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

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.

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

Correlation among chronologic age, skeletal maturity, and dental age.

PubMed

Sukhia, Rashna H; Fida, Mubassar

2010-01-01

To determine the correlation among chronologic age, skeletal maturity, and dental age in reference to both sexes. In 380 subjects (147 males and 233 females) between 7 and 17 years of age, skeletal maturity was assessed using the cervical vertebral maturation stages described by Baccetti et al. Dental age was determined using the Demirjian method. The correlation between skeletal maturity and chronologic age on one side and between skeletal maturity and dental age on the other was assessed with Spearman rank correlation coefficients. Pearson correlation coefficients were used to assess the correlation between chronologic and dental age. For both sexes, significant correlations among chronologic age, skeletal maturity, and dental age were found. The mandibular first premolar had the highest correlation with skeletal maturation in both sexes. As skeletal maturity and dental age are significantly correlated, tooth development may be used to assess a patient's skeletal maturity at an early age. © 2011 BY QUINTESSENCE PUBLISHING CO, INC.

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.

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.

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.

[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.

Insulin-like growth factors in embryonic and fetal growth and skeletal development (Review).

PubMed

Agrogiannis, Georgios D; Sifakis, Stavros; Patsouris, Efstratios S; Konstantinidou, Anastasia E

2014-08-01

The insulin-like growth factors (IGF)-I and -II have a predominant role in fetal growth and development. IGFs are involved in the proliferation, differentiation and apoptosis of fetal cells in vitro and the IGF serum concentration has been shown to be closely correlated with fetal growth and length. IGF transcripts and peptides have been detected in almost every fetal tissue from as early in development as pre‑implantation to the final maturation stage. Furthermore, IGFs have been demonstrated to be involved in limb morphogenesis. However, although ablation of Igf genes in mice resulted in growth retardation and delay in skeletal maturation, no impact on outgrowth and patterning of embryonic limbs was observed. Additionally, various molecular defects in the Igf1 and Igf1r genes in humans have been associated with severe intrauterine growth retardation and impaired skeletal maturation, but not with truncated limbs or severe skeletal dysplasia. The conflicting data between in vitro and in vivo observations with regard to bone morphogenesis suggests that IGFs may not be the sole trophic factors involved in fetal skeletal growth and that redundant mechanisms may exist in chondro- and osteogenesis. Further investigation is required in order to elucidate the functions of IGFs in skeletal development.

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.

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.

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.

Determinants of relative skeletal maturity in South African children.

PubMed

Hawley, Nicola L; Rousham, Emily K; Johnson, William; Norris, Shane A; Pettifor, John M; Cameron, Noël

2012-01-01

The variation of skeletal maturity about chronological age is a sensitive indicator of population health. Age appropriate or advanced skeletal maturity is a reflection of adequate environmental and social conditions, whereas delayed maturation suggests inadequate conditions for optimal development. There remains a paucity of data, however, to indicate which specific biological and environmental factors are associated with advancement or delay in skeletal maturity. The present study utilises longitudinal data from the South African Birth to Twenty (Bt20) study to indentify predictors of relative skeletal maturity (RSM) in early adolescence. A total of 244 black South African children (n=131 male) were included in this analysis. Skeletal maturity at age 9/10 years was assessed using the Tanner and Whitehouse III RUS technique. Longitudinal data on growth, socio-economic position and pubertal development were entered into sex-specific multivariable general linear regression models with relative skeletal maturity (skeletal age-chronological age) as the outcome. At 9/10 years of age males showed an average of 0.66 years delay in skeletal maturation relative to chronological age. Females showed an average of 1.00 year delay relative to chronological age. In males, being taller at 2 years (p<0.01) and heavier at 2 years (p<0.01) predicted less delay in RSM at age 9/10 years, independent of current size and body composition. In females, both height at 2 years and conditional weight at 2 years predicted less delay in RSM at 9/10 years (p<0.05) but this effect was mediated by current body composition. Having greater lean mass at 9/10 years was associated with less delayed RSM in females (p<0.01) as was pubertal status at the time of skeletal maturity assessment (p<0.01). This study identifies several predictors of skeletal maturation at 9/10 years, indicating a role for early life exposures in determining the rate of skeletal maturation during childhood independently of current stature. Copyright © 2011 Elsevier Inc. All rights reserved.

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

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.

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.

Skeletal muscle and fetal alcohol spectrum disorder.

PubMed

Myrie, Semone B; Pinder, Mark A

2018-04-01

Skeletal muscle is critical for mobility and many metabolic functions integral to survival and long-term health. Alcohol can affect skeletal muscle physiology and metabolism, which will have immediate and long-term consequences on health. While skeletal muscle abnormalities, including morphological, biochemical, and functional impairments, are well-documented in adults that excessively consume alcohol, there is a scarcity of information about the skeletal muscle in the offspring prenatally exposed to alcohol ("prenatal alcohol exposure"; PAE). This minireview examines the available studies addressing skeletal muscle abnormalities due to PAE. Growth restriction, fetal alcohol myopathy, and abnormalities in the neuromuscular system, which contribute to deficits in locomotion, are some direct, immediate consequences of PAE on skeletal muscle morphology and function. Long-term health consequences of PAE-related skeletal abnormalities include impaired glucose metabolism in the skeletal muscle, resulting in glucose intolerance and insulin resistance, leading to an increased risk of type 2 diabetes. In general, there is limited information on the morphological, biochemical, and functional features of skeletal abnormalities in PAE offspring. There is a need to understand how PAE affects muscle growth and function at the cellular level during early development to improve the immediate and long-term health of offspring suffering from PAE.

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

An analysis of dental development in Pleistocene Homo using skeletal growth and chronological age.

PubMed

Šešelj, Maja

2017-07-01

This study takes a new approach to interpreting dental development in Pleistocene Homo in comparison with recent modern humans. As rates of dental development and skeletal growth are correlated given age in modern humans, using age and skeletal growth in tandem yields more accurate dental development estimates. Here, I apply these models to fossil Homo to obtain more individualized predictions and interpretations of their dental development relative to recent modern humans. Proportional odds logistic regression models based on three recent modern human samples (N = 181) were used to predict permanent mandibular tooth development scores in five Pleistocene subadults: Homo erectus/ergaster, Neanderthals, and anatomically modern humans (AMHs). Explanatory variables include a skeletal growth indicator (i.e., diaphyseal femoral length), and chronological age. AMHs Lagar Velho 1 and Qafzeh 10 share delayed incisor development, but exhibit considerable idiosyncratic variation within and across tooth types, relative to each other and to the reference samples. Neanderthals Dederiyeh 1 and Le Moustier 1 exhibit delayed incisor coupled with advanced molar development, but differences are reduced when femoral diaphysis length is considered. Dental development in KNM-WT 15,000 Homo erectus/ergaster, while advanced for his age, almost exactly matches the predictions once femoral length is included in the models. This study provides a new interpretation of dental development in KNM-WT 15000 as primarily reflecting his faster rates of skeletal growth. While the two AMH specimens exhibit considerable individual variation, the Neanderthals exhibit delayed incisor development early and advanced molar development later in ontogeny. © 2017 Wiley Periodicals, Inc.

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

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.

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

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.

Early Mitochondrial Adaptations in Skeletal Muscle to Diet-Induced Obesity Are Strain Dependent and Determine Oxidative Stress and Energy Expenditure But Not Insulin Sensitivity

PubMed Central

Sena, Sandra; Sloan, Crystal; Tebbi, Ali; Han, Yong Hwan; O'Neill, Brian T.; Cooksey, Robert C.; Jones, Deborah; Holland, William L.; McClain, Donald A.; Abel, E. Dale

2012-01-01

This study sought to elucidate the relationship between skeletal muscle mitochondrial dysfunction, oxidative stress, and insulin resistance in two mouse models with differential susceptibility to diet-induced obesity. We examined the time course of mitochondrial dysfunction and insulin resistance in obesity-prone C57B and obesity-resistant FVB mouse strains in response to high-fat feeding. After 5 wk, impaired insulin-mediated glucose uptake in skeletal muscle developed in both strains in the absence of any impairment in proximal insulin signaling. Impaired mitochondrial oxidative capacity preceded the development of insulin resistant glucose uptake in C57B mice in concert with increased oxidative stress in skeletal muscle. By contrast, mitochondrial uncoupling in FVB mice, which prevented oxidative stress and increased energy expenditure, did not prevent insulin resistant glucose uptake in skeletal muscle. Preventing oxidative stress in C57B mice treated systemically with an antioxidant normalized skeletal muscle mitochondrial function but failed to normalize glucose tolerance and insulin sensitivity. Furthermore, high fat-fed uncoupling protein 3 knockout mice developed increased oxidative stress that did not worsen glucose tolerance. In the evolution of diet-induced obesity and insulin resistance, initial but divergent strain-dependent mitochondrial adaptations modulate oxidative stress and energy expenditure without influencing the onset of impaired insulin-mediated glucose uptake. PMID:22510273

[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.

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.

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...

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.

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.

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.

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.

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.

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

Influence of nasoalveolar molding on skeletal development in patients with unilateral cleft lip and palate at 5 years of age.

PubMed

Akarsu-Guven, Bengisu; Arisan, Arda; Ozgur, Figen; Aksu, Muge

2018-04-01

The aim of this retrospective study was to assess the influence of presurgical nasoalveolar molding (NAM) on skeletal development in patients with operated unilateral cleft lip and palate at 5 years of age. Lateral cephalometric radiographs of 26 unilateral cleft lip and palate patients who had undergone presurgical NAM (NAM group) and 20 unilateral cleft lip and palate patients who did not have any presurgical NAM (non-NAM group) were analyzed. The radiographs were digitally traced using Quick Ceph Studio software (version 3.5.1.r (1151); Quick Ceph Systems, San Diego, Calif). Independent samples t tests were performed for statistical analysis. No significant differences were observed in sagittal and vertical skeletal measurements between the NAM and non-NAM groups. NAM resulted in no significant difference in skeletal development in unilateral cleft lip and palate patients compared with those without NAM in early childhood. Copyright © 2018. Published by Elsevier Inc.

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.

Dependence of normal development of skeletal muscle in neonatal rats on load bearing

NASA Technical Reports Server (NTRS)

Ohira, Y.; Tanaka, T.; Yoshinaga, T.; Kawano, F.; Nomura, T.; Nonaka, I.; Allen, D. L.; Roy, R. R.; Edgerton, V. R.

2000-01-01

Antigravity function plays an important role in determining the morphological and physiological properties of the neuromuscular system. Inhibition of the normal development of the neuromuscular system is induced by hindlimb unloading during the neonatal period in rats. However, the role of gravitational loading on the development of skeletal muscle in rats is not well understood. It could be hypothesized that during the early postnatal period, i.e. when minimal weight-supporting activity occurs, the activity imposed by gravity would be of little consequence in directing the normal development of the skeletal musculature. We have addressed this issue by limiting the amount of postnatal weight-support activity of the hindlimbs of rats during the lactation period. We have focused on the development of three characteristics of the muscle fibers, i.e. size, myonuclear number and myosin heavy chain expression.

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.

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.

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.

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.

Radiologic manifestations in the musculoskeletal system of miscellaneous endocrine disorders.

PubMed

Chew, F S

1991-01-01

The manifestations of endocrine derangements in the musculoskeletal system in infancy and childhood are disturbances in growth and maturation and in adulthood are disturbances in maintenance and metabolism. Hypercortisolism during skeletal immaturity suppresses growth. In the adult, hypercortisolism leads to osteoporosis, osteonecrosis, and muscle wasting. Deficiency of growth hormone during skeletal development results in short stature. An excess of growth hormone in a skeletally immature individual results in gigantism, an excess in a skeletally mature individual results in acromegaly. Patients with gigantism have extreme height with normal body proportions. Musculoskeletal manifestations of acromegaly include soft-tissue thickening, vertebral body enlargement, characteristic hand and foot changes, and enthesal bony proliferation. Hyperthyroidism causes catabolism of protein and loss of connective tissue, which manifest as muscle wasting. Deficient levels of thyroid hormone cause defects in growth and development. Severe growth retardation from congenital hypothyroidism is rare because neonatal screening recognizes the disorder and leads to early treatment. The skeletal manifestation of hypergonadism in children is precocious growth and early skeletal maturation. Although the initial precocious growth spurt results in a tall child, early closure of the growth plates results in a short adult. Hypogonadism in the prepubertal child results in delayed adolescence and delayed skeletal maturation. Diabetes mellitus in childhood results in decreased growth, a phenomenon presumed to be secondary to nutritional abnormalities. Generalized osteoporosis and short stature are common. In the adult, generalized osteoporosis may accompany insulin-dependent diabetes mellitus if obesity is absent. Calcification of interdigital arteries of the foot is common in diabetics and uncommon in other conditions. Additional skeletal manifestations relate to complications of diabetes such as peripheral neuropathy and diabetic foot disease.

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.

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.

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.

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.

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.

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

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

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.

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.

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...

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.

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

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.

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

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.

* 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.

Matrilin-3 Is Dispensable for Mouse Skeletal Growth and Development

PubMed Central

Ko, Yaping; Kobbe, Birgit; Nicolae, Claudia; Miosge, Nicolai; Paulsson, Mats; Wagener, Raimund; Aszódi, Attila

2004-01-01

Matrilin-3 belongs to the matrilin family of extracellular matrix (ECM) proteins and is primarily expressed in cartilage. Mutations in the gene encoding human matrilin-3 (MATN-3) lead to autosomal dominant skeletal disorders, such as multiple epiphyseal dysplasia (MED), which is characterized by short stature and early-onset osteoarthritis, and bilateral hereditary microepiphyseal dysplasia, a variant form of MED characterized by pain in the hip and knee joints. To assess the function of matrilin-3 during skeletal development, we have generated Matn-3 null mice. Homozygous mutant mice appear normal, are fertile, and show no obvious skeletal malformations. Histological and ultrastructural analyses reveal endochondral bone formation indistinguishable from that of wild-type animals. Northern blot, immunohistochemical, and biochemical analyses indicated no compensatory upregulation of any other member of the matrilin family. Altogether, our findings suggest functional redundancy among matrilins and demonstrate that the phenotypes of MED disorders are not caused by the absence of matrilin-3 in cartilage ECM. PMID:14749384

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

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.

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.

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.

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.

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.

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

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.

Growth Factors and Tension-Induced Skeletal Muscle Growth

NASA Technical Reports Server (NTRS)

Vandenburgh, Herman H.

1994-01-01

The project investigated biochemical mechanisms to enhance skeletal muscle growth, and developed a computer based mechanical cell stimulator system. The biochemicals investigated in this study were insulin/(Insulin like Growth Factor) IGF-1 and Steroids. In order to analyze which growth factors are essential for stretch-induced muscle growth in vitro, we developed a defined, serum-free medium in which the differentiated, cultured avian muscle fibers could be maintained for extended periods of time. The defined medium (muscle maintenance medium, MM medium) maintains the nitrogen balance of the myofibers for 3 to 7 days, based on myofiber diameter measurements and myosin heavy chain content. Insulin and IGF-1, but not IGF-2, induced pronounced myofiber hypertrophy when added to this medium. In 5 to 7 days, muscle fiber diameters increase by 71 % to 98% compared to untreated controls. Mechanical stimulation of the avian muscle fibers in MM medium increased the sensitivity of the cells to insulin and IGF-1, based on a leftward shift of the insulin dose/response curve for protein synthesis rates. (54). We developed a ligand binding assay for IGF-1 binding proteins and found that the avian skeletal muscle cultures produced three major species of 31, 36 and 43 kD molecular weight (54) Stretch of the myofibers was found to have no significant effect on the efflux of IGF-1 binding proteins, but addition of exogenous collagen stimulated IGF-1 binding protein production 1.5 to 5 fold. Steroid hormones have a profound effect on muscle protein turnover rates in vivo, with the stress-related glucocorticoids inducing rapid skeletal muscle atrophy while androgenic steroids induce skeletal muscle growth. Exercise in humans and animals reduces the catabolic effects of glucocorticoids and may enhance the anabolic effects of androgenic steroids on skeletal muscle. In our continuing work on the involvement of exogenrus growth factors in stretch-induced avian skeletal muscle growth, we have performed experiments to determine whether mechanical stimulation of cultured avian muscle cells alters their response to anabolic steroids or glucocorticoids. In static cultures, testosterone had no effect on muscle cell growth, but 5alpha-dihydrotestosterone and the synthetic steroid stanozolol increased cell growth by up to 18% and 30%, respectively, after a three day exposure. We completed development of a new IBM-based mechanical cell stimulator system to provide greater flexibility in operating and monitoring our experiments. Our previous long term studies on myofiber growth were designed around a perfusion system of our own design. We have recently changed to performing these studies using a modified CELLCO cartridge bioreactor system Z since it has been certified as the ground-based model for the Shuttle's Space Tissue Loss (STL) F= Cell Culture Module. The current goals of this aspect of the project are three fold: 1) to design a Z cell culture system for studying avian skeletal myofiber atrophy on the Shuttle and Space Station; 0 2) to expand the use of bioreactors to cells which do not grow in either suspension or attached to the hollow fibers; and 3) to combine the bioreactor system with our computerized mechanical cell stimulator to have a better in vitro model to study tension/gravity/stretch regulation of skeletal muscle size. Preliminary studies also reported on involved : (1) how release of tension can induce rapid atrophy of tissues cultured avian skeletal muscle cells, and (2) a mechanism to transfer and maintain avian skeletal muscle organoids in modified cartridges in the Space Tissue Loss Module.

MicroRNA Transcriptome Profiles During Swine Skeletal Muscle Development

USDA-ARS?s Scientific Manuscript database

MicroRNA (miR) are a class of small RNAs that regulate gene expression by inhibiting translation of protein encoding transcripts. To evaluate the role of miR in skeletal muscle of swine, global microRNA abundance was measured at specific developmental stages including proliferating satellite cells,...

Comparative Evaluation of Dental and Skeletal Fluorosis in an Endemic Fluorosed District, Salem, Tamil Nadu.

PubMed

Ramesh, Maya; Malathi, N; Ramesh, K; Aruna, Rita Mary; Kuruvilla, Sarah

2017-11-01

High levels of fluoride in the drinking water, especially ground water, results in skeletal fluorosis which involves the bone and major joints. This study was conducted to assess the prevalence of skeletal fluorosis to compare with dental fluorosis in an endemically fluorosed population in the District of Salem, Tamil Nadu. Institutional ethical clearance was obtained. A total of 206 patients who reported to the Department of Hematology for blood investigations were the participants in this study. Age, sex, place, weight, height, dental fluorosis, and skeletal complaints were noted down. Body mass index was calculated, and statistical analysis was performed. Dental fluorosis was present in 63.1% and absent in 36.9% of the samples reported. Skeletal fluorosis was present in 24.8% and was absent in 75.2%. A large number of the patients had knee pain and difficulty in bending. Chi-square test was used for statistical analysis. Skeletal fluorosis and age were compared and P value was 0.00 and was significant. Dental fluorosis and skeletal fluorosis were compared and P value was found to be 0.000 and significant. There is a need to take measures to prevent dental and skeletal fluorosis among the residents of Salem district. Calcium balance should be maintained, and fluoride intake should be minimized to reduce the symptoms. The government should provide water with low fluoride level for drinking and cooking. Once the symptoms develop, treatment largely remains symptomatic, using analgesics and physiotherapy.

Mechanism reduction for multicomponent surrogates: A case study using toluene reference fuels

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

Niemeyer, Kyle E.; Sung, Chih-Jen

Strategies and recommendations for performing skeletal reductions of multicomponent surrogate fuels are presented, through the generation and validation of skeletal mechanisms for a three-component toluene reference fuel. Using the directed relation graph with error propagation and sensitivity analysis method followed by a further unimportant reaction elimination stage, skeletal mechanisms valid over comprehensive and high-temperature ranges of conditions were developed at varying levels of detail. These skeletal mechanisms were generated based on autoignition simulations, and validation using ignition delay predictions showed good agreement with the detailed mechanism in the target range of conditions. When validated using phenomena other than autoignition, suchmore » as perfectly stirred reactor and laminar flame propagation, tight error control or more restrictions on the reduction during the sensitivity analysis stage were needed to ensure good agreement. In addition, tight error limits were needed for close prediction of ignition delay when varying the mixture composition away from that used for the reduction. In homogeneous compression-ignition engine simulations, the skeletal mechanisms closely matched the point of ignition and accurately predicted species profiles for lean to stoichiometric conditions. Furthermore, the efficacy of generating a multicomponent skeletal mechanism was compared to combining skeletal mechanisms produced separately for neat fuel components; using the same error limits, the latter resulted in a larger skeletal mechanism size that also lacked important cross reactions between fuel components. Based on the present results, general guidelines for reducing detailed mechanisms for multicomponent fuels are discussed.« less

HIV and Bone Metabolism

PubMed Central

Ofotokun, Ighovwerha; Weitzmann, M. Neale

2013-01-01

The skeleton is an organ whose integrity is maintained by constant lifelong renewal involving coordinated removal of worn bone by osteoclasts and resynthesis of new bone by osteoblasts. In young adult humans and animals this process is homeostatic with no net gain or loss of bone mass. With natural aging and exacerbated by numerous pathological conditions, bone removal exceeds bone formation, disrupting homeostasis and resulting in bone loss. Over time, skeletal decline reaches clinical significance with development of osteopenia and eventually osteoporosis, conditions that dramatically increase bone fragility and the risk of fracture. Bone fractures can be devastating with significant morbidity and mortality. Over the last decade, it has become clear that skeletal renewal is strongly influenced by the immune system, a consequence of deep integration and centralization of common cell types and cytokine mediators, which we have termed the “immuno-skeletal interface.” Consequently, dysregulated skeletal renewal and bone loss is a common feature of inflammatory conditions associated with immune activation. Interestingly, bone loss is also associated with conditions of immunodeficiency, including infection by the human immunodeficiency virus (HIV) that leads to acquired immunodeficiency syndrome (AIDS). Disruptions to the immuno-skeletal interface drive skeletal deterioration contributing to a high rate of bone fracture in HIV infection. This review examines current knowledge concerning the prevalence and etiology of skeletal complications in HIV infection, the effect of antiretroviral therapies (ART) on the skeleton, and how disruption of the immuno-skeletal interface may underlie bone loss in HIV infection and ART. PMID:21616037

Voltage clamp methods for the study of membrane currents and SR Ca2+ release in adult skeletal muscle fibres

PubMed Central

Hernández-Ochoa, Erick O.; Schneider, Martin F.

2012-01-01

Skeletal muscle excitation-contraction (E-C)1 coupling is a process composed of multiple sequential stages, by which an action potential triggers sarcoplasmic reticulum (SR)2 Ca2+ release and subsequent contractile activation. The various steps in the E-C coupling process in skeletal muscle can be studied using different techniques. The simultaneous recordings of sarcolemmal electrical signals and the accompanying elevation in myoplasmic Ca2+, due to depolarization-initiated SR Ca2+ release in skeletal muscle fibres, have been useful to obtain a better understanding of muscle function. In studying the origin and mechanism of voltage dependency of E-C coupling a variety of different techniques have been used to control the voltage in adult skeletal fibres. Pioneering work in muscles isolated from amphibians or crustaceans used microelectrodes or ‘high resistance gap’ techniques to manipulate the voltage in the muscle fibres. The development of the patch clamp technique and its variant, the whole-cell clamp configuration that facilitates the manipulation of the intracellular environment, allowed the use of the voltage clamp techniques in different cell types, including skeletal muscle fibres. The aim of this article is to present an historical perspective of the voltage clamp methods used to study skeletal muscle E-C coupling as well as to describe the current status of using the whole-cell patch clamp technique in studies in which the electrical and Ca2+ signalling properties of mouse skeletal muscle membranes are being investigated. PMID:22306655

Mechanism reduction for multicomponent surrogates: A case study using toluene reference fuels

DOE PAGES

Niemeyer, Kyle E.; Sung, Chih-Jen

2014-11-01

Strategies and recommendations for performing skeletal reductions of multicomponent surrogate fuels are presented, through the generation and validation of skeletal mechanisms for a three-component toluene reference fuel. Using the directed relation graph with error propagation and sensitivity analysis method followed by a further unimportant reaction elimination stage, skeletal mechanisms valid over comprehensive and high-temperature ranges of conditions were developed at varying levels of detail. These skeletal mechanisms were generated based on autoignition simulations, and validation using ignition delay predictions showed good agreement with the detailed mechanism in the target range of conditions. When validated using phenomena other than autoignition, suchmore » as perfectly stirred reactor and laminar flame propagation, tight error control or more restrictions on the reduction during the sensitivity analysis stage were needed to ensure good agreement. In addition, tight error limits were needed for close prediction of ignition delay when varying the mixture composition away from that used for the reduction. In homogeneous compression-ignition engine simulations, the skeletal mechanisms closely matched the point of ignition and accurately predicted species profiles for lean to stoichiometric conditions. Furthermore, the efficacy of generating a multicomponent skeletal mechanism was compared to combining skeletal mechanisms produced separately for neat fuel components; using the same error limits, the latter resulted in a larger skeletal mechanism size that also lacked important cross reactions between fuel components. Based on the present results, general guidelines for reducing detailed mechanisms for multicomponent fuels are discussed.« less

Effects of microgravity on myogenic factor expressions during postnatal development of rat skeletal muscle

NASA Technical Reports Server (NTRS)

Inobe, Manabu; Inobe, Ikuko; Adams, Gregory R.; Baldwin, Kenneth M.; Takeda, Shin'Ichi

2002-01-01

To clarify the role of gravity in the postnatal development of skeletal muscle, we exposed neonatal rats at 7 days of age to microgravity. After 16 days of spaceflight, tibialis anterior, plantaris, medial gastrocnemius, and soleus muscles were removed from the hindlimb musculature and examined for the expression of MyoD-family transcription factors such as MyoD, myogenin, and MRF4. For this purpose, we established a unique semiquantitative method, based on RT-PCR, using specific primers tagged with infrared fluorescence. The relative expression of MyoD in the tibialis anterior and plantaris muscles and that of myogenin in the plantaris and soleus muscles were significantly reduced (P < 0.001) in the flight animals. In contrast, MRF4 expression was not changed in any muscle. These results suggest that MyoD and myogenin, but not MRF4, are sensitive to gravity-related stimuli in some skeletal muscles during postnatal development.

The p27 Pathway Modulates the Regulation of Skeletal Growth and Osteoblastic Bone Formation by Parathyroid Hormone-Related Peptide.

PubMed

Zhu, Min; Zhang, Jing; Dong, Zhan; Zhang, Ying; Wang, Rong; Karaplis, Andrew; Goltzman, David; Miao, Dengshun

2015-11-01

Parathyroid hormone-related peptide (PTHrP) 1-84 knock-in mice (Pthrp KI) develop skeletal growth retardation and defective osteoblastic bone formation. To further examine the mechanisms underlying this phenotype, microarray analyses of differential gene expression profiles were performed in long bone extracts from Pthrp KI mice and their wild-type (WT) littermates. We found that the expression levels of p27, p16, and p53 were significantly upregulated in Pthrp KI mice relative to WT littermates. To determine whether p27 was involved in the regulation by PTHrP of skeletal growth and development in vivo, we generated compound mutant mice, which were homozygous for both p27 deletion and the Pthrp KI mutation (p27(-/-) Pthrp KI). We then compared p27(-/-) Pthrp KI mice with p27(-/-), Pthrp KI, and WT littermates. Deletion of p27 in Pthrp KI mice resulted in a longer lifespan, increased body weight, and improvement in skeletal growth. At 2 weeks of age, skeletal parameters, including length of long bones, size of epiphyses, numbers of proliferating cell nuclear antigen (PCNA)-positive chondrocytes, bone mineral density, trabecular bone volume, osteoblast numbers, and alkaline phosphatase (ALP)-, type I collagen-, and osteocalcin-positive bone areas were increased in p27(-/-) mice and reduced in both Pthrp KI and p27(-/-) Pthrp KI mice compared with WT mice; however, these parameters were increased in p27(-/-) Pthrp KI mice compared with Pthrp KI mice. As well, protein expression levels of PTHR, IGF-1, and Bmi-1, and the numbers of total colony-forming unit fibroblastic (CFU-f) and ALP-positive CFU-f were similarly increased in p27(-/-) Pthrp KI mice compared with Pthrp KI mice. Our results demonstrate that deletion of p27 in Pthrp KI mice can partially rescue defects in skeletal growth and osteoblastic bone formation by enhancing endochondral bone formation and osteogenesis. These studies, therefore, indicate that the p27 pathway may function downstream in the action of PTHrP to regulate skeletal growth and development. © 2015 American Society for Bone and Mineral Research.

Embryonic development of Python sebae - I: Staging criteria and macroscopic skeletal morphogenesis of the head and limbs.

PubMed

Boughner, Julia C; Buchtová, Marcela; Fu, Katherine; Diewert, Virginia; Hallgrímsson, Benedikt; Richman, Joy M

2007-01-01

This study explores the post-ovipositional craniofacial development of the African Rock Python (Python sebae). We first describe a staging system based on external characteristics and next use whole-mount skeletal staining supplemented with Computed tomography (CT) scanning to examine skeletal development. Our results show that python embryos are in early stages of organogenesis at the time of laying, with separate facial prominences and pharyngeal clefts still visible. Limb buds are also visible. By 11 days (stage 3), the chondrocranium is nearly fully formed; however, few intramembranous bones can be detected. One week later (stage 4), many of the intramembranous upper and lower jaw bones are visible but the calvaria are not present. Skeletal elements in the limbs also begin to form. Between stages 4 (day 18) and 7 (day 44), the complete set of intramembranous bones in the jaws and calvaria develops. Hindlimb development does not progress beyond stage 6 (33 days) and remains rudimentary throughout adult life. In contrast to other reptiles, there are two rows of teeth in the upper jaw. The outer tooth row is attached to the maxillary and premaxillary bones, whereas the inner row is attached to the pterygoid and palatine bones. Erupted teeth can be seen in whole-mount stage 10 specimens and are present in an unerupted, mineralized state at stage 7. Micro-CT analysis reveals that all the young membranous bones can be recognized even out of the context of the skull. These data demonstrate intrinsic patterning of the intramembranous bones, even though they form without a cartilaginous template. In addition, intramembranous bone morphology is established prior to muscle function, which can influence bone shape through differential force application. After careful staging, we conclude that python skeletal development occurs slowly enough to observe in good detail the early stages of craniofacial skeletogenesis. Thus, reptilian animal models will offer unique opportunities for understanding the early influences that contribute to perinatal bone shape.

In utero Undernutrition Programs Skeletal and Cardiac Muscle Metabolism.

PubMed

Beauchamp, Brittany; Harper, Mary-Ellen

2015-01-01

In utero undernutrition is associated with increased risk for insulin resistance, obesity, and cardiovascular disease during adult life. A common phenotype associated with low birth weight is reduced skeletal muscle mass. Given the central role of skeletal muscle in whole body metabolism, alterations in its mass as well as its metabolic characteristics may contribute to disease risk. This review highlights the metabolic alterations in cardiac and skeletal muscle associated with in utero undernutrition and low birth weight. These tissues have high metabolic demands and are known to be sites of major metabolic dysfunction in obesity, type 2 diabetes, and cardiovascular disease. Recent research demonstrates that mitochondrial energetics are decreased in skeletal and cardiac muscles of adult offspring from undernourished mothers. These effects apparently lead to the development of a thrifty phenotype, which may represent overall a compensatory mechanism programmed in utero to handle times of limited nutrient availability. However, in an environment characterized by food abundance, the effects are maladaptive and increase adulthood risks of metabolic disease.

In utero Undernutrition Programs Skeletal and Cardiac Muscle Metabolism

PubMed Central

Beauchamp, Brittany; Harper, Mary-Ellen

2016-01-01

In utero undernutrition is associated with increased risk for insulin resistance, obesity, and cardiovascular disease during adult life. A common phenotype associated with low birth weight is reduced skeletal muscle mass. Given the central role of skeletal muscle in whole body metabolism, alterations in its mass as well as its metabolic characteristics may contribute to disease risk. This review highlights the metabolic alterations in cardiac and skeletal muscle associated with in utero undernutrition and low birth weight. These tissues have high metabolic demands and are known to be sites of major metabolic dysfunction in obesity, type 2 diabetes, and cardiovascular disease. Recent research demonstrates that mitochondrial energetics are decreased in skeletal and cardiac muscles of adult offspring from undernourished mothers. These effects apparently lead to the development of a thrifty phenotype, which may represent overall a compensatory mechanism programmed in utero to handle times of limited nutrient availability. However, in an environment characterized by food abundance, the effects are maladaptive and increase adulthood risks of metabolic disease. PMID:26779032

In vivo two-photon imaging of macrophage activities in skeletal muscle regeneration

NASA Astrophysics Data System (ADS)

Qin, Zhongya; Long, Yanyang; Sun, Qiqi; He, Sicong; Li, Xuesong; Chen, Congping; Wu, Zhenguo; Qu, Jianan Y.

2018-02-01

Macrophages are essential for the regeneration of skeletal muscle after injury. It has been demonstrated that depletion of macrophages results in delay of necrotic fiber phagocytosis and decreased size of regenerated myofibers. In this work, we developed a multi-modal two-photon microscope system for in vivo study of macrophage activities in the regenerative and fibrotic healing process of injured skeletal muscles. The system is capable to image the muscles based on the second harmonic generation (SHG) and two-photon excited fluorescence (TPEF) signals simultaneously. The dynamic activities of macrophages and muscle satellite cells are recorded in different time windows post the muscle injury. Moreover, we found that infiltrating macrophages emitted strong autofluorescence in the injured skeletal muscle of mouse model, which has not been reported previously. The macrophage autofluorescence was characterized in both spectral and temporal domains. The information extracted from the autofluorescence signals may facilitate the understanding on the formation mechanisms and possible applications in biological research related to skeletal muscle regeneration.

Skeletal and cardiac muscle pericytes: Functions and therapeutic potential

PubMed Central

Murray, Iain R.; Baily, James E.; Chen, William C.W.; Dar, Ayelet; Gonzalez, Zaniah N.; Jensen, Andrew R.; Petrigliano, Frank A.; Deb, Arjun; Henderson, Neil C.

2017-01-01

Pericytes are periendothelial mesenchymal cells residing within the microvasculature. Skeletal muscle and cardiac pericytes are now recognized to fulfill an increasing number of functions in normal tissue homeostasis, including contributing to microvascular function by maintaining vessel stability and regulating capillary flow. In the setting of muscle injury, pericytes contribute to a regenerative microenvironment through release of trophic factors and by modulating local immune responses. In skeletal muscle, pericytes also directly enhance tissue healing by differentiating into myofibers. Conversely, pericytes have also been implicated in the development of disease states, including fibrosis, heterotopic ossication and calcification, atherosclerosis, and tumor angiogenesis. Despite increased recognition of pericyte heterogeneity, it is not yet clear whether specific subsets of pericytes are responsible for individual functions in skeletal and cardiac muscle homeostasis and disease. PMID:27595928

Management of severe skeletal Class III malocclusion with bimaxillary orthognathic surgery

PubMed Central

Haryani, Jitesh; Nagar, Amit; Mehrotra, Divya; Ranabhatt, Rani

2016-01-01

Orthognathic surgery in conjunction with fixed orthodontics is a common indication for interdisciplinary management of severe skeletal Class III malocclusion. A thorough analysis of pretreatment investigations and development of a surgical visual treatment objective is essential to plan the type of surgical technique required. Bimaxillary orthognathic surgery is the most common type of surgical procedure for severe skeletal discrepancies. The present case report is a combined ortho-surgical team management of a skeletally Class III patient. The severity of the case required bilateral upper first premolar extraction for dentoalveolar decompensation and simultaneous “Two-jaw surgery” with maxillary advancement of 4 mm and mandibular setback of 7 mm. Postsurgery, a pleasing good facial profile was achieved with Class II molar relation and positive overjet. PMID:27994433

Percutaneous epiphysiodesis using transphyseal screws for limb-length discrepancies: high variability among growth predictor models.

