengthening progenitor proliferation enhances the potential for both intramuscular adipogenesis and fibrogenesis, leading to the elevation of both marbling and connective tissue content in the resulting meat product. Furthermore, given the bipotent developmental potential of progenitor cells, enhancing their conversion to adipogenesis reduces fibrogenesis, which likely results in the overall improvement of marbling (more intramuscular adipocytes) and tenderness (less connective tissue) of meat. Fibrogenesis is mainly regulated by the transforming growth factor (TGF) β signaling pathway and its regulatory cascade. In addition, extracellular matrix, a part of the intramuscular connective tissue, provides a niche environment for regulating myogenic differentiation of satellite cells and muscle growth. Despite rapid progress, many questions remain in the role of extracellular matrix on muscle development, and factors determining the early differentiation of myogenic, adipogenic and fibrogenic cells, which warrant further studies.

Six Month Report on Tissue Cultured Avian Skeletal Myofibers in the STL/A Module Aboard STS-77

NASA Technical Reports Server (NTRS)

Vandenburgh, Herman H.

1997-01-01

Space travel is know to effect skeletal muscle, causing rapid and pronounced atrophy in humans and animals, even when strenuous exercise is used as a countermeasure. The cellular and molecular bases of this atrophy are unknown. Space travel may cause muscle atrophy by a direct effect on the muscle fibers and/or indirectly by reducing circulating levels of growth factors such as growth hormone. The recent development of a tissue culture incubator system for Shuttle Middeck basic science experiments [Space Tissue Loss (STL) Module] by the Walter Reed Army Institute of Research (WRAIR) allows the study of the effects of space travel directly on isolated skeletal myofibers. Avian bioartificial skeletal muscle 'organoids' containing differentiated skeletal myofibers and connective tissue fibroblasts were flown aboard the Space Shuttle (Space Transportation System, STS) on Flight STS-77, a repeat of a similar experiment flown on STS-66. The results from these two flight experiments show for the first time that space travel has a direct effect on skeletal muscle cells separate from any systemic effects resulting from altered circulating growth factors.

Skeletal muscle wasting: new role of nonclassical renin-angiotensin system.

PubMed

Cabello-Verrugio, Claudio; Rivera, Juan C; Garcia, Dominga

2017-05-01

Skeletal muscle can be affected by many physiological and pathological conditions that contribute to the development of muscle weakness, including skeletal muscle loss, inflammatory processes, or fibrosis. Therefore, research into therapeutic treatment alternatives or alleviation of these effects on skeletal muscle is of great importance. Recent studies have shown that angiotensin (1-7) [Ang-(1-7)] - a vasoactive peptide of the nonclassical axis in the renin-angiotensin system (RAS) - and its Mas receptor are expressed in skeletal muscle. Ang-(1-7), through its Mas receptor, prevents or diminishes deleterious effects induced by skeletal muscle disease or injury. Specifically, the Ang-(1-7)-Mas receptor axis modulates molecular mechanisms involved in muscle mass regulation, such as the ubiquitin proteasome pathway, the insulin-like growth factor type 1/Akt (protein kinase B) pathway, or myonuclear apoptosis, and also inflammation and fibrosis pathways. Although further research into this topic and the possible side effects of Ang-(1-7) is necessary, these findings are promising, and suggest that the Ang-(1-7)-Mas axis can be considered a possible therapeutic target for treating patients with muscular disorders.

Bone scintigraphy in hypervitaminosis A

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, J.H.; Hayon, I.I.

1985-04-01

The diagnosis of vitamin A intoxification may be difficult at the time of initial presentation. The radionuclide bone scan in cases of vitamin A toxicity may serve as a more sensitive indicator of the presence of this disease than radiographs in the initial evaluation and follow-up of patients with skeletal involvement. This is achieved at a lower radiation dose to the patient. The authors present a case in which bone scintigraphy played a crucial role in the early identification of this disorder. The radionuclide examination was the first method that indicated the presence of this disorder, significantly before changes demonstrablemore » on conventional radiography. The clinical and scintigraphic appearance of this process should be recognized to allow identification of hypervitaminosis A before the clinical symptoms become severe or permanent skeletal deformities result.« less

Risk factors for postoperative retropharyngeal hematoma after anterior cervical spine surgery.

PubMed

O'Neill, Kevin R; Neuman, Brian; Peters, Colleen; Riew, K Daniel

2014-02-15

Retrospective review of prospective database. To investigate risk factors involved in the development of anterior cervical hematomas and determine any impact on patient outcomes. Postoperative (PO) hematomas after anterior cervical spine surgery require urgent recognition and treatment to avoid catastrophic patient morbidity or death. Current studies of PO hematomas are limited. Cervical spine surgical procedures performed on adults by the senior author at a single academic institution from 1995 to 2012 were evaluated. Demographic data, surgical history, operative data, complications, and neck disability index (NDI) scores were recorded prospectively. Cases complicated by PO hematoma were reviewed, and time until hematoma development and surgical evacuation were determined. Patients who developed a hematoma (HT group) were compared with those that did not (no-HT group) to identify risk factors. NDI outcomes were compared at early (<11 mo) and late (>11 mo) time points. There were 2375 anterior cervical spine surgical procedures performed with 17 occurrences (0.7%) of PO hematoma. In 11 patients (65%) the hematoma occurred within 24 hours PO, whereas 6 patients (35%) presented at an average of 6 days postoperatively. All underwent hematoma evacuation, with 2 patients (12%) requiring emergent cricothyroidotomy. Risk factors for hematoma were found to be (1) the presence of diffuse idiopathic skeletal hyperostosis (relative risk = 13.2, 95% confidence interval = 3.2-54.4), (2) presence of ossification of the posterior longitudinal ligament (relative risk = 6.8, 95% confidence interval = 2.3-20.6), (3) therapeutic heparin use (relative risk 148.8, 95% confidence interval = 91.3-242.5), (4) longer operative time, and (5) greater number of surgical levels. The occurrence of a PO hematoma was not found to have a significant impact on either early (HT: 30, no-HT: 28; P = 0.86) or late average NDI scores (HT: 28, no-HT 31; P = 0.76). With fast recognition and treatment, no long-term detriment from PO anterior cervical hematoma was found. We identified risk factors to be (1) presence of diffuse idiopathic skeletal hyperostosis, (2) presence of ossification of the posterior longitudinal ligament, (3) therapeutic heparin use, (4) longer operative time, and (5) greater number of surgical levels. 4.

Canadian Sedentary Behaviour Guidelines for the Early Years (aged 0-4 years).