PubMed

Monier, Bryan C; Aronsson, David D; Sun, Michael

2015-10-01

Percutaneous epiphysiodesis using transphyseal screws (PETS) was developed as a minimally invasive outpatient procedure to address limb-length discrepancy (LLD) that allowed immediate postoperative weight bearing and was potentially reversible by removing the screws. The aims of our study were to report our results using PETS for LLD and evaluate the accuracy of three growth predictor models. Sixteen patients with an average age of 14 years were treated for LLD using PETS. Thirteen patients had screws inserted in a parallel fashion and 3 had crossed screws. We compared the predicted LLD at skeletal maturity using the three growth predictor methods with the actual LLD at skeletal maturity and preoperative LLD with the final LLD at skeletal maturity. The mean LLD at skeletal maturity between the predicted and final measurements was 0.2 cm using the Green-Anderson method, 1.4 cm using the Moseley method, and -0.1 cm using the Paley method. The mean preoperative LLD of 3.1 cm was corrected to 1.7 cm at skeletal maturity (p < 0.001). Six patients complained of pain over the screw heads; however, no patient developed an infection or angular deformity. The three growth predictor methods predicted the final LLD within an average of 1.4 cm, but there was high variability. Although PETS improved the LLD by a mean of 1.4 cm, we believe the results would have been better if PETS was performed at an earlier skeletal age.

Correlation between chronological age, cervical vertebral maturation and Fishman's skeletal maturity indicators in southern Chinese.

PubMed

Alkhal, Hessa Abdulla; Wong, Ricky W K; Rabie, A Bakr M

2008-07-01

To investigate the correlation between chronological age, cervical vertebral maturation (CVM), and Fishman's hand-wrist skeletal maturity indicators in southern Chinese. Four hundred contemporary hand-wrist and lateral cephalometric radiographs of southern Chinese subjects were randomly selected and analyzed. The female subjects were between 10 and 15 years of age, and the male subjects were between 12 and 17 years of age; all subjects were within the circumpubertal period. The CVM was assessed using the method developed by Baccetti and coworkers, but the hand-wrist maturation was assessed using the method developed by Fishman. These two methods and the chronological age were correlated using the Spearman rank correlation analysis. The CVM was significantly correlated with the hand-wrist skeletal age (Spearman r male = 0.9206, female = 0.9363). All patients in the cervical maturation stage (CS3) of CVM were discovered to be in the skeletal maturational indicator (SMI2 or SMI3) stages of hand-wrist maturation (HWM), which was around the peak of the growth spurt. Low correlations were found between the CVM and chronological age (male r = 0.7577; female r = 0.7877) and between the HWM and chronological age (male r = 0.7492; female r = 0.7758). CVM is a valid indicator of skeletal growth during the circumpubertal and has a high correlation with the HWM for the southern Chinese population. However, the low correlations found between the chronological age and both CVM and HWM showed that the chronological age was not suitable to measure skeletal maturity.

Mandibular dimensional changes and skeletal maturity.

PubMed

Subramaniam, Priya; Naidu, Premila

2010-10-01

Growth and development of the human face provides a fascinating interplay of form and function. Among the various facial bones, the mandible plays a very important role during various growth-modification therapies. These treatment modalities will yield a better result in less time if properly correlated with skeletal maturity. It is very essential to know where the site of growth occurs and also the time when it occurs or ceases to occur. This study was conducted to assess the mandibular dimensions at various stages of skeletal maturation. The subjects included 6 to 18-year-old children who were grouped according to their middle phalanx of the third finger stages of skeletal maturity. Lateral cephalographs were taken and, from their cephalometric tracings, linear and angular measurements of the mandible were made. The values obtained were subjected to statistical analysis. Results showed that the mandibular height, length and symphysis thickness increased with skeletal maturity. An increase in angles SNB (Sella, Nasion, Supramentale) and L1-MP (Long axis lower incisors- Mandibular plane) and a decrease in the gonial angle and ANB (Subspinale, Nasion, Supramentale) angle were observed. The study showed a significant correlation between mandibular growth and skeletal maturity.

Quantitative sonoelastography for the in vivo assessment of skeletal muscle viscoelasticity

NASA Astrophysics Data System (ADS)

Hoyt, Kenneth; Kneezel, Timothy; Castaneda, Benjamin; Parker, Kevin J.

2008-08-01

A novel quantitative sonoelastography technique for assessing the viscoelastic properties of skeletal muscle tissue was developed. Slowly propagating shear wave interference patterns (termed crawling waves) were generated using a two-source configuration vibrating normal to the surface. Theoretical models predict crawling wave displacement fields, which were validated through phantom studies. In experiments, a viscoelastic model was fit to dispersive shear wave speed sonoelastographic data using nonlinear least-squares techniques to determine frequency-independent shear modulus and viscosity estimates. Shear modulus estimates derived using the viscoelastic model were in agreement with that obtained by mechanical testing on phantom samples. Preliminary sonoelastographic data acquired in healthy human skeletal muscles confirm that high-quality quantitative elasticity data can be acquired in vivo. Studies on relaxed muscle indicate discernible differences in both shear modulus and viscosity estimates between different skeletal muscle groups. Investigations into the dynamic viscoelastic properties of (healthy) human skeletal muscles revealed that voluntarily contracted muscles exhibit considerable increases in both shear modulus and viscosity estimates as compared to the relaxed state. Overall, preliminary results are encouraging and quantitative sonoelastography may prove clinically feasible for in vivo characterization of the dynamic viscoelastic properties of human skeletal muscle.

Current Methods for Skeletal Muscle Tissue Repair and Regeneration

PubMed Central

Liu, Juan; Saul, Dominik; Böker, Kai Oliver; Ernst, Jennifer; Lehman, Wolfgang

2018-01-01

Skeletal muscle has the capacity of regeneration after injury. However, for large volumes of muscle loss, this regeneration needs interventional support. Consequently, muscle injury provides an ongoing reconstructive and regenerative challenge in clinical work. To promote muscle repair and regeneration, different strategies have been developed within the last century and especially during the last few decades, including surgical techniques, physical therapy, biomaterials, and muscular tissue engineering as well as cell therapy. Still, there is a great need to develop new methods and materials, which promote skeletal muscle repair and functional regeneration. In this review, we give a comprehensive overview over the epidemiology of muscle tissue loss, highlight current strategies in clinical treatment, and discuss novel methods for muscle regeneration and challenges for their future clinical translation. PMID:29850487

Pharmacology of manipulating lean body mass

PubMed Central

Sepulveda, Patricio V; Bush, Ernest D; Baar, Keith

2015-01-01

Summary Dysfunction and wasting of skeletal muscle as a consequence of illness decreases the length and quality of life. Currently, there are few, if any, effective treatments available to address these conditions. Hence, the existence of this unmet medical need has fuelled large scientific efforts.Fortunately, these efforts have shown many of the underlying mechanisms adversely affecting skeletal muscle health.With increased understanding have come breakthrough disease-specific and broad spectrum interventions, some progressing through clinical development.The present review focuses its attention on the role of the antagonistic process regulating skeletal muscle mass before branching into prospective promising therapeutic targets and interventions. Special attention is given to therapies in development against cancer cachexia and Duchenne muscular dystrophy before closing remarks on design and conceptualization of future therapies are presented to the reader. PMID:25311629

Identification and characterization of MicroRNAs expressed in chicken skeletal muscle

USDA-ARS?s Scientific Manuscript database

MicroRNAs (miRNAs, miRs) encompass a class of small noncoding RNAs that negatively regulate gene expression. MicroRNAs play an essential role in skeletal muscle, determining the proper development and maintenance of this tissue. In comparison to other organs and tissues, the full set of muscle miRNA...

Hip fracture risk in older US adults by treatment eligibility status based on new National Osteoporosis Foundation Guidance

USDA-ARS?s Scientific Manuscript database

Vitamin D receptors have been shown to be present in human skeletal muscle using different techniques. We developed a multi-staining immunofluorescent method to detect vitamin D receptor expression and colocalize it with myosin heavy chain isoform expression in skeletal muscle biopsies in older fema...

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

Skeletal Malocclusion: A Developmental Disorder With a Life-Long Morbidity

PubMed Central

Joshi, Nishitha; Hamdan, Ahmad M.; Fakhouri, Walid D.

2014-01-01

The likelihood of birth defects in orofacial tissues is high due to the structural and developmental complexity of the face and the susceptibility to intrinsic and extrinsic perturbations. Skeletal malocclusion is caused by the distortion of the proper mandibular and/or maxillary growth during fetal development. Patients with skeletal malocclusion may suffer from dental deformities, bruxism, teeth crowding, trismus, mastication difficulties, breathing obstruction and digestion disturbance if the problem is left untreated. In this review, we focused on skeletal malocclusion that affects 27.9% of the US population with different severity levels. We summarized the prevalence of class I, II and III of malocclusion in different ethnic groups and discussed the most frequent medical disorders associated with skeletal malocclusion. Dental anomalies that lead to malocclusion such as tooth agenesis, crowding, missing teeth and abnormal tooth size are not addressed in this review. We propose a modified version of malocclusion classification for research purposes to exhibit a clear distinction between skeletal vs. dental malocclusion in comparison to Angle’s classification. In addition, we performed a cross-sectional analysis on orthodontic (malocclusion) data through the BigMouth Dental Data Repository to calculate potential association between malocclusion with other medical conditions. In conclusion, this review emphasizes the need to identify genetic and environmental factors that cause or contribute risk to skeletal malocclusion and the possible association with other medical conditions to improve assessment, prognosis and therapeutic approaches. PMID:25247012

Creation of a predictive equation to estimate fat-free mass and the ratio of fat-free mass to skeletal size using morphometry in lean working farm dogs.

PubMed

Leung, Y M; Cave, N J; Hodgson, B A S

2018-06-27

To develop an equation that accurately estimates fat-free mass (FFM) and the ratio of FFM to skeletal size or mass, using morphometric measurements in lean working farm dogs, and to examine the association between FFM derived from body condition score (BCS) and FFM measured using isotope dilution. Thirteen Huntaway and seven Heading working dogs from sheep and beef farms in the Waikato region of New Zealand were recruited based on BCS (BCS <3, 3-4, >4) using a nine-point scale. Bodyweight, BCS, and morphometric measurements (head length and circumference, body length, thoracic girth, and fore and hind limb length) were recorded for each dog, and body composition was measured using an isotopic dilution technique. A new variable using morphometric measurements, termed skeletal size, was created using principal component analysis. Models for predicting FFM, leanST (FFM minus skeletal mass) and ratios of FFM and leanST to skeletal size or mass were generated using multiple linear regression analysis. Mean FFM of the 20 dogs, measured by isotope dilution, was 22.1 (SD 4.4) kg and the percentage FFM of bodyweight was 87.0 (SD 5.0)%. Median BCS was 3.0 (min 1, max 6). Bodyweight, breed, age and skeletal size or mass were associated with measured FFM (p<0.001). There was a good correlation between predicted FFM and measured FFM (R 2 =0.96), and for the ratio of predicted FFM to skeletal size and measured values (R 2 =0.99). Correlation coefficients were higher for the ratio FFM and leanST to skeletal size than for ratios using skeletal mass. There was a positive correlation between BCS-derived fat mass as a percentage of bodyweight and fat mass percentage determined using isotope dilution (R 2 =0.65). As expected, the predictive equation was accurate in estimating FFM when tested on the same group of dogs used to develop the equation. The significance of breed, independent of skeletal size, in predicting FFM indicates that individual breed formulae may be required. Future studies that apply these equations on a greater population of working Huntaway and Heading dogs are needed to establish the utility of these equations on a large scale. Such studies could ascertain if there is a ratio for lean mass to skeletal size below which the risk of injury or disease increases. If these equations prove useful they would provide an objective and non-invasive measure to determine when welfare in individual dogs is compromised by underfeeding.

Patterns of linear growth and skeletal maturation from birth to 18 years of age in overweight young adults.

PubMed

Johnson, W; Stovitz, S D; Choh, A C; Czerwinski, S A; Towne, B; Demerath, E W

2012-04-01

To estimate differences in skeletal maturity and stature from birth to age 18 years between individuals who are overweight vs normal weight in young adulthood. Weight, length and height, and relative skeletal age (skeletal-chronological age) were assessed annually from birth to age 18 years in 521 subjects (255 women) in the Fels Longitudinal Study who were overweight or obese (body mass index (BMI) >25 kg m(-2), n=131) or normal weight (n=390) in young adulthood (18-30 years). Generalized estimating equations were used to test for skeletal maturity and stature differences by young adult BMI status. Differences in height increased during puberty, being significant for girls at ages 10 to 12 years, and for boys at ages 11 to 13 years (P-values<0.001), with overweight or obese adults being ∼3 cm taller at those ages than normal weight adults. These differences then diminished so that by age 18 years, overweight or obese adults were not significantly different in stature to their normal weight peers. Differences in skeletal maturity were similar, but more pervasive; overweight or obese adults were more skeletally advanced throughout childhood. Skeletal maturity differences peaked at chronological age 12 in boys and 14 in girls (P-values<0.001), with overweight or obese adults being ∼1 year more advanced than normal weight adults. This descriptive study is the first to track advanced skeletal maturity and linear growth acceleration throughout infancy, childhood and adolescence in individuals who become overweight, showing that differences occur primarily around the time of the pubertal growth spurt. Increased BMI in children on a path to becoming overweight adults precedes an advancement in skeletal development and subsequently tall stature during puberty. Further work is required to assess the predictive value of accelerated pubertal height growth for assessing obesity risk in a variety of populations.

Recent developments in metabolic bone diseases: a gnathic perspective.

PubMed

Raubenheimer, Erich J; Noffke, Claudia E; Hendrik, Hilde D

2014-12-01

Metabolic bone diseases often are asymptomatic and progress sub clinically. Many patients present at a late stage with catastrophic skeletal and extra skeletal complications. In this article, we provide an overview of normal bone remodeling and a synopsis of recent developments in the following conditions: osteoporosis, rickets/osteomalacia, endocrine-induced bone disease, chronic kidney disease-mineral bone disorder and Paget's disease of bone. Our discussion will emphasize the clinical and microscopic manifestations of these diseases in the jaws.

Core-binding factor beta interacts with Runx2 and is required for skeletal development.

PubMed

Yoshida, Carolina A; Furuichi, Tatsuya; Fujita, Takashi; Fukuyama, Ryo; Kanatani, Naoko; Kobayashi, Shinji; Satake, Masanobu; Takada, Kenji; Komori, Toshihisa

2002-12-01

Core-binding factor beta (CBFbeta, also called polyomavirus enhancer binding protein 2beta (PEBP2B)) is associated with an inversion of chromosome 16 and is associated with acute myeloid leukemia in humans. CBFbeta forms a heterodimer with RUNX1 (runt-related transcription factor 1), which has a DNA binding domain homologous to the pair-rule protein runt in Drosophila melanogaster. Both RUNX1 and CBFbeta are essential for hematopoiesis. Haploinsufficiency of another runt-related protein, RUNX2 (also called CBFA1), causes cleidocranial dysplasia in humans and is essential in skeletal development by regulating osteoblast differentiation and chondrocyte maturation. Mice deficient in Cbfb (Cbfb(-/-)) die at midgestation, so the function of Cbfbeta in skeletal development has yet to be ascertained. To investigate this issue, we rescued hematopoiesis of Cbfb(-/-) mice by introducing Cbfb using the Gata1 promoter. The rescued Cbfb(-/-) mice recapitulated fetal liver hematopoiesis in erythroid and megakaryocytic lineages and survived until birth, but showed severely delayed bone formation. Although mesenchymal cells differentiated into immature osteoblasts, intramembranous bones were poorly formed. The maturation of chondrocytes into hypertrophic cells was markedly delayed, and no endochondral bones were formed. Electrophoretic mobility shift assays and reporter assays showed that Cbfbeta was necessary for the efficient DNA binding of Runx2 and for Runx2-dependent transcriptional activation. These findings indicate that Cbfbeta is required for the function of Runx2 in skeletal development.

Barium-induced skeletal muscle paralysis in the rat, and its relationship to human familial periodic paralysis

PubMed Central

Schott, G. D.; McArdle, B.

1974-01-01

An in vivo study of skeletal muscle paralysis induced by intravenous barium chloride has been made in curarized and non-curarized rats. The influence of potassium and calcium chlorides, propranolol, ouabain, and prior adrenalectomy on the paralysis has also been studied. Paralysis is found to be due to a direct effect on skeletal muscle, and to correlate well with the development of hypokalaemia. Possible mechanisms of action of barium are discussed, and attention is drawn to the similarity between barium poisoning and hypokalaemic familial periodic paralysis. PMID:4813426

Abnormal Canine Bone Development Associated with Hypergravity Exposure

NASA Technical Reports Server (NTRS)

Morgan, J. P.; Fisher, G. L.; McNeill, K. L.; Oyama, J.

1979-01-01

Chronic centrifugation of 85- to 92-day-old Beagles at 2.0 x g and 2.6 x g for 26 weeks during the time of active skeletal growth caused skeletal abnormalities in the radius and the ulna of ten of 11 dogs. The pattern of change mimicked that found in naturally occurring and experimentally induced premature distal ulnar physeal closure or delayed growth at this physis. Minimal changes in bone density were detected by sensitive photon absorptiometric techniques. Skeletal abnormalities also were found in five of the six cage-control dogs, although the run-control dogs were radiographically normal.

Skeletal muscle cutpoints associated with elevated physical disability risk in older men and women.

PubMed

Janssen, Ian; Baumgartner, Richard N; Ross, Robert; Rosenberg, Irwin H; Roubenoff, Ronenn

2004-02-15

The purpose of this study was to determine skeletal muscle cutpoints for identifying elevated physical disability risk in older adults. Subjects included 4,449 older (> or = 60 years) participants from the Third National Health and Nutrition Examination Survey during 1988-1994. Physical disability was assessed by questionnaire, and bioimpedance was used to estimate skeletal muscle, which was normalized for height. Receiver operating characteristics were used to develop the skeletal muscle cutpoints associated with a high likelihood of physical disability. Odds for physical disability were compared in subjects whose measures fell above and below these cutpoints. Skeletal muscle cutpoints of 5.76-6.75 and < or =5.75 kg/m2 were selected to denote moderate and high physical disability risk in women. The corresponding values in men were 8.51-10.75 and < or =8.50 kg/m2. Compared with women with low-risk skeletal muscle values, women with moderate- and high-risk skeletal muscle values had odds for physical disability of 1.41 (95% confidence interval (CI): 0.97, 2.04) and 3.31 (95% CI: 1.91, 5.73), respectively. The corresponding odds in men were 3.65 (95% CI: 1.92, 6.94) and 4.71 (95% CI: 2.28, 9.74). This study presents skeletal muscle cutpoints for physical disability risk in older adults. Future applications of these cutpoints include the comparison of morbidity risk in older persons with normal muscle mass and those with sarcopenia, the determination and comparison of sarcopenia prevalences, and the estimation of health-care costs attributable to sarcopenia.

Insulin resistance after a 72-h fast is associated with impaired AS160 phosphorylation and accumulation of lipid and glycogen in human skeletal muscle

PubMed Central

Vendelbo, M. H.; Clasen, B. F. F.; Treebak, J. T.; Møller, L.; Krusenstjerna-Hafstrøm, T.; Madsen, M.; Nielsen, T. S.; Stødkilde-Jørgensen, H.; Pedersen, S. B.; Jørgensen, J. O. L.; Goodyear, L. J.; Wojtaszewski, J. F. P.; Møller, N.

2012-01-01

During fasting, human skeletal muscle depends on lipid oxidation for its energy substrate metabolism. This is associated with the development of insulin resistance and a subsequent reduction of insulin-stimulated glucose uptake. The underlying mechanisms controlling insulin action on skeletal muscle under these conditions are unresolved. In a randomized design, we investigated eight healthy subjects after a 72-h fast compared with a 10-h overnight fast. Insulin action on skeletal muscle was assessed by a hyperinsulinemic euglycemic clamp and by determining insulin signaling to glucose transport. In addition, substrate oxidation, skeletal muscle lipid content, regulation of glycogen synthesis, and AMPK signaling were assessed. Skeletal muscle insulin sensitivity was reduced profoundly in response to a 72-h fast and substrate oxidation shifted to predominantly lipid oxidation. This was associated with accumulation of both lipid and glycogen in skeletal muscle. Intracellular insulin signaling to glucose transport was impaired by regulation of phosphorylation at specific sites on AS160 but not TBC1D1, both key regulators of glucose uptake. In contrast, fasting did not impact phosphorylation of AMPK or insulin regulation of Akt, both of which are established upstream kinases of AS160. These findings show that insulin resistance in muscles from healthy individuals is associated with suppression of site-specific phosphorylation of AS160, without Akt or AMPK being affected. This impairment of AS160 phosphorylation, in combination with glycogen accumulation and increased intramuscular lipid content, may provide the underlying mechanisms for resistance to insulin in skeletal muscle after a prolonged fast. PMID:22028408

Development of a novel spike-like auxiliary skeletal anchorage device to enhance miniscrew stability.

PubMed

Miyawaki, Shouichi; Tomonari, Hiroshi; Yagi, Takakazu; Kuninori, Takaharu; Oga, Yasuhiko; Kikuchi, Masafumi

2015-08-01

Miniscrews are frequently used for skeletal anchorage during edgewise treatment, and their clinical use has been verified. However, their disadvantage is an approximately 15% failure rate, which is primarily attributed to the low mechanical stability between the miniscrew and cortical bone and to the miniscrew's close proximity to the dental root. To solve these problems, we developed a novel spike-like auxiliary skeletal anchorage device for use with a miniscrew to increase its stability. The retention force was compared between miniscrews with and without the auxiliary skeletal anchorage device at each displacement of the miniscrew. The combined unit was also implanted into the bones of 2 rabbits in vivo, and implantation was visually assessed at 4 weeks postoperatively while the compression force was applied. The retention force of the combined unit was significantly and approximately 3 to 5 times stronger on average than that of the miniscrew alone at each displacement. The spiked portion of the auxiliary anchorage device embedded into the cortical bone of the hind limb at approximately a 0.3-mm depth at 4 weeks postimplantation in both rabbits. The auxiliary skeletal anchorage device may increase miniscrew stability, allow a shortened miniscrew, and enable 3-dimensional absolute anchorage. Further evaluation of its clinical application is necessary. Copyright © 2015 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

Requirement for ErbB2/ErbB signaling in developing cartilage and bone.

PubMed

Fisher, Melanie C; Clinton, Gail M; Maihle, Nita J; Dealy, Caroline N

2007-08-01

During endochondral ossification, the skeletal elements of vertebrate limbs form and elongate via coordinated control of chondrocyte and osteoblast differentiation and proliferation. The role of signaling by the ErbB family of receptor tyrosine kinases, which consists of ErbB1 (epidermal growth factor receptor or EGFR), ErbB2, ErbB3 and ErbB4, has been little studied during cartilage and bone development. Signaling by the ErbB network generates a diverse array of cellular responses via formation of ErbB dimers activated by distinct ligands that produce distinct signal outputs. Herstatin is a soluble ErbB2 receptor that acts in a dominant negative fashion to inhibit ErbB signaling by binding to endogenous ErbB receptors, preventing functional dimer formation. Here, we examine the effects of Herstatin on limb skeletal element development in transgenic mice, achieved via Prx1 promoter-driven expression in limb cartilage and bone. The limb skeletal elements of Prx1-Herstatin embryos are shortened, and chondrocyte maturation and osteoblast differentiation are delayed. In addition, proliferation by chondrocytes and periosteal cells of Prx1-Herstatin limb skeletal elements is markedly reduced. Our study identifies requirements for ErbB signaling in the maintenance of chondrocyte and osteoblast proliferation involved in the timely progression of chondrocyte maturation and periosteal osteoblast differentiation.

Skeletal sequelae of radiation therapy for malignant childhood tumors

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

Butler, M.S.; Robertson, W.W. Jr.; Rate, W.

1990-02-01

One hundred forty-three patients who received radiation therapy for childhood tumors, and survived to the age of skeletal maturity, were studied by retrospective review of oncology records and roentgenograms. Diagnoses for the patients were the following: Hodgkin's lymphoma (44), Wilms's tumor (30), acute lymphocytic leukemia (26), non-Hodgkin's lymphoma (18), Ewing's sarcoma (nine), rhabdomyosarcoma (six), neuroblastoma (six), and others (four). Age at the follow-up examination averaged 18 years (range, 14-28 years). Average length of follow-up study was 9.9 years (range, two to 18 years). Asymmetry of the chest and ribs was seen in 51 (36%) of these children. Fifty (35%) hadmore » scoliosis; 14 had kyphosis. In two children, the scoliosis was treated with a brace, while one developed significant kyphosing scoliosis after laminectomy and had spinal fusion. Twenty-three (16%) patients complained of significant pain at the radiation sites. Twelve of the patients developed leg-length inequality; eight of those were symptomatic. Three patients developed second primary tumors. Currently, the incidence of significant skeletal sequelae is lower and the manifestations are less severe than reported in the years from 1940 to 1970. The reduction in skeletal complications may be attributed to shielding of growth centers, symmetric field selection, decreased total radiation doses, and sequence changes in chemotherapy.« less

Biomechanical model of batoid (skates and rays) pectoral fins predicts the influence of skeletal structure on fin kinematics: implications for bio-inspired design.

PubMed

Russo, R S; Blemker, S S; Fish, F E; Bart-Smith, H

2015-06-16

Growing interest in the development of bio-inspired autonomous underwater vehicles (AUVs) has motivated research in understanding the mechanisms behind the propulsion systems of marine animals. For example, the locomotive behavior of rays (Batoidea) by movement of the pectoral fins is of particular interest due to their superior performance characteristics over contemporary AUV propulsion systems. To better understand the mechanics of pectoral fin propulsion, this paper introduces a biomechanical model that simulates how batoid skeletal structures function to achieve the swimming locomotion observed in nature. Two rays were studied, Dasyatis sabina (Atlantic ray), and Rhinoptera bonasus (cownose ray). These species were selected because they exhibit very different swimming styles (undulation versus oscillation), but all use primarily their pectoral fins for propulsion (unlike electric rays or guitarfishes). Computerized tomography scans of each species were taken to image the underlying structure, which reveal a complex system of cartilaginous joints and linkages. Data collected from these images were used to quantify the complete skeletal morphometry of each batoid fin. Morphological differences were identified in the internal cartilage arrangement between each species including variations in the orientation of the skeletal elements, or radials, and the joint patterns between them, called the inter-radial joint pattern. These data were used as the primary input into the biomechanical model to couple a given ray skeletal structure with various swimming motions. A key output of the model is an estimation of the uniaxial strain that develops in the skeletal connective tissue in order for the structure to achieve motions observed during swimming. Tensile load tests of this connective tissue were conducted to further investigate the implications of the material strain predictions. The model also demonstrates that changes in the skeletal architecture (e.g., joint positioning) will effect fin deformation characteristics. Ultimately, the results of this study can be used to guide the design of optimally performing bio-inspired AUVs.

Objective evaluation of cervical vertebral bone age' its reliability in comparison with hand-wrist bone age: by TW3 method.

PubMed

Prasad, Cms Krishna; Reddy, Vamsi Nilay; Sreedevi, Gojja; Ponnada, Swaroopa Rani; Priya, K Padma; Naik, B Raveendra

2013-09-01

The aim of this study was to establish the validity of a new method for evaluating skeletal maturation by assessing the 3rd and 4th cervical vertebrae seen in the cephalometric radiograph. This study consisted of a sample of 50 patients in the age group of 8 to 14 years of age. Chronologically, they were divided into six groups, based on the age consisting of a minimum of six to a maximum of 10 subjects. All the patients included in the study were females. The selected subjects were clinically examined and then age and date of birth of the patient in years and months was noted. Then lateral cephalograms and hand-wrist radiographs of the patient were taken on the same day with good clarity and contrast. The results suggested that cervical vertebral bone age on cephalometric radiographs calculated with this method is as reliable at estimating bone age as is the Tanner-Whitehouse 3 (TW3) method on hand-wrist radiographs. By determining the cervical vertebral bone age, skeletal maturity can be evaluated in a detailed and objective manner with cephalometric radiographs. The ability to accurately appraise skeletal maturity from cervical vertebral maturation, without the need for additional radiographs, has the potential to improve orthodontic diagnostic and therapeutic decisions. The technique's simplicity and ease of use should encourage this method as a frst level diagnostic tool to assess skeletal maturation. Clinical signifcance: This study revealed that the timing and sequence of ossifcation of the bones in hand and wrist and cervical vertebrae were able to relate the skeletal development of the various skeletal maturity indicators to a child's development. This method provided a mean with which one can determine the skeletal maturity of a person and thereby determine whether the possibility of potential growth existed.

MicroCT-Based Skeletal Models for Use in Tomographic Voxel Phantoms for Radiological Protection

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

Bolch, Wesley

The University of Florida (UF) proposes to develop two high-resolution image-based skeletal dosimetry models for direct use by ICRP Committee 2’s Task Group on Dose Calculation in their forthcoming Reference Voxel Male (RVM) and Reference Voxel Female (RVF) whole-body dosimetry phantoms. These two phantoms are CT-based, and thus do not have the image resolution to delineate and perform radiation transport modeling of the individual marrow cavities and bone trabeculae throughout their skeletal structures. Furthermore, new and innovative 3D microimaging techniques will now be required for the skeletal tissues following Committee 2’s revision of the target tissues of relevance for radiogenicmore » bone cancer induction. This target tissue had been defined in ICRP Publication 30 as a 10-μm cell layer on all bone surfaces of trabecular and cortical bone. The revised target tissue is now a 50-μm layer within the marrow cavities of trabecular bone only and is exclusive of the marrow adipocytes. Clearly, this new definition requires the use of 3D microimages of the trabecular architecture not available from past 2D optical studies of the adult skeleton. With our recent acquisition of two relatively young cadavers (males of age 18-years and 40-years), we will develop a series of reference skeletal models that can be directly applied to (1) the new ICRP reference voxel man and female phantoms developed for the ICRP, and (2) pediatric phantoms developed to target the ICRP reference children. Dosimetry data to be developed will include absorbed fractions for internal beta and alpha-particle sources, as well as photon and neutron fluence-to-dose response functions for direct use in external dosimetry studies of the ICRP reference workers and members of the general public« less

Expression of porcine myostatin prodomain genomic sequence leads to a decrease in muscle growth, but significant intramuscular fat accretion in transgenic pigs.

USDA-ARS?s Scientific Manuscript database

Myostatin, a member of TGF-beta superfamily, is a dominant inhibitor of skeletal muscle development and growth. Previously, skeletal muscle-specific over-expression of myostatin prodomain cDNA (5’-region 886 nucleotide) dramatically increased growth performance and muscle mass in transgenic mice. I...

Evaluation of Vocational Technical Education. Phase II. A Skeletal Model with Suggested Research and Development Activities.

ERIC Educational Resources Information Center

New Educational Directions, Crawfordsville, IN.

Phase 2 of this project presents a skeletal model for evaluating vocational education programs which can be applied to secondary, post-secondary, and adult education programs. The model addresses 13 main components of the vocational education system: descriptive information, demonstration of need, student recruitment and selection, curriculum,…

[Metabolic processes in rat skeletal muscle after a flight on the Kosmos-936 biosatellite].

PubMed

Nosova, E A; Veresotskaia, N A; Kolchina, E V; Kurkina, L M; Belitskaia, R A

1981-01-01

The study of skeletal muscles of rats flown on Cosmos-936 demonstrated different metabolic reactions in muscle fibers of different function and type to weightlessness and Earth gravity. The data obtained gave evidence that artificial gravity may considerably prevent metabolic changes in muscles developing in response to specific effects of weightlessness.

Transcriptional profiling identifies differentially expressed genes in developing turkey skeletal muscle

PubMed Central

2011-01-01

Background Skeletal muscle growth and development from embryo to adult consists of a series of carefully regulated changes in gene expression. Understanding these developmental changes in agriculturally important species is essential to the production of high quality meat products. For example, consumer demand for lean, inexpensive meat products has driven the turkey industry to unprecedented production through intensive genetic selection. However, achievements of increased body weight and muscle mass have been countered by an increased incidence of myopathies and meat quality defects. In a previous study, we developed and validated a turkey skeletal muscle-specific microarray as a tool for functional genomics studies. The goals of the current study were to utilize this microarray to elucidate functional pathways of genes responsible for key events in turkey skeletal muscle development and to compare differences in gene expression between two genetic lines of turkeys. To achieve these goals, skeletal muscle samples were collected at three critical stages in muscle development: 18d embryo (hyperplasia), 1d post-hatch (shift from myoblast-mediated growth to satellite cell-modulated growth by hypertrophy), and 16wk (market age) from two genetic lines: a randombred control line (RBC2) maintained without selection pressure, and a line (F) selected from the RBC2 line for increased 16wk body weight. Array hybridizations were performed in two experiments: Experiment 1 directly compared the developmental stages within genetic line, while Experiment 2 directly compared the two lines within each developmental stage. Results A total of 3474 genes were differentially expressed (false discovery rate; FDR < 0.001) by overall effect of development, while 16 genes were differentially expressed (FDR < 0.10) by overall effect of genetic line. Ingenuity Pathways Analysis was used to group annotated genes into networks, functions, and canonical pathways. The expression of 28 genes involved in extracellular matrix regulation, cell death/apoptosis, and calcium signaling/muscle function, as well as genes with miscellaneous function was confirmed by qPCR. Conclusions The current study identified gene pathways and uncovered novel genes important in turkey muscle growth and development. Future experiments will focus further on several of these candidate genes and the expression and mechanism of action of their protein products. PMID:21385442

Chapter 2. Calcineurin signaling and the slow oxidative skeletal muscle fiber type.

PubMed

Mallinson, Joanne; Meissner, Joachim; Chang, Kin-Chow

2009-01-01

Calcineurin, also known as protein phosphatase 2B (PP2B), is a calcium-calmodulin-dependent phosphatase. It couples intracellular calcium to dephosphorylate selected substrates resulting in diverse biological consequences depending on cell type. In mammals, calcineurin's functions include neuronal growth, development of cardiac valves and hypertrophy, activation of lymphocytes, and the regulation of ion channels and enzymes. This chapter focuses on the key roles of calcineurin in skeletal muscle differentiation, regeneration, and fiber type conversion to an oxidative state, all of which are crucial to muscle development, metabolism, and functional adaptations. It seeks to integrate the current knowledge of calcineurin signaling in skeletal muscle and its interactions with other prominent regulatory pathways and their signaling intermediates to form a molecular overview that could provide directions for possible future exploitations in human metabolic health.

Tissue engineering strategies in spinal arthrodesis: the clinical imperative and challenges to clinical translation.

PubMed

Evans, Nick R; Davies, Evan M; Dare, Chris J; Oreffo, Richard Oc

2013-01-01

Skeletal disorders requiring the regeneration or de novo production of bone present considerable reconstructive challenges and are one of the main driving forces for the development of skeletal tissue engineering strategies. The skeletal or mesenchymal stem cell is a fundamental requirement for osteogenesis and plays a pivotal role in the design and application of these strategies. Research activity has focused on incorporating the biological role of the mesenchymal stem cell with the developing fields of material science and gene therapy in order to create a construct that is not only capable of inducing host osteoblasts to produce bone, but is also osteogenic in its own right. This review explores the clinical need for reparative approaches in spinal arthrodesis, identifying recent tissue engineering strategies employed to promote spinal fusion, and considers the ongoing challenges to successful clinical translation.