PubMed

Tremblay, Mark S; Leblanc, Allana G; Carson, Valerie; Choquette, Louise; Connor Gorber, Sarah; Dillman, Carrie; Duggan, Mary; Gordon, Mary Jane; Hicks, Audrey; Janssen, Ian; Kho, Michelle E; Latimer-Cheung, Amy E; Leblanc, Claire; Murumets, Kelly; Okely, Anthony D; Reilly, John J; Stearns, Jodie A; Timmons, Brian W; Spence, John C

2012-04-01

The Canadian Society for Exercise Physiology (CSEP), with assistance from multiple partners, stakeholders, and researchers, developed the first Canadian Sedentary Behaviour Guidelines for the Early Years (aged 0-4 years). These national guidelines are in response to a call from health and health care professionals, child care providers, and fitness practitioners for guidance on sedentary behaviour in the early years. The guideline development process followed the Appraisal of Guidelines for Research Evaluation (AGREE) II framework. The recommendations are informed by evidence from a systematic review that examined the relationships between sedentary behaviour (predominantly screen time) and health indicators (healthy body weight, bone and skeletal health, motor skill development, psychosocial health, cognitive development, and cardio-metabolic disease risk factors) for three age groups (infants aged <1 year; toddlers aged 1-2 years; preschoolers aged 3-4 years). Evidence from the review was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The new guidelines include a preamble to provide context, followed by the specific recommendations. The final guidelines benefitted from extensive on-line consultations with input from >900 domestic and international stakeholders, end-users, and key informants. The final guidelines state: for healthy growth and development, caregivers should minimize the time infants (aged <1 year), toddlers (aged 1-2 years), and preschoolers (aged 3-4 years) spend being sedentary during waking hours. This includes prolonged sitting or being restrained (e.g., stroller, high chair) for more than 1 h at a time. For those under 2 years, screen time (e.g., TV, computer, electronic games) is not recommended. For children 2-4 years, screen time should be limited to under 1 h per day; less is better.

Satellite-like cells contribute to pax7-dependent skeletal muscle repair in adult zebrafish

PubMed Central

Berberoglu, Michael A.; Gallagher, Thomas L.; Morrow, Zachary T.; Talbot, Jared C.; Hromowyk, Kimberly J.; Tenente, Inês M.; Langenau, David M.; Amacher, Sharon L.

2017-01-01

Satellite cells, also known as muscle stem cells, are responsible for skeletal muscle growth and repair in mammals. Pax7 and Pax3 transcription factors are established satellite cell markers required for muscle development and regeneration, and there is great interest in identifying additional factors that regulate satellite cell proliferation, differentiation, and/or skeletal muscle regeneration. Due to the powerful regenerative capacity of many zebrafish tissues, even in adults, we are exploring the regenerative potential of adult zebrafish skeletal muscle. Here, we show that adult zebrafish skeletal muscle contains cells similar to mammalian satellite cells. Adult zebrafish satellite-like cells have dense heterochromatin, express Pax7 and Pax3, proliferate in response to injury, and show peak myogenic responses 4–5 days post-injury (dpi). Furthermore, using a pax7a-driven GFP reporter, we present evidence implicating satellite-like cells as a possible source of new muscle. In lieu of central nucleation, which distinguishes regenerating myofibers in mammals, we describe several characteristics that robustly identify newly-forming myofibers from surrounding fibers in injured adult zebrafish muscle. These characteristics include partially overlapping expression in satellite cells and regenerating myofibers of two RNA-binding proteins Rbfox2 and Rbfoxl1, known to regulate embryonic muscle development and function. Finally, by analyzing pax7a; pax7b double mutant zebrafish, we show that Pax7 is required for adult skeletal muscle repair, as it is in the mouse. PMID:28279710

Expression and functional characterization of Smyd1a in myofibril organization of skeletal muscles.

PubMed

Gao, Jie; Li, Junling; Li, Bao-Jun; Yagil, Ezra; Zhang, Jianshe; Du, Shao Jun

2014-01-01

Smyd1, the founding member of the Smyd family including Smyd-1, 2, 3, 4 and 5, is a SET and MYND domain containing protein that plays a key role in myofibril assembly in skeletal and cardiac muscles. Bioinformatic analysis revealed that zebrafish genome contains two highly related smyd1 genes, smyd1a and smyd1b. Although Smyd1b function is well characterized in skeletal and cardiac muscles, the function of Smyd1a is, however, unknown. To investigate the function of Smyd1a in muscle development, we isolated smyd1a from zebrafish, and characterized its expression and function during muscle development via gene knockdown and transgenic expression approaches. The results showed that smyd1a was strongly expressed in skeletal muscles of zebrafish embryos. Functional analysis revealed that knockdown of smyd1a alone had no significant effect on myofibril assembly in zebrafish skeletal muscles. However, knockdown of smyd1a and smyd1b together resulted in a complete disruption of myofibril organization in skeletal muscles, a phenotype stronger than knockdown of smyd1a or smyd1b alone. Moreover, ectopic expression of zebrafish smyd1a or mouse Smyd1 transgene could rescue the myofibril defects from the smyd1b knockdown in zebrafish embryos. Collectively, these data indicate that Smyd1a and Smyd1b share similar biological activity in myofibril assembly in zebrafish embryos. However, Smyd1b appears to play a major role in this process.

Puberty in subjects with complete androgen insensitivity syndrome.

PubMed

Papadimitriou, Dimitrios T; Linglart, Agnès; Morel, Yves; Chaussain, Jean-Louis

2006-01-01

Androgen receptor defects affect the regulation of the gonadotropic axis. However, little is known about the timing of pubertal maturation in complete androgen insensitivity syndrome (CAIS). To evaluate growth, skeletal maturation and gonadotropin and sex steroid secretion in patients with CAIS and intact gonads at puberty. Clinical, auxological and hormonal evaluation of 9 patients with CAIS from birth up to 17 years of age, prior to gonadectomy, in a single institution, retrospective study. Breast development occurred at a median age of 11.1 years, thumb sesamoid appeared at 11.5 years, and peak height velocity at 12.3 years, all consistent with average female values. However, median adult male height (+1.2 SDS) was closer to the patients' male target height (-0.3 SDS). Plasma testosterone levels rose early compared to normal boys. LH (basal and GnRH-stimulated) increased rapidly, above normal male values, in early puberty. This retrospective evaluation of a limited number of cases with a heterogeneous pattern of follow-up suggests that patients with CAIS may enter puberty at an age closer to female standards. These results imply a major role of direct androgen action, in utero or in early life, in determining the pattern of pubertal gonadotropin maturation.

Ponticulus posticus is a frequent radiographic finding on lateral cephalograms in nevoid basal cell carcinoma syndrome (Gorlin-Goltz syndrome).

PubMed

Friedrich, Reinhard E

2014-12-01

Nevoid basal cell carcinoma syndrome (NBCCS) is a predisposition to a rare tumor type with a variable phenotype. Besides tumors, skeletal alterations, such as bifid ribs or frontal bossing constitute the phenotype. Recently, a variant of the first cervical vertebra, the ponticulus posticus, was reported to occur in 50% of patients with NBCCS as revealed by analysis of lateral cephalograms. Lateral cephalograms of eight patients with NBCCS were studied for the presence of ponticulus posticus. The ponticulus posticus was present in all patients. In one case, a series of cephalograms performed during a period of 20 years allowed the slow and continuous recording of a ponticulus posticus formation. Besides the predisposition to developing neoplasms, NBCCS also affects bone development. Some diagnostic criteria for NBCCS rely on certain osseous transformations either in hard tissues, e.g. keratocystic odontogenic tumor in jaws, or in soft tissues, e.g. calcification of the falx cerebri. Furthermore, the physiognomy can be affected by skeletal alterations, e.g. frontal bossing or hypertelorism. Given this wide spectrum of osseous involvement in NBCCS, the high prevalence rate of ponticulus posticus should be added to the relevant diagnostic findings of the skull and vertebral column. However, the onset of ponticulus posticus formation in the life of such patients is unclear and thus the relevance of this finding in early diagnosis of NBCCS remains to be elucidated. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Mandibular asymmetry and the fourth dimension.

PubMed

Kaban, Leonard B

2009-03-01

This paper represents more than 30 years of discussion and collaboration with Drs Joseph Murray and John Mulliken in an attempt to understand growth patterns over time (ie, fourth dimension) in patients with hemifacial microsomia (HFM). This is essential for the development of rational treatment protocols for children and adults with jaw asymmetry. Traditionally, HFM was thought of as a unilateral deformity, but it was recognized that 20% to 30% of patients had bilateral abnormalities. However, early descriptions of skeletal correction addressed almost exclusively lengthening of the short (affected) side of the face. Based on longitudinal clinical observations of unoperated HFM patients, we hypothesized that abnormal mandibular growth is the earliest skeletal manifestation and that restricted growth of the mandible plays a pivotal role in progressive distortion of both the ipsilateral and contralateral facial skeleton. This hypothesis explains the progressive nature of the asymmetry in patients with HFM and provides the rationale for surgical lengthening of the mandible in children to prevent end-stage deformity. During the past 30 years, we have learned that this phenomenon of progressive distortion of the adjacent and contralateral facial skeleton occurs with other asymmetric mandibular undergrowth (tumor resection, radiation therapy, or posttraumatic defects) and overgrowth (mandibular condylar hyperplasia) conditions. In this paper, I describe the progression of deformity with time in patients with mandibular asymmetry as a result of undergrowth and overgrowth. Understanding these concepts is critical for the development of rational treatment protocols for adults with end-stage asymmetry and for children to minimize secondary deformity.

Hypertension is a characteristic complication of X-linked hypophosphatemia.

PubMed

Nakamura, Yoshie; Takagi, Masaki; Takeda, Ryojun; Miyai, Kentaro; Hasegawa, Yukihiro

2017-03-31

X-linked hypophosphatemia (XLH) is a group of rare disorders caused by defective proximal tubular reabsorption of phosphate. Mutations in the PHEX gene are responsible for the majority of cases. There are very few reports of long-term complications of XLH other than skeletal and dental diseases. The aim of this study was to identify the phenotypic presentation of XLH during adulthood including complications other than skeletal and dental diseases. The clinical and biochemical phenotype of 22 adult patients with a PHEX gene mutation were examined retrospectively from their medical records. 6 patients had hypertension. The average age of hypertension onset was 29.0 years. Secondary hyperparathyroidism preceded the development of hypertension in 5 patients. 1 patient developed tertiary hyperparathyroidism. 15 patients had nephrocalcinosis. 2 patients had chronic renal dysfunction. Patients with hypertension had a significantly lower eGFR (p=0.010) compared to patients without hypertension. No significant difference was found in any other parameters. To examine the genotype-phenotype correlation, 10 adult males were chosen for analysis. No significant genotype-phenotype correlation analysis was revealed in any of the complications. However, there was a possibility that the age at nephrocalcinosis onset was younger in the non-missense mutation group than in the missense mutation group (p=0.063). This study corroborated the view that early-onset hypertension could be one of the characteristic complications seen in XLH patients. Considering the limited number of our patients, further study is necessary to address a potential cause of hypertension. XLH patients require careful lifelong treatment.

Deformation strain is the main physical driver for skeletal precursors to undergo osteogenesis in earlier stages of osteogenic cell maturation.

PubMed

Ramani-Mohan, Ram-Kumar; Schwedhelm, Ivo; Finne-Wistrand, Anna; Krug, Melanie; Schwarz, Thomas; Jakob, Franz; Walles, Heike; Hansmann, Jan

2018-03-01

Mesenchymal stem cells play a major role during bone remodelling and are thus of high interest for tissue engineering and regenerative medicine applications. Mechanical stimuli, that is, deformation strain and interstitial fluid-flow-induced shear stress, promote osteogenic lineage commitment. However, the predominant physical stimulus that drives early osteogenic cell maturation is not clearly identified. The evaluation of each stimulus is challenging, as deformation and fluid-flow-induced shear stress interdepend. In this study, we developed a bioreactor that was used to culture mesenchymal stem cells harbouring a strain-responsive AP-1 luciferase reporter construct, on porous scaffolds. In addition to the reporter, mineralization and vitality of the cells was investigated by alizarin red staining and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Quantification of the expression of genes associated to bone regeneration and bone remodelling was used to confirm alizarin red measurements. Controlled perfusion and deformation of the 3-dimensional scaffold facilitated the alteration of the expression of osteogenic markers, luciferase activity, and calcification. To isolate the specific impact of scaffold deformation, a computational model was developed to derive a perfusion flow profile that results in dynamic shear stress conditions present in periodically loaded scaffolds. In comparison to actually deformed scaffolds, a lower expression of all measured readout parameters indicated that deformation strain is the predominant stimulus for skeletal precursors to undergo osteogenesis in earlier stages of osteogenic cell maturation. Copyright © 2017 John Wiley & Sons, Ltd.

CT evaluation of timing for ossification of the medial clavicular epiphysis in a contemporary Western Australian population.

PubMed

Franklin, Daniel; Flavel, Ambika

2015-05-01

The clavicle is the first bone to ossify in the developing embryo and the last to complete epiphyseal union. It is the latter sustained period of growth that has attracted the interest of skeletal biologists and forensic practitioners alike, who collectively recognize the important opportunity this bone affords to estimate skeletal age across the prenatal to early adult lifespan. Current research is largely directed towards evaluating the applicability of assessing fusion in the medial epiphysis, specifically for determining age of majority in the living. This study aims to contribute further insights, and inform medicolegal practice, by evaluating the Schmeling five-stage system for the assessment of clavicular development in a Western Australian population. We retrospectively evaluated high-resolution multiple detector computed tomography (MDCT) scans of 388 individuals (210 male; 178 female) between 10 and 35 years of age. Scans are viewed in axial and multiplanar reconstructed (MPR) images using OsiriX®. Fusion status is scored according to a five-stage system. Transition analysis is used to calculate age ranges and determine the mean age for transition between an unfused, fusing and fused status. The maximum likelihood estimates (in years) for transition from unfused to fusing is 20.60 (male) and 19.19 (female); transition from fusing to complete fusion is 21.92 (male) and 21.47 (female). Results of the present study confirm the reliability of the assessed method and demonstrate remarkable consistency to data reported for other global populations.