Skeletal muscle mitochondrial health and spinal cord injury.

PubMed

O'Brien, Laura C; Gorgey, Ashraf S

2016-10-18

Mitochondria are the main source of cellular energy production and are dynamic organelles that undergo biogenesis, remodeling, and degradation. Mitochondrial dysfunction is observed in a number of disease states including acute and chronic central or peripheral nervous system injury by traumatic brain injury, spinal cord injury (SCI), and neurodegenerative disease as well as in metabolic disturbances such as insulin resistance, type II diabetes and obesity. Mitochondrial dysfunction is most commonly observed in high energy requiring tissues like the brain and skeletal muscle. In persons with chronic SCI, changes to skeletal muscle may include remarkable atrophy and conversion of muscle fiber type from oxidative to fast glycolytic, combined with increased infiltration of intramuscular adipose tissue. These changes contribute to a proinflammatory environment, glucose intolerance and insulin resistance. The loss of metabolically active muscle combined with inactivity predisposes individuals with SCI to type II diabetes and obesity. The contribution of skeletal muscle mitochondrial density and electron transport chain activity to the development of the aforementioned comorbidities following SCI is unclear. A better understanding of the mechanisms involved in skeletal muscle mitochondrial dynamics is imperative to designing and testing effective treatments for this growing population. The current editorial will review ways to study mitochondrial function and the importance of improving skeletal muscle mitochondrial health in clinical populations with a special focus on chronic SCI.

Impact of Perturbed Pancreatic β-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism

PubMed Central

Cochran, Blake J.; Hou, Liming; Manavalan, Anil Paul Chirackal; Moore, Benjamin M.; Tabet, Fatiha; Sultana, Afroza; Cuesta Torres, Luisa; Tang, Shudi; Shrestha, Sudichhya; Senanayake, Praween; Patel, Mili; Ryder, William J.; Bongers, Andre; Maraninchi, Marie; Wasinger, Valerie C.; Westerterp, Marit; Tall, Alan R.; Barter, Philip J.

2016-01-01

Elevated pancreatic β-cell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The β-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of β-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify β-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes. PMID:27702832

Diacylglycerol kinase-δ regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics.

PubMed

Jiang, Lake Q; de Castro Barbosa, Thais; Massart, Julie; Deshmukh, Atul S; Löfgren, Lars; Duque-Guimaraes, Daniella E; Ozilgen, Arda; Osler, Megan E; Chibalin, Alexander V; Zierath, Juleen R

2016-01-01

Decrease of AMPK-related signal transduction and insufficient lipid oxidation contributes to the pathogenesis of obesity and type 2 diabetes. Previously, we identified that diacylglycerol kinase-δ (DGKδ), an enzyme involved in triglyceride biosynthesis, is reduced in skeletal muscle from type 2 diabetic patients. Here, we tested the hypothesis that DGKδ plays a role in maintaining appropriate AMPK action in skeletal muscle and energetic aspects of contraction. Voluntary running activity was reduced in DGKδ(+/-) mice, but glycogen content and mitochondrial markers were unaltered, suggesting that DGKδ deficiency affects skeletal muscle energetics but not mitochondrial protein abundance. We next determined the role of DGKδ in AMPK-related signal transduction and lipid metabolism in isolated skeletal muscle. AMPK activation and signaling were reduced in DGKδ(+/-) mice, concomitant with impaired lipid oxidation and elevated incorporation of free fatty acids into triglycerides. Strikingly, DGKδ deficiency impaired work performance, as evident by altered force production and relaxation dynamics in response to repeated contractions. In conclusion, DGKδ deficiency impairs AMPK signaling and lipid metabolism, thereby highlighting the deleterious role of excessive lipid metabolites in the development of peripheral insulin resistance and type 2 diabetes pathogenesis. DGKδ deficiency also influences skeletal muscle energetics, which may lead to low physical activity levels in type 2 diabetes. Copyright © 2016 the American Physiological Society.

Preventive Effects of Poloxamer 188 on Muscle Cell Damage Mechanics Under Oxidative Stress.

PubMed

Wong, Sing Wan; Yao, Yifei; Hong, Ye; Ma, Zhiyao; Kok, Stanton H L; Sun, Shan; Cho, Michael; Lee, Kenneth K H; Mak, Arthur F T

2017-04-01

High oxidative stress can occur during ischemic reperfusion and chronic inflammation. It has been hypothesized that such oxidative challenges could contribute to clinical risks such as deep tissue pressure ulcers. Skeletal muscles can be challenged by inflammation-induced or reperfusion-induced oxidative stress. Oxidative stress reportedly can lower the compressive damage threshold of skeletal muscles cells, causing actin filament depolymerization, and reduce membrane sealing ability. Skeletal muscles thus become easier to be damaged by mechanical loading under prolonged oxidative exposure. In this study, we investigated the preventive effect of poloxamer 188 (P188) on skeletal muscle cells against extrinsic oxidative challenges (H 2 O 2 ). It was found that with 1 mM P188 pre-treatment for 1 h, skeletal muscle cells could maintain their compressive damage threshold. The actin polymerization dynamics largely remained stable in term of the expression of cofilin, thymosin beta 4 and profilin. Laser photoporation demonstrated that membrane sealing ability was preserved even as the cells were challenged by H 2 O 2 . These findings suggest that P188 pre-treatment can help skeletal muscle cells retain their normal mechanical integrity in oxidative environments, adding a potential clinical use of P188 against the combined challenge of mechanical-oxidative stresses. Such effect may help to prevent deep tissue ulcer development.

Prolonged Culture of Aligned Skeletal Myotubes on Micromolded Gelatin Hydrogels

PubMed Central

Bettadapur, Archana; Suh, Gio C.; Geisse, Nicholas A.; Wang, Evelyn R.; Hua, Clara; Huber, Holly A.; Viscio, Alyssa A.; Kim, Joon Young; Strickland, Julie B.; McCain, Megan L.

2016-01-01

In vitro models of skeletal muscle are critically needed to elucidate disease mechanisms, identify therapeutic targets, and test drugs pre-clinically. However, culturing skeletal muscle has been challenging due to myotube delamination from synthetic culture substrates approximately one week after initiating differentiation from myoblasts. In this study, we successfully maintained aligned skeletal myotubes differentiated from C2C12 mouse skeletal myoblasts for three weeks by utilizing micromolded (μmolded) gelatin hydrogels as culture substrates, which we thoroughly characterized using atomic force microscopy (AFM). Compared to polydimethylsiloxane (PDMS) microcontact printed (μprinted) with fibronectin (FN), cell adhesion on gelatin hydrogel constructs was significantly higher one week and three weeks after initiating differentiation. Delamination from FN-μprinted PDMS precluded robust detection of myotubes. Compared to a softer blend of PDMS μprinted with FN, myogenic index, myotube width, and myotube length on μmolded gelatin hydrogels was similar one week after initiating differentiation. However, three weeks after initiating differentiation, these parameters were significantly higher on μmolded gelatin hydrogels compared to FN-μprinted soft PDMS constructs. Similar results were observed on isotropic versions of each substrate, suggesting that these findings are independent of substrate patterning. Our platform enables novel studies into skeletal muscle development and disease and chronic drug testing in vitro. PMID:27350122

The Skeletal Site-Specific Role of Connective Tissue Growth Factor in Prenatal Osteogenesis

PubMed Central

Lambi, Alex G.; Pankratz, Talia L.; Mundy, Christina; Gannon, Maureen; Barbe, Mary F.; Richtsmeier, Joan T.; Popoff, Steven N.

2013-01-01

Background Connective tissue growth factor (CTGF/CCN2) is a matricellular protein that is highly expressed during bone development. Mice with global CTGF ablation (knockout, KO) have multiple skeletal dysmorphisms and perinatal lethality. A quantitative analysis of the bone phenotype has not been conducted. Results We demonstrated skeletal site-specific changes in growth plate organization, bone microarchitecture, and shape and gene expression levels in CTGF KO compared with wild-type mice. Growth plate malformations included reduced proliferation zone and increased hypertrophic zone lengths. Appendicular skeletal sites demonstrated decreased metaphyseal trabecular bone, while having increased mid-diaphyseal bone and osteogenic expression markers. Axial skeletal analysis showed decreased bone in caudal vertebral bodies, mandibles, and parietal bones in CTGF KO mice, with decreased expression of osteogenic markers. Analysis of skull phenotypes demonstrated global and regional differences in CTGF KO skull shape resulting from allometric (size-based) and nonallometric shape changes. Localized differences in skull morphology included increased skull width and decreased skull length. Dysregulation of the transforming growth factor-β-CTGF axis coupled with unique morphologic traits provides a potential mechanistic explanation for the skull phenotype. Conclusions We present novel data on a skeletal phenotype in CTGF KO mice, in which ablation of CTGF causes site-specific aberrations in bone formation. PMID:23073844

Muscle contraction controls skeletal morphogenesis through regulation of chondrocyte convergent extension.

PubMed

Shwartz, Yulia; Farkas, Zsuzsanna; Stern, Tomer; Aszódi, Attila; Zelzer, Elazar

2012-10-01

Convergent extension driven by mediolateral intercalation of chondrocytes is a key process that contributes to skeletal growth and morphogenesis. While progress has been made in deciphering the molecular mechanism that underlies this process, the involvement of mechanical load exerted by muscle contraction in its regulation has not been studied. Using the zebrafish as a model system, we found abnormal pharyngeal cartilage morphology in both chemically and genetically paralyzed embryos, demonstrating the importance of muscle contraction for zebrafish skeletal development. The shortening of skeletal elements was accompanied by prominent changes in cell morphology and organization. While in control the cells were elongated, chondrocytes in paralyzed zebrafish were smaller and exhibited a more rounded shape, confirmed by a reduction in their length-to-width ratio. The typical columnar organization of cells was affected too, as chondrocytes in various skeletal elements exhibited abnormal stacking patterns, indicating aberrant intercalation. Finally, we demonstrate impaired chondrocyte intercalation in growth plates of muscle-less Sp(d) mouse embryos, implying the evolutionary conservation of muscle force regulation of this essential morphogenetic process.Our findings provide a new perspective on the regulatory interaction between muscle contraction and skeletal morphogenesis by uncovering the role of muscle-induced mechanical loads in regulating chondrocyte intercalation in two different vertebrate models. Copyright © 2012 Elsevier Inc. All rights reserved.

Caffeine at a Moderate Dose Did Not Affect the Skeletal System of Rats with Streptozotocin-Induced Diabetes.

PubMed

Folwarczna, Joanna; Janas, Aleksandra; Cegieła, Urszula; Pytlik, Maria; Śliwiński, Leszek; Matejczyk, Magdalena; Nowacka, Anna; Rudy, Karolina; Krivošíková, Zora; Štefíková, Kornélia; Gajdoš, Martin

2017-10-30

Diabetes may lead to the development of osteoporosis. Coffee drinking, apart from its health benefits, is taken into consideration as an osteoporosis risk factor. Data from human and animal studies on coffee and caffeine bone effects are inconsistent. The aim of the study was to investigate effects of caffeine at a moderate dose on the skeletal system of rats in two models of experimental diabetes induced by streptozotocin. Effects of caffeine administered orally (20 mg/kg aily for four weeks) were investigated in three-month-old female Wistar rats, which, two weeks before the start of caffeine administration, received streptozotocin (60 mg/kg, intraperitoneally) alone or streptozotocin after nicotinamide (230 mg/kg, intraperitoneally). Bone turnover markers, mass, mineral density, histomorphometric parameters, and mechanical properties were examined. Streptozotocin induced diabetes, with profound changes in the skeletal system due to increased bone resorption and decreased bone formation. Although streptozotocin administered after nicotinamide induced slight increases in glucose levels at the beginning of the experiment only, slight, but significant unfavorable changes in the skeletal system were demonstrated. Administration of caffeine did not affect the investigated skeletal parameters of rats with streptozotocin-induced disorders. In conclusion, caffeine at a moderate dose did not exert a damaging effect on the skeletal system of diabetic rats.

[Molecular design of anti-MRSA drugs].

PubMed

Hanaki, H

1997-05-01

The true nature of resistance of methicillin-resistant Staphylococcus aureus (MRSA) is penicillin-binding protein 2' (PBP2'). Affinities of almost all beta-lactam antibiotics to PBP2' were very low. Therefore, MRSA which produces PBP2' shows resistance to all beta-lactam antibiotics. However, PBP2' has a different affinity to each beta-lactam antibiotic. For this reason, we thought that some derivatives of beta-lactam compounds could have high affinity to PBP2'. Accordingly, we developed cephem compounds which are more stabile and safe than previous penicillin and carbapenem compounds. Firstly, we investigated the side chain at C-7 position on 2-thioisocephem skeletal. Hydroxyimino-aminothiazol at C-7 position on 2-thioisocephem skeletal had the strongest activity against MRSA. Secondly, we investigated the linkage styles at C-3 position on 2-thioisocephem skeletal which were methylene, vinyl, and propylene. The compound of vinyl linkage style at C-3 position on 2-thioisocephem skeletal showed high activity against MRSA. Finally, we investigated 1-thiocephem, 2-thioisocephem, and 2-oxaisocephem as cephem-skeletals. Simultaneously, we studied C-3 linkage styles which were methylene, vinyl, and propylene. From these results, we found out that the compound of hydroxyiminoaminothiazol at C-7 position and vinyl linkage style at C-3 position on 1-thiocephem skeletal has superb activity against MRSA.

Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging

PubMed Central

Umanskaya, Alisa; Santulli, Gaetano; Andersson, Daniel C.; Reiken, Steven R.; Marks, Andrew R.

2014-01-01

Age-related skeletal muscle dysfunction is a leading cause of morbidity that affects up to half the population aged 80 or greater. Here we tested the effects of increased mitochondrial antioxidant activity on age-dependent skeletal muscle dysfunction using transgenic mice with targeted overexpression of the human catalase gene to mitochondria (MCat mice). Aged MCat mice exhibited improved voluntary exercise, increased skeletal muscle specific force and tetanic Ca2+ transients, decreased intracellular Ca2+ leak and increased sarcoplasmic reticulum (SR) Ca2+ load compared with age-matched wild type (WT) littermates. Furthermore, ryanodine receptor 1 (the sarcoplasmic reticulum Ca2+ release channel required for skeletal muscle contraction; RyR1) from aged MCat mice was less oxidized, depleted of the channel stabilizing subunit, calstabin1, and displayed increased single channel open probability (Po). Overall, these data indicate a direct role for mitochondrial free radicals in promoting the pathological intracellular Ca2+ leak that underlies age-dependent loss of skeletal muscle function. This study harbors implications for the development of novel therapeutic strategies, including mitochondria-targeted antioxidants for treatment of mitochondrial myopathies and other healthspan-limiting disorders. PMID:25288763

Fenoterol did not enhance glucocorticoid-induced skeletal changes in male rats.

PubMed

Folwarczna, Joanna; Nowińska, Barbara; Śliwiński, Leszek; Pytlik, Maria; Cegieła, Urszula; Betka, Anna

2011-01-01

Glucocorticoids and β(2)-adrenergic receptor agonists are the most commonly used drugs in the treatment of asthma. Both therapies are potentially dangerous to the skeletal system. The aim of the present study was to investigate the effects of fenoterol, a β(2)-receptor agonist, on the development of bone changes induced by glucocorticoid (prednisolone) administration in mature male rats. The experiments were carried out on 24-week-old male Wistar rats. The effects of prednisolone 21-hemisuccinate sodium salt (7 mg/kg s.c. daily) or/and fenoterol hydrobromide (1.4 mg/kg i.p. daily), administered for 4 weeks, on the skeletal system were studied. Bone turnover markers, geometric parameters, mass, mass of bone mineral in the tibia, femur and L-4 vertebra, bone histomorphometric parameters and mechanical properties of tibial metaphysis, femoral diaphysis and femoral neck were determined. Both prednisolone and fenoterol had damaging effects on the skeletal system of mature male rats. However, concurrent administration of fenoterol and prednisolone did not result in the intensification of the deleterious skeletal effect of either drug administered separately.

The Difference in Cervical Vertebral Skeletal Maturation between Cleft Lip/Palate and Non-Cleft Lip/Palate Orthodontic Patients.

PubMed

Batwa, Waeil; Almoammar, Khalid; Aljohar, Aziza; Alhussein, Abdullah; Almujel, Saad; Zawawi, Khalid H

2018-01-01

The aim was to evaluate differences in the cervical vertebral skeletal maturity of unilateral cleft lip and palate (UCLP) and non-cleft lip/palate (non-CLP) Saudi male orthodontic patients. This cross-sectional multicenter study took place at the dental school, King Saud University and King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, between October 2014 and September 2015. The records of Saudi male orthodontic patients with UCLP ( n = 69) were collected. Cervical vertebral maturation was assessed using their cephalometric radiographs. The records of 138 age-matched non-CLP Saudi male orthodontic patients served as controls. There was a significant difference in skeletal maturity between the UCLP and non-CLP groups, as evident in the delayed skeletal development among the UCLP participants. Moreover, pubertal growth spurt onset was significantly earlier in the non-cleft participants in comparison with the UCLP participants ( p = 0.009). There is delayed skeletal maturity among the UCLP Saudi male population in comparison with their non-CLP age-matched peers.

Genes Contributing to Genetic Variation of Muscling in Sheep

PubMed Central

Tellam, Ross L.; Cockett, Noelle E.; Vuocolo, Tony; Bidwell, Christopher A.

2012-01-01

Selective breeding programs aiming to increase the productivity and profitability of the sheep meat industry use elite, progeny tested sires. The broad genetic traits of primary interest in the progeny of these sires include skeletal muscle yield, fat content, eating quality, and reproductive efficiency. Natural mutations in sheep that enhance muscling have been identified, while a number of genome scans have identified and confirmed quantitative trait loci (QTL) for skeletal muscle traits. The detailed phenotypic characteristics of sheep carrying these mutations or QTL affecting skeletal muscle show a number of common biological themes, particularly changes in developmental growth trajectories, alterations of whole animal morphology, and a shift toward fast twitch glycolytic fibers. The genetic, developmental, and biochemical mechanisms underpinning the actions of some of these genetic variants are described. This review critically assesses this research area, identifies gaps in knowledge, and highlights mechanistic linkages between genetic polymorphisms and skeletal muscle phenotypic changes. This knowledge may aid the discovery of new causal genetic variants and in some cases lead to the development of biochemical and immunological strategies aimed at enhancing skeletal muscle. PMID:22952470

Alendronate increases skeletal mass of growing rats during unloading by inhibiting resorption of calcified cartilage

NASA Technical Reports Server (NTRS)

Bikle, D. D.; Morey-Holton, E. R.; Doty, S. B.; Currier, P. A.; Tanner, S. J.; Halloran, B. P.

1994-01-01

Loss of bone mass during periods of skeletal unloading remains an important clinical problem. To determine the extent to which resorption contributes to the relative loss of bone during skeletal unloading of the growing rat and to explore potential means of preventing such bone loss, 0.1 mg P/kg alendronate was administered to rats before unloading of the hindquarters. Skeletal unloading markedly reduced the normal increase in tibial mass and calcium content during the 9 day period of observation, primarily by decreasing bone formation, although bone resorption was also modestly stimulated. Alendronate not only prevented the relative loss of skeletal mass during unloading but led to a dramatic increase in calcified tissue in the proximal tibia compared with the vehicle-treated unloaded or normally loaded controls. Bone formation, however, assessed both by tetracycline labeling and by [3H]proline and 45Ca incorporation, was suppressed by alendronate treatment and further decreased by skeletal unloading. Total osteoclast number increased in alendronate-treated animals, but values were similar to those in controls when corrected for the increased bone area. However, the osteoclasts had poorly developed brush borders and appeared not to engage the bone surface when examined at the ultrastructural level. We conclude that alendronate prevents the relative loss of mineralized tissue in growing rats subjected to skeletal unloading, but it does so primarily by inhibiting the resorption of the primary and secondary spongiosa, leading to altered bone modeling in the metaphysis.

Skeletal maturity assessment using mandibular canine calcification stages.

PubMed

Džemidžić, Vildana; Tiro, Alisa; Zukanović, Amila; Redžić, Ismeta; Nakaš, Enita

2016-11-01

The aims of this study were: to investigate the relationship between mandibular canine calcification stages and skeletal maturity; and to evaluate whether the mandibular canine calcification stages may be used as a reliable diagnostic tool for skeletal maturity assessment. This study included 151 subjects: 81 females and 70 males, with ages ranging from 9 to 16 years (mean age: 12.29±1.86 years). The inclusion criteria for subjects were as follows: age between 9 and 16 years; good general health without any hormonal, nutritional, growth or dental development problems. Subjects who were undergoing or had previously received orthodontic treatment were not included in this study. The calcification stages of the left permanent mandibular canine were assessed according to the method of Demirjian, on panoramic radiographs. Assessment of skeletal maturity was carried out using the cervical vertebral maturation index (CVMI), as proposed by the Hassel-Farman method, on lateral cephalograms. The correlation between the calcification stages of mandibular canine and skeletal maturity was estimated separately for male and female subjects. Correlation coefficients between calcification stages of mandibular canine and skeletal maturity were 0.895 for male and 0.701 for female subjects. A significant correlation was found between the calcification stages of the mandibular canine and skeletal maturity. The calcification stages of the mandibular canine show a satisfactory diagnostic performance only for assessment of pre-pubertal growth phase. Copyright © 2016 by Academy of Sciences and Arts of Bosnia and Herzegovina.

New method for evaluation of cervical vertebral maturation based on angular measurements.

PubMed

Alhadlaq, Adel M; Al-Shayea, Eman I

2013-04-01

To investigate the validity of a new approach to assess the cervical vertebral maturation based on angular measurements of the lower border concavity of cervical vertebral bodies. Hand-wrist and lateral cephalometric radiographs of 197 male subjects with age range of 10-15 years attending the orthodontic clinic at King Saud University, Riyadh, Kingdom of Saudi Arabia were utilized. The study was carried out between September 2009 and May 2011. The study sample was divided into 6 groups (group 1: 10 years to group 6: 15 years) based on the chronological age of the subject. The skeletal age of the subjects was determined using Greulich and Pyle's standard radiographic atlas, and skeletal maturation was assessed by Fishman's skeletal maturity indicators. The cervical vertebral maturation (CVM) of subjects was determined using angular measurements of the second, third, and fourth cervical vertebral bodies. The validity of the newly developed method was assessed by examining the correlation between CVM stages determined by the angular measurements and the skeletal maturation level as determined by the standard hand-wrist methods. A significant correlation (r=0.94) was found between the angular CVM stages and the skeletal age determined by Greulich and Pyle's atlas from hand-wrist radiographs. Also, a high correlation (r=0.94) was found between the angular CVM stages and the Fishman's hand-wrist skeletal maturity indicators. The new angular measurement approach to determine CVM is valid and has the potential to be applied in assessing skeletal maturity level in growing male children.

Skeletal Muscle Fascicle Arrangements Can Be Reconstructed Using a Laplacian Vector Field Simulation

PubMed Central

Choi, Hon Fai; Blemker, Silvia S.

2013-01-01

Skeletal muscles are characterized by a large diversity in anatomical architecture and function. Muscle force and contraction are generated by contractile fiber cells grouped in fascicle bundles, which transmit the mechanical action between origin and insertion attachments of the muscle. Therefore, an adequate representation of fascicle arrangements in computational models of skeletal muscles is important, especially when investigating three-dimensional muscle deformations in finite element models. However, obtaining high resolution in vivo measurements of fascicle arrangements in skeletal muscles is currently still challenging. This motivated the development of methods in previous studies to generate numerical representations of fascicle trajectories using interpolation templates. Here, we present an alternative approach based on the hypothesis of a rotation and divergence free (Laplacian) vector field behavior which reflects observed physical characteristics of fascicle trajectories. To obtain this representation, the Laplace equation was solved in anatomical reconstructions of skeletal muscle shapes based on medical images using a uniform flux boundary condition on the attachment areas. Fascicle tracts were generated through a robust flux based tracing algorithm. The concept of this approach was demonstrated in two-dimensional synthetic examples of typical skeletal muscle architectures. A detailed evaluation was performed in an example of the anatomical human tibialis anterior muscle which showed an overall agreement with measurements from the literature. The utility and capability of the proposed method was further demonstrated in other anatomical examples of human skeletal muscles with a wide range of muscle shapes and attachment morphologies. PMID:24204878

The Central Nervous System and Bone Metabolism: An Evolving Story.

PubMed

Dimitri, Paul; Rosen, Cliff

2017-05-01

Our understanding of the control of skeletal metabolism has undergone a dynamic shift in the last two decades, primarily driven by our understanding of energy metabolism. Evidence demonstrating that leptin not only influences bone cells directly, but that it also plays a pivotal role in controlling bone mass centrally, opened up an investigative process that has changed the way in which skeletal metabolism is now perceived. Other central regulators of bone metabolism have since been identified including neuropeptide Y (NPY), serotonin, endocannabinoids, cocaine- and amphetamine-regulated transcript (CART), adiponectin, melatonin and neuromedin U, controlling osteoblast and osteoclast differentiation, proliferation and function. The sympathetic nervous system was originally identified as the predominant efferent pathway mediating central signalling to control skeleton metabolism, in part regulated through circadian genes. More recent evidence points to a role of the parasympathetic nervous system in the control of skeletal metabolism either through muscarinic influence of sympathetic nerves in the brain or directly via nicotinic receptors on osteoclasts, thus providing evidence for broader autonomic skeletal regulation. Sensory innervation of bone has also received focus again widening our understanding of the complex neuronal regulation of bone mass. Whilst scientific advance in this field of bone metabolism has been rapid, progress is still required to understand how these model systems work in relation to the multiple confounders influencing skeletal metabolism, and the relative balance in these neuronal systems required for skeletal growth and development in childhood and maintaining skeletal integrity in adulthood.

The Correlation of Skeletal and Cardiac Muscle Dysfunction in Duchenne Muscular Dystrophy.

PubMed

Posner, Andrew D; Soslow, Jonathan H; Burnette, W Bryan; Bian, Aihua; Shintani, Ayumi; Sawyer, Douglas B; Markham, Larry W

2016-01-01

Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle and cardiac dysfunction. While skeletal muscle dysfunction precedes cardiomyopathy, the relationship between the progressive decline in skeletal and cardiac muscle function is unclear. This relationship is especially important given that the myocardial effects of many developing DMD therapies are largely unknown. Our objective was to assess the relationship between progression of skeletal muscle weakness and onset of cardiac dysfunction in DMD. A total of 77 DMD subjects treated at a single referral center were included. Demographic information, quantitative muscle testing (QMT), subjective muscle strength, cardiac function, and current and retrospective medications were collected. A Spearman rank correlation was used to evaluate for an association between subjective strength and fractional shortening. The effects of total QMT and arm QMT on fractional shortening were examined in generalized least square with and without adjustments for age, ambulatory status, and duration of corticosteroids and cardiac specific medications. We found a significant correlation between maintained subjective skeletal muscle arm and leg strength and maintained cardiac function as defined by fractional shortening (rho=0.47, p=0.004 and rho=0.48, p=0.003, respectively). We also found a significant association between QMT and fractional shortening among non-ambulatory DMD subjects (p=0.03), while this association was not significant in ambulatory subjects. Our findings allow us to conclude that in this population, there exists a significant relationship between skeletal muscle and cardiac function in non-ambulatory DMD patients. While this does not imply a causal relationship, a possible association between skeletal and cardiac muscle function suggests that researchers should carefully monitor cardiac function, even when the primary outcome measures are not cardiac in nature.

Melanocortin 4 Receptor Activation Attenuates Mitochondrial Dysfunction in Skeletal Muscle of Diabetic Rats.

PubMed

Zhang, Hao-Hao; Liu, Jiao; Qin, Gui-Jun; Li, Xia-Lian; Du, Pei-Jie; Hao, Xiao; Zhao, Di; Tian, Tian; Wu, Jing; Yun, Meng; Bai, Yan-Hui

2017-11-01

A previous study has confirmed that the central melanocortin system was able to mediate skeletal muscle AMP-activated protein kinase (AMPK) activation in mice fed a high-fat diet, while activation of the AMPK signaling pathway significantly induced mitochondrial biogenesis. Our hypothesis was that melanocortin 4 receptor (MC4R) was involved in the development of skeletal muscle injury in diabetic rats. In this study, we treated diabetic rats intracerebroventricularly with MC4R agonist R027-3225 or antagonist SHU9119, respectively. Then, we measured the production of reactive oxygen species (ROS), the levels of malondialdehyde (MDA) and glutathione (GSH), the mitochondrial DNA (mtDNA) content and mitochondrial biogenesis, and the protein levels of p-AMPK, AMPK, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), sirtuin 1 (SIRT1), and manganese superoxide dismutase (MnSOD) in the skeletal muscle of diabetic rats. The results showed that there was significant skeletal muscle injury in the diabetic rats along with serious oxidative stress and decreased mitochondrial biogenesis. Treatment with R027-3225 reduced oxidative stress and induced mitochondrial biogenesis in skeletal muscle, and also activated the AMPK-SIRT1-PGC-1α signaling pathway. However, diabetic rats injected with MC4R antagonist SHU9119 showed an aggravated oxidative stress and mitochondrial dysfunction in skeletal muscle. In conclusion, our results revealed that MC4R activation was able to attenuate oxidative stress and mitochondrial dysfunction in skeletal muscle induced by diabetes partially through activating the AMPK-SIRT1-PGC-1α signaling pathway. J. Cell. Biochem. 118: 4072-4079, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

The structure of and origin of nodular chromite from the Troodos ophiolite, Cyprus, revealed using high-resolution X-ray computed tomography and electron backscatter diffraction

NASA Astrophysics Data System (ADS)

Prichard, H. M.; Barnes, S. J.; Godel, B.; Reddy, S. M.; Vukmanovic, Z.; Halfpenny, A.; Neary, C. R.; Fisher, P. C.

2015-03-01

Nodular chromite is a characteristic feature of ophiolitic podiform chromitite and there has been much debate about how it forms. Nodular chromite from the Troodos ophiolite in Cyprus is unusual in that it contains skeletal crystals enclosed within the centres of the nodules and interstitial to them. 3D imaging and electron backscatter diffraction have shown that the skeletal crystals within the nodules are single crystals that are surrounded by a rim of polycrystalline chromite. 3D analysis reveals that the skeletal crystals are partially or completely formed cage or hopper structures elongated along the < 111 > axis. The rim is composed of a patchwork of chromite grains that are truncated on the outer edge of the rim. The skeletal crystals formed first from a magma supersaturated in chromite and silicate minerals crystallised from melt trapped between the chromite skeletal crystal blades as they grew. The formation of skeletal crystals was followed by a crystallisation event which formed a silicate-poor rim of chromite grains around the skeletal crystals. These crystals show a weak preferred orientation related to the orientation of the core skeletal crystal implying that they formed by nucleation and growth on this core, and did not form by random mechanical aggregation. Patches of equilibrium adcumulate textures within the rim attest to in situ development of such textures. The nodules were subsequently exposed to chromite undersaturated magma resulting in dissolution, recorded by truncated grain boundaries in the rim and a smooth outer surface to the nodule. None of these stages of formation require a turbulent magma. Lastly the nodules impinged on each other causing local deformation at points of contact.

Supplementation of lactobacilli improves growth, regulates microbiota composition and suppresses skeletal anomalies in juvenile pike-perch (Sander lucioperca) reared in recirculating aquaculture system (RAS): A pilot study.

PubMed

Ljubobratovic, Uros; Kosanovic, Dejana; Vukotic, Goran; Molnar, Zsuzsanna; Stanisavljevic, Nemanja; Ristovic, Tijana; Peter, Geza; Lukic, Jovanka; Jeney, Galina

2017-12-01

This research aimed to test the effects of lactobacilli, applied to cultured pike-perch, either through hydrolyzed OTOHIME fish diet, or through Artemia nauplii, on fish growth, microbiota balance and skeletal development. On the 12th Day Post Hatching (DPH) fish were divided into following treatment groups: two groups received the combination of OTOHIME and nauplii enriched either with Lactobacillus paracasei BGHN14+Lactobacillus rhamnosus BGT10 or with Lactobacillus reuteri BGGO6-55+Lactobacillus salivarius BGHO1, and one group received OTOHIME hydrolyzed by BGHN14+BGT10 and non-enriched nauplii. Control group received non-enriched nauplii and non-hydrolyzed OTOHIME. The treatment lasted 14days and fish were sacrificed on the 26th DPH for the assessment of digestive enzyme activity and microbiota composition. Individual total lengths and individual body weights were recorded at the end of the treatments, on the 26th DPH, and also on the 45th DPH, in parallel with the evaluation of skeletal deformities and fish survival. Our results indicated positive effect of Artemia enriched with BGGO6-55+BGHO1 on fish growth, skeletal development and trypsin to chymotrypsin activity ratio (T/C), as an indicator of protein digestibility. Hydrolysis of OTOHIME was also associated with better skeletal development, higher T/C values and lower levels of Aeromonas and Mycobacterium spp., which are important fish pathogens. Though additional testing in larger cohort studies is needed, these observations are promising in terms of usage of probiotics for improved environmentally friendly production of pike-perch in Recirculating Aquaculture System (RAS). Copyright © 2017 Elsevier Ltd. All rights reserved.

Stem cells, angiogenesis and muscle healing: a potential role in massage therapies?

PubMed

Best, Thomas M; Gharaibeh, Burhan; Huard, Johnny

2013-11-01

Skeletal muscle injuries are among the most common and frequently disabling injuries sustained by athletes. Repair of injured skeletal muscle is an area that continues to present a challenge for sports medicine clinicians and researchers due, in part, to complete muscle recovery being compromised by development of fibrosis leading to loss of function and susceptibility to re-injury. Injured skeletal muscle goes through a series of coordinated and interrelated phases of healing including degeneration, inflammation, regeneration and fibrosis. Muscle regeneration initiated shortly after injury can be limited by fibrosis which affects the degree of recovery and predisposes the muscle to reinjury. It has been demonstrated in animal studies that antifibrotic agents that inactivate transforming growth factor (TGF)-β1 have been effective at decreasing scar tissue formation. Several studies have also shown that vascular endothelial growth factor (VEGF) can increase the efficiency of skeletal muscle repair by increasing angiogenesis and, at the same time, reducing the accumulation of fibrosis. We have isolated and thoroughly characterised a population of skeletal muscle-derived stem cells (MDSCs) that enhance repair of damaged skeletal muscle fibres by directly differentiating into myofibres and secreting paracrine factors that promote tissue repair. Indeed, we have found that MDSCs transplanted into skeletal and cardiac muscles have been successful at repair probably because of their ability to secrete VEGF that works in a paracrine fashion. The application of these techniques to the study of sport-related muscle injuries awaits investigation. Other useful strategies to enhance skeletal muscle repair through increased vascularisation may include gene therapy, exercise, neuromuscular electrical stimulation and, potentially, massage therapy. Based on recent studies showing an accelerated recovery of muscle function from intense eccentric exercise through massage-based therapies, we believe that this treatment modality offers a practical and non-invasive form of therapy for skeletal muscle injuries. However, the biological mechanism(s) behind the beneficial effect of massage are still unclear and require further investigation using animal models and potentially randomised, human clinical studies.

Stem cells, angiogenesis and muscle healing: a potential role in massage therapies?