Molecular events underlying skeletal muscle atrophy and the development of effective countermeasures

NASA Technical Reports Server (NTRS)

Booth, F. W.; Criswell, D. S.

1997-01-01

Skeletal muscle adapts to loading; atrophying when exposed to unloading on Earth or in spaceflight. Significant atrophy (decreases in muscle fiber cross-section of 11-24%) in humans has been noted after only 5 days in space. Since muscle strength is determined both by muscle cross-section and synchronization of motor unit recruitment, a loss in muscle size weakens astronauts, which would increase risks to their safety if an emergency required maximal muscle force. Numerous countermeasures have been tested to prevent atrophy. Resistant exercise together with growth hormone and IGF-I are effective countermeasures to unloading as most atrophy is prevented in animal models. The loss of muscle protein is due to an early decrease in protein synthesis rate and a later increase in protein degradation. The initial decrease in protein synthesis is a result of decreased protein translation, caused by a prolongation in the elongation rate. A decrease in HSP70 by a sight increase in ATP may be the factors prolonging elongation rate. Increases in the activities of proteolytic enzymes and in ubiquitin contribute to the increased protein degradation rate in unloaded muscle. Numerous mRNA concentrations have been shown to be altered in unloaded muscles. Decreases in mRNAs for contractile proteins usually occur after the initial fall in protein synthesis rates. Much additional research is needed to determine the mechanism by which muscle senses the absence of gravity with an adaptive atrophy. The development of effective countermeasures to unloading atrophy will require more research.

Maternal obesity reduces oxidative capacity in fetal skeletal muscle of Japanese macaques

PubMed Central

McCurdy, Carrie E.; Hetrick, Byron; Houck, Julie; Drew, Brian G.; Kaye, Spencer; Lashbrook, Melanie; Bergman, Bryan C.; Takahashi, Diana L.; Dean, Tyler A.; Gertsman, Ilya; Hansen, Kirk C.; Philp, Andrew; Hevener, Andrea L.; Chicco, Adam J.; Aagaard, Kjersti M.; Grove, Kevin L.; Friedman, Jacob E.

2016-01-01

Maternal obesity is proposed to alter the programming of metabolic systems in the offspring, increasing the risk for developing metabolic diseases; however, the cellular mechanisms remain poorly understood. Here, we used a nonhuman primate model to examine the impact of a maternal Western-style diet (WSD) alone, or in combination with obesity (Ob/WSD), on fetal skeletal muscle metabolism studied in the early third trimester. We find that fetal muscle responds to Ob/WSD by upregulating fatty acid metabolism, mitochondrial complex activity, and metabolic switches (CPT-1, PDK4) that promote lipid utilization over glucose oxidation. Ob/WSD fetuses also had reduced mitochondrial content, diminished oxidative capacity, and lower mitochondrial efficiency in muscle. The decrease in oxidative capacity and glucose metabolism was persistent in primary myotubes from Ob/WSD fetuses despite no additional lipid-induced stress. Switching obese mothers to a healthy diet prior to pregnancy did not improve fetal muscle mitochondrial function. Lastly, while maternal WSD alone led only to intermediary changes in fetal muscle metabolism, it was sufficient to increase oxidative damage and cellular stress. Our findings suggest that maternal obesity or WSD, alone or in combination, leads to programmed decreases in oxidative metabolism in offspring muscle. These alterations may have important implications for future health. PMID:27734025

Experimental West Nile virus infection in Eastern Screech Owls (Megascops asio)

USGS Publications Warehouse

Nemeth, N.M.; Hahn, D.C.; Gould, D.H.; Bowen, R.A.

2006-01-01

Eastern Screech Owls (EASOs) were experimentally infected with the pathogenic New York 1999 strain of West Nile virus (WNV) by subcutaneous injection or per os. Two of nine subcutaneously inoculated birds died or were euthanatized on 8 or 9 days postinfection (DPI) after <24 hr of lethargy and recumbency. All subcutaneously inoculated birds developed levels of viremia that are likely infectious to mosquitoes, with peak viremia levels ranging from 105.0 to 109.6 plaque-forming units/ml. Despite the viremia, the remaining seven birds did not display signs of illness. All birds alive beyond 5 DPI seroconverted, although the morbid birds demonstrated significantly lower antibody titers than the clinically normal birds. Cagemates of infected birds did not become infected. One of five orally exposed EASOs became viremic and seroconverted, whereas WNV infection in the remaining four birds was not evident. All infected birds shed virus via the oral and cloacal route. Early during infection, WNV targeted skin, spleen, esophagus, and skeletal muscle. The two morbid owls had myocardial and skeletal muscle necrosis and mild encephalitis and nephritis, whereas some of the clinically healthy birds that were sacrificed on 14 DPI had myocardial arteritis and renal phlebitis. WNV is a significant pathogen of EASOs, causing pathologic lesions with varying clinical outcomes.

Mitophagy is required for mitochondrial biogenesis and myogenic differentiation of C2C12 myoblasts.

PubMed

Sin, Jon; Andres, Allen M; Taylor, David J R; Weston, Thomas; Hiraumi, Yoshimi; Stotland, Aleksandr; Kim, Brandon J; Huang, Chengqun; Doran, Kelly S; Gottlieb, Roberta A

2016-01-01

Myogenesis is a crucial process governing skeletal muscle development and homeostasis. Differentiation of primitive myoblasts into mature myotubes requires a metabolic switch to support the increased energetic demand of contractile muscle. Skeletal myoblasts specifically shift from a highly glycolytic state to relying predominantly on oxidative phosphorylation (OXPHOS) upon differentiation. We have found that this phenomenon requires dramatic remodeling of the mitochondrial network involving both mitochondrial clearance and biogenesis. During early myogenic differentiation, autophagy is robustly upregulated and this coincides with DNM1L/DRP1 (dynamin 1-like)-mediated fragmentation and subsequent removal of mitochondria via SQSTM1 (sequestosome 1)-mediated mitophagy. Mitochondria are then repopulated via PPARGC1A/PGC-1α (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha)-mediated biogenesis. Mitochondrial fusion protein OPA1 (optic atrophy 1 [autosomal dominant]) is then briskly upregulated, resulting in the reformation of mitochondrial networks. The final product is a myotube replete with new mitochondria. Respirometry reveals that the constituents of these newly established mitochondrial networks are better primed for OXPHOS and are more tightly coupled than those in myoblasts. Additionally, we have found that suppressing autophagy with various inhibitors during differentiation interferes with myogenic differentiation. Together these data highlight the integral role of autophagy and mitophagy in myogenic differentiation.

Vitamin D in Saudi Arabia: Prevalence,distribution and disease associations.