PubMed

Best, Thomas M; Gharaibeh, Burhan; Huard, Johnny

2013-06-01

Skeletal muscle injuries are among the most common and frequently disabling injuries sustained by athletes. Repair of injured skeletal muscle is an area that continues to present a challenge for sports medicine clinicians and researchers due, in part, to complete muscle recovery being compromised by development of fibrosis leading to loss of function and susceptibility to re-injury. Injured skeletal muscle goes through a series of coordinated and interrelated phases of healing including degeneration, inflammation, regeneration and fibrosis. Muscle regeneration initiated shortly after injury can be limited by fibrosis which affects the degree of recovery and predisposes the muscle to reinjury. It has been demonstrated in animal studies that antifibrotic agents that inactivate transforming growth factor (TGF)-β1 have been effective at decreasing scar tissue formation. Several studies have also shown that vascular endothelial growth factor (VEGF) can increase the efficiency of skeletal muscle repair by increasing angiogenesis and, at the same time, reducing the accumulation of fibrosis. We have isolated and thoroughly characterised a population of skeletal muscle-derived stem cells (MDSCs) that enhance repair of damaged skeletal muscle fibres by directly differentiating into myofibres and secreting paracrine factors that promote tissue repair. Indeed, we have found that MDSCs transplanted into skeletal and cardiac muscles have been successful at repair probably because of their ability to secrete VEGF that works in a paracrine fashion. The application of these techniques to the study of sport-related muscle injuries awaits investigation. Other useful strategies to enhance skeletal muscle repair through increased vascularisation may include gene therapy, exercise, neuromuscular electrical stimulation and, potentially, massage therapy. Based on recent studies showing an accelerated recovery of muscle function from intense eccentric exercise through massage-based therapies, we believe that this treatment modality offers a practical and non-invasive form of therapy for skeletal muscle injuries. However, the biological mechanism(s) behind the beneficial effect of massage are still unclear and require further investigation using animal models and potentially randomised, human clinical studies.

Epiphyseal maturity indicators at the knee and their relationship to chronological age: results of an Irish population study.

PubMed

O'Connor, Jean E; Coyle, Joseph; Spence, Liam D; Last, Jason

2013-09-01

Skeletal maturation is divisible to three main components; the time of appearance of an ossification center, its change in morphology and time of fusion to a primary ossification center. With regard to the knee, the intermediate period between appearance and fusion of the ossification centers extends over a period of greater than 10 years. This study aims to investigate radiographically the age at which morphological changes of the epiphyses at the knee occur in a modern Irish population. Radiographs of 221 subjects (137 males; 84 females) aged 9-19 years were examined. Seven nonmetric indicators of maturity were assessed using criteria modified from the Roche, Wainer, and Thissen method and Pyle and Hoerr's atlas of the knee. Reference charts are presented which display the timeline for each of the grades of development of the seven indicators. Mean age was found to increase significantly with successive grades of development of each of the seven indicators. A significant difference was noted between males and females at the same grade of development for six of the seven indicators. The narrowest age range reported for a single grade of development was 2.2 years for Grade 2 of development of the tibial tuberosity for males. The information on changing morphology of the epiphyses at the knee in the present study may provide an adjunct to methods used for evaluation of skeletal maturity before surgery for orthopedic disorders or to evaluate skeletal age in clinical scenarios where either delayed or precocious skeletal maturation is suspected. Copyright © 2012 Wiley Periodicals, Inc.

MiR-27b Promotes Muscle Development by Inhibiting MDFI Expression.

PubMed

Hou, Lianjie; Xu, Jian; Jiao, Yiren; Li, Huaqin; Pan, Zhicheng; Duan, Junli; Gu, Ting; Hu, Chingyuan; Wang, Chong

2018-01-01

Skeletal muscle plays an essential role in the body movement. However, injuries to the skeletal muscle are common. Lifelong maintenance of skeletal muscle function largely depends on preserving the regenerative capacity of muscle. Muscle satellite cells proliferation, differentiation, and myoblast fusion play an important role in muscle regeneration after injury. Therefore, understanding of the mechanisms associated with muscle development during muscle regeneration is essential for devising the alternative treatments for muscle injury in the future. Edu staining, qRT-PCR and western blot were used to evaluate the miR-27b effects on pig muscle satellite cells (PSCs) proliferation and differentiation in vitro. Then, we used bioinformatics analysis and dual-luciferase reporter assay to predict and confirm the miR-27b target gene. Finally, we elucidate the target gene function on muscle development in vitro and in vivo through Edu staining, qRT-PCR, western blot, H&E staining and morphological observation. miR-27b inhibits PSCs proliferation and promotes PSCs differentiation. And the miR-27b target gene, MDFI, promotes PSCs proliferation and inhibits PSCs differentiation in vitro. Furthermore, interfering MDFI expression promotes mice muscle regeneration after injury. our results conclude that miR-27b promotes PSCs myogenesis by targeting MDFI. These results expand our understanding of muscle development mechanism in which miRNAs and genes work collaboratively in regulating skeletal muscle development. Furthermore, this finding has implications for obtaining the alternative treatments for patients with the muscle injury. © 2018 The Author(s). Published by S. Karger AG, Basel.

Msx genes are expressed in the carapacial ridge of turtle shell: a study of the European pond turtle, Emys orbicularis.

PubMed

Vincent, Christine; Bontoux, Martine; Le Douarin, Nicole M; Pieau, Claude; Monsoro-Burq, Anne-Hélène

2003-09-01

The turtle shell forms by extensive ossification of dermis ventrally and dorsally. The carapacial ridge (CR) controls early dorsal shell formation and is thought to play a similar role in shell growth as the apical ectodermal ridge during limb development. However, the molecular mechanisms underlying carapace development are still unknown. Msx genes are involved in the development of limb mesenchyme and of various skeletal structures. In particular, precocious Msx expression is recorded in skeletal precursors that develop close to the ectoderm, such as vertebral spinous processes or skull. Here, we have studied the embryonic expression of Msx genes in the European pond turtle, Emys orbicularis. The overall Msx expression in head, limb, and trunk is similar to what is observed in other vertebrates. We have focused on the CR area and pre-skeletal shell condensations. The CR expresses Msx genes transiently, in a pattern similar to that of fgf10. In the future carapace domain, the dermis located dorsal to the spinal cord expresses Msx genes, as in other vertebrates, but we did not see expansion of this expression in the dermis located more laterally, on top of the dermomyotomes. In the ventral plastron, although the dermal osseous condensations form in the embryonic Msx-positive somatopleura, we did not observe enhanced Msx expression around these elements. These observations may indicate that common mechanisms participate in limb bud and CR early development, but that pre-differentiation steps differ between shell and other skeletal structures and involve other gene activities than that of Msx genes.

Genetic engineering for skeletal regenerative medicine.

PubMed

Gersbach, Charles A; Phillips, Jennifer E; García, Andrés J

2007-01-01

The clinical challenges of skeletal regenerative medicine have motivated significant advances in cellular and tissue engineering in recent years. In particular, advances in molecular biology have provided the tools necessary for the design of gene-based strategies for skeletal tissue repair. Consequently, genetic engineering has emerged as a promising method to address the need for sustained and robust cellular differentiation and extracellular matrix production. As a result, gene therapy has been established as a conventional approach to enhance cellular activities for skeletal tissue repair. Recent literature clearly demonstrates that genetic engineering is a principal factor in constructing effective methods for tissue engineering approaches to bone, cartilage, and connective tissue regeneration. This review highlights this literature, including advances in the development of efficacious gene carriers, novel cell sources, successful delivery strategies, and optimal target genes. The current status of the field and the challenges impeding the clinical realization of these approaches are also discussed.

New Perspectives on Pharyngeal Dorsoventral Patterning in Development and Evolution of the Vertebrate Jaw

PubMed Central

Medeiros, Daniel Meulemans; Crump, J. Gage

2012-01-01

Patterning of the vertebrate facial skeleton involves the progressive partitioning of neural-crest-derived skeletal precursors into distinct subpopulations along the anteroposterior (AP) and dorsoventral (DV) axes. Recent evidence suggests that complex interactions between multiple signaling pathways, in particular Endothelin-1 (Edn1), Bone Morphogenetic Protein (BMP), and Jagged-Notch, are needed to pattern skeletal precursors along the DV axis. Rather than directly determining the morphology of individual skeletal elements, these signals appear to act through several families of transcription factors, including Dlx, Msx, and Hand, to establish dynamic zones of skeletal differentiation. Provocatively, this patterning mechanism is largely conserved from mouse and zebrafish to the jawless vertebrate, lamprey. This implies that the diversification of the vertebrate facial skeleton, including the evolution of the jaw, was driven largely by modifications downstream of a conversed pharyngeal DV patterning program. PMID:22960284

Large Eddy Simulation of Turbulent Combustion

DTIC Science & Technology

2005-10-01

a new method to automatically generate skeletal kinetic mechanisms for surrogate fuels, using the directed relation graph method with error...propagation, was developed. These mechanisms are guaranteed to match results obtained using detailed chemistry within a user- defined accuracy for any...specified target. They can be combined together to produce adequate chemical models for surrogate fuels. A library containing skeletal mechanisms of various

Growth factor involvement in tension-induced skeletal muscle growth

NASA Technical Reports Server (NTRS)

Vandenburgh, Herman W.

1987-01-01

New muscle tissue culture techniques were developed to grow embryonic skeletal myofibers which are able to differentiate into more adultlike myofibers. Studies on mechanical simulation of cultured muscle cell growth will now be more directly applicable to mechanically-induced growth in adult muscle, and lead to better models for understanding muscle tissue atrophy caused by disuse in the microgravity of space.

Bilingual Skills Training Program. Barbering/Cosmetology. Module 4.0: Skeletal System.

ERIC Educational Resources Information Center

Northern New Mexico Community Coll., El Rito.

This module on the skeletal system is the fourth of ten (CE 028 308-318) in the barbering/cosmetology course of a bilingual skill training program. (A Vocabulary Development Workbook for modules 6-10 is available as CE 028 313.) The course is designed to furnish theoretical and laboratory experience. Module objectives are for students to develop…

Activation by insulin and amino acids of signaling components leading to translation initiation in skeletal muscle of neonatal pigs is developmentally regulated

USDA-ARS?s Scientific Manuscript database

Insulin and amino acids act independently to stimulate protein synthesis in skeletal muscle of neonatal pigs, and the responses decrease with development. The purpose of this study was to compare the separate effects of fed levels of INS and AA on the activation of signaling components leading to tr...

Regulation of skeletal myotube formation and alignment by nanotopographically controlled cell-secreted extracellular matrix.

PubMed

Jiao, Alex; Moerk, Charles T; Penland, Nisa; Perla, Mikael; Kim, Jinsung; Smith, Alec S T; Murry, Charles E; Kim, Deok-Ho

2018-06-01

Skeletal muscle has a well-organized tissue structure comprised of aligned myofibers and an encasing extracellular matrix (ECM) sheath or lamina, within which reside satellite cells. We hypothesize that the organization of skeletal muscle tissues in culture can affect both the structure of the deposited ECM and the differentiation potential of developing myotubes. Furthermore, we posit that cellular and ECM cues can be a strong determinant of myoblast fusion and morphology in 3D tissue culture environments. To test these, we utilized a thermoresponsive nanofabricated substratum to engineer anisotropic sheets of myoblasts which could then be transferred and stacked into multilayered tissues. Within such engineered tissues, we found that myoblasts rapidly sense topography and deposit structurally organized ECM proteins. Furthermore, the initial tissue structure was found to exert significant control over myoblast fusion and eventual myotube organization. These results highlight the importance of ECM structure on myoblast fusion and organization, and provide insights into substrate-mediated control of myotube formation in the development of novel, more effective, engineered skeletal muscle tissues. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1543-1551, 2018. © 2018 Wiley Periodicals, Inc.

Characterization of porcine SKIP gene in skeletal muscle development: polymorphisms, association analysis, expression and regulation of cell growth in C2C12 cells.

PubMed

Xiong, Qi; Chai, Jin; Deng, Changyan; Jiang, Siwen; Liu, Yang; Huang, Tao; Suo, Xiaojun; Zhang, Nian; Li, Xiaofeng; Yang, Qianping; Chen, Mingxin; Zheng, Rong

2012-12-01

Skeletal muscle and kidney-enriched inositol phosphatase (SKIP) was identified as a 5'-inositol phosphatase that hydrolyzes phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3) to PI(3,4)P2 and negatively regulates insulin-induced phosphatidylinositol 3-kinase signaling in skeletal muscle. In this study, two new single nucleotide polymorphisms (SNPs) in porcine SKIP introns 1 and 6 were detected. The C1092T locus in intron 1 showed significant associations with some meat traits, whereas the A17G locus in intron 6 showed significant associations with some carcass traits. Expression analysis showed that porcine SKIP is upregulated at d 65 of gestation and Meishan fetuses have higher and prolonged expression of SKIP compared to Large White at d 100 of gestation. Ectopic expression of porcine SKIP decreased insulin-induced cell proliferation and promoted serum starvation-induced cell cycle arrest in G0/G1 phase in C2C12. Our results suggest that SKIP plays a negative regulatory role in skeletal muscle development partly by preventing cell proliferation. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

Systemic bioinformatics analysis of skeletal muscle gene expression profiles of sepsis

PubMed Central

Yang, Fang; Wang, Yumei

2018-01-01

Sepsis is a type of systemic inflammatory response syndrome with high morbidity and mortality. Skeletal muscle dysfunction is one of the major complications of sepsis that may also influence the outcome of sepsis. The aim of the present study was to explore and identify potential mechanisms and therapeutic targets of sepsis. Systemic bioinformatics analysis of skeletal muscle gene expression profiles from the Gene Expression Omnibus was performed. Differentially expressed genes (DEGs) in samples from patients with sepsis and control samples were screened out using the limma package. Differential co-expression and coregulation (DCE and DCR, respectively) analysis was performed based on the Differential Co-expression Analysis package to identify differences in gene co-expression and coregulation patterns between the control and sepsis groups. Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways of DEGs were identified using the Database for Annotation, Visualization and Integrated Discovery, and inflammatory, cancer and skeletal muscle development-associated biological processes and pathways were identified. DCE and DCR analysis revealed several potential therapeutic targets for sepsis, including genes and transcription factors. The results of the present study may provide a basis for the development of novel therapeutic targets and treatment methods for sepsis. PMID:29805480

A cell-autonomous requirement for neutral sphingomyelinase 2 in bone mineralization

PubMed Central

Khavandgar, Zohreh; Poirier, Christophe; Clarke, Christopher J.; Li, Jingjing; Wang, Nicholas; McKee, Marc D.; Hannun, Yusuf A.

2011-01-01

A deletion mutation called fro (fragilitas ossium) in the murine Smpd3 (sphingomyelin phosphodiesterase 3) gene leads to a severe skeletal dysplasia. Smpd3 encodes a neutral sphingomyelinase (nSMase2), which cleaves sphingomyelin to generate bioactive lipid metabolites. We examined endochondral ossification in embryonic day 15.5 fro/fro mouse embryos and observed impaired apoptosis of hypertrophic chondrocytes and severely undermineralized cortical bones in the developing skeleton. In a recent study, it was suggested that nSMase2 activity in the brain regulates skeletal development through endocrine factors. However, we detected Smpd3 expression in both embryonic and postnatal skeletal tissues in wild-type mice. To investigate whether nSMase2 plays a cell-autonomous role in these tissues, we examined the in vitro mineralization properties of fro/fro osteoblast cultures. fro/fro cultures mineralized less than the control osteoblast cultures. We next generated fro/fro;Col1a1-Smpd3 mice, in which osteoblast-specific expression of Smpd3 corrected the bone abnormalities observed in fro/fro embryos without affecting the cartilage phenotype. Our data suggest tissue-specific roles for nSMase2 in skeletal tissues. PMID:21788370

Elevated Nicotinamide Phosphoribosyl Transferase in Skeletal Muscle Augments Exercise Performance and Mitochondrial Respiratory Capacity Following Exercise Training

PubMed Central

Brouwers, Bram; Stephens, Natalie A.; Costford, Sheila R.; Hopf, Meghan E.; Ayala, Julio E.; Yi, Fanchao; Xie, Hui; Li, Jian-Liang; Gardell, Stephen J.; Sparks, Lauren M.; Smith, Steven R.

2018-01-01

Mice overexpressing NAMPT in skeletal muscle (NamptTg mice) develop higher exercise endurance and maximal aerobic capacity (VO2max) following voluntary exercise training compared to wild-type (WT) mice. Here, we aimed to investigate the mechanisms underlying by determining skeletal muscle mitochondrial respiratory capacity in NamptTg and WT mice. Body weight and body composition, tissue weight (gastrocnemius, quadriceps, soleus, heart, liver, and epididymal white adipose tissue), skeletal muscle and liver glycogen content, VO2max, skeletal muscle mitochondrial respiratory capacity (measured by high-resolution respirometry), skeletal muscle gene expression (measured by microarray and qPCR), and skeletal muscle protein content (measured by Western blot) were determined following 6 weeks of voluntary exercise training (access to running wheel) in 13-week-old male NamptTg (exercised NamptTg) mice and WT (exercised WT) mice. Daily running distance and running time during the voluntary exercise training protocol were recorded. Daily running distance (p = 0.51) and running time (p = 0.85) were not significantly different between exercised NamptTg mice and exercised WT mice. VO2max was higher in exercised NamptTg mice compared to exercised WT mice (p = 0.02). Body weight (p = 0.92), fat mass (p = 0.49), lean mass (p = 0.91), tissue weight (all p > 0.05), and skeletal muscle (p = 0.72) and liver (p = 0.94) glycogen content were not significantly different between exercised NamptTg mice and exercised WT mice. Complex I oxidative phosphorylation (OXPHOS) respiratory capacity supported by fatty acid substrates (p < 0.01), maximal (complex I+II) OXPHOS respiratory capacity supported by glycolytic (p = 0.02) and fatty acid (p < 0.01) substrates, and maximal uncoupled respiratory capacity supported by fatty acid substrates (p < 0.01) was higher in exercised NamptTg mice compared to exercised WT mice. Transcriptomic analyses revealed differential expression for genes involved in oxidative metabolism in exercised NamptTg mice compared to exercised WT mice, specifically, enrichment for the gene set related to the SIRT3-mediated signaling pathway. SIRT3 protein content correlated with NAMPT protein content (r = 0.61, p = 0.04). In conclusion, NamptTg mice develop higher exercise capacity following voluntary exercise training compared to WT mice, which is paralleled by higher mitochondrial respiratory capacity in skeletal muscle. The changes in SIRT3 targets suggest that these effects are due to remodeling of mitochondrial function. PMID:29942262

Skeletal muscle and nuclear hormone receptors: implications for cardiovascular and metabolic disease.

PubMed

Smith, Aaron G; Muscat, George E O

2005-10-01

Skeletal muscle is a major mass peripheral tissue that accounts for approximately 40% of the total body mass and a major player in energy balance. It accounts for >30% of energy expenditure, is the primary tissue of insulin stimulated glucose uptake, disposal, and storage. Furthermore, it influences metabolism via modulation of circulating and stored lipid (and cholesterol) flux. Lipid catabolism supplies up to 70% of the energy requirements for resting muscle. However, initial aerobic exercise utilizes stored muscle glycogen but as exercise continues, glucose and stored muscle triglycerides become important energy substrates. Endurance exercise increasingly depends on fatty acid oxidation (and lipid mobilization from other tissues). This underscores the importance of lipid and glucose utilization as an energy source in muscle. Consequently skeletal muscle has a significant role in insulin sensitivity, the blood lipid profile, and obesity. Moreover, caloric excess, obesity and physical inactivity lead to skeletal muscle insulin resistance, a risk factor for the development of type II diabetes. In this context skeletal muscle is an important therapeutic target in the battle against cardiovascular disease, the worlds most serious public health threat. Major risk factors for cardiovascular disease include dyslipidemia, hypertension, obesity, sedentary lifestyle, and diabetes. These risk factors are directly influenced by diet, metabolism and physical activity. Metabolism is largely regulated by nuclear hormone receptors which function as hormone regulated transcription factors that bind DNA and mediate the patho-physiological regulation of gene expression. Metabolism and activity, which directly influence cardiovascular disease risk factors, are primarily driven by skeletal muscle. Recently, many nuclear receptors expressed in skeletal muscle have been shown to improve glucose tolerance, insulin resistance, and dyslipidemia. Skeletal muscle and nuclear receptors are rapidly emerging as critical targets in the battle against cardiovascular disease risk factors. Understanding the function of nuclear receptors in skeletal muscle has enormous pharmacological utility for the treatment of cardiovascular disease. This review focuses on the molecular regulation of metabolism by nuclear receptors in skeletal muscle in the context of dyslipidemia and cardiovascular disease.

Smpd3 Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development

PubMed Central

Li, Jingjing; Manickam, Garthiga; Ray, Seemun; Oh, Chun-do; Yasuda, Hideyo; Moffatt, Pierre

2016-01-01

Sphingomyelin phosphodiesterase 3 (SMPD3), a lipid-metabolizing enzyme present in bone and cartilage, has been identified to be a key regulator of skeletal development. A homozygous loss-of-function mutation called fragilitas ossium (fro) in the Smpd3 gene causes poor bone and cartilage mineralization resulting in severe congenital skeletal deformities. Here we show that Smpd3 expression in ATDC5 chondrogenic cells is downregulated by parathyroid hormone-related peptide through transcription factor SOX9. Furthermore, we show that transgenic expression of Smpd3 in the chondrocytes of fro/fro mice corrects the cartilage but not the bone abnormalities. Additionally, we report the generation of Smpd3flox/flox mice for the tissue-specific inactivation of Smpd3 using the Cre-loxP system. We found that the skeletal phenotype in Smpd3flox/flox; Osx-Cre mice, in which the Smpd3 gene is ablated in both late-stage chondrocytes and osteoblasts, closely mimics the skeletal phenotype in fro/fro mice. On the other hand, Smpd3flox/flox; Col2a1-Cre mice, in which the Smpd3 gene is knocked out in chondrocytes only, recapitulate the fro/fro mouse cartilage phenotype. This work demonstrates that Smpd3 expression in both chondrocytes and osteoblasts is required for normal endochondral bone development. PMID:27325675

Skeletal maturation in individuals with Down's syndrome: Comparison between PGS curve, cervical vertebrae and bones of the hand and wrist

PubMed Central

Carinhena, Glauber; Siqueira, Danilo Furquim; Sannomiya, Eduardo Kazuo

2014-01-01

Introduction This study was conducted with the aim of adapting the methods developed by Martins and Sakima to assess skeletal maturation by cervical vertebrae in the pubertal growth spurt (PGS) curve. It also aimed to test the reliability and agreement between those methods and the method of hand and wrist radiograph when compared two by two and all together. Methods The sample comprised 72 radiographs, with 36 lateral radiographs of the head and 36 hand-wrist radiographs of 36 subjects with Down's syndrome (DS), 13 female and 23 male, aged between 8 years and 6 months and 18 years and 7 months, with an average age of 13 years and 10 months. Results and Conclusions Results revealed that adapting the methods developed by Martins and Sakima to assess skeletal maturation by cervical vertebrae in the curve of PGS is practical and useful in determining the stage of growth and development of individuals. The stages of maturation evaluated by cervical vertebrae and ossification centers observed in radiographs of the hand and wrist were considered reliable, with excellent level of agreement between the methods by Hassel and Farman as well as Baccetti, Franchi and McNamara Jr and Martins and Sakima. Additionally, results revealed an agreement that ranged between reasonable to good for the three methods used to assess the skeletal maturation, showing statistical significance. PMID:25279522

Skeletal maturation in individuals with Down's syndrome: comparison between PGS curve, cervical vertebrae and bones of the hand and wrist.

PubMed

Carinhena, Glauber; Siqueira, Danilo Furquim; Sannomiya, Eduardo Kazuo

2014-01-01

This study was conducted with the aim of adapting the methods developed by Martins and Sakima to assess skeletal maturation by cervical vertebrae in the pubertal growth spurt (PGS) curve. It also aimed to test the reliability and agreement between those methods and the method of hand and wrist radiograph when compared two by two and all together.  The sample comprised 72 radiographs, with 36 lateral radiographs of the head and 36 hand-wrist radiographs of 36 subjects with Down's syndrome (DS), 13 female and 23 male, aged between 8 years and 6 months and 18 years and 7 months, with an average age of 13 years and 10 months.  Results revealed that adapting the methods developed by Martins and Sakima to assess skeletal maturation by cervical vertebrae in the PGS curve is practical and useful in determining the stage of growth and development of individuals. The stages of maturation evaluated by cervical vertebrae and ossification centers observed in radiographs of the hand and wrist were considered reliable, with excellent level of agreement between the methods by Hassel and Farman as well as Baccetti, Franchi and McNamara Jr and Martins and Sakima. Additionally, results revealed an agreement that ranged between reasonable to good for the three methods used to assess the skeletal maturation, showing statistical significance.

The role of mitochondrial DNA damage at skeletal muscle oxidative stress on the development of type 2 diabetes.

PubMed

Dos Santos, Julia Matzenbacher; de Oliveira, Denise Silva; Moreli, Marcos Lazaro; Benite-Ribeiro, Sandra Aparecida

2018-04-20

Reduced cellular response to insulin in skeletal muscle is one of the major components of the development of type 2 diabetes (T2D). Mitochondrial dysfunction involves in the accumulation of toxic reactive oxygen species (ROS) that leads to insulin resistance. The aim of this study was to verify the involvement of mitochondrial DNA damage at ROS generation in skeletal muscle during development of T2D. Wistar rats were fed a diet containing 60% fat over 8 weeks and at day 14 a single injection of STZ (25 mg/kg) was administered (T2D-induced). Control rats received standard food and an injection of citrate buffer. Blood and soleus muscle were collected. Abdominal fat was quantified as well as glucose, triglyceride, LDL, HDL, and total cholesterol in plasma and mtDNA copy number, cytochrome b (cytb) mRNA, 8-hydroxyguanosine, and 8-isoprostane (a marker of ROS) in soleus muscle. T2D-induced animal presented similar characteristics to humans that develop T2D such as changes in blood glucose, abdominal fat, LDL, HDL and cholesterol total. In soleus muscle 8-isoprostane, mtDNA copy number and 8-hydroxyguanosine were increased, while cytb mRNA was decreased in T2D. Our results suggest that in the development of T2D, when risks factors of T2D are present, intracellular oxidative stress increases in skeletal muscle and is associated with a decrease in cytb transcription. To overcome this process mtDNA increased but due to the proximity of ROS generation, mtDNA remains damaged by oxidation leading to an increase in ROS in a vicious cycle accounting to the development of insulin resistance and further T2D.

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

Forensic SNP Genotyping with SNaPshot: Development of a Novel In-house SBE Multiplex SNP Assay.

PubMed

Zar, Mian Sahib; Shahid, Ahmad Ali; Shahzad, Muhammad Saqib; Shin, Kyoung-Jin; Lee, Hwan Young; Lee, Sang-Seob; Israr, Muhammad; Wiegand, Peter; Kulstein, Galina

2018-04-10

This study introduces a newly developed in-house SNaPshot single-base extension (SBE) multiplex assay for forensic single nucleotide polymorphism (SNP) genotyping of fresh and degraded samples. The assay was validated with fresh blood samples from four different populations. In addition, altogether 24 samples from skeletal remains were analyzed with the multiplex. Full SNP profiles could be obtained from 14 specimens, while ten remains showed partial SNP profiles. Minor allele frequencies (MAF) of bone samples and different populations were compared and used for association of skeletal remains with a certain population. The results reveal that the SNPs of the bone samples are genetically close to the Pathan population. The findings show that the new multiplex system can be utilized for SNP genotyping of degraded and forensic relevant skeletal material, enabling to provide additional investigative leads in criminal cases. © 2018 American Academy of Forensic Sciences.

Measurement of Contractile Stress Generated by Cultured Rat Muscle on Silicon Cantilevers for Toxin Detection and Muscle Performance Enhancement

DTIC Science & Technology

2010-06-01

muscle . J Clin Invest 117: 2388–2391. 13. Close R (1964) Dynamic properties of fast and slow skeletal muscles of the rat during development. J Physiol...cultured skeletal muscle [30], which reported average peak twitch stress values of 2.9 kPa (reported as specific peak twitch force in units of kN/m2), but...demonstrates that the myotubes were driven down a path towards a more mature phenotype, in the process developing fast - twitch isoforms of myosin, while

Skeletal responses to spaceflight

NASA Technical Reports Server (NTRS)

Morey-Holton, Emily R.; Arnaud, Sara B.

1991-01-01

The effect of gravity on the skeletal development and on the bone composition and its regulation in vertebrates is discussed. Results are presented from spaceflight and ground studies in both man and rat on the effect of microgravity on the bone-mineral metabolism (in both species) and on bone maturation and growth (in rats). Special attention is given to a ground-based flight-simulation rat model developed at NASA's Ames Research Center for studies of bone structure at the molecular, organ, and whole-body levels and to comparisons of estimated results with spaceflight data.

Deletion of Core-binding factor β (Cbfβ) in mesenchymal progenitor cells provides new insights into Cbfβ/Runxs complex function in cartilage and bone development

PubMed Central

Wu, Mengrui; Li, Chenguan; Zhu, Guochun; Wang, Yiping; Jules, Joel; Lu, Yun; McConnell, Matthew; Wang, Yong-Jun; Shao, Jian-Zhong; Li, Yi-Ping; Chen, Wei

2015-01-01

Core-binding factor β (Cbfβ) is a subunit of the Cbf family of heterodimeric transcription factors which plays a critical role in skeletal development through its interaction with the Cbfα subunits, also known as Runt-related transcription factors (Runxs). However, the mechanism by which Cbfβ regulates cartilage and bone development remains unclear. Existing Cbfβ-deficient mouse models cannot specify the role of Cbfβ in skeletal cell lineage. Herein, we sought to specifically address the role of Cbfβ in cartilage and bone development by using a conditional knockout (CKO) approach. A mesenchymal-specific Cbfβ CKO mouse model was generated by using the Dermo1-Cre mouse line to specifically delete Cbfβ in mesenchymal stem cells, which give rise to osteoblasts and chondrocytes. Surprisingly, the mutant mice had under-developed larynx and tracheal cartilage causing alveolus defects which led to death shortly after birth from suffocation. Also, the mutant mice exhibited severe skeletal deformities from defective intramembranous and endochondral ossification, owing to delayed chondrocyte maturation and impaired osteoblast differentiation. Almost all bones of the mutant mice, including the calvariae, vertebrae, tibiae, femurs, ribs, limbs and sternums were defective. Importantly, we showed that Cbfβ was expressed throughout the skeleton during both embryonic and postnatal development, which explains the multiple-skeletal defects observed in the mutant mice. Consistently, Cbfβ deficiency impaired both chondrocyte proliferation and hypertrophy zone hypertrophy during growth-plate development in the long bones of mutant mice. Notably, Cbfβ, Runx1 and Runx2 displayed different expression patterns in the growth plates of the wildtype mice indicating that Cbfβ/Runx1 complex and Cbfβ/Runx2 complex may regulate chondrocyte proliferation and hypertrophy, respectively, in a spatial and temporal manner. Cbfβ deletion in the mesenchymal progenitors impacted bone development by dramatically down-regulating Collagen X (Col X) and Osterix (Osx), but had a dispensable effect on osteoclast development. Collectively, the results demonstrate that Cbfβ mediates cartilage and bone development by interacting with Runx1 and Runx2 to regulate the expressions of Col X and Osx for chondrocyte and osteoblast development. These findings not only reveal a critical role for Cbfβ in cartilage and bone development, but also facilitate the design of novel therapeutic approaches for skeletal diseases. PMID:24798493

Deletion of core-binding factor β (Cbfβ) in mesenchymal progenitor cells provides new insights into Cbfβ/Runxs complex function in cartilage and bone development.

PubMed

Wu, Mengrui; Li, Chenguan; Zhu, Guochun; Wang, Yiping; Jules, Joel; Lu, Yun; McConnell, Matthew; Wang, Yong-Jun; Shao, Jian-Zhong; Li, Yi-Ping; Chen, Wei

2014-08-01

Core-binding factor β (Cbfβ) is a subunit of the Cbf family of heterodimeric transcription factors, which plays a critical role in skeletal development through its interaction with the Cbfα subunits, also known as Runt-related transcription factors (Runxs). However, the mechanism by which Cbfβ regulates cartilage and bone development remains unclear. Existing Cbfβ-deficient mouse models cannot specify the role of Cbfβ in skeletal cell lineage. Herein, we sought to specifically address the role of Cbfβ in cartilage and bone development by using a conditional knockout (CKO) approach. A mesenchymal-specific Cbfβ CKO mouse model was generated by using the Dermo1-Cre mouse line to specifically delete Cbfβ in mesenchymal stem cells, which give rise to osteoblasts and chondrocytes. Surprisingly, the mutant mice had under-developed larynx and tracheal cartilage, causing alveolus defects that led to death shortly after birth from suffocation. Also, the mutant mice exhibited severe skeletal deformities from defective intramembranous and endochondral ossification, owing to delayed chondrocyte maturation and impaired osteoblast differentiation. Almost all bones of the mutant mice, including the calvariae, vertebrae, tibiae, femurs, ribs, limbs and sternums were defective. Importantly, we showed that Cbfβ was expressed throughout the skeleton during both embryonic and postnatal development, which explains the multiple-skeletal defects observed in the mutant mice. Consistently, Cbfβ deficiency impaired both chondrocyte proliferation and hypertrophy zone hypertrophy during growth-plate development in the long bones of mutant mice. Notably, Cbfβ, Runx1 and Runx2 displayed different expression patterns in the growth plates of the wild-type mice, indicating that Cbfβ/Runx1 complex and Cbfβ/Runx2 complex may regulate chondrocyte proliferation and hypertrophy, respectively, in a spatial and temporal manner. Cbfβ deletion in the mesenchymal progenitors affected bone development by dramatically down-regulating Collagen X (Col X) and Osterix (Osx) but had a dispensable effect on osteoclast development. Collectively, the results demonstrate that Cbfβ mediates cartilage and bone development by interacting with Runx1 and Runx2 to regulate the expressions of Col X and Osx for chondrocyte and osteoblast development. These findings not only reveal a critical role for Cbfβ in cartilage and bone development but also facilitate the design of novel therapeutic approaches for skeletal diseases. Copyright © 2014. Published by Elsevier Inc.

Human skeletal muscle drug transporters determine local exposure and toxicity of statins.

PubMed

Knauer, Michael J; Urquhart, Bradley L; Meyer zu Schwabedissen, Henriette E; Schwarz, Ute I; Lemke, Christopher J; Leake, Brenda F; Kim, Richard B; Tirona, Rommel G

2010-02-05

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, are important drugs used in the treatment and prevention of cardiovascular disease. Although statins are well tolerated, many patients develop myopathy manifesting as muscle aches and pain. Rhabdomyolysis is a rare but severe toxicity of statins. Interindividual differences in the activities of hepatic membrane drug transporters and metabolic enzymes are known to influence statin plasma pharmacokinetics and risk for myopathy. Interestingly, little is known regarding the molecular determinants of statin distribution into skeletal muscle and its relevance to toxicity. We sought to identify statin transporters in human skeletal muscle and determine their impact on statin toxicity in vitro. We demonstrate that the uptake transporter OATP2B1 (human organic anion transporting polypeptide 2B1) and the efflux transporters, multidrug resistance-associated protein (MRP)1, MRP4, and MRP5 are expressed on the sarcolemmal membrane of human skeletal muscle fibers and that atorvastatin and rosuvastatin are substrates of these transporters when assessed using a heterologous expression system. In an in vitro model of differentiated, primary human skeletal muscle myoblast cells, we demonstrate basal membrane expression and drug efflux activity of MRP1, which contributes to reducing intracellular statin accumulation. Furthermore, we show that expression of human OATP2B1 in human skeletal muscle myoblast cells by adenoviral vectors increases intracellular accumulation and toxicity of statins and such effects were abrogated when cells overexpressed MRP1. These results identify key membrane transporters as modulators of skeletal muscle statin exposure and toxicity.

Surgical management of patients with a history of early Le Fort III advancement after they have attained skeletal maturity.

PubMed

Caterson, E J; Shetye, Pradip R; Grayson, Barry H; McCarthy, Joseph G

2013-10-01

The classic Le Fort III procedure was recommended in syndromic craniosynostotic children to reduce exorbitism, improve airway function, and decrease dysmorphism. This study reports on a cohort of syndromic craniosynostosis patients who have undergone early primary subcranial (classic Tessier) Le Fort III advancement and who have been followed longitudinally through skeletal maturity and beyond. In this study, the Le Fort III advancements all occurred between the ages of 3 to 5 years, with a mean age of 4.6 years. Subsequently, these early Le Fort III patients were followed throughout development with longitudinal dental, medical, radiographic, and photographic evaluations conducted through skeletal maturity and beyond. For study inclusion, the patients had to have preoperative medical photographs and cephalometric studies at 6 months and 1, 5, and 10 years postoperatively after the primary Le Fort III advancement as well as cephalometric documentation 6 months and 1 year after the secondary midface advancement after skeletal maturity. After early or primary Le Fort III advancement, there was no evidence of relapse and only minimal anterior or horizontal postoperative growth of the midface. However, there was also a return of occlusal disharmony from "anticipated" mandibular growth, approaching a maximum at skeletal maturity. The dysmorphic concave facial profile and malocclusion, and airway and ocular considerations, provided the impetus for secondary midface surgery after skeletal maturity was attained. The data demonstrate that early Le Fort III advancement performed before the age of mixed dentition does not obviate the need for a secondary advancement after skeletal maturity is reached. Therapeutic, IV.

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.

Myostatin inhibition by a follistatin-derived peptide ameliorates the pathophysiology of muscular dystrophy model mice.

PubMed

Tsuchida, K

2008-07-01

Gene-targeted therapies, such as adeno-associated viral vector (AAV)-mediated gene therapy and cell-mediated therapy using myogenic stem cells, are hopeful molecular strategies for muscular dystrophy. In addition, drug therapies based on the pathophysiology of muscular dystrophy patients are desirable. Multidisciplinary approaches to drug design would offer promising therapeutic strategies. Myostatin, a member of the transforming growth factor-beta superfamily, is predominantly produced by skeletal muscle and negatively regulates the growth and differentiation of cells of the skeletal muscle lineage. Myostatin inhibition would increase the skeletal muscle mass and prevent muscle degeneration, regardless of the type of muscular dystrophy. Myostatin inhibitors include myostatin antibodies, myostatin propeptide, follistatin and follistatin-related protein. Although follistatin possesses potent myostatin-inhibiting activity, it works as an efficient inhibitor of activins. Unlike myostatin, activins regulate the growth and differentiation of nearly all cell types, including cells of the gonads, pituitary gland and skeletal muscle. We have developed a myostatin-specific inhibitor derived from follistatin, designated FS I-I. Transgenic mice expressing this myostatin-inhibiting peptide under the control of a skeletal muscle-specific promoter showed increased skeletal muscle mass and strength. mdx mice were crossed with FS I-I transgenic mice and any improvement of the pathological signs was investigated. The resulting mdx/FS I-I mice exhibited increased skeletal muscle mass and reduced cell infiltration in muscles. Muscle strength was also recovered in mdx/FS I-I mice. Our data indicate that myostatin inhibition by this follistatin-derived peptide has therapeutic potential for muscular dystrophy.

[Current validation of the Greulich and Pyle atlas for the determination of skeletal age].

PubMed

Beek, F J A

2003-04-12

The radiological atlas of Greulich and Pyle published in 1959 has been validated for the modern measurement of skeletal development in a population of white school-age children from Rotterdam. This is a useful study result. Although contemporary children grow to become much taller than in previous generations, this increased growth potential is apparently realised within the same time span.

Heat Shock Proteins Are Important Mediators of Skeletal Muscle Insulin Sensitivity

PubMed Central

Geiger, Paige C.; Gupte, Anisha A.

2013-01-01

Endogenous heat shock proteins (HSP) are decreased in disease states associated with insulin resistance and aging. Induction of HSPs has been shown to decrease oxidative stress, inhibit inflammatory pathways, and enhance metabolic characteristics in skeletal muscle. As such, HSPs have the potential to function as an important defense system against the development of insulin resistance and type 2 diabetes. PMID:21088604

Non-Lethal Weapons The Use Radiofrequency/Microwave Energy for Stunning/Immobilization

DTIC Science & Technology

2008-11-26

0.75 to 1 GHz RF fields on skeletal muscle contraction using fixed frequencies and just recently implementing frequency sweep paradigms; 4) initiation...This basic research initiative is geared ultimately toward developing effective and safe non-lethal technologies that alter skeletal muscle ... contraction and/or neural functioning via radiofrequency (RF)/microwave (MW) electromagnetic radiation. Major accomplishments included 1) near completion of

Non-Lethal Weapons for Use Rediofrequency/Microwave Energy for Stunning/Immobilization

DTIC Science & Technology

2008-11-14

of 0.75 to 1 GHz RF fields on skeletal muscle contraction using fixed frequencies and just recently implementing frequency sweep paradigms; (4...This basic research initiative is geared ultimately toward developing effective and safe non-lethal technologies that alter skeletal muscle ... contraction and/or neural functioning via radiofrequency (RF)/microwave (MW) electromagnetic radiation. Major accomplishments included: (1) near completion of

Ca2+/calmodulin-dependent transcriptional pathways: potential mediators of skeletal muscle growth and development.

PubMed

Al-Shanti, Nasser; Stewart, Claire E

2009-11-01

The loss of muscle mass with age and disuse has a significant impact on the physiological and social well-being of the aged; this is an increasingly important problem as the population becomes skewed towards older age. Exercise has psychological benefits but it also impacts on muscle protein synthesis and degradation, increasing muscle tissue volume in both young and older individuals. Skeletal muscle hypertrophy involves an increase in muscle mass and cross-sectional area and associated increased myofibrillar protein content. Attempts to understand the molecular mechanisms that underlie muscle growth, development and maintenance, have focused on characterising the molecular pathways that initiate, maintain and regenerate skeletal muscle. Such understanding may aid in improving targeted interventional therapies for age-related muscle loss and muscle wasting associated with diseases. Two major routes through which skeletal muscle development and growth are regulated are insulin-like growth factor I (IGF-I) and Ca(2+)/calmodulin-dependent transcriptional pathways. Many reviews have focused on understanding the signalling pathways of IGF-I and its receptor, which govern skeletal muscle hypertrophy. However, alternative molecular signalling pathways such as the Ca(2+)/calmodulin-dependent transcriptional pathways should also be considered as potential mediators of muscle growth. These latter pathways have received relatively little attention and the purpose herein is to highlight the progress being made in the understanding of these pathways and associated molecules: calmodulin, calmodulin kinases (CaMKs), calcineurin and nuclear factor of activated T-cell (NFAT), which are involved in skeletal muscle regulation. We describe: (1) how conformational changes in the Ca(2+) sensor calmodulin result in the exposure of binding pockets for the target proteins (CaMKs and calcineurin). (2) How Calmodulin consequently activates either the Ca(2+)/calmodulin-dependent kinases pathways (via CaMKs) or calmodulin-dependent serine/threonine phosphatases (via calcineurin). (3) How calmodulin kinases alter transcription in the nucleus through the phosphorylation, deactivation and translocation of histone deacetylase 4 (HDAC4) from the nucleus to the cytoplasm. (4) How calcineurin transmits signals to the nucleus through the dephosphorylation and translocation of NFAT from the cytoplasm to the nucleus.

Longitudinal study of the effects of chronic hypothyroidism on skeletal muscle in dogs.

PubMed

Rossmeisl, John H; Duncan, Robert B; Inzana, Karen D; Panciera, David L; Shelton, G Diane

2009-07-01

To study the effects of experimentally induced hypothyroidism on skeletal muscle and characterize any observed myopathic abnormalities in dogs. 9 female, adult mixed-breed dogs; 6 with hypothyroidism induced with irradiation with 131 iodine and 3 untreated control dogs. Clinical examinations were performed monthly. Electromyographic examinations; measurement of plasma creatine kinase, alanine aminotransferase, aspartate aminotransferase, lactate, and lactate dehydrogenase isoenzyme activities; and skeletal muscle morphologic-morphometric examinations were performed prior to and every 6 months for 18 months after induction of hypothyroidism. Baseline, 6-month, and 18-month assessments of plasma, urine, and skeletal muscle carnitine concentrations were also performed. Hypothyroid dogs developed electromyographic and morphologic evidence of myopathy by 6 months after treatment, which persisted throughout the study, although these changes were subclinical at all times. Hypothyroid myopathy was associated with significant increases in plasma creatine kinase, aspartate aminotransferase, and lactate dehydrogenase 5 isoenzyme activities and was characterized by nemaline rod inclusions, substantial and progressive predominance of type I myofibers, decrease in mean type II fiber area, subsarcolemmal accumulations of abnormal mitochondria, and myofiber degeneration. Chronic hypothyroidism was associated with substantial depletion in skeletal muscle free carnitine. Chronic, experimentally induced hypothyroidism resulted in substantial but subclinical phenotypic myopathic changes indicative of altered muscle energy metabolism and depletion of skeletal muscle carnitine. These abnormalities may contribute to nonspecific clinical signs, such as lethargy and exercise intolerance, often reported in hypothyroid dogs.

Protein kinase N2 regulates AMP kinase signaling and insulin responsiveness of glucose metabolism in skeletal muscle.

PubMed

Ruby, Maxwell A; Riedl, Isabelle; Massart, Julie; Åhlin, Marcus; Zierath, Juleen R

2017-10-01

Insulin resistance is central to the development of type 2 diabetes and related metabolic disorders. Because skeletal muscle is responsible for the majority of whole body insulin-stimulated glucose uptake, regulation of glucose metabolism in this tissue is of particular importance. Although Rho GTPases and many of their affecters influence skeletal muscle metabolism, there is a paucity of information on the protein kinase N (PKN) family of serine/threonine protein kinases. We investigated the impact of PKN2 on insulin signaling and glucose metabolism in primary human skeletal muscle cells in vitro and mouse tibialis anterior muscle in vivo. PKN2 knockdown in vitro decreased insulin-stimulated glucose uptake, incorporation into glycogen, and oxidation. PKN2 siRNA increased 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling while stimulating fatty acid oxidation and incorporation into triglycerides and decreasing protein synthesis. At the transcriptional level, PKN2 knockdown increased expression of PGC-1α and SREBP-1c and their target genes. In mature skeletal muscle, in vivo PKN2 knockdown decreased glucose uptake and increased AMPK phosphorylation. Thus, PKN2 alters key signaling pathways and transcriptional networks to regulate glucose and lipid metabolism. Identification of PKN2 as a novel regulator of insulin and AMPK signaling may provide an avenue for manipulation of skeletal muscle metabolism. Copyright © 2017 the American Physiological Society.

Role of inhibition of osteogenesis function by Sema4D/Plexin-B1 signaling pathway in skeletal fluorosis in vitro.

PubMed

Liu, Xiao-li; Song, Jing; Liu, Ke-jian; Wang, Wen-peng; Xu, Chang; Zhang, Yu-zeng; Liu, Yun

2015-10-01

Skeletal fluorosis is a chronically metabolic bone disease with extensive hyperostosis osteosclerosis caused by long time exposure to fluoride. Skeletal fluorosis brings about a series of abnormal changes of the extremity, such as joint pain, joint stiffness, bone deformity, etc. Differentiation and maturation of osteoblasts were regulated by osteoclasts via Sema4D/Plexin-B1 signaling pathway. Furthermore, the differentiation and maturation of osteoclasts are conducted by osteoblasts via RANKL/RANK/OPG pathway. Both of these processes form a feedback circuit which is a key link in skeletal fluorosis. In this study, an osteoblast-osteoclast co-culture model in vitro was developed to illustrate the mechanism of skeletal fluorosis. With the increase of fluoride concentration, the expression level of Sema4D was decreased and TGF-β1 was increased continuously. OPG/RANKL mRNA level, however, increased gradually. On the basis of that, the inhibition of Sema4D/Plexin-B1/RhoA/ROCK signaling pathway caused by fluoride promoted the level of TGF-β1 and activated the proliferation of osteoblasts. In addition, osteroprotegerin (OPG) secreted by osteoblasts was up-regulated by fluoride. The competitive combination of OPG and RANKL was strengthened and the combination of RANKL and RANK was hindered. And then the differentiation and maturation of osteoclasts were inhibited, and bone absorption was weakened, leading to skeletal fluorosis.

Dentofacial transverse development in Koreans according to skeletal maturation: A cross-sectional study.

PubMed

Hwang, Soonshin; Noh, Yoonjeong; Choi, Yoon Jeong; Chung, Chooryung; Lee, Hye Sun; Kim, Kyung-Ho

2018-01-01

The aim of this study was to establish the normative data of dentofacial transverse dimensions according to the skeletal maturation stage in Korean adolescents with good occlusion, assess gender differences and determine correlations between transverse variables. A total of 577 Korean subjects between ages 7 to 19 years and exhibiting skeletal Class I occlusion were categorized by skeletal maturation index (SMI) of Fishman using hand-wrist radiographs. Dentofacial transverse dimensions were assessed using posteroanterior cephalograms. Independent two-sample t -tests were used to analyze differences between genders. Pearson correlation coefficient was used to determine the correlation between transverse measurements. Dentofacial transverse norms relevant to skeletal maturation stages were established. The average maxillomandibular width difference and ratio at growth completion was 22.16 mm and 77.01% for males; 23.70 mm and 74.06% for females, respectively. Males had greater facial, maxillary and mandibular widths compared to females at every SMI stage. The maxillary and mandibular intermolar widths showed the strongest correlation for both sexes (r = 0.826 for males, r = 0.725 for females). Dentofacial transverse norms of Korean adolescents were established according to developmental stage. All dentofacial widths were greater in males at growth completion. Maxillary and mandibular intermolar widths were strongly correlated. This study may serve as a guideline for the assessment of dentofacial transverse growth according to skeletal maturation stage in Korean adolescents with good occlusion.

Mesodermal iPSC–derived progenitor cells functionally regenerate cardiac and skeletal muscle

PubMed Central

Quattrocelli, Mattia; Swinnen, Melissa; Giacomazzi, Giorgia; Camps, Jordi; Barthélemy, Ines; Ceccarelli, Gabriele; Caluwé, Ellen; Grosemans, Hanne; Thorrez, Lieven; Pelizzo, Gloria; Muijtjens, Manja; Verfaillie, Catherine M.; Blot, Stephane; Janssens, Stefan; Sampaolesi, Maurilio

2015-01-01

Conditions such as muscular dystrophies (MDs) that affect both cardiac and skeletal muscles would benefit from therapeutic strategies that enable regeneration of both of these striated muscle types. Protocols have been developed to promote induced pluripotent stem cells (iPSCs) to differentiate toward cardiac or skeletal muscle; however, there are currently no strategies to simultaneously target both muscle types. Tissues exhibit specific epigenetic alterations; therefore, source-related lineage biases have the potential to improve iPSC-driven multilineage differentiation. Here, we determined that differential myogenic propensity influences the commitment of isogenic iPSCs and a specifically isolated pool of mesodermal iPSC-derived progenitors (MiPs) toward the striated muscle lineages. Differential myogenic propensity did not influence pluripotency, but did selectively enhance chimerism of MiP-derived tissue in both fetal and adult skeletal muscle. When injected into dystrophic mice, MiPs engrafted and repaired both skeletal and cardiac muscle, reducing functional defects. Similarly, engraftment into dystrophic mice of canine MiPs from dystrophic dogs that had undergone TALEN-mediated correction of the MD-associated mutation also resulted in functional striatal muscle regeneration. Moreover, human MiPs exhibited the same capacity for the dual differentiation observed in murine and canine MiPs. The findings of this study suggest that MiPs should be further explored for combined therapy of cardiac and skeletal muscles. PMID:26571398

Treatment with the anti-IL-6 receptor antibody attenuates muscular dystrophy via promoting skeletal muscle regeneration in dystrophin-/utrophin-deficient mice.

PubMed

Wada, Eiji; Tanihata, Jun; Iwamura, Akira; Takeda, Shin'ichi; Hayashi, Yukiko K; Matsuda, Ryoichi

2017-10-27

Chronic increases in the levels of the inflammatory cytokine interleukin-6 (IL-6) in serum and skeletal muscle are thought to contribute to the progression of muscular dystrophy. Dystrophin/utrophin double-knockout (dKO) mice develop a more severe and progressive muscular dystrophy than the mdx mice, the most common murine model of Duchenne muscular dystrophy (DMD). In particular, dKO mice have smaller body sizes and muscle diameters, and develop progressive kyphosis and fibrosis in skeletal and cardiac muscles. As mdx mice and DMD patients, we found that IL-6 levels in the skeletal muscle were significantly increased in dKO mice. Thus, in this study, we aimed to analyze the effects of IL-6 receptor (IL-6R) blockade on the muscle pathology of dKO mice. Male dKO mice were administered an initial injection (200 mg/kg intraperitoneally (i.p.)) of either the anti-IL-6R antibody MR16-1 or an isotype-matched control rat IgG at the age of 14 days, and were then given weekly injections (25 mg/kg i.p.) until 90 days of age. Treatment of dKO mice with the MR16-1 antibody successfully inhibited the IL-6 pathway in the skeletal muscle and resulted in a significant reduction in the expression levels of phosphorylated signal transducer and activator of transcription 3 in the skeletal muscle. Pathologically, a significant increase in the area of embryonic myosin heavy chain-positive myofibers and muscle diameter, and reduced fibrosis in the quadriceps muscle were observed. These results demonstrated the therapeutic effects of IL-6R blockade on promoting muscle regeneration. Consistently, serum creatine kinase levels were decreased. Despite these improvements observed in the limb muscles, degeneration of the diaphragm and cardiac muscles was not ameliorated by the treatment of mice with the MR16-1 antibody. As no adverse effects of treatment with the MR16-1 antibody were observed, our results indicate that the anti-IL-6R antibody is a potential therapy for muscular dystrophy particularly for promoting skeletal muscle regeneration.

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

Bone mineral density, chemical composition and biomechanical properties of the tibia of female rats exposed to cadmium since weaning up to skeletal maturity.

PubMed

Brzóska, M M; Majewska, K; Moniuszko-Jakoniuk, J

2005-10-01

The influence of exposure to cadmium (Cd) during skeletal development on the risk of bone fractures at the stage of skeletal maturity was investigated on a female rat model of human exposure. The tibias of rats treated with 1, 5 or 50 mg Cd/l in drinking water for 3, 6, 9 and 12 months (since weaning) were used. The exposure to Cd dose- and time-dependently influenced the tibia bone mineral density (BMD) and chemical composition. In skeletally matured animals, at each level of the exposure to Cd, the BMD at the whole tibia and its diaphysis as well as the percentage of minerals content in the bone, including the content of zinc, copper and iron, were decreased compared to control. Moreover, in the 50 mg Cd/l group, the percentage of organic components content increased. The Cd-induced changes, at all levels of exposure, resulted in weakening in the yield strength and fracture strength of the tibia (a three-point bending test of the diaphysis and compression test with vertical loading) of the skeletally matured females. A very important and clinically useful finding of this study is that a decrease (even by several percent) in the tibia BMD results in weakness in the bone biomechanical properties and that the BMD may predict the risk of its fracture at the exposure to Cd. Moreover, the results together with our previous findings seem to suggest that tibia, due to higher vulnerability of its diaphysis, compared to the femoral diaphysis, to damage by Cd may be more useful than femur to investigate the effect of Cd on the cortical bone. The present study revealed that a low exposure to Cd (1 mg Cd/l), corresponding to low human environmental exposure, during the skeletal development affects the tibia mineral status leading to weakening in its mechanical properties at the skeletal maturity. The findings allow for the conclusion that environmental exposure to Cd during childhood and adolescence may enhance the risk of low BMD and fractures at adulthood.

[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.

M-cadherin and its sisters in development of striated muscle.

PubMed

Kaufmann, U; Martin, B; Link, D; Witt, K; Zeitler, R; Reinhard, S; Starzinski-Powitz, A

1999-04-01

Cadherins are calcium-dependent, transmembrane intercellular adhesion proteins with morphoregulatory functions in the development and maintenance of tissues. In the development of striated muscle, the expression and function of mainly M-, N-, and R-cadherin has been studied so far. While these three cadherins are expressed in skeletal muscle cells, of these only N-cadherin is expressed in cardiac muscle. In this review, M-, N-, and R-cadherin are discussed as important players in the terminal differentiation and possibly also in the commitment of skeletal muscle cells. Furthermore, reports are described which evaluate the essential role of N-cadherin in the formation of heart tissue.

An eye on the head: the development and evolution of craniofacial muscles.

PubMed

Sambasivan, Ramkumar; Kuratani, Shigeru; Tajbakhsh, Shahragim

2011-06-01

Skeletal muscles exert diverse functions, enabling both crushing with great force and movement with exquisite precision. A remarkably distinct repertoire of genes and ontological features characterise this tissue, and recent evidence has shown that skeletal muscles of the head, the craniofacial muscles, are evolutionarily, morphologically and molecularly distinct from those of the trunk. Here, we review the molecular basis of craniofacial muscle development and discuss how this process is different to trunk and limb muscle development. Through evolutionary comparisons of primitive chordates (such as amphioxus) and jawless vertebrates (such as lampreys) with jawed vertebrates, we also provide some clues as to how this dichotomy arose.

Treatment of inherently unstable open or infected fractures by open wound management and external skeletal fixation.

PubMed

Ness, M G

2006-02-01

To assess the use of external skeletal fixation with open wound management for the treatment of inherently unstable open or infected fractures in dogs. A retrospective review of 10 cases. Fracture stabilisation and wound management required only a single anaesthetic, and despite the challenging nature of these injuries, the final outcome was acceptable or good in every case. However, minor complications associated with the fixator pins were quite common, and two dogs developed complications which required additional surgery. Open management of wounds, even when bone was exposed, proved to be an effective technique, and external skeletal fixators were usually effective at maintaining stability throughout an inevitably extended fracture healing period.

Skeletal Metabolism, Fracture Risk, and Fracture Outcomes in Type 1 and Type 2 Diabetes

PubMed Central

Civitelli, Roberto; Hofbauer, Lorenz C.; Khosla, Sundeep; Lecka-Czernik, Beata; Schwartz, Ann V.

2016-01-01

Fracture risk is significantly increased in both type 1 and type 2 diabetes, and individuals with diabetes experience worse fracture outcomes than normoglycemic individuals. Factors that increase fracture risk include lower bone mass in type 1 diabetes and compromised skeletal quality and strength despite preserved bone density in type 2 diabetes, as well as the effects of comorbidities such as diabetic macro- and microvascular complications. In this Perspective, we assess the developing scientific knowledge regarding the epidemiology and pathophysiology of skeletal fragility in patients with diabetes and the emerging data on the prediction, treatment, and outcomes of fractures in individuals with type 1 and type 2 diabetes. PMID:27329951

cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration

PubMed Central

Stewart, Randi

2012-01-01

Among organ systems, skeletal muscle is perhaps the most structurally specialized. The remarkable subcellular architecture of this tissue allows it to empower movement with instructions from motor neurons. Despite this high degree of specialization, skeletal muscle also has intrinsic signaling mechanisms that allow adaptation to long-term changes in demand and regeneration after acute damage. The second messenger adenosine 3′,5′-monophosphate (cAMP) not only elicits acute changes within myofibers during exercise but also contributes to myofiber size and metabolic phenotype in the long term. Strikingly, sustained activation of cAMP signaling leads to pronounced hypertrophic responses in skeletal myofibers through largely elusive molecular mechanisms. These pathways can promote hypertrophy and combat atrophy in animal models of disorders including muscular dystrophy, age-related atrophy, denervation injury, disuse atrophy, cancer cachexia, and sepsis. cAMP also participates in muscle development and regeneration mediated by muscle precursor cells; thus, downstream signaling pathways may potentially be harnessed to promote muscle regeneration in patients with acute damage or muscular dystrophy. In this review, we summarize studies implicating cAMP signaling in skeletal muscle adaptation. We also highlight ligands that induce cAMP signaling and downstream effectors that are promising pharmacological targets. PMID:22354781

Use of mRNA expression signatures to discover small molecule inhibitors of skeletal muscle atrophy

PubMed Central

Adams, Christopher M.; Ebert, Scott M.; Dyle, Michael C.

2017-01-01

Purpose of review Here, we discuss a recently developed experimental strategy for discovering small molecules with potential to prevent and treat skeletal muscle atrophy. Recent findings Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression, which generate complex but measurable patterns of positive and negative changes in skeletal muscle mRNA levels (a.k.a. mRNA expression signatures of muscle atrophy). Many bioactive small molecules generate their own characteristic mRNA expression signatures, and by identifying small molecules whose signatures approximate mirror images of muscle atrophy signatures, one may identify small molecules with potential to prevent and/or reverse muscle atrophy. Unlike a conventional drug discovery approach, this strategy does not rely on a predefined molecular target but rather exploits the complexity of muscle atrophy to identify small molecules that counter the entire spectrum of pathological changes in atrophic muscle. We discuss how this strategy has been used to identify two natural compounds, ursolic acid and tomatidine, that reduce muscle atrophy and improve skeletal muscle function. Summary Discovery strategies based on mRNA expression signatures can elucidate new approaches for preserving and restoring muscle mass and function. PMID:25807353

Use of mRNA expression signatures to discover small molecule inhibitors of skeletal muscle atrophy.

PubMed

Adams, Christopher M; Ebert, Scott M; Dyle, Michael C

2015-05-01

Here, we discuss a recently developed experimental strategy for discovering small molecules with potential to prevent and treat skeletal muscle atrophy. Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression, which generate complex but measurable patterns of positive and negative changes in skeletal muscle mRNA levels (a.k.a. mRNA expression signatures of muscle atrophy). Many bioactive small molecules generate their own characteristic mRNA expression signatures, and by identifying small molecules whose signatures approximate mirror images of muscle atrophy signatures, one may identify small molecules with potential to prevent and/or reverse muscle atrophy. Unlike a conventional drug discovery approach, this strategy does not rely on a predefined molecular target but rather exploits the complexity of muscle atrophy to identify small molecules that counter the entire spectrum of pathological changes in atrophic muscle. We discuss how this strategy has been used to identify two natural compounds, ursolic acid and tomatidine, that reduce muscle atrophy and improve skeletal muscle function. Discovery strategies based on mRNA expression signatures can elucidate new approaches for preserving and restoring muscle mass and function.

Mutations in the Neuroblastoma Amplified Sequence gene in a family affected by Acrofrontofacionasal Dysostosis type 1.

PubMed

Palagano, Eleonora; Zuccarini, Giulia; Prontera, Paolo; Borgatti, Renato; Stangoni, Gabriela; Elisei, Sandro; Mantero, Stefano; Menale, Ciro; Forlino, Antonella; Uva, Paolo; Oppo, Manuela; Vezzoni, Paolo; Villa, Anna; Merlo, Giorgio R; Sobacchi, Cristina

2018-06-19

Acrofrontofacionasal Dysostosis type 1 (AFFND1) is an extremely rare, autosomal recessive syndrome, comprising facial and skeletal abnormalities, short stature and intellectual disability. We analyzed an Indian family with two affected siblings by exome sequencing and identified a novel homozygous truncating mutation in the Neuroblastoma-Amplified Sequence (NBAS) gene in the patients' genome. Mutations in the NBAS gene have recently been associated with different phenotypes mainly involving skeletal formation, liver and cognitive development. The NBAS protein has been implicated in two key cellular processes, namely the non-sense mediated decay and the Golgi-to-Endoplasmic Reticulum retrograde traffic. Both functions were impaired in HEK293T cells overexpressing the truncated NBAS protein, as assessed by Real-Time PCR, Western blot analysis, co-immunoprecipitation, and immunofluorescence analysis. We examined the expression of NBAS protein in mouse embryos at various developmental stages by immunohistochemistry, and detected expression in developing chondrogenic and osteogenic structures of the skeleton as well as in the cortex, hippocampus and cerebellum, which is compatible with a role in bone and brain development. Functional genetics in the zebrafish model showed that depletion of endogenous z-nbas in fish embryos results in defective morphogenesis of chondrogenic cranial skeletal elements. Overall, our data point to a conserved function of NBAS in skeletal morphogenesis during development, support the hypothesis of a causative role of the mutated NBAS gene in the pathogenesis of AFFND1 and extend the spectrum of phenotypes associated with defects in this gene. Copyright © 2018 Elsevier Inc. All rights reserved.

Dental and skeletal maturation in female adolescents with temporomandibular joint osteoarthritis.

PubMed

Kang, J-H; Yang, I-H; Hyun, H-K; Lee, J-Y

2017-11-01

Occurrence of temporomandibular disorders (TMDs) and temporomandibular joint (TMJ) osteoarthritis (OA) during adolescence may have interactions with mandibular and dental development. The aim of the present study was to investigate relationships between occurrence of TMD and TMJ OA and extents of dental and skeletal development in juvenile female patients. In total, 95 female adolescents (age range, 11-15 years) were selected. Among them, 15 subjects (control) had no signs of TMD, 39 TMD patients did not have OA (TMDnoOA), 17 TMD patients were at initial stage of TMJ OA (TMJOA), and 27 patients showed progressive stage of TMJ OA (TMJOA). Dental age was estimated by Demirjian's stages used in a previous study with Korean adolescents. Craniofacial parameters and cervical vertebrae maturation (CVM) stages, representing skeletal maturity levels, were measured using lateral cephalograms. The estimated dental age was significantly lower than chronological age in all groups, but CVM differences were not statistically significant. Dental age was the lowest, and differences between the chronological age and estimated dental age were the highest among initial stage of TMJOAs followed by progressive stage of TMJOAs, TMDnoOAs and control and were not associated with CVM stages. Cephalometric parameters revealed significant clockwise rotation of the mandible among the TMJOAs compared with controls and TMDnoOAs and were not associated with CVM stages as well. The juvenile female patients with TMD, particularly TMJ OA, showed retarded dental development, mandibular backward positioning and hyperdivergent facial profiles. The TMJ OA may be associated with retarded dental development but not with skeletal maturations. © 2017 John Wiley & Sons Ltd.

Creating Interactions between Tissue-Engineered Skeletal Muscle and the Peripheral Nervous System.

PubMed

Smith, Alec S T; Passey, Samantha L; Martin, Neil R W; Player, Darren J; Mudera, Vivek; Greensmith, Linda; Lewis, Mark P

2016-01-01

Effective models of mammalian tissues must allow and encourage physiologically (mimetic) correct interactions between co-cultured cell types in order to produce culture microenvironments as similar as possible to those that would normally occur in vivo. In the case of skeletal muscle, the development of such a culture model, integrating multiple relevant cell types within a biomimetic scaffold, would be of significant benefit for investigations into the development, functional performance, and pathophysiology of skeletal muscle tissue. Although some work has been published regarding the behaviour of in vitro muscle models co-cultured with organotypic slices of CNS tissue or with stem cell-derived neurospheres, little investigation has so far been made regarding the potential to maintain isolated motor neurons within a 3D biomimetic skeletal muscle culture platform. Here, we review the current state of the art for engineering neuromuscular contacts in vitro and provide original data detailing the development of a 3D collagen-based model for the co-culture of primary muscle cells and motor neurons. The devised culture system promotes increased myoblast differentiation, forming arrays of parallel, aligned myotubes on which areas of nerve-muscle contact can be detected by immunostaining for pre- and post-synaptic proteins. Quantitative RT-PCR results indicate that motor neuron presence has a positive effect on myotube maturation, suggesting neural incorporation influences muscle development and maturation in vitro. The importance of this work is discussed in relation to other published neuromuscular co-culture platforms along with possible future directions for the field. © 2016 S. Karger AG, Basel.

Exposure to a PBDE/OH-BDE mixture alters juvenile zebrafish (Danio rerio) development

PubMed Central

Macaulay, Laura J.; Chernick, Melissa; Chen, Albert; Hinton, David E.; Bailey, Jordan M.; Kullman, Seth W.; Levin, Edward D.; Stapleton, Heather M.

2017-01-01

Polybrominated diphenyl ethers (PBDEs) and halogenated phenolic compounds (e.g., hydroxylated BDEs (OH-BDEs)) arecontaminants detected together frequently in human tissues, and are structurally similar to thyroid hormones (TH). THs partially mediate metamorphic transitions between life stages in zebrafish, making this a critical developmental window which may be uniquely vulnerable to chemicals disrupting thyroid signaling. In this study, zebrafish were exposed to 6-OH-BDE-47 (30 nM) alone or to a low (30 μg/L) or high dose (600 μg/L) mixture of PentaBDEs, 6-OH-BDE-47 (0.5–6 μg/L), & 2,4,6 tribromophenol (TBP) (5–100 μg/L) during juvenile development (9–23 days post fertilization; dpf) and evaluated for developmental endpoints mediated by TH signaling. Fish were sampled at three time points and examined for developmental and skeletal morphology, apical thyroid and skeletal gene markers, and modifications in swimming behavior (as adults). Exposure to the high mixture resulted in > 85% mortality within one week of exposure, despite being below reported acute toxicity thresholds for individual congeners. The low mixture and 6-OH-BDE-47 groups exhibited reductions in body length and delayed maturation, specifically relating to swim bladder,?, fin, and pigmentation development. Reduced skeletal ossification was also observed in 6-OH-BDE-47 treated fish. Assessment of thyroid and osteochondral gene regulatory networks demonstrated significantly increased expression of genes that regulate skeletal development and THs. Overall, these results indicate that exposures to PBDEs/OH-BDEs mixtures adversely impact zebrafish maturation during metamorphosis. PMID:27329031

Incidence of hypocalcemia in patients receiving denosumab for prevention of skeletal-related events in bone metastasis.

PubMed

Yerram, Prakirthi; Kansagra, Shraddha; Abdelghany, Osama

2017-04-01

Background Denosumab therapy is commonly used for the prevention of skeletal-related events in patients with bone metastasis. However, a common side effect of denosumab is hypocalcemia. Objective The aim of the study is to determine the incidence of hypocalcemia in patients receiving denosumab for prevention of skeletal-related events in bone metastasis and evaluate risk factors for developing hypocalcemia. Methods This was a retrospective medication use evaluation reviewing the incidence of hypocalcemia in patients receiving outpatient denosumab for prevention of skeletal-related events at Yale-New Haven Hospital. Additionally, various risk factors were reviewed to determine their risk of developing hypocalcemia. Results As per Common Terminology Criteria for Adverse Events v4.03, of the 106 patients included in the study population, 37 (35%) patients had an incidence of hypocalcemia within 30 days of denosumab administration. Fourteen patients (13.2%) had an incidence of grade 1, 13 patients (12.3%) had an incidence of grade 2 hypocalcemia, and 7 patients (6.6%) had an incidence of grade 3 hypocalcemia. Grade 4 hypocalcemia occurred in three (2.8%) patients. Calcium supplementation did not decrease the risk of developing hypocalcemia. Patients who had one or more episodes of acute kidney insufficiency were at a higher risk of developing hypocalcemia (odds ratio = 7.5 (95% confidence interval = 1.8-36.3), p = 0.001). Conclusion This study found that the overall incidence of hypocalcemia and severe hypocalcemia was higher than reported in clinical trials. Additionally, calcium supplementation did not have an effect on incidence of hypocalcemia, while patients who experienced acute kidney insufficiency while on denosumab had a higher likelihood of developing hypocalcemia.

Muscle Attenuation Is Associated With Newly Developed Hypertension in Men of African Ancestry.