PubMed

Al-Daghri, Nasser M

2018-01-01

More than 33 years have passed since the first paper highlighting vitamin D deficiency as a public health concern in Saudi Arabia was published in 1983. Despite "early" detection,it wasn't until the year 2010 where the interest in vitamin D research grew exponentially worldwide and was finally visible in Saudi clinical and academic areas. Since then,many landmark studies have been generated with regards to the physiologic functions of vitamin D,both skeletal and extra-skeletal. This review is limited to the prevalence,distribution A systematic review on the prevalence studies done in KSA from 2011 to 2016 was done and revealed that the prevalence of vitamin D deficiency (<50nmol/l) in Saudi Arabia among different populations (adults,children and adolescents,newborns and pregnant/lactating women) is 81.0% (Confidence Interval 95% 68.0-90.0),in line with most neighboring Gulf countries. Vitamin D deficiency in KSA has been mostly associated with bone and insulin-resistant diseases but limited data are available to prove causality. In conclusion,there is a need to develop local consensus guidelines that will identify candidates for screening,monitoring and treating those who are at most risk for vitamin D deficiency complications. Copyright © 2016 Elsevier Ltd. All rights reserved.

Social networking between cells of the foetal skeleton: the importance of thyroid hormones.

PubMed

Farquharson, Colin

2011-08-01

In this issue of Journal of Endocrinology, Lanham et al. investigated the effects of hypothyroidism on the developing skeleton of the ovine foetus in utero. Their analyses indicated that, following thyroidectomy, bone growth, structure and mechanical properties were all altered at late gestation or at term. Adrenalectomy, whilst preventing the prepartum rise in triiodothyronine, did not modify skeletal development. The hypothyroid-mediated skeletal defects of the developing foetus described in this study may have clinical implications for bone health in later life.

Neuromuscular Junction Formation between Human Stem cell-derived Motoneurons and Human Skeletal Muscle in a Defined System

PubMed Central

Guo, Xiufang; Gonzalez, Mercedes; Stancescu, Maria; Vandenburgh, Herman; Hickman, James

2011-01-01

Functional in vitro models composed of human cells will constitute an important platform in the next generation of system biology and drug discovery. This study reports a novel human-based in vitro Neuromuscular Junction (NMJ) system developed in a defined serum-free medium and on a patternable non-biological surface. The motoneurons and skeletal muscles were derived from fetal spinal stem cells and skeletal muscle stem cells. The motoneurons and skeletal myotubes were completely differentiated in the co-culture based on morphological analysis and electrophysiology. NMJ formation was demonstrated by phase contrast microscopy, immunocytochemistry and the observation of motoneuron-induced muscle contractions utilizing time lapse recordings and their subsequent quenching by D-Tubocurarine. Generally, functional human based systems would eliminate the issue of species variability during the drug development process and its derivation from stem cells bypasses the restrictions inherent with utilization of primary human tissue. This defined human-based NMJ system is one of the first steps in creating functional in vitro systems and will play an important role in understanding NMJ development, in developing high information content drug screens and as test beds in preclinical studies for spinal or muscular diseases/injuries such as muscular dystrophy, Amyotrophic lateral sclerosis and spinal cord repair. PMID:21944471

Neuromuscular junction formation between human stem cell-derived motoneurons and human skeletal muscle in a defined system.

PubMed

Guo, Xiufang; Gonzalez, Mercedes; Stancescu, Maria; Vandenburgh, Herman H; Hickman, James J

2011-12-01

Functional in vitro models composed of human cells will constitute an important platform in the next generation of system biology and drug discovery. This study reports a novel human-based in vitro Neuromuscular Junction (NMJ) system developed in a defined serum-free medium and on a patternable non-biological surface. The motoneurons and skeletal muscles were derived from fetal spinal stem cells and skeletal muscle stem cells. The motoneurons and skeletal myotubes were completely differentiated in the co-culture based on morphological analysis and electrophysiology. NMJ formation was demonstrated by phase contrast microscopy, immunocytochemistry and the observation of motoneuron-induced muscle contractions utilizing time-lapse recordings and their subsequent quenching by d-Tubocurarine. Generally, functional human based systems would eliminate the issue of species variability during the drug development process and its derivation from stem cells bypasses the restrictions inherent with utilization of primary human tissue. This defined human-based NMJ system is one of the first steps in creating functional in vitro systems and will play an important role in understanding NMJ development, in developing high information content drug screens and as test beds in preclinical studies for spinal or muscular diseases/injuries such as muscular dystrophy, Amyotrophic lateral sclerosis and spinal cord repair. Copyright © 2011 Elsevier Ltd. All rights reserved.

[Skeletal anchorage in the past, today and tomorrow].

PubMed

Melsen, Birte; Dalstra, Michel

2017-03-01

Skeletal anchorage was not introduced as an alternative to conventional anchorage modalities. The first skeletal anchorage was a ligature through a hole in the infrazygomatic crest. This was replaced by surgical screws and finally the TADs, which were optimized with respect to the material and morphology, were developed. A bracket-like head allows for the use of the mini-implant as indirect anchorage, but should not be a tool for lost control resulting from badly planned biomechanics or failing compliance. Skeletal anchorage should serve as an adjunct to correct biomechanics, to enable treatments that could not be performed prior to the introduction of skeletal anchorage. The aim of this study was to test the hypothesis that temporary anchorage mini-screws help maintain bone density, height and width of alveolar processes in the extraction sites, and thus prevent the thinning of the alveolar ridge usually observed. In adult patients with degenerated dentitions the application of skeletal anchorage can allow for the displacement of teeth where no anchorage units are present, but also for the redevelopment and maintenance of atrophic alveolar bone. The basis for the optimal use of skeletal anchorage is that the correct line of action for the desired tooth displacement is defined and the necessary force system constructed either with the skeletal anchorage as direct or as indirect anchorage. After a period, during which osseointegrated implants were used as anchorage for tooth movement and bone maintenance, it was accepted that the mini-implants could serve also as anchorage for skeletal displacements avoiding loading of teeth. © EDP Sciences, SFODF, 2017.

Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis.

PubMed

Hughes, Alexandria; Oxford, Alexandra E; Tawara, Ken; Jorcyk, Cheryl L; Oxford, Julia Thom

2017-03-20

Chondrocytes of the growth plate undergo apoptosis during the process of endochondral ossification, as well as during the progression of osteoarthritis. Although the regulation of this process is not completely understood, alterations in the precisely orchestrated programmed cell death during development can have catastrophic results, as exemplified by several chondrodystrophies which are frequently accompanied by early onset osteoarthritis. Understanding the mechanisms that underlie chondrocyte apoptosis during endochondral ossification in the growth plate has the potential to impact the development of therapeutic applications for chondrodystrophies and associated early onset osteoarthritis. In recent years, several chondrodysplasias and collagenopathies have been recognized as protein-folding diseases that lead to endoplasmic reticulum stress, endoplasmic reticulum associated degradation, and the unfolded protein response. Under conditions of prolonged endoplasmic reticulum stress in which the protein folding load outweighs the folding capacity of the endoplasmic reticulum, cellular dysfunction and death often occur. However, unfolded protein response (UPR) signaling is also required for the normal maturation of chondrocytes and osteoblasts. Understanding how UPR signaling may contribute to cartilage pathophysiology is an essential step toward therapeutic modulation of skeletal disorders that lead to osteoarthritis.