PubMed

Zhao, Qian; Zmuda, Joseph M; Kuipers, Allison L; Bunker, Clareann H; Patrick, Alan L; Youk, Ada O; Miljkovic, Iva

2017-05-01

Increased ectopic adipose tissue infiltration in skeletal muscle is associated with insulin resistance and diabetes mellitus. We evaluated whether change in skeletal muscle adiposity predicts subsequent development of hypertension in men of African ancestry, a population sample understudied in previous studies. In the Tobago Health Study, a prospective longitudinal study among men of African ancestry (age range 40-91 years), calf intermuscular adipose tissue, and skeletal muscle attenuation were measured with computed tomography. Hypertension was defined as a systolic blood pressure ≥140 mm Hg, or a diastolic blood pressure ≥90 mm Hg, or receiving antihypertensive medications. Logistic regression was performed with adjustment for age, insulin resistance, baseline and 6-year change in body mass index, baseline and 6-year change in waist circumference, and other potential confounding factors. Among 746 normotensive men at baseline, 321 (43%) developed hypertension during the mean 6.2 years of follow-up. Decreased skeletal muscle attenuation was associated with newly developed hypertension after adjustment for baseline and 6-year change of body mass index (odds ratio [95% confidence interval] per SD, 1.3 [1.0-1.6]) or baseline and 6-year change of waist circumference (odds ratio [95% confidence interval] per SD, 1.3 [1.0-1.6]). No association was observed between increased intermuscular adipose tissue and hypertension. Our novel findings show that decreased muscle attenuation is associated with newly developed hypertension among men of African ancestry, independent of general and central adiposity and insulin resistance. Further studies are needed to adjust for inflammation, visceral and other ectopic adipose tissue depots, and to confirm our findings in other population samples. © 2017 American Heart Association, Inc.

Coordinated development of the limb musculoskeletal system: Tendon and muscle patterning and integration with the skeleton.

PubMed

Huang, Alice H

2017-09-15

Functional movement and stability of the limb depends on an organized and fully integrated musculoskeletal system composed of skeleton, muscle, and tendon. Much of our current understanding of musculoskeletal development is based on studies that focused on the development and differentiation of individual tissues. Likewise, research on patterning events have been largely limited to the primary skeletal elements and the mechanisms that regulate soft tissue patterning, the development of the connections between tissues, and their interdependent development are only beginning to be elucidated. This review will therefore highlight recent exciting discoveries in this field, with an emphasis on tendon and muscle patterning and their integrated development with the skeleton and skeletal attachments. Copyright © 2017 Elsevier Inc. 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

Role of Thyroid Hormones in Skeletal Development and Bone Maintenance

PubMed Central

Bassett, J. H. Duncan

2016-01-01

The skeleton is an exquisitely sensitive and archetypal T3-target tissue that demonstrates the critical role for thyroid hormones during development, linear growth, and adult bone turnover and maintenance. Thyrotoxicosis is an established cause of secondary osteoporosis, and abnormal thyroid hormone signaling has recently been identified as a novel risk factor for osteoarthritis. Skeletal phenotypes in genetically modified mice have faithfully reproduced genetic disorders in humans, revealing the complex physiological relationship between centrally regulated thyroid status and the peripheral actions of thyroid hormones. Studies in mutant mice also established the paradigm that T3 exerts anabolic actions during growth and catabolic effects on adult bone. Thus, the skeleton represents an ideal physiological system in which to characterize thyroid hormone transport, metabolism, and action during development and adulthood and in response to injury. Future analysis of T3 action in individual skeletal cell lineages will provide new insights into cell-specific molecular mechanisms and may ultimately identify novel therapeutic targets for chronic degenerative diseases such as osteoporosis and osteoarthritis. This review provides a comprehensive analysis of the current state of the art. PMID:26862888

Identification of a distant cis-regulatory element controlling pharyngeal arch-specific expression of zebrafish gdf6a/radar

PubMed Central

Reed, Nykolaus P.; Mortlock, Douglas P.

2011-01-01

Skeletal formation is an essential and intricately regulated part of vertebrate development. Humans and mice deficient in Growth and Differentiation Factor 6 (Gdf6) have numerous skeletal abnormalities including joint fusions and cartilage reductions. The expression of Gdf6 is dynamic and in part regulated by distant evolutionarily conserved cis-regulatory elements. radar/gdf6a is a zebrafish ortholog of Gdf6 and has an essential role in embryonic patterning. Here we show that radar is transcribed in the cells surrounding and between the developing cartilages of the ventral pharyngeal arches, similar to mouse Gdf6. A 312 bp evolutionarily conserved region (ECR5), 122 kilobases downstream, drives expression in a pharyngeal arch-specific manner similar to endogenous radar/gdf6a. Deletion analysis identified a 78 bp region within ECR5 that is essential for transgene activity. This work illustrates that radar is regulated in the pharyngeal arches by a distant conserved element and suggests radar has similar functions in skeletal development in fish and mammals. PMID:20201106

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

Telomere correlations during early life in a long-lived seabird.

PubMed

Schmidt, Jacob E; Sirman, Aubrey E; Kittilson, Jeffrey D; Clark, Mark E; Reed, Wendy L; Heidinger, Britt J

2016-12-01

Telomere dynamics in blood cells have been linked to aging in a variety of organisms. However, whether blood telomeres are correlated with telomeres in other parts of the body is not well known, especially during early life when telomere loss is expected to be most rapid. We investigated this question in Franklin's gulls (Leucophaeus pipixcan) by measuring telomere lengths in blood and several other tissues including: heart, liver, and skeletal muscle at the end of embryonic (n=31) and post-natal development (n=20). In late-stage embryos, blood telomeres were significantly positively correlated with heart and skeletal muscle, but not liver telomeres. However, at the end of post-natal development, there were no significant correlations among blood telomeres and telomeres in any other tissues. In late-stage embryos, heart telomeres were significantly longer than blood, liver, and skeletal muscle telomeres, but at the end of post-natal development telomere lengths did not significantly differ among tissues. These results suggest that blood telomere length is not necessarily indicative of other tissues at all stages of development and highlights the importance of understanding any functional consequences of tissue specific telomere dynamics in early life. Copyright © 2016 Elsevier Inc. All rights reserved.

Three-Dimensional Culture Model of Skeletal Muscle Tissue with Atrophy Induced by Dexamethasone.

PubMed

Shimizu, Kazunori; Genma, Riho; Gotou, Yuuki; Nagasaka, Sumire; Honda, Hiroyuki

2017-06-15

Drug screening systems for muscle atrophy based on the contractile force of cultured skeletal muscle tissues are required for the development of preventive or therapeutic drugs for atrophy. This study aims to develop a muscle atrophy model by inducing atrophy in normal muscle tissues constructed on microdevices capable of measuring the contractile force and to verify if this model is suitable for drug screening using the contractile force as an index. Tissue engineered skeletal muscles containing striated myotubes were prepared on the microdevices for the study. The addition of 100 µM dexamethasone (Dex), which is used as a muscle atrophy inducer, for 24 h reduced the contractile force significantly. An increase in the expression of Atrogin-1 and MuRF-1 in the tissues treated with Dex was established. A decrease in the number of striated myotubes was also observed in the tissues treated with Dex. Treatment with 8 ng/mL Insulin-like Growth Factor (IGF-I) for 24 h significantly increased the contractile force of the Dex-induced atrophic tissues. The same treatment, though, had no impact on the force of the normal tissues. Thus, it is envisaged that the atrophic skeletal muscle tissues induced by Dex can be used for drug screening against atrophy.

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

Three-Dimensional Culture Model of Skeletal Muscle Tissue with Atrophy Induced by Dexamethasone

PubMed Central

Shimizu, Kazunori; Genma, Riho; Gotou, Yuuki; Nagasaka, Sumire; Honda, Hiroyuki

2017-01-01

Drug screening systems for muscle atrophy based on the contractile force of cultured skeletal muscle tissues are required for the development of preventive or therapeutic drugs for atrophy. This study aims to develop a muscle atrophy model by inducing atrophy in normal muscle tissues constructed on microdevices capable of measuring the contractile force and to verify if this model is suitable for drug screening using the contractile force as an index. Tissue engineered skeletal muscles containing striated myotubes were prepared on the microdevices for the study. The addition of 100 µM dexamethasone (Dex), which is used as a muscle atrophy inducer, for 24 h reduced the contractile force significantly. An increase in the expression of Atrogin-1 and MuRF-1 in the tissues treated with Dex was established. A decrease in the number of striated myotubes was also observed in the tissues treated with Dex. Treatment with 8 ng/mL Insulin-like Growth Factor (IGF-I) for 24 h significantly increased the contractile force of the Dex-induced atrophic tissues. The same treatment, though, had no impact on the force of the normal tissues. Thus, it is envisaged that the atrophic skeletal muscle tissues induced by Dex can be used for drug screening against atrophy. PMID:28952535

Assessing the skeletal age from a hand radiograph: automating the Tanner-Whitehouse method

NASA Astrophysics Data System (ADS)

Niemeijer, Meindert; van Ginneken, Bram; Maas, Casper A.; Beek, Frederik J. A.; Viergever, Max A.

2003-05-01

The skeletal maturity of children is usually assessed from a standard radiograph of the left hand and wrist. An established clinical method to determine the skeletal maturity is the Tanner-Whitehouse (TW2) method. This method divides the skeletal development into several stages (labelled A, B, ...,I). We are developing an automated system based on this method. In this work we focus on assigning a stage to one region of interest (ROI), the middle phalanx of the third finger. We classify each ROI as follows. A number of ROIs which have been assigned a certain stage by a radiologist are used to construct a mean image for that stage. For a new input ROI, landmarks are detected by using an Active Shape Model. These are used to align the mean images with the input image. Subsequently the correlation between each transformed mean stage image and the input is calculated. The input ROI can be assigned to the stage with the highest correlation directly, or the values can be used as features in a classifier. The method was tested on 71 cases ranging from stage E to I. The ROI was staged correctly in 73.2% of all cases and in 97.2% of all incorrectly staged cases the error was not more than one stage.

Harnessing Sphingosine-1-Phosphate Signaling and Nanotopographical Cues To Regulate Skeletal Muscle Maturation and Vascularization.

PubMed

Tsui, Jonathan H; Janebodin, Kajohnkiart; Ieronimakis, Nicholas; Yama, David M P; Yang, Hee Seok; Chavanachat, Rakchanok; Hays, Aislinn L; Lee, Haeshin; Reyes, Morayma; Kim, Deok-Ho

2017-12-26

Despite possessing substantial regenerative capacity, skeletal muscle can suffer from loss of function due to catastrophic traumatic injury or degenerative disease. In such cases, engineered tissue grafts hold the potential to restore function and improve patient quality of life. Requirements for successful integration of engineered tissue grafts with the host musculature include cell alignment that mimics host tissue architecture and directional functionality, as well as vascularization to ensure tissue survival. Here, we have developed biomimetic nanopatterned poly(lactic-co-glycolic acid) substrates conjugated with sphingosine-1-phosphate (S1P), a potent angiogenic and myogenic factor, to enhance myoblast and endothelial maturation. Primary muscle cells cultured on these functionalized S1P nanopatterned substrates developed a highly aligned and elongated morphology and exhibited higher expression levels of myosin heavy chain, in addition to genes characteristic of mature skeletal muscle. We also found that S1P enhanced angiogenic potential in these cultures, as evidenced by elevated expression of endothelial-related genes. Computational analyses of live-cell videos showed a significantly improved functionality of tissues cultured on S1P-functionalized nanopatterns as indicated by greater myotube contraction displacements and velocities. In summary, our study demonstrates that biomimetic nanotopography and S1P can be combined to synergistically regulate the maturation and vascularization of engineered skeletal muscles.

Skeletal Characterization of the Fgfr3 Mouse Model of Achondroplasia Using Micro-CT and MRI Volumetric Imaging.

PubMed

Shazeeb, Mohammed Salman; Cox, Megan K; Gupta, Anurag; Tang, Wen; Singh, Kuldeep; Pryce, Cynthia T; Fogle, Robert; Mu, Ying; Weber, William D; Bangari, Dinesh S; Ying, Xiaoyou; Sabbagh, Yves

2018-01-11

Achondroplasia, the most common form of dwarfism, affects more than a quarter million people worldwide and remains an unmet medical need. Achondroplasia is caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene which results in over-activation of the receptor, interfering with normal skeletal development leading to disproportional short stature. Multiple mouse models have been generated to study achondroplasia. The characterization of these preclinical models has been primarily done with 2D measurements. In this study, we explored the transgenic model expressing mouse Fgfr3 containing the achondroplasia mutation G380R under the Col2 promoter (Ach). Survival and growth rate of the Ach mice were reduced compared to wild-type (WT) littermates. Axial skeletal defects and abnormalities of the sternebrae and vertebrae were observed in the Ach mice. Further evaluation of the Ach mouse model was performed by developing 3D parameters from micro-computed tomography (micro-CT) and magnetic resonance imaging (MRI). The 3-week-old mice showed greater differences between the Ach and WT groups compared to the 6-week-old mice for all parameters. Deeper understanding of skeletal abnormalities of this model will help guide future studies for evaluating novel and effective therapeutic approaches for the treatment of achondroplasia.

Favorable effect of moderate dose caffeine on the skeletal system in ovariectomized rats.

PubMed

Folwarczna, Joanna; Pytlik, Maria; Zych, Maria; Cegieła, Urszula; Kaczmarczyk-Sedlak, Ilona; Nowińska, Barbara; Sliwiński, Leszek

2013-10-01

Caffeine, a methylxanthine present in coffee, has been postulated to be responsible for an increased risk of osteoporosis in coffee drinkers; however, the data are inconsistent. The aim of the present study was to investigate the effects of a moderate dose of caffeine on the skeletal system of rats with normal and decreased estrogen level (developing osteoporosis due to estrogen deficiency). The experiments were carried out on mature nonovariectomized and ovariectomized Wistar rats, divided into control rats and rats receiving caffeine once daily, 20 mg/kg p.o., for 4 wk. Serum bone turnover markers, bone mass, mass of bone mineral, calcium and phosphorus content, histomorphometric parameters, and bone mechanical properties were examined. Caffeine favorably affected the skeletal system of ovariectomized rats, slightly inhibiting the development of bone changes induced by estrogen deficiency (increasing bone mineralization, and improving the strength and structure of cancellous bone). Moreover, it favorably affected mechanical properties of compact bone. There were no significant effects of caffeine in rats with normal estrogen levels. In conclusion, results of the present study indicate that low-to-moderate caffeine intake may exert some beneficial effects on the skeletal system of mature organisms. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

Temporal analysis of reciprocal miRNA-mRNA expression patterns predicts regulatory networks during differentiation in human skeletal muscle cells

PubMed Central

Sjögren, Rasmus J. O.; Egan, Brendan; Katayama, Mutsumi; Zierath, Juleen R.

2014-01-01

microRNAs (miRNAs) are short noncoding RNAs that regulate gene expression through posttranscriptional repression of target genes. miRNAs exert a fundamental level of control over many developmental processes, but their role in the differentiation and development of skeletal muscle from myogenic progenitor cells in humans remains incompletely understood. Using primary cultures established from human skeletal muscle satellite cells, we performed microarray profiling of miRNA expression during differentiation of myoblasts (day 0) into myotubes at 48 h intervals (day 2, 4, 6, 8, and 10). Based on a time-course analysis, we identified 44 miRNAs with altered expression [false discovery rate (FDR) < 5%, fold change > ±1.2] during differentiation, including the marked upregulation of the canonical myogenic miRNAs miR-1, miR-133a, miR-133b, and miR-206. Microarray profiling of mRNA expression at day 0, 4, and 10 identified 842 and 949 genes differentially expressed (FDR < 10%) at day 4 and 10, respectively. At day 10, 42% of altered transcripts demonstrated reciprocal expression patterns in relation to the directional change of their in silico predicted regulatory miRNAs based on analysis using Ingenuity Pathway Analysis microRNA Target Filter. Bioinformatic analysis predicted networks of regulation during differentiation including myomiRs miR-1/206 and miR-133a/b, miRNAs previously established in differentiation including miR-26 and miR-30, and novel miRNAs regulated during differentiation of human skeletal muscle cells such as miR-138-5p and miR-20a. These reciprocal expression patterns may represent new regulatory nodes in human skeletal muscle cell differentiation. This analysis serves as a reference point for future studies of human skeletal muscle differentiation and development in healthy and disease states. PMID:25547110

Skeletal maturity and body size of teenage Belgian track and field athletes.

PubMed

Malina, R M; Beunen, G; Wellens, R; Claessens, A

1986-01-01

Attained skeletal maturity (TW2 RUS method), skeletal maturity relative to chronological age, and body size of national-level Belgian track and field athletes 15 to 18 years of age were considered. Among the 47 male athletes, 29 (62%) were skeletally mature, while 15 (52%) of the 29 female athletes were skeletally mature. There appeared to be a predominance of skeletally mature individuals among male sprinters and jumpers, while a majority of female sprinters were not skeletally mature. Both skeletally mature and immature individuals were rather evenly represented in the other track and field categories, with the exception of female throwers, who were skeletally mature. Mean statures and weights of skeletally mature and immature 16-, 17-and 18-year-old male athletes did not differ significantly, though the skeletally mature tended to be heavier. In contrast, the skeletally mature female athletes, on the average, were taller and heavier than the skeletally immature, although the differences among the small groups were not statistically significant.

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.

A Human Pluripotent Stem Cell Model of Facioscapulohumeral Muscular Dystrophy-Affected Skeletal Muscles.

PubMed

Caron, Leslie; Kher, Devaki; Lee, Kian Leong; McKernan, Robert; Dumevska, Biljana; Hidalgo, Alejandro; Li, Jia; Yang, Henry; Main, Heather; Ferri, Giulia; Petek, Lisa M; Poellinger, Lorenz; Miller, Daniel G; Gabellini, Davide; Schmidt, Uli

2016-09-01

: Facioscapulohumeral muscular dystrophy (FSHD) represents a major unmet clinical need arising from the progressive weakness and atrophy of skeletal muscles. The dearth of adequate experimental models has severely hampered our understanding of the disease. To date, no treatment is available for FSHD. Human embryonic stem cells (hESCs) potentially represent a renewable source of skeletal muscle cells (SkMCs) and provide an alternative to invasive patient biopsies. We developed a scalable monolayer system to differentiate hESCs into mature SkMCs within 26 days, without cell sorting or genetic manipulation. Here we show that SkMCs derived from FSHD1-affected hESC lines exclusively express the FSHD pathogenic marker double homeobox 4 and exhibit some of the defects reported in FSHD. FSHD1 myotubes are thinner when compared with unaffected and Becker muscular dystrophy myotubes, and differentially regulate genes involved in cell cycle control, oxidative stress response, and cell adhesion. This cellular model will be a powerful tool for studying FSHD and will ultimately assist in the development of effective treatments for muscular dystrophies. This work describes an efficient and highly scalable monolayer system to differentiate human pluripotent stem cells (hPSCs) into skeletal muscle cells (SkMCs) and demonstrates disease-specific phenotypes in SkMCs derived from both embryonic and induced hPSCs affected with facioscapulohumeral muscular dystrophy. This study represents the first human stem cell-based cellular model for a muscular dystrophy that is suitable for high-throughput screening and drug development. ©AlphaMed Press.

Integrative Analyses of miRNA-mRNA Interactions Reveal let-7b, miR-128 and MAPK Pathway Involvement in Muscle Mass Loss in Sex-Linked Dwarf Chickens

PubMed Central

Luo, Wen; Lin, Shumao; Li, Guihuan; Nie, Qinghua; Zhang, Xiquan

2016-01-01

The sex-linked dwarf (SLD) chicken is an ideal model system for understanding growth hormone (GH)-action and growth hormone receptor (GHR) function because of its recessive mutation in the GHR gene. Skeletal muscle mass is reduced in the SLD chicken with a smaller muscle fiber diameter. Our previous study has presented the mRNA and miRNA expression profiles of the SLD chicken and normal chicken between embryo day 14 and seven weeks of age. However, the molecular mechanism of GHR-deficient induced muscle mass loss is still unclear, and the key molecules and pathways underlying the GHR-deficient induced muscle mass loss also remain to be illustrated. Here, by functional network analysis of the differentially expressed miRNAs and mRNAs between the SLD and normal chickens, we revealed that let-7b, miR-128 and the MAPK pathway might play key roles in the GHR-deficient induced muscle mass loss, and that the reduced cell division and growth are potential cellular processes during the SLD chicken skeletal muscle development. Additionally, we also found some genes and miRNAs involved in chicken skeletal muscle development, through the MAPK, PI3K-Akt, Wnt and Insulin signaling pathways. This study provides new insights into the molecular mechanism underlying muscle mass loss in the SLD chickens, and some regulatory networks that are crucial for chicken skeletal muscle development. PMID:26927061

Ginsenoside Rb1 improves energy metabolism in the skeletal muscle of an animal model of postoperative fatigue syndrome.

PubMed

Tan, Shan-Jun; Li, Ning; Zhou, Feng; Dong, Qian-Tong; Zhang, Xiao-Dong; Chen, Bi-Cheng; Yu, Zhen

2014-10-01

Postoperative fatigue syndrome (POFS) is a common clinical complication followed by almost every major abdominal surgery. Ginsenoside Rb1 (GRb1), a principle ginsenoside in ginseng, could exert a potent anti-fatigue effect on POFS. However, the mechanism is still unknown. Previous studies revealed that alterations in the energy metabolism in the skeletal muscle may play a vital role in the development and progression of fatigue. In the present study, we investigate the effect of GRb1 on energy metabolism in the skeletal muscle of a rat model of POFS induced by major small intestinal resection. GRb1 (10 mg/kg) was intraperitoneally administrated once daily for 1, 3, 7, and 10 d from the operation day, respectively. The locomotor activity was recorded every day, and total food intake was calculated starting from 24 h after surgery. After GRb1 treatment was completed, blood and skeletal muscle were sampled. The level of blood glucose was determined by an automatic biochemical analyzer. The content of adenosine triphosphate (ATP) in skeletal muscle was determined by high-performance liquid chromatography. The activity of energy metabolic enzymes Na(+)-K(+)-ATPase, pyruvate kinase, and succinate dehydrogenase (SDH) was assessed by commercially available kits. The results revealed that GRb1 could increase locomotor activity of POFS rats and significantly increase their total food intake postoperatively (P < 0.05). Furthermore, GRb1 also significantly increased ATP content in the skeletal muscle of POFS rats (P < 0.05). Meanwhile, the activity of Na(+)-K(+)-ATPase and SDH in the skeletal muscle of POFS rats was enhanced by GRb1 (P < 0.05). However, no significant differences in blood glucose and pyruvate kinase were found between the POFS and GRb1 treatment rats (P > 0.05). These results suggest that GRb1 may improve skeletal muscle energy metabolism in POFS, and the underlying mechanism may be associated with an increase in the content of ATP and an enhancement in the activity of energy metabolic enzymes such as Na(+)-K(+)-ATPase ATPase and SDH in the skeletal muscle. Copyright © 2014 Elsevier Inc. All rights reserved.

FRZB1 rs2242070 polymorphisms is associated with brick tea type skeletal fluorosis in Kazakhs, but not in Tibetans, China.

PubMed

Yang, Yanmei; Zhao, Qiaoshi; Liu, Yang; Liu, Xiaona; Chu, Yanru; Yan, Huazhu; Fan, Yumei; Huo, Simeng; Wang, Limei; Lou, Qun; Guo, Ning; Sun, Dianjun; Gao, Yanhui

2018-05-21

Skeletal fluorosis is a metabolic bone and joint disease caused by excessive accumulation of fluoride in the bones. Compared with Kazakhs, Tibetans are more likely to develop moderate and severe brick tea type skeletal fluorosis, although they have similar fluoride exposure. Single nucleotide polymorphisms (SNPs) in frizzled-related protein (FRZB) have been associated with osteoarthritis, but their association with the risk of skeletal fluorosis has not been reported. In this paper, we investigated the association of three SNPs (rs7775, rs2242070 and rs9288087) in FRZB1with brick tea type skeletal fluorosis risk in a cross-sectional case-control study conducted in Sinkiang and Qinghai, China. A total of 598 individuals, including 308 Tibetans and 290 Kazakhs, were enrolled in this study, in which cases and controls were 221 and 377, respectively. The skeletal fluorosis was diagnosed according to the Chinese diagnostic criteria of endemic skeletal fluorosis (WS192-2008). The fluoride content in tea water or urine was detected using the fluoride ion electrode. SNPs were assessed using the Sequenom MassARRAY system. Binary logistic regressions found evidence of association with rs2242070 AA genotype in only Kazakh participants [odds ratio (OR) 0.417, 95% CI 0.216-0.807, p = 0.009], but not in Tibetans. When stratified by age, this protective effect of AA genotype in rs2242070 was pronounced in Kazakh participants aged 46-65 (OR 0.321, 95% CI 0.135-0.764, p = 0.010). This protective association with AA genotype in rs2242070 in Kazakhs also appeared to be stronger with tea fluoride intake > 3.5 mg/day (OR 0.396, 95% CI 0.182-0.864, p = 0.020). Our data suggest there might be differential genetic influence on skeletal fluorosis risk in Kazakh and Tibetan participants and that this difference might be modified by tea fluoride intake.

Effects of the belt electrode skeletal muscle electrical stimulation system on lower extremity skeletal muscle activity: Evaluation using positron emission tomography.

PubMed

Numata, Hitoaki; Nakase, Junsuke; Inaki, Anri; Mochizuki, Takafumi; Oshima, Takeshi; Takata, Yasushi; Kinuya, Seigo; Tsuchiya, Hiroyuki

2016-01-01

Lower-extremity muscle weakness in athletes after lower limb trauma or surgery can hinder their return to sports, and the associated muscle atrophy may lead to deterioration in performance after returning to sports. Recently, belt electrode skeletal muscle electrical stimulation (B-SES) which can contract all the lower limb skeletal muscles simultaneously was developed. However, no study has evaluated skeletal muscle activity with B-SES. Since only superficial muscles as well as a limited number of muscles can be investigated using electromyography, we investigated whether positron emission tomography (PET) can evaluate the activity of all the skeletal muscles in the body simultaneously. The purpose of this study was to evaluate the effectiveness of the B-SES system using PET. Twelve healthy males (mean age, 24.3 years) were divided into two groups. The subjects in the control group remained in a sitting position for 10 min, and [(18)F] fluorodeoxyglucose (FDG) was intravenously injected. In the exercise group, subjects exercised using the B-SES system for 20 min daily for three consecutive days as a pre-test exercise. On the measurement day, they exercised for 10 min, received an injection of FDG, and exercised for another 10 min. PET-computed tomography images were obtained in each group 60 min after the FDG injection. Regions of interest were drawn in each lower-extremity muscle. We compared each skeletal muscle metabolism using the standardized uptake value. In the exercise group, FDG accumulation in the gluteus maximus, gluteus medius, gluteus minimus, quadriceps femoris, sartorius, and hamstrings was significantly higher than the muscles in the control (P < 0.05). Exercise with B-SES increased the skeletal muscle activity of the gluteal muscles as well as the most lower-extremity muscles simultaneously. Copyright © 2015 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

PAX3/7 EXPRESSION COINCIDES WITH MYOD DURING CHRONIC SKELETAL MUSCLE OVERLOAD

PubMed Central

Hyatt, Jon-Philippe K.; McCall, Gary E.; Kander, Elizabeth M.; Zhong, Hui; Roy, Roland R.; Huey, Kimberly A.

2009-01-01

Paired box (Pax) proteins 3 and 7 are key determinants for embryonic skeletal muscle development by initiating myogenic regulatory factor (MRF) gene expression. We show that Pax3 and 7 participate in adult skeletal muscle plasticity during the initial responses to chronic overload (≤7 days) and appear to coordinate MyoD expression, a member of the MRF family of genes. Pax3 and 7 mRNA were higher than control within 12 h after initiation of overload, preceded the increase in MyoD mRNA on day 1, and peaked on day 2. On days 3 and 7, Pax7 mRNA remained higher than control, suggesting that satellite cell self-renewal was occurring. Pax3 and 7 and MyoD protein levels were higher than control on days 2 and 3. These data indicate that Pax3 and 7 coordinate the recapitulation of developmental-like regulatory mechanisms in response to growth-inducing stimuli in adult skeletal muscle, presumably through activation of satellite cells. PMID:18508329

Signalling and the control of skeletal muscle size

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

Otto, Anthony; Patel, Ketan, E-mail: ketan.patel@reading.ac.uk

2010-11-01

Skeletal muscle is highly adaptive to environmental stimuli and can alter its mass accordingly. This tissue is almost unique in that it can increase its size through two distinct mechanisms. It can grow through a cellular process mediated by cell fusion, or it can increase its size simply by increasing its protein content. Understanding how these processes are regulated is crucial for the development of potential therapies against debilitating skeletal muscle wasting diseases. Two key signalling molecules, Insulin like Growth Factor (IGF) and GDF-8/myostatin, have emerged in recent years to be potent regulators of skeletal muscle size. In this reviewmore » we bring together recent data highlighting the important and novel aspects of both molecules and their signalling pathways, culminating in a discussion of the cellular and tissue phenotypic outcomes of their stimulation or antagonism. We emphasise the complex regulatory mechanisms and discuss the temporal and spatial differences that control their action, understanding of which is crucial to further their use as potential therapeutic targets.« less

Strategies for cell manipulation and skeletal tissue engineering using high-throughput polymer blend formulation and microarray techniques.

PubMed

Khan, Ferdous; Tare, Rahul S; Kanczler, Janos M; Oreffo, Richard O C; Bradley, Mark

2010-03-01

A combination of high-throughput material formulation and microarray techniques were synergistically applied for the efficient analysis of the biological functionality of 135 binary polymer blends. This allowed the identification of cell-compatible biopolymers permissive for human skeletal stem cell growth in both in vitro and in vivo applications. The blended polymeric materials were developed from commercially available, inexpensive and well characterised biodegradable polymers, which on their own lacked both the structural requirements of a scaffold material and, critically, the ability to facilitate cell growth. Blends identified here proved excellent templates for cell attachment, and in addition, a number of blends displayed remarkable bone-like architecture and facilitated bone regeneration by providing 3D biomimetic scaffolds for skeletal cell growth and osteogenic differentiation. This study demonstrates a unique strategy to generate and identify innovative materials with widespread application in cell biology as well as offering a new reparative platform strategy applicable to skeletal tissues. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Fatigue mechanisms in patients with cancer: effects of tumor necrosis factor and exercise on skeletal muscle

NASA Technical Reports Server (NTRS)

St Pierre, B. A.; Kasper, C. E.; Lindsey, A. M.

1992-01-01

Fatigue is a common adverse effect of cancer and its therapy. However, the specific mechanisms underlying cancer fatigue are unclear. One physiologic mechanism may involve changes in skeletal muscle protein stores or metabolite concentration. A reduction in skeletal muscle protein stores may result from endogenous tumor necrosis factor (TNF) or from TNF administered as antineoplastic therapy. This muscle wasting would require patients to exert an unusually high amount of effort to generate adequate contractile force during exercise performance or during extended periods of sitting or standing. This additional effort could result in the onset of fatigue. Additionally, cancer fatigue may develop or become exacerbated during exercise as a consequence of changes in the concentration of skeletal muscle metabolites. These biochemical alterations may interfere with force that is produced by the muscle contractile proteins. These physiologic changes may play a role in the decision to include exercise in the rehabilitation plans of patients with cancer. They also may affect ideas about fatigue.

Congenital myopathy associated with the triadin knockout syndrome

PubMed Central

Redhage, Keeley R.; Tester, David J.; Ackerman, Michael J.; Selcen, Duygu

2017-01-01

Objective: Triadin is a component of the calcium release complex of cardiac and skeletal muscle. Our objective was to analyze the skeletal muscle phenotype of the triadin knockout syndrome. Methods: We performed clinical evaluation, analyzed morphologic features by light and electron microscopy, and immunolocalized triadin in skeletal muscle. Results: A 6-year-old boy with lifelong muscle weakness had a triadin knockout syndrome caused by compound heterozygous null mutations in triadin. Light microscopy of a deltoid muscle specimen shows multiple small abnormal spaces in all muscle fibers. Triadin immunoreactivity is absent from type 1 fibers and barely detectable in type 2 fibers. Electron microscopy reveals focally distributed dilation and degeneration of the lateral cisterns of the sarcoplasmic reticulum and loss of the triadin anchors from the preserved lateral cisterns. Conclusions: Absence of triadin in humans can result in a congenital myopathy associated with profound pathologic alterations in components of the sarcoplasmic reticulum. Why only some triadin-deficient patients develop a skeletal muscle phenotype remains an unsolved question. PMID:28202702

Satellite cells in human skeletal muscle plasticity

PubMed Central

Snijders, Tim; Nederveen, Joshua P.; McKay, Bryon R.; Joanisse, Sophie; Verdijk, Lex B.; van Loon, Luc J. C.; Parise, Gianni

2015-01-01

Skeletal muscle satellite cells are considered to play a crucial role in muscle fiber maintenance, repair and remodeling. Our knowledge of the role of satellite cells in muscle fiber adaptation has traditionally relied on in vitro cell and in vivo animal models. Over the past decade, a genuine effort has been made to translate these results to humans under physiological conditions. Findings from in vivo human studies suggest that satellite cells play a key role in skeletal muscle fiber repair/remodeling in response to exercise. Mounting evidence indicates that aging has a profound impact on the regulation of satellite cells in human skeletal muscle. Yet, the precise role of satellite cells in the development of muscle fiber atrophy with age remains unresolved. This review seeks to integrate recent results from in vivo human studies on satellite cell function in muscle fiber repair/remodeling in the wider context of satellite cell biology whose literature is largely based on animal and cell models. PMID:26557092

STIM1 signaling controls store operated calcium entry required for development and contractile function in skeletal muscle

PubMed Central

Stiber, Jonathan; Hawkins, April; Zhang, Zhu-Shan; Wang, Sunny; Burch, Jarrett; Graham, Victoria; Ward, Cary C.; Seth, Malini; Finch, Elizabeth; Malouf, Nadia; Williams, R. Sanders; Eu, Jerry P.; Rosenberg, Paul

2009-01-01

It is now well established that stromal interaction molecule 1 (STIM1) is the calcium sensor of endoplasmic reticulum (ER) stores required to activate store-operated calcium entry (SOC) channels at the surface of non-excitable cells. Yet little is known about STIM1 in excitable cells such as striated muscle where the complement of calcium regulatory molecules is rather disparate from that of non-excitable cells. Here, we show that STIM1 is expressed in both myotubes and adult skeletal muscle. Myotubes lacking functional STIM1 fail to exhibit SOC and fatigue rapidly. Moreover, mice lacking functional STIM1 die perinatally from a skeletal myopathy. In addition, STIM1 haploinsufficiency confers a contractile defect only under conditions where rapid refilling of stores would be needed. These findings provide novel insight to the role of STIM1 in skeletal muscle and suggest that STIM1 has a universal role as an ER/SR calcium sensor in both excitable and non-excitable cells. PMID:18488020

Combination of small RNAs for skeletal muscle regeneration.

PubMed

Kim, NaJung; Yoo, James J; Atala, Anthony; Lee, Sang Jin

2016-03-01

Selectively controlling the expression of the target genes through RNA interference (RNAi) has significant therapeutic potential for injuries or diseases of tissues. We used this strategy to accelerate and enhance skeletal muscle regeneration for the treatment of muscular atrophy. In this study, we used myostatin small interfering (si)RNA (siGDF-8), a major inhibitory factor in the development and postnatal regeneration of skeletal muscle and muscle-specific microRNAs (miR-1 and -206) to further accelerate muscle regeneration. This combination of 3 small RNAs significantly improved the gene expression of myogenic regulatory factors in vitro, suggesting myogenic activation. Moreover, cell proliferation and myotube formation improved without compromising each other, which indicates the myogenic potential of this combination of small RNAs. The recovery of chemically injured tibialis anterior muscles in rats was significantly accelerated, both functionally and structurally. This novel combination of siRNA and miRNAs has promising therapeutic potential to improve in situ skeletal muscle regeneration. © FASEB.

mRNA Expression Signatures of Human Skeletal Muscle Atrophy Identify a Natural Compound that Increases Muscle Mass

PubMed Central

Kunkel, Steven D.; Suneja, Manish; Ebert, Scott M.; Bongers, Kale S.; Fox, Daniel K.; Malmberg, Sharon E.; Alipour, Fariborz; Shields, Richard K.; Adams, Christopher M.

2011-01-01

SUMMARY Skeletal muscle atrophy is a common and debilitating condition that lacks a pharmacologic therapy. To develop a potential therapy, we identified 63 mRNAs that were regulated by fasting in both human and mouse muscle, and 29 mRNAs that were regulated by both fasting and spinal cord injury in human muscle. We used these two unbiased mRNA expression signatures of muscle atrophy to query the Connectivity Map, which singled out ursolic acid as a compound whose signature was opposite to those of atrophy-inducing stresses. A natural compound enriched in apples, ursolic acid reduced muscle atrophy and stimulated muscle hypertrophy in mice. It did so by enhancing skeletal muscle insulin/IGF-I signaling, and inhibiting atrophy-associated skeletal muscle mRNA expression. Importantly, ursolic acid’s effects on muscle were accompanied by reductions in adiposity, fasting blood glucose and plasma cholesterol and triglycerides. These findings identify a potential therapy for muscle atrophy and perhaps other metabolic diseases. PMID:21641545

The Dynamic Behaviour and Shock Recovery of a Porcine Skeletal Muscle Tissue

NASA Astrophysics Data System (ADS)

Wilgeroth, James; Hazell, Paul; Appleby-Thomas, Gareth

2011-06-01

Modern-day ballistic armours provide a high degree of protection to the individual. However, the effects of non-penetrating projectiles, blast, and high-energy blunt impact events may still cause severe tissue trauma/remote injury. The energies corresponding to such events allow for the formation and transmission of shock waves within body tissues. Consequently, the nature of trauma inflicted upon such soft tissues is likely to be intimately linked to their interaction with the shock waves that propagate through them. Notably, relatively little is known about the effect of shock upon the structure of biological materials, such as skeletal muscle tissue. In this study plate-impact experiments have been used to interrogate the dynamic response of a porcine skeletal muscle tissue under one-dimensional shock loading conditions. Additionally, development of a soft-capture system that has allowed recovery of shocked skeletal muscle tissue specimens is discussed and comparison made between experimental diagnostics and hydrocode simulations of the experiment.

The skeletal vascular system - Breathing life into bone tissue.

PubMed

Stegen, Steve; Carmeliet, Geert

2017-08-26

During bone development, homeostasis and repair, a dense vascular system provides oxygen and nutrients to highly anabolic skeletal cells. Characteristic for the vascular system in bone is the serial organization of two capillary systems, each typified by specific morphological and physiological features. Especially the arterial capillaries mediate the growth of the bone vascular system, serve as a niche for skeletal and hematopoietic progenitors and couple angiogenesis to osteogenesis. Endothelial cells and osteoprogenitor cells interact not only physically, but also communicate to each other by secretion of growth factors. A vital angiogenic growth factor is vascular endothelial growth factor and its expression in skeletal cells is controlled by osteogenic transcription factors and hypoxia signaling, whereas the secretion of angiocrine factors by endothelial cells is regulated by Notch signaling, blood flow and possibly hypoxia. Bone loss and impaired fracture repair are often associated with reduced and disorganized blood vessel network and therapeutic targeting of the angiogenic response may contribute to enhanced bone regeneration. Copyright © 2017 Elsevier Inc. All rights reserved.

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

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.

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.

Dicarbonyl stress and glyoxalase enzyme system regulation in human skeletal muscle.

PubMed

Mey, Jacob T; Blackburn, Brian K; Miranda, Edwin R; Chaves, Alec B; Briller, Joan; Bonini, Marcelo G; Haus, Jacob M

2018-02-01

Skeletal muscle insulin resistance is a hallmark of Type 2 diabetes (T2DM) and may be exacerbated by protein modifications by methylglyoxal (MG), known as dicarbonyl stress. The glyoxalase enzyme system composed of glyoxalase 1/2 (GLO1/GLO2) is the natural defense against dicarbonyl stress, yet its protein expression, activity, and regulation remain largely unexplored in skeletal muscle. Therefore, this study investigated dicarbonyl stress and the glyoxalase enzyme system in the skeletal muscle of subjects with T2DM (age: 56 ± 5 yr.; BMI: 32 ± 2 kg/m 2 ) compared with lean healthy control subjects (LHC; age: 27 ± 1 yr.; BMI: 22 ± 1 kg/m 2 ). Skeletal muscle biopsies obtained from the vastus lateralis at basal and insulin-stimulated states of the hyperinsulinemic (40 mU·m -2 ·min -1 )-euglycemic (5 mM) clamp were analyzed for proteins related to dicarbonyl stress and glyoxalase biology. At baseline, T2DM had increased carbonyl stress and lower GLO1 protein expression (-78.8%), which inversely correlated with BMI, percent body fat, and HOMA-IR, while positively correlating with clamp-derived glucose disposal rates. T2DM also had lower NRF2 protein expression (-31.6%), which is a positive regulator of GLO1, while Keap1 protein expression, a negative regulator of GLO1, was elevated (207%). Additionally, insulin stimulation during the clamp had a differential effect on NRF2, Keap1, and MG-modified protein expression. These data suggest that dicarbonyl stress and the glyoxalase enzyme system are dysregulated in T2DM skeletal muscle and may underlie skeletal muscle insulin resistance. Whether these phenotypic differences contribute to the development of T2DM warrants further investigation.

An Old Problem: Aging and Skeletal-Muscle-Strain Injury.

PubMed

Baker, Brent A

2017-04-01

Clinical Scenario: Even though chronological aging is an inevitable phenomenological consequence occurring in every living organism, it is biological aging that may be the most significant factor challenging our quality of life. Development of functional limitations, resulting from improper maintenance and restoration of various organ systems, ultimately leads to reduced health and independence. Skeletal muscle is an organ system that, when challenged, is often injured in response to varying stimuli. Overt muscle-strain injury can be traumatic, clinically diagnosable, properly managed, and a remarkably common event, yet our contemporary understanding of how age and environmental stressors affect the initial and subsequent induction of injury and how the biological processes resulting from this event are modifiable and, eventually, lead to functional restoration and healing of skeletal muscle and adjacent tissues is presently unclear. Even though the secondary injury response to and recovery from "contraction-induced" skeletal-muscle injury are impaired with aging, there is no scientific consensus as to the exact mechanism responsible for this event. Given the multitude of investigative approaches, particular consideration given to the appropriateness of the muscle-injury model, or research paradigm, is critical so that outcomes may be physiologically relevant and translational. In this case, methods implementing stretch-shortening contractions, the most common form of muscle movements used by all mammals during physical movement, work, and activity, are highlighted. Understanding the fundamental evidence regarding how aging influences the responsivity of skeletal muscle to strain injury is vital for informing how clinicians approach and implement preventive strategies, as well as therapeutic interventions. From a practical perspective, maintaining or improving the overall health and tissue quality of skeletal muscle as one ages will positively affect skeletal muscle's safety threshold and responsivity, which may reduce incidence of injury, improve recovery time, and lessen overall fiscal burdens.

Monoclonal Antibody Fragments for Targeting Therapeutics to Growth Plate Cartilage | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at The Eunice Kennedy Shriver National Institute on Child Health and Human Development (NICHD) have discovered monoclonal antibodies that bind to matrilin-3, a protein specifically expressed in cartilage tissue, that could be used for treating or inhibiting growth plate disorders, such as a skeletal dysplasia or short stature. The monoclonal antibodies can also be used to target therapeutic agents, such as anti-arthritis agents, to cartilage tissue. NICHD seeks statements of capability or interest from parties interested in collaborative research to co-develop, evaluate, or commercialize treatment of skeletal disorders using targeting antibodies.

Modeling of skeletal members using polyurethane foam

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

Sena, J.M.F.; Weaver, R.W.

1983-11-01

At the request of the University of New Mexico's Maxwell Museum of Anthropology, members of the Plastic Section in the Process Development Division at SNLA undertook the special project of the Chaco Lady. The project consisted of polyurethane foam casting of a disinterred female skull considered to be approximately 1000 years old. Rubber latex molds, supplied by the UNM Anthropology Department, were used to produce the polymeric skull requested. The authors developed for the project a modified foaming process which will be used in future polyurethane castings of archaeological artifacts and contemporary skeletal members at the University.

Development of a bedrest muscle stress apparatus

NASA Technical Reports Server (NTRS)

Booher, C. R.; Hooper, S. L.; Setzer, D. N.

1979-01-01

In attempting further to define the deleterious effects of spaceflight on the human body, measurement systems and techniques were devised to determine the loss of skeletal muscle strength and tone as a result of spaceflight exposure. In order to determine how the muscle degradation process progresses with time during nonuse, a system for measuring muscle stress during bedrest was developed. The Bedrest Muscle Stress Apparatus is configured to slip snugly over the foot board of a standard hospital bed. Data collected with this device correlated well with pre- and post-bedrest data collected with the original skeletal muscle stress apparatus.

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

Branched-chain amino acid-rich diet improves skeletal muscle wasting caused by cigarette smoke in rats.

PubMed

Tomoda, Koichi; Kubo, Kaoru; Hino, Kazuo; Kondoh, Yasunori; Nishii, Yasue; Koyama, Noriko; Yamamoto, Yoshifumi; Yoshikawa, Masanori; Kimura, Hiroshi

2014-04-01

Cigarette smoke induces skeletal muscle wasting by a mechanism not yet fully elucidated. Branched-chain amino acids (BCAA) in the skeletal muscles are useful energy sources during exercise or systemic stresses. We investigated the relationship between skeletal muscle wasting caused by cigarette smoke and changes in BCAA levels in the plasma and skeletal muscles of rats. Furthermore, the effects of BCAA-rich diet on muscle wasting caused by cigarette smoke were also investigated. Wistar Kyoto (WKY) rats that were fed with a control or a BCAA-rich diet were exposed to cigarette smoke for four weeks. After the exposure, the skeletal muscle weight and BCAA levels in plasma and the skeletal muscles were measured. Cigarette smoke significantly decreased the skeletal muscle weight and BCAA levels in both plasma and skeletal muscles, while a BCAA-rich diet increased the skeletal muscle weight and BCAA levels in both plasma and skeletal muscles that had decreased by cigarette smoke exposure. In conclusion, skeletal muscle wasting caused by cigarette smoke was related to the decrease of BCAA levels in the skeletal muscles, while a BCAA-rich diet may improve cases of cigarette smoke-induced skeletal muscle wasting.

Gene expression deregulation in postnatal skeletal muscle of TK2 deficient mice reveals a lower pool of proliferating myogenic progenitor cells.

PubMed

Paredes, João A; Zhou, Xiaoshan; Höglund, Stefan; Karlsson, Anna

2013-01-01

Loss of thymidine kinase 2 (TK2) causes a heterogeneous myopathic form of mitochondrial DNA (mtDNA) depletion syndrome (MDS) in humans that predominantly affects skeletal muscle tissue. In mice, TK2 deficiency also affects several tissues in addition to skeletal muscle, including brain, heart, adipose tissue, kidneys and causes death about 3 weeks after birth. We analysed skeletal muscle and heart muscle tissues of Tk2 knockout mice at postnatal development phase and observed that TK2 deficient pups grew slower and their skeletal muscles appeared significantly underdeveloped, whereas heart was close to normal in size. Both tissues showed mtDNA depletion and mitochondria with altered ultrastructure, as revealed by transmission electron microscopy. Gene expression microarray analysis showed a strong down-regulation of genes involved in cell cycle and cell proliferation in both tissues, suggesting a lower pool of undifferentiated proliferating cells. Analysis of isolated primary myoblasts from Tk2 knockout mice showed slow proliferation, less ability to differentiate and signs of premature senescence, even in absence of mtDNA depletion. Our data demonstrate that TK2 deficiency disturbs myogenic progenitor cells function in postnatal skeletal muscle and we propose this as one of the causes of underdeveloped phenotype and myopathic characteristic of the TK2 deficient mice, in addition to the progressive mtDNA depletion, mitochondrial damage and respiratory chain deficiency in post-mitotic differentiated tissue.

Gene Expression Deregulation in Postnatal Skeletal Muscle of TK2 Deficient Mice Reveals a Lower Pool of Proliferating Myogenic Progenitor Cells

PubMed Central

Paredes, João A.; Zhou, Xiaoshan; Höglund, Stefan; Karlsson, Anna

2013-01-01

Loss of thymidine kinase 2 (TK2) causes a heterogeneous myopathic form of mitochondrial DNA (mtDNA) depletion syndrome (MDS) in humans that predominantly affects skeletal muscle tissue. In mice, TK2 deficiency also affects several tissues in addition to skeletal muscle, including brain, heart, adipose tissue, kidneys and causes death about 3 weeks after birth. We analysed skeletal muscle and heart muscle tissues of Tk2 knockout mice at postnatal development phase and observed that TK2 deficient pups grew slower and their skeletal muscles appeared significantly underdeveloped, whereas heart was close to normal in size. Both tissues showed mtDNA depletion and mitochondria with altered ultrastructure, as revealed by transmission electron microscopy. Gene expression microarray analysis showed a strong down-regulation of genes involved in cell cycle and cell proliferation in both tissues, suggesting a lower pool of undifferentiated proliferating cells. Analysis of isolated primary myoblasts from Tk2 knockout mice showed slow proliferation, less ability to differentiate and signs of premature senescence, even in absence of mtDNA depletion. Our data demonstrate that TK2 deficiency disturbs myogenic progenitor cells function in postnatal skeletal muscle and we propose this as one of the causes of underdeveloped phenotype and myopathic characteristic of the TK2 deficient mice, in addition to the progressive mtDNA depletion, mitochondrial damage and respiratory chain deficiency in post-mitotic differentiated tissue. PMID:23341978

Dentofacial transverse development in Koreans according to skeletal maturation: A cross-sectional study

PubMed Central

Hwang, Soonshin; Noh, Yoonjeong; Choi, Yoon Jeong; Chung, Chooryung; Lee, Hye Sun

2018-01-01

Objective The aim of this study was to establish the normative data of dentofacial transverse dimensions according to the skeletal maturation stage in Korean adolescents with good occlusion, assess gender differences and determine correlations between transverse variables. Methods A total of 577 Korean subjects between ages 7 to 19 years and exhibiting skeletal Class I occlusion were categorized by skeletal maturation index (SMI) of Fishman using hand-wrist radiographs. Dentofacial transverse dimensions were assessed using posteroanterior cephalograms. Independent two-sample t-tests were used to analyze differences between genders. Pearson correlation coefficient was used to determine the correlation between transverse measurements. Results Dentofacial transverse norms relevant to skeletal maturation stages were established. The average maxillomandibular width difference and ratio at growth completion was 22.16 mm and 77.01% for males; 23.70 mm and 74.06% for females, respectively. Males had greater facial, maxillary and mandibular widths compared to females at every SMI stage. The maxillary and mandibular intermolar widths showed the strongest correlation for both sexes (r = 0.826 for males, r = 0.725 for females). Conclusions Dentofacial transverse norms of Korean adolescents were established according to developmental stage. All dentofacial widths were greater in males at growth completion. Maxillary and mandibular intermolar widths were strongly correlated. This study may serve as a guideline for the assessment of dentofacial transverse growth according to skeletal maturation stage in Korean adolescents with good occlusion. PMID:29291187

Inhibition of platelet-derived growth factor signaling prevents muscle fiber growth during skeletal muscle hypertrophy.

PubMed

Sugg, Kristoffer B; Korn, Michael A; Sarver, Dylan C; Markworth, James F; Mendias, Christopher L

2017-03-01

The platelet-derived growth factor receptors alpha and beta (PDGFRα and PDGFRβ) mark fibroadipogenic progenitor cells/fibroblasts and pericytes in skeletal muscle, respectively. While the role that these cells play in muscle growth and development has been evaluated, it was not known whether the PDGF receptors activate signaling pathways that control transcriptional and functional changes during skeletal muscle hypertrophy. To evaluate this, we inhibited PDGFR signaling in mice subjected to a synergist ablation muscle growth procedure, and performed analyses 3 and 10 days after induction of hypertrophy. The results from this study indicate that PDGF signaling is required for fiber hypertrophy, extracellular matrix production, and angiogenesis that occur during muscle growth. © 2017 Federation of European Biochemical Societies.

Image analysis for skeletal evaluation of carpal bones

NASA Astrophysics Data System (ADS)

Ko, Chien-Chuan; Mao, Chi-Wu; Lin, Chi-Jen; Sun, Yung-Nien

1995-04-01

The assessment of bone age is an important field to the pediatric radiology. It provides very important information for treatment and prediction of skeletal growth in a developing child. So far, various computerized algorithms for automatically assessing the skeletal growth have been reported. Most of these methods made attempt to analyze the phalangeal growth. The most fundamental step in these automatic measurement methods is the image segmentation that extracts bones from soft-tissue and background. These automatic segmentation methods of hand radiographs can roughly be categorized into two main approaches that are edge and region based methods. This paper presents a region-based carpal-bone segmentation approach. It is organized into four stages: contrast enhancement, moment-preserving thresholding, morphological processing, and region-growing labeling.

LB1 and LB6 Homo floresiensis are not modern human (Homo sapiens) cretins.

PubMed

Brown, Peter

2012-02-01

Excavations in the late Pleistocene deposits at Liang Bua cave, Flores, have uncovered the skeletal remains of several small-bodied and small-brained hominins in association with stone artefacts and the bones of Stegodon. Due to their combination of plesiomorphic, unique and derived traits, they were ascribed to a new species, Homo floresiensis, which, along with Stegodon, appears to have become extinct ∼17 ka (thousand years ago). However, recently it has been argued that several characteristics of H. floresiensis were consistent with dwarfism and evidence of delayed development in modern human (Homo sapiens) myxoedematous endemic (ME) cretins. This research compares the skeletal and dental morphology in H. floresiensis with the clinical and osteological indicators of cretinism, and the traits that have been argued to be associated with ME cretinism in LB1 and LB6. Contrary to published claims, morphological and statistical comparisons did not identify the distinctive skeletal and dental indicators of cretinism in LB1 or LB6 H. floresiensis. Brain mass, skeletal proportions, epiphyseal union, orofacial morphology, dental development, size of the pituitary fossa and development of the paranasal sinuses, vault bone thickness and dimensions of the hands and feet all distinguish H. floresiensis from modern humans with ME cretinism. The research team responsible for the diagnosis of ME cretinism had not examined the original H. floresiensis skeletal materials, and perhaps, as a result, their research confused taphonomic damage with evidence of disease, and thus contained critical errors of fact and interpretation. Behavioural scenarios attempting to explain the presence of cretinous H. sapiens in the Liang Bua Pleistocene deposits, but not unaffected H. sapiens, are both unnecessary and not supported by the available archaeological and geochronological evidence from Flores. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones

PubMed Central

Hevener, Andrea L.; Olefsky, Jerrold M.; Reichart, Donna; Nguyen, M.T. Audrey; Bandyopadyhay, Gautam; Leung, Ho-Yin; Watt, Matthew J.; Benner, Chris; Febbraio, Mark A.; Nguyen, Anh-Khoi; Folian, Brian; Subramaniam, Shankar; Gonzalez, Frank J.; Glass, Christopher K.; Ricote, Mercedes

2007-01-01

PPARγ is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPARγ in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPARγ-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPARγ following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPARγ in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs. PMID:17525798

Leptin administration affects growth and skeletal development in a rat intrauterine growth restriction model: preliminary study.

PubMed

Bar-El Dadon, Shimrit; Shahar, Ron; Katalan, Vered; Monsonego-Ornan, Efrat; Reifen, Ram

2011-09-01

Skeletal abnormalities are one of the hallmarks of growth delay during gestation. The aim of this study was to determine changes induced by leptin in skeletal growth and development in a rat model of intrauterine growth retardation (IUGR) and to elucidate the possible underlying mechanisms. Intrauterine growth retardation was induced prepartum and the effects of leptin to mothers prenatally or to offspring postnatally were studied. Radii were harvested and tested mechanically and structurally. Tibias were evaluated for growth-plate morphometry. On day 40 postpartum, total bone length and mineral density and tibial growth-plate width and numbers of cells within its zones of offspring treated with leptin were significantly greater than in the control group. Postnatal leptin administration in an IUGR model improves the structural properties and elongation rate of bone. These findings could pave the way to preventing some phenotypic presentations of IUGR. Copyright © 2011 Elsevier Inc. All rights reserved.

A minimally sufficient model for rib proximal-distal patterning based on genetic analysis and agent-based simulations

PubMed Central

Mah, In Kyoung

2017-01-01

For decades, the mechanism of skeletal patterning along a proximal-distal axis has been an area of intense inquiry. Here, we examine the development of the ribs, simple structures that in most terrestrial vertebrates consist of two skeletal elements—a proximal bone and a distal cartilage portion. While the ribs have been shown to arise from the somites, little is known about how the two segments are specified. During our examination of genetically modified mice, we discovered a series of progressively worsening phenotypes that could not be easily explained. Here, we combine genetic analysis of rib development with agent-based simulations to conclude that proximal-distal patterning and outgrowth could occur based on simple rules. In our model, specification occurs during somite stages due to varying Hedgehog protein levels, while later expansion refines the pattern. This framework is broadly applicable for understanding the mechanisms of skeletal patterning along a proximal-distal axis. PMID:29068314

Role of IGF1 and EFN-EPH signaling in skeletal metabolism.

PubMed

Lindsey, Richard C; Rundle, Charles H; Mohan, Subburaman

2018-07-01

Insulin-like growth factor 1(IGF1) and ephrin ligand (EFN)-receptor (EPH) signaling are both crucial for bone cell function and skeletal development and maintenance. IGF1 signaling is the major mediator of growth hormone-induced bone growth, but a host of different signals and factors regulate IGF1 signaling at the systemic and local levels. Disruption of the Igf1 gene results in reduced peak bone mass in both experimental animal models and humans. Additionally, EFN-EPH signaling is a complex system which, particularly through cell-cell interactions, contributes to the development and differentiation of many bone cell types. Recent evidence has demonstrated several ways in which the IGF1 and EFN-EPH signaling pathways interact with and depend upon each other to regulate bone cell function. While much remains to be elucidated, the interaction between these two signaling pathways opens a vast array of new opportunities for investigation into the mechanisms of and potential therapies for skeletal conditions such as osteoporosis and fracture repair. © 2018 Society for Endocrinology.

Development and Implementation of a Transversely Isotropic Hyperelastic Constitutive Model With Two Fiber Families to Represent Anisotropic Soft Biological Tissues

DTIC Science & Technology

2014-06-01

brain tissue and skeletal muscles , is also discussed. transversely isotropic hyperelastic, two fiber families, nearly incompressible, anisotropic...comprised of fibrous structures, such as muscles , ligaments, tendons, intervertebral discs and the brain, often exhibit strong anisotropy along these fiber ...directions, e.g., collagen fibers of the cornea, striated muscle fibers in skeletal muscles , multiple axonal directions within the brain. In each case

Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4.

PubMed

Bullard, Steven A; Seo, Seongjin; Schilling, Birgit; Dyle, Michael C; Dierdorff, Jason M; Ebert, Scott M; DeLau, Austin D; Gibson, Bradford W; Adams, Christopher M

2016-08-19

Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle proteins that associate with Gadd45a as it induces atrophy in mouse skeletal muscle fibers in vivo We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, MEKK4, a mitogen-activated protein kinase kinase kinase that was not previously known to play a role in skeletal muscle atrophy. Furthermore, we found that, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is both sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into the way that skeletal muscle atrophy occurs at the molecular level. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Developmental Programming in Response to Intrauterine Growth Restriction Impairs Myoblast Function and Skeletal Muscle Metabolism

PubMed Central

Yates, D. T.; Macko, A. R.; Nearing, M.; Chen, X.; Rhoads, R. P.; Limesand, S. W.

2012-01-01

Fetal adaptations to placental insufficiency alter postnatal metabolic homeostasis in skeletal muscle by reducing glucose oxidation rates, impairing insulin action, and lowering the proportion of oxidative fibers. In animal models of intrauterine growth restriction (IUGR), skeletal muscle fibers have less myonuclei at birth. This means that myoblasts, the sole source for myonuclei accumulation in fibers, are compromised. Fetal hypoglycemia and hypoxemia are complications that result from placental insufficiency. Hypoxemia elevates circulating catecholamines, and chronic hypercatecholaminemia has been shown to reduce fetal muscle development and growth. We have found evidence for adaptations in adrenergic receptor expression profiles in myoblasts and skeletal muscle of IUGR sheep fetuses with placental insufficiency. The relationship of β-adrenergic receptors shifts in IUGR fetuses because Adrβ2 expression levels decline and Adrβ1 expression levels are unaffected in myofibers and increased in myoblasts. This adaptive response would suppress insulin signaling, myoblast incorporation, fiber hypertrophy, and glucose oxidation. Furthermore, this β-adrenergic receptor expression profile persists for at least the first month in IUGR lambs and lowers their fatty acid mobilization. Developmental programming of skeletal muscle adrenergic receptors partially explains metabolic and endocrine differences in IUGR offspring, and the impact on metabolism may result in differential nutrient utilization. PMID:22900186

miR-378 attenuates muscle regeneration by delaying satellite cell activation and differentiation in mice.

PubMed

Zeng, Ping; Han, Wanhong; Li, Changyin; Li, Hu; Zhu, Dahai; Zhang, Yong; Liu, Xiaohong

2016-09-01

Skeletal muscle mass and homeostasis during postnatal muscle development and regeneration largely depend on adult muscle stem cells (satellite cells). We recently showed that global overexpression of miR-378 significantly reduced skeletal muscle mass in mice. In the current study, we used miR-378 transgenic (Tg) mice to assess the in vivo functional effects of miR-378 on skeletal muscle growth and regeneration. Cross-sectional analysis of skeletal muscle tissues showed that the number and size of myofibers were significantly lower in miR-378 Tg mice than in wild-type mice. Attenuated cardiotoxin-induced muscle regeneration in miR-378 Tg mice was found to be associated with delayed satellite cell activation and differentiation. Mechanistically, miR-378 was found to directly target Igf1r in muscle cells both in vitro and in vivo These miR-378 Tg mice may provide a model for investigating the physiological and pathological roles of skeletal muscle in muscle-associated diseases in humans, particularly in sarcopenia. © The Author 2016. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Nonshivering thermogenesis in king penguin chicks. I. Role of skeletal muscle.

PubMed

Duchamp, C; Barré, H; Rouanet, J L; Lanni, A; Cohen-Adad, F; Berne, G; Brebion, P

1991-12-01

In cold-acclimatized (CA) king penguin chicks exhibiting nonshivering thermogenesis (NST), protein content and cytochrome oxidase (CO) activity of tissue homogenates were measured together with protein content, CO, and respiration rates of isolated mitochondria from skeletal muscle (gastrocnemius and pectoralis) and liver. The comparison was made with chicks reared at thermoneutrality (TN) for at least 3 wk. In CA chicks showing a NST despite the lack of brown adipose tissue, an increase in thermogenic capacity was observed in skeletal muscle in which the oxidative capacity rose (+28% and +50% in gastrocnemius and pectoralis muscles, respectively), whereas no change occurred in the liver. Oxidative capacity of skeletal muscle increased together with the development of mitochondrial inner membrane plus cristae in muscles of CA chicks contrary to their TN littermates (+30 to +50%). Subsarcolemmal mitochondria of CA chicks had a higher protein content (+65% in gastrocnemius muscle) and higher oxidative capacities than in controls. The lower respiratory control ratio of these mitochondria might result from a low ADP phosphorylation rate. No change occurred in the intermyofibrillar fraction nor in liver mitochondria. These findings together with earlier results obtained in cold-acclimated ducklings indicate the marked and suited adaptation of skeletal muscle and in particular of subsarcolemmal mitochondria allowing them to play a role in NST.

Ca2+/Calmodulin-dependent kinase II signaling causes skeletal overgrowth and premature chondrocyte maturation.

PubMed

Taschner, Michael J; Rafigh, Mehran; Lampert, Fabienne; Schnaiter, Simon; Hartmann, Christine

2008-05-01

The long bones of vertebrate limbs originate from cartilage templates and are formed by the process of endochondral ossification. This process requires that chondrocytes undergo a progressive maturation from proliferating to postmitotic prehypertrophic to mature, hypertrophic chondrocytes. Coordinated control of proliferation and maturation regulates growth of the skeletal elements. Various signals and pathways have been implicated in orchestrating these processes, but the underlying intracellular molecular mechanisms are often not entirely known. Here we demonstrated in the chick using replication-competent retroviruses that constitutive activation of Calcium/Calmodulin-dependent kinase II (CaMKII) in the developing wing resulted in elongation of skeletal elements associated with premature differentiation of chondrocytes. The premature maturation of chondrocytes was a cell-autonomous effect of constitutive CaMKII signaling associated with down-regulation of cell-cycle regulators and up-regulation of chondrocyte maturation markers. In contrast, the elongation of the skeletal elements resulted from a non-cell autonomous up-regulation of the Indian hedgehog responsive gene encoding Parathyroid-hormone-related peptide. Reduction of endogenous CaMKII activity by overexpressing an inhibitory peptide resulted in shortening of the skeletal elements associated with a delay in chondrocyte maturation. Thus, CaMKII is an essential component of intracellular signaling pathways regulating chondrocyte maturation.

Raloxifene improves skeletal properties in an animal model of cystic chronic kidney disease

PubMed Central

Newman, Christopher L.; Creecy, Amy; Granke, Mathilde; Nyman, Jeffry S.; Tian, Nannan; Hammond, Max A.; Wallace, Joseph M.; Brown, Drew M.; Chen, Neal; Moe, Sharon M.; Allen, Matthew R.

2015-01-01

Patients with chronic kidney disease (CKD) have an increased risk of fracture. Raloxifene is a mild anti-resorptive agent that reduces fracture risk in the general population. Here we assessed the impact of raloxifene on the skeletal properties of animals with progressive CKD. Male Cy/+ rats that develop autosomal dominant cystic kidney disease were treated with either vehicle or raloxifene for five weeks. They were assessed for changes in mineral metabolism and skeletal parameters (microCT, histology, whole bone mechanics, and material properties). Their normal littermates served as controls. Animals with CKD had significantly higher parathyroid hormone levels compared to normal controls as well as inferior structural and mechanical skeletal properties. Raloxifene treatment resulted in lower bone remodeling rates and higher cancellous bone volume in the rats with CKD. While it had little effect on cortical bone geometry it resulted in higher energy to fracture and modulus of toughness values than vehicle-treated rats with CKD, achieving levels equivalent to normal controls. Animals treated with raloxifene had superior tissue-level mechanical properties as assessed by nanoindentation and higher collagen D-periodic spacing as assessed by atomic force microscopy. Thus, raloxifene can positively impact whole bone mechanical properties in CKD through its impact on skeletal material properties. PMID:26489025

Patient's Skeletal Muscle Radiation Attenuation and Sarcopenic Obesity are Associated with Postoperative Morbidity after Neoadjuvant Chemoradiation and Resection for Rectal Cancer.

PubMed

Berkel, Annefleur E M; Klaase, Joost M; de Graaff, Feike; Brusse-Keizer, Marjolein G J; Bongers, Bart C; van Meeteren, Nico L U

2018-06-13

To investigate the relation between skeletal muscle measurements (muscle mass, radiation attenuation, and sarcopenic obesity), postoperative morbidity, and survival after treatment of locally advanced rectal cancer. This explorative retrospective study identified 99 consecutive patients who underwent neoadjuvant chemoradiation and surgery between January 2007 and May 2012. Skeletal muscle mass was measured as total psoas area and total abdominal muscle area (TAMA) at 3 anatomical levels using the patient's preoperative computed tomography scan. Radiation attenuation was measured using corresponding mean Hounsfield units for TAMA. Sarcopenic obesity was defined as body mass index above 25 kg·m-2 combined with skeletal muscle mass index below the sex-specific median. Postoperative complications were graded by using the -Clavien-Dindo classification. Twenty-five patients (25.3%) developed a grade 3-5 complication. Lower radiation attenuation was independently associated with overall (p = 0.003) and grade 3-5 complications (p = 0.002). Sarcopenic obesity was associated with overall complications (all p < 0.05). Skeletal muscle measurements and survival were not significantly related. Radiation attenuation was associated with overall and grade 3-5 postoperative morbidity after neoadjuvant chemoradiation and non-laparoscopic resection for rectal cancer. Sarcopenic obesity was associated with overall complications. © 2018 S. Karger AG, Basel.

Ligand-induced rapid skeletal muscle atrophy in HSA-Fv2E-PERK transgenic mice.

PubMed

Miyake, Masato; Kuroda, Masashi; Kiyonari, Hiroshi; Takehana, Kenji; Hisanaga, Satoshi; Morimoto, Masatoshi; Zhang, Jun; Oyadomari, Miho; Sakaue, Hiroshi; Oyadomari, Seiichi

2017-01-01

Formation of 43S and 48S preinitiation complexes plays an important role in muscle protein synthesis. There is no muscle-wasting mouse model caused by a repressed 43S preinitiation complex assembly. The aim of the present study was to develop a convenient mouse model of skeletal muscle wasting with repressed 43S preinitiation complex assembly. A ligand-activatable PERK derivative Fv2E-PERK causes the phosphorylation of eukaryotic initiation factor 2α (eIF2α), which inhibits 43S preinitiation complex assembly. Thus, muscle atrophic phenotypes, intracellular signaling pathways, and intracellular free amino acid profiles were investigated in human skeletal muscle α-actin (HSA) promoter-driven Fv2E-PERK transgenic (Tg) mice. HSA-Fv2E-PERK Tg mice treated with the artificial dimerizer AP20187 phosphorylates eIF2α in skeletal muscles and leads to severe muscle atrophy within a few days of ligand injection. Muscle atrophy was accompanied by a counter regulatory activation of mTORC1 signaling. Moreover, intracellular free amino acid levels were distinctively altered in the skeletal muscles of HSA-Fv2E-PERK Tg mice. As a novel model of muscle wasting, HSA-Fv2E-PERK Tg mice provide a convenient tool for studying the pathogenesis of muscle loss and for assessing putative therapeutics.

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.

Primary skeletal muscle cells cultured on gelatin bead microcarriers develop structural and biochemical features characteristic of adult skeletal muscle.

PubMed

Kubis, Hans-Peter; Scheibe, Renate J; Decker, Brigitte; Hufendiek, Karsten; Hanke, Nina; Gros, Gerolf; Meissner, Joachim D

2016-04-01

A primary skeletal muscle cell culture, in which myoblasts derived from newborn rabbit hindlimb muscles grow on gelatin bead microcarriers in suspension and differentiate into myotubes, has been established previously. In the course of differentiation and beginning spontaneous contractions, these multinucleated myotubes do not detach from their support. Here, we describe the development of the primary myotubes with respect to their ultrastructural differentiation. Scanning electron microscopy reveals that myotubes not only grow around the surface of one carrier bead but also attach themselves to neighboring carriers, forming bridges between carriers. Transmission electron microscopy demonstrates highly ordered myofibrils, T-tubules, and sarcoplasmic reticulum. The functionality of the contractile apparatus is evidenced by contractile activity that occurs spontaneously or can be elicited by electrostimulation. Creatine kinase activity increases steadily until day 20 of culture. Regarding the expression of isoforms of myosin heavy chains (MHC), we could demonstrate that from day 16 on, no non-adult MHC isoform mRNAs are present. Instead, on day 28 the myotubes express predominantly adult fast MHCIId/x mRNA and protein. This MHC pattern resembles that of fast muscles of adult rabbits. In contrast, primary myotubes grown on matrigel-covered culture dishes express substantial amounts of non-adult MHC protein even on day 21. To conclude, primary myotubes grown on microcarriers in their later stages exhibit many features of adult skeletal muscle and characteristics of fast type II fibers. Thus, the culture represents an excellent model of adult fast skeletal muscle, for example, when investigating molecular mechanisms of fast-to-slow fiber-type transformation. © 2015 International Federation for Cell Biology.