Histological and Transcriptomic Changes in Male Zebrafish Testes Due to Early Life Exposure to Low Level 2,3,7,8-Tetrachlorodibenzo-p-Dioxin.

PubMed

Baker, Bridget B; Yee, Jeremiah S; Meyer, Danielle N; Yang, Doris; Baker, Tracie R

2016-10-01

We have shown that zebrafish (Danio rerio) are an excellent model for evaluating the link between early life stage exposure to environmental chemicals and disease in adulthood and subsequent unexposed generations. Previously, we used this model to identify transgenerational effects of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]) on skeletal development, sex ratio, and reproductive capacity. Transgenerational inheritance of TCDD toxicity, notably decreased reproductive capacity, appears to be mediated through the male germ line. Thus, we examine testicular tissue for structural and gene expression changes using histology, microarray, and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Histological analysis revealed decreased spermatozoa with concurrent increase in spermatogonia, and decreased germinal epithelium thickness in TCDD-exposed males compared with controls. We also identified altered expression of genes associated with testis development, steroidogenesis, spermatogenesis, hormone metabolism, and xenobiotic response. Altered genes are in pathways involving lipid metabolism, molecular transport, small molecule biochemistry, cell morphology, and metabolism of vitamins and minerals. These data will inform future investigations to elucidate the mechanism of adult-onset and transgenerational infertility due to TCDD exposure in zebrafish.

Developmental Patterning as a Quantitative Trait: Genetic Modulation of the Hoxb6 Mutant Skeletal Phenotype

PubMed Central

Kappen, Claudia

2016-01-01

The process of patterning along the anterior-posterior axis in vertebrates is highly conserved. The function of Hox genes in the axis patterning process is particularly well documented for bone development in the vertebral column and the limbs. We here show that Hoxb6, in skeletal elements at the cervico-thoracic junction, controls multiple independent aspects of skeletal pattern, implicating discrete developmental pathways as substrates for this transcription factor. In addition, we demonstrate that Hoxb6 function is subject to modulation by genetic factors. These results establish Hox-controlled skeletal pattern as a quantitative trait modulated by gene-gene interactions, and provide evidence that distinct modifiers influence the function of conserved developmental genes in fundamental patterning processes. PMID:26800342

Evidence for prosauropod dinosaur gastroliths in the Bull Run Formation (Upper Triassic, Norian) of Virginia

USGS Publications Warehouse

Weems, Robert E.; Culp, Michelle J.; Wings, Oliver

2007-01-01

Definitive criteria for distinguishing gastroliths from sedimentary clasts are lacking for many depositional settings, and many reported occurrences of gastroliths either cannot be verified or have been refuted. We discuss four occurrences of gastrolith-like stones (category 6 exoliths) not found within skeletal remains from the Upper Triassic Bull Run Formation of northern Virginia, USA. Despite their lack of obvious skeletal association, the most parsimonious explanation for several characteristics of these stones is their prolonged residence in the gastric mills of large animals. These characteristics include 1) typical gastrolith microscopic surface texture, 2) evidence of pervasive surface wear on many of these stones that has secondarily removed variable amounts of thick weathering rinds typically found on these stones, and 3) a width/length-ratio modal peak for these stones that is more strongly developed than in any population of fluvial or fanglomerate stones of any age found in this region. When taken together, these properties of the stones can be explained most parsimoniously by animal ingestion and gastric-mill abrasion. The size of these stones indicates the animals that swallowed them were large, and the best candidate is a prosauropod dinosaur, possibly an ancestor of the Early Jurassic gastrolith-producing prosauropod Massospondylus or Ammosaurus.Skeletal evidence for Upper Triassic prosauropods is lacking in the Newark Supergroup basins; footprints (Agrestipus hottoni and Eubrontes isp.) from the Bull Run Formation in the Culpeper basin previously ascribed to prosauropods are now known to be underprints (Brachychirotherium parvum) of an aetosaur and underprints (Kayentapus minor) of a ceratosaur. The absence of prosauropod skeletal remains or footprints in all but the uppermost (upper Rhaetian) Triassic rocks of the Newark Supergroup is puzzling because prosauropod remains are abundant elsewhere in the world in Upper Triassic (Carnian, Norian, and lower Rhaetian) continental strata. The apparent scarcity of prosauropods in Upper Triassic strata of the Newark Supergroup is interpreted as an artifact of ecological partitioning, created by the habitat range and dietary preferences of phytosaurs and by the preservational biases at that time within the lithofacies of the Newark Supergroup basins.

A novel approach for studying the temporal modulation of embryonic skeletal development using organotypic bone cultures and microcomputed tomography.

PubMed

Kanczler, Janos M; Smith, Emma L; Roberts, Carol A; Oreffo, Richard O C

2012-10-01

Understanding the structural development of embryonic bone in a three dimensional framework is fundamental to developing new strategies for the recapitulation of bone tissue in latter life. We present an innovative combined approach of an organotypic embryonic femur culture model, microcomputed tomography (μCT) and immunohistochemistry to examine the development and modulation of the three dimensional structures of the developing embryonic femur. Isolated embryonic chick femurs were organotypic (air/liquid interface) cultured for 10 days in either basal, chondrogenic, or osteogenic supplemented culture conditions. The growth development and modulating effects of basal, chondrogenic, or osteogenic culture media of the embryonic chick femurs was investigated using μCT, immunohistochemistry, and histology. The growth and development of noncultured embryonic chick femur stages E10, E11, E12, E13, E15, and E17 were very closely correlated with increased morphometric indices of bone formation as determined by μCT. After 10 days in the organotpyic culture set up, the early aged femurs (E10 and E11) demonstrated a dramatic response to the chondrogenic or osteogenic culture conditions compared to the basal cultured femurs as determined by a change in μCT morphometric indices and modified expression of chondrogenic and osteogenic markers. Although the later aged femurs (E12 and E13) increased in size and structure after 10 days organotpypic culture, the effects of the osteogenic and chondrogenic organotypic cultures on these femurs were not significantly altered compared to basal conditions. We have demonstrated that the embryonic chick femur organotpyic culture model combined with the μCT and immunohistochemical analysis can provide an integral methodology for investigating the modulation of bone development in an ex vivo culture setting. Hence, these interdisciplinary techniques of μCT and whole organ bone cultures will enable us to delineate some of the temporal, structural developmental paradigms and modulation of bone tissue formation to underpin innovative skeletal regenerative technology for clinical therapeutic strategies in musculoskeletal trauma and diseases.

Skeletal Muscle Pathophysiology: The Emerging Role of Spermine Oxidase and Spermidine

PubMed Central

Duranti, Guglielmo; Sabatini, Stefania; Ceci, Roberta; Mariottini, Paolo

2018-01-01

Skeletal muscle comprises approximately 40% of the total body mass. Preserving muscle health and function is essential for the entire body in order to counteract chronic diseases such as type II diabetes, cardiovascular diseases, and cancer. Prolonged physical inactivity, particularly among the elderly, causes muscle atrophy, a pathological state with adverse outcomes such as poor quality of life, physical disability, and high mortality. In murine skeletal muscle C2C12 cells, increased expression of the spermine oxidase (SMOX) enzyme has been found during cell differentiation. Notably, SMOX overexpression increases muscle fiber size, while SMOX reduction was enough to induce muscle atrophy in multiple murine models. Of note, the SMOX reaction product spermidine appears to be involved in skeletal muscle atrophy/hypertrophy. It is effective in reactivating autophagy, ameliorating the myopathic defects of collagen VI-null mice. Moreover, spermidine treatment, if combined with exercise, can affect D-gal-induced aging-related skeletal muscle atrophy. This review hypothesizes a role for SMOX during skeletal muscle differentiation and outlines its role and that of spermidine in muscle atrophy. The identification of new molecular pathways involved in the maintenance of skeletal muscle health could be beneficial in developing novel therapeutic lead compounds to treat muscle atrophy. PMID:29443878

Action of Obestatin in Skeletal Muscle Repair: Stem Cell Expansion, Muscle Growth, and Microenvironment Remodeling

PubMed Central

Gurriarán-Rodríguez, Uxía; Santos-Zas, Icía; González-Sánchez, Jessica; Beiroa, Daniel; Moresi, Viviana; Mosteiro, Carlos S; Lin, Wei; Viñuela, Juan E; Señarís, José; García-Caballero, Tomás; Casanueva, Felipe F; Nogueiras, Rubén; Gallego, Rosalía; Renaud, Jean-Marc; Adamo, Sergio; Pazos, Yolanda; Camiña, Jesús P

2015-01-01

The development of therapeutic strategies for skeletal muscle diseases, such as physical injuries and myopathies, depends on the knowledge of regulatory signals that control the myogenic process. The obestatin/GPR39 system operates as an autocrine signal in the regulation of skeletal myogenesis. Using a mouse model of skeletal muscle regeneration after injury and several cellular strategies, we explored the potential use of obestatin as a therapeutic agent for the treatment of trauma-induced muscle injuries. Our results evidenced that the overexpression of the preproghrelin, and thus obestatin, and GPR39 in skeletal muscle increased regeneration after muscle injury. More importantly, the intramuscular injection of obestatin significantly enhanced muscle regeneration by simulating satellite stem cell expansion as well as myofiber hypertrophy through a kinase hierarchy. Added to the myogenic action, the obestatin administration resulted in an increased expression of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) and the consequent microvascularization, with no effect on collagen deposition in skeletal muscle. Furthermore, the potential inhibition of myostatin during obestatin treatment might contribute to its myogenic action improving muscle growth and regeneration. Overall, our data demonstrate successful improvement of muscle regeneration, indicating obestatin is a potential therapeutic agent for skeletal muscle injury and would benefit other myopathies related to muscle regeneration. PMID:25762009

Action of obestatin in skeletal muscle repair: stem cell expansion, muscle growth, and microenvironment remodeling.

PubMed

Gurriarán-Rodríguez, Uxía; Santos-Zas, Icía; González-Sánchez, Jessica; Beiroa, Daniel; Moresi, Viviana; Mosteiro, Carlos S; Lin, Wei; Viñuela, Juan E; Señarís, José; García-Caballero, Tomás; Casanueva, Felipe F; Nogueiras, Rubén; Gallego, Rosalía; Renaud, Jean-Marc; Adamo, Sergio; Pazos, Yolanda; Camiña, Jesús P

2015-06-01

The development of therapeutic strategies for skeletal muscle diseases, such as physical injuries and myopathies, depends on the knowledge of regulatory signals that control the myogenic process. The obestatin/GPR39 system operates as an autocrine signal in the regulation of skeletal myogenesis. Using a mouse model of skeletal muscle regeneration after injury and several cellular strategies, we explored the potential use of obestatin as a therapeutic agent for the treatment of trauma-induced muscle injuries. Our results evidenced that the overexpression of the preproghrelin, and thus obestatin, and GPR39 in skeletal muscle increased regeneration after muscle injury. More importantly, the intramuscular injection of obestatin significantly enhanced muscle regeneration by simulating satellite stem cell expansion as well as myofiber hypertrophy through a kinase hierarchy. Added to the myogenic action, the obestatin administration resulted in an increased expression of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) and the consequent microvascularization, with no effect on collagen deposition in skeletal muscle. Furthermore, the potential inhibition of myostatin during obestatin treatment might contribute to its myogenic action improving muscle growth and regeneration. Overall, our data demonstrate successful improvement of muscle regeneration, indicating obestatin is a potential therapeutic agent for skeletal muscle injury and would benefit other myopathies related to muscle regeneration.

Neural-Thyroid Interaction on Skeletal Isomyosin in Zero Gravity

NASA Technical Reports Server (NTRS)

Baldwin, Kenneth M.

2000-01-01

The primary goal of the project was to develop a ground based model to first study the role of the nerve and of thyroid hormone (T3) in the regulation of body growth and skeletal muscle growth and differentiation in rodents. A primary objective was to test the hypothesis that normal weight bearing activity is essential for the development of antigravity, slow twitch skeletal muscle and the corresponding slow myosin heavy chain (MHC) gene; whereas, T3 was obligatory for general body and muscle growth and the establishment of fast MHC phenotype in typically fast locomoter muscles. These ground based experiments would provide both the efficacy and background for a spaceflight experiment (referred to as the Neurolab Mission) jointly sponsored by the NIH and NASA.

Myostatin regulates miR-431 expression via the Ras-Mek-Erk signaling pathway.

PubMed

Wu, Rimao; Li, Hu; Li, Tingting; Zhang, Yong; Zhu, Dahai

2015-05-29

MicroRNAs (miRNAs) play critical regulatory roles in controlling myogenic development both in vitro and in vivo; however, the molecular mechanisms underlying transcriptional regulation of miRNA genes in skeletal muscle cells are largely unknown. Here, using a microarray hybridization approach, we identified myostatin-regulated miRNA genes in skeletal muscle tissues by systematically searching miRNAs that are differentially expressed between wild-type and myostatin-null mice during development. We found that 116 miRNA genes were differentially expressed in muscles between these mice across different developmental stages. We further characterized myostatin-regulated miR-431 was upregulated in skeletal muscle tissues of myostatin-null mice. In functional studies, we found that overexpression of miR-431 in C2C12 myoblast cells attenuated myostatin-induced suppression of myogenic differentiation. Mechanistic studies further demonstrated that myostatin acted through the Ras-Mek-Erk signaling pathway to transcriptionally regulate miR-431 expression C2C12 cells. Our findings provide new insight into the mechanisms underlying transcriptional regulation of miRNA genes by myostatin during skeletal muscle development. Copyright © 2015 Elsevier Inc. All rights reserved.

skNAC, a Smyd1-interacting transcription factor, is involved in cardiac development and skeletal muscle growth and regeneration.

PubMed

Park, Chong Yon; Pierce, Stephanie A; von Drehle, Morgan; Ivey, Kathryn N; Morgan, Jayson A; Blau, Helen M; Srivastava, Deepak

2010-11-30

Cardiac and skeletal muscle development and maintenance require complex interactions between DNA-binding proteins and chromatin remodeling factors. We previously reported that Smyd1, a muscle-restricted histone methyltransferase, is essential for cardiogenesis and functions with a network of cardiac regulatory proteins. Here we show that the muscle-specific transcription factor skNAC is the major binding partner for Smyd1 in the developing heart. Targeted deletion of skNAC in mice resulted in partial embryonic lethality by embryonic day 12.5, with ventricular hypoplasia and decreased cardiomyocyte proliferation that were similar but less severe than in Smyd1 mutants. Expression of Irx4, a ventricle-specific transcription factor down-regulated in hearts lacking Smyd1, also depended on the presence of skNAC. Viable skNAC(-/-) adult mice had reduced postnatal skeletal muscle growth and impaired regenerative capacity after cardiotoxin-induced injury. Satellite cells isolated from skNAC(-/-) mice had impaired survival compared with wild-type littermate satellite cells. Our results indicate that skNAC plays a critical role in ventricular cardiomyocyte expansion and regulates postnatal skeletal muscle growth and regeneration in mice.

Pregnancy and Smoothelin-like Protein 1 (SMTNL1) Deletion Promote the Switching of Skeletal Muscle to a Glycolytic Phenotype in Human and Mice.

PubMed

Lontay, Beata; Bodoor, Khaldon; Sipos, Adrienn; Weitzel, Douglas H; Loiselle, David; Safi, Rachid; Zheng, Donghai; Devente, James; Hickner, Robert C; McDonnell, Donald P; Ribar, Thomas; Haystead, Timothy A

2015-07-17

Pregnancy promotes physiological adaptations throughout the body, mediated by the female sex hormones progesterone and estrogen. Changes in the metabolic properties of skeletal muscle enable the female body to cope with the physiological challenges of pregnancy and may also be linked to the development of insulin resistance. We conducted global microarray, proteomic, and metabolic analyses to study the role of the progesterone receptor and its transcriptional regulator, smoothelin-like protein 1 (SMTNL1) in the adaptation of skeletal muscle to pregnancy. We demonstrate that pregnancy promotes fiber-type changes from an oxidative to glycolytic isoform in skeletal muscle. This phenomenon is regulated through an interaction between SMTNL1 and progesterone receptor, which alters the expression of contractile and metabolic proteins. smtnl1(-/-) mice are metabolically less efficient and show impaired glucose tolerance. Pregnancy antagonizes these effects by inducing metabolic activity and increasing glucose tolerance. Our results suggest that SMTNL1 has a role in mediating the actions of steroid hormones to promote fiber switching in skeletal muscle during pregnancy. Our findings also bear on the management of gestational diabetes that develops as a complication of pregnancy in ~4% of women. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Cavin4b/Murcb Is Required for Skeletal Muscle Development and Function in Zebrafish

PubMed Central

Housley, Michael P.; Njaine, Brian; Ricciardi, Filomena; Stone, Oliver A.; Hölper, Soraya; Krüger, Marcus; Kostin, Sawa; Stainier, Didier Y. R.

2016-01-01

Skeletal muscles provide metazoans with the ability to feed, reproduce and avoid predators. In humans, a heterogeneous group of genetic diseases, termed muscular dystrophies (MD), lead to skeletal muscle dysfunction. Mutations in the gene encoding Caveolin-3, a principal component of the membrane micro-domains known as caveolae, cause defects in muscle maintenance and function; however it remains unclear how caveolae dysfunction underlies MD pathology. The Cavin family of caveolar proteins can form membrane remodeling oligomers and thus may also impact skeletal muscle function. Changes in the distribution and function of Cavin4/Murc, which is predominantly expressed in striated muscles, have been reported to alter caveolae structure through interaction with Caveolin-3. Here, we report the generation and phenotypic analysis of murcb mutant zebrafish, which display impaired swimming capacity, skeletal muscle fibrosis and T-tubule abnormalities during development. To understand the mechanistic importance of Murc loss of function, we assessed Caveolin-1 and 3 localization and found it to be abnormal. We further identified an in vivo function for Murc in Erk signaling. These data link Murc with developmental defects in T-tubule formation and progressive muscle dysfunction, thereby providing a new candidate for the etiology of muscular dystrophy. PMID:27294373

Thyroid hormones and skeletal muscle — new insights and potential implications

PubMed Central

Salvatore, Domenico; Simonides, Warner S.; Dentice, Monica; Zavacki, Ann Marie; Larsen, P. Reed

2014-01-01

Thyroid hormone signalling regulates crucial biological functions, including energy expenditure, thermogenesis, development and growth. The skeletal muscle is a major target of thyroid hormone signalling. The type two (DIO2) and three (DIO3) iodothyronine deiodinases have been identified in skeletal muscle. DIO2 expression is tightly regulated and catalyzes outer ring monodeiodination of the secreted prohormone tetraiodothyronine (T4) to generate the active hormone triiodothyronine (T3). T3 may remain in the myocyte to signal through nuclear receptors or exit the cell to mix with the extracellular pool. By contrast, DIO3 inactivates T3 through removal of an inner ring iodine. Regulation of the expression and activity of deiodinases constitutes a cell-autonomous, pre-receptor mechanism for controlling the intracellular concentration of T3. This local control of T3 activity is crucial during the various phases of myogenesis. Here, we review the roles of T3 in skeletal muscle development and homeostasis, with a focus on the emerging local deiodinase-mediated control of T3 signalling. Moreover, we discuss these novel findings in the context of both muscle homeostasis and pathology, and examine how they can be therapeutically harnessed to improve satellite cell-mediated muscle repair in patients with skeletal muscle disorders, muscle atrophy or injury. PMID:24322650

Neuromuscular junction formation between human stem-cell-derived motoneurons and rat skeletal muscle in a defined system.

PubMed

Guo, Xiufang; Das, Mainak; Rumsey, John; Gonzalez, Mercedes; Stancescu, Maria; Hickman, James

2010-12-01

To date, the coculture of motoneurons (MNs) and skeletal muscle in a defined in vitro system has only been described in one study and that was between rat MNs and rat skeletal muscle. No in vitro studies have demonstrated human MN to rat muscle synapse formation, although numerous studies have attempted to implant human stem cells into rat models to determine if they could be of therapeutic use in disease or spinal injury models, although with little evidence of neuromuscular junction (NMJ) formation. In this report, MNs differentiated from human spinal cord stem cells, together with rat skeletal myotubes, were used to build a coculture system to demonstrate that NMJ formation between human MNs and rat skeletal muscles is possible. The culture was characterized by morphology, immunocytochemistry, and electrophysiology, while NMJ formation was demonstrated by immunocytochemistry and videography. This defined system provides a highly controlled reproducible model for studying the formation, regulation, maintenance, and repair of NMJs. The in vitro coculture system developed here will be an important model system to study NMJ development, the physiological and functional mechanism of synaptic transmission, and NMJ- or synapse-related disorders such as amyotrophic lateral sclerosis, as well as for drug screening and therapy design.