Reversing sex steroid deficiency and optimizing skeletal development in the adolescent with gonadal failure.

PubMed

Vanderschueren, Dirk; Vandenput, Liesbeth; Boonen, Steven

2005-01-01

During puberty, the acquisition of skeletal mass and areal bone mineral density (BMD) mainly reflects an increase in bone size (length and perimeters) and not true volumetric BMD. Sexual dimorphism in bone mass and areal BMD is also explained by differences in bone size (longer and wider bones in males) and not by differences in volumetric BMD. Androgens stimulate skeletal growth by activation of the androgen receptor, whereas estrogens (following aromatization of androgens and stimulation of estrogen receptors) have a biphasic effect on skeletal growth during puberty. Recent evidence from clinical cases has shown that many of the growth-promoting effects of the sex steroids are mediated through estrogens rather than androgens. In addition, skeletal maturation and epiphyseal fusion are also estrogen-dependent in both sexes. Nevertheless, independent actions of androgens in these processes also occur. Both sex steroids maintain volumetric BMD during puberty. Androgens interact with the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis neonatally, resulting in a sexual dimorphic GH pattern during puberty, whereas estrogens stimulate GH and hereby IGF-I in both sexes. Hypogonadism in adolescents impairs not only bone size but also maintenance of volumetric BMD, hereby severely reducing peak areal BMD. Delayed puberty in boys and Turner's syndrome in women impair both bone length and size, reducing areal BMD. Whether volumetric BMD is also reduced and whether fracture risk is increased in these conditions remains controversial. Replacing sex steroids according to a biphasic pattern (starting at low doses and ending at high-normal doses) seems the safest approach to reach targeted height and to optimize bone development.

Transgenic mice expressing mutant Pinin exhibit muscular dystrophy, nebulin deficiency and elevated expression of slow-type muscle fiber genes

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

Wu, Hsu-Pin; Hsu, Shu-Yuan; Wu, Wen-Ai

Highlights: •Pnn CCD domain functions as a dominant negative mutant regulating Pnn expression and function. •Pnn CCD mutant Tg mice have a muscle wasting phenotype during development and show dystrophic histological features. •Pnn mutant muscles are susceptible to slow fiber type gene transition and NEB reduction. •The Tg mouse generated by overexpression of the Pnn CCD domain displays many characteristics resembling NEB{sup +/−} mice. -- Abstract: Pinin (Pnn) is a nuclear speckle-associated SR-like protein. The N-terminal region of the Pnn protein sequence is highly conserved from mammals to insects, but the C-terminal RS domain-containing region is absent in lower species.more » The N-terminal coiled-coil domain (CCD) is, therefore, of interest not only from a functional point of view, but also from an evolutionarily standpoint. To explore the biological role of the Pnn CCD in a physiological context, we generated transgenic mice overexpressing Pnn mutant in skeletal muscle. We found that overexpression of the CCD reduces endogenous Pnn expression in cultured cell lines as well as in transgenic skeletal muscle fibers. Pnn mutant mice exhibited reduced body mass and impaired muscle function during development. Mutant skeletal muscles show dystrophic histological features with muscle fibers heavily loaded with centrally located myonuclei. Expression profiling and pathway analysis identified over-representation of genes in gene categories associated with muscle contraction, specifically those related to slow type fiber. In addition nebulin (NEB) expression level is repressed in Pnn mutant skeletal muscle. We conclude that Pnn downregulation in skeletal muscle causes a muscular dystrophic phenotype associated with NEB deficiency and the CCD domain is incapable of replacing full length Pnn in terms of functional capacity.« less

Comparative Postembryonic Skeletal Ontogeny in Two Sister Lineages of Old World Tree Frogs (Rhacophoridae: Taruga, Polypedates)

PubMed Central

Senevirathne, Gayani; Kerney, Ryan

2017-01-01

Rhacophoridae, a family of morphologically cryptic frogs, with many genetically distinct evolutionary lineages, is understudied with respect to skeletal morphology, life history traits and skeletal ontogeny. Here we analyze two species each from two sister lineages, Taruga and Polypedates, and compare their postembryonic skeletal ontogeny, larval chondrocrania and adult osteology in the context of a well-resolved phylogeny. We further compare these ontogenetic traits with the direct-developing Pseudophilautus silus. For each species, we differentially stained a nearly complete developmental series of tadpoles from early postembryonic stages through metamorphosis to determine the intraspecific and interspecific differences of cranial and postcranial bones. Chondrocrania of the four species differ in 1) size; 2) presence/absence of anterolateral and posterior process; and 3) shape of the suprarostral cartilages. Interspecific variation of ossification sequences is limited during early stages, but conspicuous during later development. Early cranial ossification is typical of other anuran larvae, where the frontoparietal, exoccipital and parasphenoid ossify first. The ossification sequences of the cranial bones vary considerably within the four species. Both species of Taruga show a faster cranial ossification rate than Polypedates. Seven cranial bones form when larvae near metamorphic climax. Ossification of all 18 cranial bones is initiated by larval Gosner stage 46 in T. eques. However, some cranial bone formation is not initiated until after metamorphosis in the other three species. Postcranial sequence does not vary significantly. The comparison of adult osteology highlights two characters, which have not been previously recorded: presence/absence of the parieto-squamosal plates and bifurcated base of the omosternum. This study will provide a starting point for comparative analyses of rhacophorid skeletal ontogeny and facilitate the study of the evolution of ontogenetic repatterning associated with the life history variation in the family. PMID:28060923

Biomaterials based strategies for skeletal muscle tissue engineering: existing technologies and future trends.

PubMed

Qazi, Taimoor H; Mooney, David J; Pumberger, Matthias; Geissler, Sven; Duda, Georg N

2015-01-01

Skeletal muscles have a robust capacity to regenerate, but under compromised conditions, such as severe trauma, the loss of muscle functionality is inevitable. Research carried out in the field of skeletal muscle tissue engineering has elucidated multiple intrinsic mechanisms of skeletal muscle repair, and has thus sought to identify various types of cells and bioactive factors which play an important role during regeneration. In order to maximize the potential therapeutic effects of cells and growth factors, several biomaterial based strategies have been developed and successfully implemented in animal muscle injury models. A suitable biomaterial can be utilized as a template to guide tissue reorganization, as a matrix that provides optimum micro-environmental conditions to cells, as a delivery vehicle to carry bioactive factors which can be released in a controlled manner, and as local niches to orchestrate in situ tissue regeneration. A myriad of biomaterials, varying in geometrical structure, physical form, chemical properties, and biofunctionality have been investigated for skeletal muscle tissue engineering applications. In the current review, we present a detailed summary of studies where the use of biomaterials favorably influenced muscle repair. Biomaterials in the form of porous three-dimensional scaffolds, hydrogels, fibrous meshes, and patterned substrates with defined topographies, have each displayed unique benefits, and are discussed herein. Additionally, several biomaterial based approaches aimed specifically at stimulating vascularization, innervation, and inducing contractility in regenerating muscle tissues are also discussed. Finally, we outline promising future trends in the field of muscle regeneration involving a deeper understanding of the endogenous healing cascades and utilization of this knowledge for the development of multifunctional, hybrid, biomaterials which support and enable muscle regeneration under compromised conditions. Copyright © 2015 Elsevier Ltd. All rights reserved.

The role of the renin-angiotensin system in the development of insulin resistance in skeletal muscle.

PubMed

Henriksen, Erik J; Prasannarong, Mujalin

2013-09-25

The canonical renin-angiotensin system (RAS) involves the initial action of renin to cleave angiotensinogen to angiotensin I (ANG I), which is then converted to ANG II by the angiotensin converting enzyme (ACE). ANG II plays a critical role in numerous physiological functions, and RAS overactivity underlies many conditions of cardiovascular dysregulation. In addition, ANG II, by acting on both endothelial and myocellular AT1 receptors, can induce insulin resistance by increasing cellular oxidative stress, leading to impaired insulin signaling and insulin-stimulated glucose transport activity. This insulin resistance associated with RAS overactivity, when coupled with progressive ß-cell dysfunction, eventually leads to the development of type 2 diabetes. Interventions that target RAS overactivity, including ACE inhibitors, ANG II receptor blockers, and, most recently, renin inhibitors, are effective both in reducing hypertension and in improving whole-body and skeletal muscle insulin action, due at least in part to enhanced Akt-dependent insulin signaling and insulin-dependent glucose transport activity. ANG-(1-7), which is produced from ANG II by the action of ACE2 and acts via Mas receptors, can counterbalance the deleterious actions of the ACE/ANG II/AT1 receptor axis on the insulin-dependent glucose transport system in skeletal muscle. This beneficial effect of the ACE2/ANG-(1-7)/Mas receptor axis appears to depend on the activation of Akt. Collectively, these findings underscore the importance of RAS overactivity in the multifactorial etiology of insulin resistance in skeletal muscle, and provide support for interventions that target the RAS to ameliorate both cardiovascular dysfunctions and insulin resistance in skeletal muscle tissue. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

PI3K-mediated PDGFRα signaling regulates survival and proliferation in skeletal development through p53-dependent intracellular pathways

PubMed Central

Fantauzzo, Katherine A.; Soriano, Philippe

2014-01-01

Previous studies have identified phosphatidylinositol 3-kinase (PI3K) as the main downstream effector of PDGFRα signaling during murine skeletal development. Autophosphorylation mutant knock-in embryos in which PDGFRα is unable to bind PI3K (PdgfraPI3K/PI3K) exhibit skeletal defects affecting the palatal shelves, shoulder girdle, vertebrae, and sternum. To identify proteins phosphorylated by Akt downstream from PI3K-mediated PDGFRα signaling, we immunoprecipitated Akt phosphorylation substrates from PDGF-AA-treated primary mouse embryonic palatal mesenchyme (MEPM) lysates and analyzed the peptides by nanoliquid chromatography coupled to tandem mass spectrometry (nano-LC-MS/MS). Our analysis generated a list of 56 proteins, including 10 that regulate cell survival and proliferation. We demonstrate that MEPM cell survival is impaired in the presence of a PI3K inhibitor and that PdgfraPI3K/PI3K-derived MEPMs do not proliferate in response to PDGF-AA treatment. Several of the identified Akt phosphorylation targets, including Ybox1, mediate cell survival through regulation of p53. We show that Ybox1 binds both the Trp53 promoter and the p53 protein and that expression of Trp53 is significantly decreased upon PDGF-AA treatment in MEPMs. Finally, we demonstrate that introduction of a Trp53-null allele attenuates the vertebral defects found in PdgfraPI3K/PI3K neonates. Our findings identify p53 as a novel effector downstream from PI3K-engaged PDGFRα signaling that regulates survival and proliferation during skeletal development in vivo. PMID:24788519

An Essential Physiological Role for MCT8 in Bone in Male Mice

PubMed Central

Leitch, Victoria D.; Di Cosmo, Caterina; Liao, Xiao-Hui; O’Boy, Sam; Galliford, Thomas M.; Evans, Holly; Croucher, Peter I.; Boyde, Alan; Dumitrescu, Alexandra; Weiss, Roy E.; Refetoff, Samuel; Williams, Graham R.

2017-01-01

T3 is an important regulator of skeletal development and adult bone maintenance. Thyroid hormone action requires efficient transport of T4 and T3 into target cells. We hypothesized that monocarboxylate transporter (MCT) 8, encoded by Mct8 on the X-chromosome, is an essential thyroid hormone transporter in bone. To test this hypothesis, we determined the juvenile and adult skeletal phenotypes of male Mct8 knockout mice (Mct8KO) and Mct8D1D2KO compound mutants, which additionally lack the ability to convert the prohormone T4 to the active hormone T3. Prenatal skeletal development was normal in both Mct8KO and Mct8D1D2KO mice, whereas postnatal endochondral ossification and linear growth were delayed in both Mct8KO and Mct8D1D2KO mice. Furthermore, bone mass and mineralization were decreased in adult Mct8KO and Mct8D1D2KO mice, and compound mutants also had reduced bone strength. Delayed bone development and maturation in Mct8KO and Mct8D1D2KO mice is consistent with decreased thyroid hormone action in growth plate chondrocytes despite elevated serum T3 concentrations, whereas low bone mass and osteoporosis reflects increased thyroid hormone action in adult bone due to elevated systemic T3 levels. These studies identify an essential physiological requirement for MCT8 in chondrocytes, and demonstrate a role for additional transporters in other skeletal cells during adult bone maintenance. PMID:28637283

Mandibular growth and dentoalveolar development in the treatment of class II, division 1, malocclusion using Balters Bionator according to the skeletal maturation.

PubMed

dos Santos-Pinto, Paulo Roberto; Martins, Lídia Parsekian; dos Santos-Pinto, Ary; Gandini Júnior, Luiz Gonzaga; Raveli, Dirceu Barnabé; dos Santos-Pinto, Cristiane Celli Matheus

2013-01-01

The purpose of the study was to evaluate the influence of the skeletal maturation in the mandibular and dentoalveolar growth and development during the Class II, division 1, malocclusion correction with Balters bionator. Three groups of children with Class II, division 1, malocclusion were evaluated. Two of them were treated for one year with the bionator of Balters appliance in different skeletal ages (Group 1: 6 children, 7 to 8 years old and Group 2: 10 children, 9 to 10 years old) and the other one was followed without treatment ( 7 children, 8 to 9 years old). Lateral 45 degree cephalometric radiographs were used for the evaluation of the mandibular growth and dentoalveolar development. Tantalum metallic implants were used as fixed and stable references for radiograph superimposition and data acquisition. Student's t test was used in the statistical analysis of the displacement of the points in the condyle, ramus, mandibular base and dental points. One-fixed criteria analysis of variance was used to evaluate group differences (95% of level of significance). The intragroup evaluation showed that all groups present significant skeletal growth for all points analyzed (1.2 to 3.7 mm), but in an intergroup comparison, the increments of the mandibular growth in the condyle, ramus and mandibular base were not statically different. For the dentoalveolar modifications, the less mature children showed greater labial inclination of the lower incisors (1.86 mm) and the most mature children showed greater first permanent molar extrusion (4.8 mm).

Regulatory elements driving the expression of skeletal lineage reporters differ during bone development and adulthood.

PubMed

Stiers, Pieter-Jan; van Gastel, Nick; Moermans, Karen; Stockmans, Ingrid; Carmeliet, Geert

2017-12-01

To improve bone healing or regeneration more insight in the fate and role of the different skeletal cell types is required. Mouse models for fate mapping and lineage tracing of skeletal cells, using stage-specific promoters, have advanced our understanding of bone development, a process that is largely recapitulated during bone repair. However, validation of these models is often only performed during development, whereas proof of the activity and specificity of the used promoters during the bone regenerative process is limited. Here, we show that the regulatory elements of the 6kb collagen type II promoter are not adequate to drive gene expression during bone repair. Similarly, the 2.3kb promoter of collagen type I lacks activity in adult mice, but the 3.2kb promoter is suitable. Furthermore, Cre-mediated fate mapping allows the visualization of progeny, but this label retention may hinder to distinguish these cells from ones with active expression of the marker at later time points. Together, our results show that the lineage-specific regulatory elements driving gene expression during bone development differ from those required later in life and during bone repair, and justify validation of lineage-specific cell tracing and gene silencing strategies during fracture healing and bone regenerative applications. Copyright © 2017 Elsevier Inc. All rights reserved.

Oxandrolone treatment of constitutional short stature in boys during adolescence: effect on linear growth, bone age, pubic hair, and testicular development.

PubMed

Marti-Henneberg, C; Niirianen, A K; Rappaport, R

1975-05-01

Seventeen constitutionally short boys were studied throughout puberty. Nine received oxandrolone (0.1 mg/kg/day). Treatment was started before onset of puberty. Eight boys served as control subjects. No significant increase in linear growth or skeletal maturation was observed in the treated group. Likewise the peak height velocity was unchanged. Pubic hair developed similarly in both groups in relation to chronologic and skeletal age. The only significant difference was a diminution in testicular volume index during treatment after bone age of 12 years and until bone age of 14 6/12 years.

Naturally derived and synthetic scaffolds for skeletal muscle reconstruction☆

PubMed Central

Wolf, Matthew T.; Dearth, Christopher L.; Sonnenberg, Sonya B.; Loboa, Elizabeth G.; Badylak, Stephen F.

2017-01-01

Skeletal muscle tissue has an inherent capacity for regeneration following injury. However, severe trauma, such as volumetric muscle loss, overwhelms these natural muscle repair mechanisms prompting the search for a tissue engineering/regenerative medicine approach to promote functional skeletal muscle restoration. A desirable approach involves a bioscaffold that simultaneously acts as an inductive microenvironment and as a cell/drug delivery vehicle to encourage muscle ingrowth. Both biologically active, naturally derived materials (such as extracellular matrix) and carefully engineered synthetic polymers have been developed to provide such a muscle regenerative environment. Next generation naturally derived/synthetic “hybrid materials” would combine the advantageous properties of these materials to create an optimal platform for cell/drug delivery and possess inherent bioactive properties. Advances in scaffolds using muscle tissue engineering are reviewed herein. PMID:25174309

Total Body Scanning with Strontium-85 in the Diagnosis of Metastatic Bone Disease

PubMed Central

Simpson, W. J.; Orange, R. P.

1965-01-01

To demonstrate skeletal metastases before radiographic changes were apparent, Sr85 scans were carried out on 46 patients who complained of sketetal pain but whose radiographs were negative. Positive scans were obtained in 34 patients, 20 of whom were subsequently shown to have metastases; three did not have skeletal metastases a year or more later; the outcome is unknown in 11 patients. Twelve patients had negative scans: three ultimately developed metastases, six did not, and three were inconclusive. Autoradiographs demonstrated Sr85 concentrations in areas of reactive osteogenesis. Although not specific for skeletal metastases, Sr85 scans are most helpful in substantiating this diagnosis when radiographic changes are absent. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6 PMID:5839221

A comparison of skeletal maturity assessed by radiological and ultrasonic methods.

PubMed

Utczas, Katinka; Muzsnai, Agota; Cameron, Noel; Zsakai, Annamaria; Bodzsar, Eva B

2017-07-08

The estimation of skeletal maturity is a useful tool in pediatric practice to determine the degree of delay or advancement in growth disorders and the effectiveness of treatment in conditions that influence linear growth. Skeletal maturity of children is commonly assessed using either Greulich-Pyle (GP) or Tanner-Whitehouse methods (TW2 and TW3). However, a less invasive ultrasonic method, that does not use ionizing radiation, has been suggested for use in epidemiological studies of skeletal maturity. The main purpose of the present study was to determine the accuracy of an ultrasonic method based on the GP maturity indicators compared to the standard GP radiographic method. Skeletal maturity of 1502 healthy children, aged from 6 to 18 years, was estimated by quantitative ultrasound and compared to GP bone ages estimated from left hand and wrist radiographs of a subsample of 47 randomly selected participants. The ultrasonic bone age estimation demonstrated very strong correlations with all the radiological age estimations. The correlation coefficients ranged between 0.895 and 0.958, and the strongest correlation of ultrasonic skeletal maturity estimation was found with the Tanner-Whitehouse RUS method. The ultrasonic bone age estimation is suggested for use between the chronological ages of 8.5-16.0 years in boys and 7.5-15.0 years in girls. The ultrasonic bone age estimation is suggested for use in epidemiological surveys since the sensitivity for screening for not normal bone development is appropriate, at least within the 8-15 years age interval. © 2017 Wiley Periodicals, Inc.

Crucial yet divergent roles of mitochondrial redox state in skeletal muscle vs. brown adipose tissue energetics.

PubMed

Mailloux, Ryan J; Adjeitey, Cyril Nii-Klu; Xuan, Jian Ying; Harper, Mary-Ellen

2012-01-01

Reduced glutathione (GSH) is the major determinant of redox balance in mitochondria and as such is fundamental in the control of cellular bioenergetics. GSH is also the most important nonprotein antioxidant molecule in cells. Surprisingly, the effect of redox environment has never been examined in skeletal muscle and brown adipose tissue (BAT), two tissues that have exceptional dynamic range and that are relevant to the development of obesity and related diseases. Here, we show that the redox environment plays crucial, yet divergent, roles in modulating mitochondrial bioenergetics in skeletal muscle and BAT. Skeletal muscle mitochondria were found to naturally have a highly reduced environment (GSH/GSSG≈46), and this was associated with fairly high (∼40%) rates of state 4 (nonphosphorylating) respiration and decreased reactive oxygen species (ROS) emission. The deglutathionylation of uncoupling protein 3 (UCP3) following an increase in the reductive potential of mitochondria results in a further increase in nonphosphorylating respiration (∼20% in situ). BAT mitochondria were found to have a much more oxidized status (GSH/GSSG≈13) and had basal reactive oxygen species emission that was higher (∼250% increase in ROS generation) than that in skeletal muscle mitochondria. When redox status was subsequently increased (i.e., more reduced), UCP1-mediated uncoupling was more sensitive to GDP inhibition. Surprisingly, BAT was found to be devoid of glutaredoxin-2 (Grx2) expression, while there was abundant expression in skeletal muscle. Taken together, these findings reveal the importance of redox environment in controlling bioenergetic functions in both tissues, and the highly unique characteristics of BAT in this regard.

Imaging of Skeletal Disorders Caused by Fibroblast Growth Factor Receptor Gene Mutations.

PubMed

Sargar, Kiran M; Singh, Achint K; Kao, Simon C

2017-10-01

Fibroblast growth factors and fibroblast growth factor receptors (FGFRs) play important roles in human axial and craniofacial skeletal development. FGFR1, FGFR2, and FGFR3 are crucial for both chondrogenesis and osteogenesis. Mutations in the genes encoding FGFRs, types 1-3, are responsible for various skeletal dysplasias and craniosynostosis syndromes. Many of these disorders are relatively common in the pediatric population, and diagnosis is often challenging. These skeletal disorders can be classified based on which FGFR is affected. Skeletal disorders caused by type 1 mutations include Pfeiffer syndrome (PS) and osteoglophonic dysplasia, and disorders caused by type 2 mutations include Crouzon syndrome (CS), Apert syndrome (AS), and PS. Disorders caused by type 3 mutations include achondroplasia, hypochondroplasia, thanatophoric dysplasia (TD), severe achondroplasia with developmental delay and acanthosis nigricans, Crouzonodermoskeletal syndrome, and Muenke syndrome. Most of these mutations are inherited in an autosomal dominant fashion and are gain-of-function-type mutations. Imaging plays a key role in the evaluation of these skeletal disorders. Knowledge of the characteristic imaging and clinical findings can help confirm the correct diagnosis and guide the appropriate molecular genetic tests. Some characteristics and clinical findings include premature fusion of cranial sutures and deviated broad thumbs and toes in PS; premature fusion of cranial sutures and syndactyly of the hands and feet in AS; craniosynostosis, ocular proptosis, and absence of hand and foot abnormalities in CS; rhizomelic limb shortening, caudal narrowing of the lumbar interpediculate distance, small and square iliac wings, and trident hands in achondroplasia; and micromelia, bowing of the femora, and platyspondyly in TD. © RSNA, 2017.

PUFAs acutely affect triacylglycerol-derived skeletal muscle fatty acid uptake and increase postprandial insulin sensitivity.

PubMed

Jans, Anneke; Konings, Ellen; Goossens, Gijs H; Bouwman, Freek G; Moors, Chantalle C; Boekschoten, Mark V; Afman, Lydia A; Müller, Michael; Mariman, Edwin C; Blaak, Ellen E

2012-04-01

Dietary fat quality may influence skeletal muscle lipid processing and fat accumulation, thereby modulating insulin sensitivity. The objective was to examine the acute effects of meals with various fatty acid (FA) compositions on skeletal muscle FA processing and postprandial insulin sensitivity in obese, insulin-resistant men. In a single-blind, randomized, crossover study, 10 insulin-resistant men consumed 3 high-fat mixed meals (2.6 MJ), which were high in SFAs, MUFAs, or PUFAs. Fasting and postprandial skeletal muscle FA processing was examined by measuring differences in arteriovenous concentrations across the forearm muscle. [²H₂]Palmitate was infused intravenously to label endogenous triacylglycerol and FFAs in the circulation, and [U-¹³C]palmitate was added to the meal to label chylomicron-triacylglycerol. Skeletal muscle biopsy samples were taken to assess intramuscular lipid metabolism and gene expression. Insulin and glucose responses (AUC) after the SFA meal were significantly higher than those after the PUFA meal (P = 0.006 and 0.033, respectively). Uptake of triacylglycerol-derived FAs was lower in the postprandial phase after the PUFA meal than after the other meals (AUC₆₀₋₂₄₀; P = 0.02). The fractional synthetic rate of the triacylglycerol, diacylglycerol, and phospholipid pool was higher after the MUFA meal than after the SFA meal. PUFA induced less transcriptional downregulation of oxidative pathways than did the other meals. PUFAs reduced triacylglycerol-derived skeletal muscle FA uptake, which was accompanied by higher postprandial insulin sensitivity, a more transcriptional oxidative phenotype, and altered intramyocellular lipid partitioning and may therefore be protective against the development of insulin resistance.

The Human Skeletal Muscle Proteome Project: a reappraisal of the current literature

PubMed Central

Gonzalez‐Freire, Marta; Semba, Richard D.; Ubaida‐Mohien, Ceereena; Fabbri, Elisa; Scalzo, Paul; Højlund, Kurt; Dufresne, Craig; Lyashkov, Alexey

2016-01-01

Abstract Skeletal muscle is a large organ that accounts for up to half the total mass of the human body. A progressive decline in muscle mass and strength occurs with ageing and in some individuals configures the syndrome of ‘sarcopenia’, a condition that impairs mobility, challenges autonomy, and is a risk factor for mortality. The mechanisms leading to sarcopenia as well as myopathies are still little understood. The Human Skeletal Muscle Proteome Project was initiated with the aim to characterize muscle proteins and how they change with ageing and disease. We conducted an extensive review of the literature and analysed publically available protein databases. A systematic search of peer‐reviewed studies was performed using PubMed. Search terms included ‘human’, ‘skeletal muscle’, ‘proteome’, ‘proteomic(s)’, and ‘mass spectrometry’, ‘liquid chromatography‐mass spectrometry (LC‐MS/MS)’. A catalogue of 5431 non‐redundant muscle proteins identified by mass spectrometry‐based proteomics from 38 peer‐reviewed scientific publications from 2002 to November 2015 was created. We also developed a nosology system for the classification of muscle proteins based on localization and function. Such inventory of proteins should serve as a useful background reference for future research on changes in muscle proteome assessed by quantitative mass spectrometry‐based proteomic approaches that occur with ageing and diseases. This classification and compilation of the human skeletal muscle proteome can be used for the identification and quantification of proteins in skeletal muscle to discover new mechanisms for sarcopenia and specific muscle diseases that can be targeted for the prevention and treatment. PMID:27897395

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.

Disrupted Membrane Structure and Intracellular Ca2+ Signaling in Adult Skeletal Muscle with Acute Knockdown of Bin1

PubMed Central

Tjondrokoesoemo, Andoria; Park, Ki Ho; Ferrante, Christopher; Komazaki, Shinji; Lesniak, Sebastian; Brotto, Marco; Ko, Jae-Kyun; Zhou, Jingsong; Weisleder, Noah; Ma, Jianjie

2011-01-01

Efficient intracellular Ca2+ ([Ca2+]i) homeostasis in skeletal muscle requires intact triad junctional complexes comprised of t-tubule invaginations of plasma membrane and terminal cisternae of sarcoplasmic reticulum. Bin1 consists of a specialized BAR domain that is associated with t-tubule development in skeletal muscle and involved in tethering the dihydropyridine receptors (DHPR) to the t-tubule. Here, we show that Bin1 is important for Ca2+ homeostasis in adult skeletal muscle. Since systemic ablation of Bin1 in mice results in postnatal lethality, in vivo electroporation mediated transfection method was used to deliver RFP-tagged plasmid that produced short –hairpin (sh)RNA targeting Bin1 (shRNA-Bin1) to study the effect of Bin1 knockdown in adult mouse FDB skeletal muscle. Upon confirming the reduction of endogenous Bin1 expression, we showed that shRNA-Bin1 muscle displayed swollen t-tubule structures, indicating that Bin1 is required for the maintenance of intact membrane structure in adult skeletal muscle. Reduced Bin1 expression led to disruption of t-tubule structure that was linked with alterations to intracellular Ca2+ release. Voltage-induced Ca2+ released in isolated single muscle fibers of shRNA-Bin1 showed that both the mean amplitude of Ca2+ current and SR Ca2+ transient were reduced when compared to the shRNA-control, indicating compromised coupling between DHPR and ryanodine receptor 1. The mean frequency of osmotic stress induced Ca2+ sparks was reduced in shRNA-Bin1, indicating compromised DHPR activation. ShRNA-Bin1 fibers also displayed reduced Ca2+ sparks' amplitude that was attributed to decreased total Ca2+ stores in the shRNA-Bin1 fibers. Human mutation of Bin1 is associated with centronuclear myopathy and SH3 domain of Bin1 is important for sarcomeric protein organization in skeletal muscle. Our study showing the importance of Bin1 in the maintenance of intact t-tubule structure and ([Ca2+]i) homeostasis in adult skeletal muscle could provide mechanistic insight on the potential role of Bin1 in skeletal muscle contractility and pathology of myopathy. PMID:21984944

Skeletal muscle is a biological example of a linear electroactive actuator

NASA Astrophysics Data System (ADS)

Lieber, Richard L.

1999-05-01

Skeletal muscle represents a classic biological example of a structure-function relationship. This paper reviews basic muscle anatomy and demonstrates how molecular motion on the order of nm distances is converted into the macroscopic movements that are possible with skeletal muscle. Muscle anatomy provides a structural basis for understanding the basic mechanical properties of skeletal muscle -- namely, the length-tension relationship and the force-velocity relationships. The length-tension relationship illustrates that muscle force generation is extremely length dependent due to the interdigitation of the contractile filaments. The force-velocity relationship is characterized by a rapid force drop in muscle with increasing shortening velocity and a rapid rise in force when muscles are forced to lengthen. Finally, muscle architecture -- the number and arrangement of muscle fibers -- has a profound effect on the magnitude of muscle force generated and the magnitude of muscle excursion. These concepts demonstrate the elegant manner in which muscle acts as a biologically regenerating linear motor. These concepts can be used in developing artificial muscles as well as in performing surgical reconstructive procedures with various donor muscles.

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.

Impact of placental insufficiency on fetal skeletal muscle growth

PubMed Central

Hay, William W.

2016-01-01

Intrauterine growth restriction (IUGR) caused by placental insufficiency is one of the most common and complex problems in perinatology, with no known cure. In pregnancies affected by placental insufficiency, a poorly functioning placenta restricts nutrient supply to the fetus and prevents normal fetal growth. Among other significant deficits in organ development, the IUGR fetus characteristically has less lean body and skeletal muscle mass than their appropriately-grown counterparts. Reduced skeletal muscle growth is not fully compensated after birth, as individuals who were born small for gestational age (SGA) from IUGR have persistent reductions in muscle mass and strength into adulthood. The consequences of restricted muscle growth and accelerated postnatal “catch-up” growth in the form of adiposity may contribute to the increased later life risk for visceral adiposity, peripheral insulin resistance, diabetes, and cardiovascular disease in individuals who were formerly IUGR. This review will discuss how an insufficient placenta results in impaired fetal skeletal muscle growth and how lifelong reductions in muscle mass might contribute to increased metabolic disease risk in this vulnerable population. PMID:26994511

The digital atlas of skeletal maturity by Gilsanz and Ratib: a suitable alternative for age estimation of living individuals in criminal proceedings?

PubMed

Schmidt, Sven; Nitz, Inna; Schulz, Ronald; Tsokos, Michael; Schmeling, Andreas

2009-11-01

As a collection of radiographic standards of the normal hand development with a homogenous degree of maturity of all skeletal elements, the digital atlas of skeletal maturity by Gilsanz and Ratib combines the possibilities of digital imaging with the principle of a conventional atlas method. The present paper analyses the forensic applicability of skeletal age assessment according to Gilsanz and Ratib to age estimation in criminal proceedings. For this, the hand X-rays of 180 children and adolescents aged 10-18 years old were examined retrospectively. For the entire age range, the minima and maxima, the mean values and standard deviations as well as the medians with upper and lower quartiles are specified by sex. For the legally relevant age groups from 14 to 18 years, there is a risk of overestimation of the chronological age of up to 7.2 months in females. The method of Gilsanz and Ratib is therefore only suitable to forensic age estimation in criminal proceedings to a limited extent.

Pharmacological rescue of the dystrophin-glycoprotein complex in Duchenne and Becker skeletal muscle explants by proteasome inhibitor treatment.

PubMed

Assereto, Stefania; Stringara, Silvia; Sotgia, Federica; Bonuccelli, Gloria; Broccolini, Aldobrando; Pedemonte, Marina; Traverso, Monica; Biancheri, Roberta; Zara, Federico; Bruno, Claudio; Lisanti, Michael P; Minetti, Carlo

2006-02-01

In this report, we have developed a novel method to identify compounds that rescue the dystrophin-glycoprotein complex (DGC) in patients with Duchenne or Becker muscular dystrophy. Briefly, freshly isolated skeletal muscle biopsies (termed skeletal muscle explants) from patients with Duchenne or Becker muscular dystrophy were maintained under defined cell culture conditions for a 24-h period in the absence or presence of a specific candidate compound. Using this approach, we have demonstrated that treatment with a well-characterized proteasome inhibitor, MG-132, is sufficient to rescue the expression of dystrophin, beta-dystroglycan, and alpha-sarcoglycan in skeletal muscle explants from patients with Duchenne or Becker muscular dystrophy. These data are consistent with our previous findings regarding systemic treatment with MG-132 in a dystrophin-deficient mdx mouse model (Bonuccelli G, Sotgia F, Schubert W, Park D, Frank PG, Woodman SE, Insabato L, Cammer M, Minetti C, and Lisanti MP. Am J Pathol 163: 1663-1675, 2003). Our present results may have important new implications for the possible pharmacological treatment of Duchenne or Becker muscular dystrophy in humans.

Causes, mechanisms and management of paediatric osteoporosis.

PubMed

Mäkitie, Outi

2013-08-01

Osteoporosis, a skeletal disorder characterized by compromised bone strength and an increased risk of fractures, is an important paediatric disorder that involves almost all paediatric subspecialties. Osteogenesis imperfecta is the most common form of childhood-onset primary osteoporosis, but several other forms are also known. Secondary osteoporosis is caused by an underlying chronic illness or its treatment. The most common causes of secondary osteoporosis include chronic systemic inflammation, glucocorticoid use and neuromuscular disabilities. The skeletal sequelae can present in childhood as low-energy peripheral and vertebral fractures, or become evident in adulthood as low bone mass and an increased propensity to develop osteoporosis. Management should aim at prevention, as interventions to treat symptomatic osteoporosis in the paediatric age group are scarce. Bisphosphonates are the principal pharmacological agents that can be used in this setting, but data on their efficacy and safety in paediatric populations remain inadequate, especially in patients with secondary osteoporosis. Consequently, it is important to understand the potential skeletal effects of paediatric illnesses and their therapies in order to institute effective and timely prevention of skeletal complications.

Study of muscle cell dedifferentiation after skeletal muscle injury of mice with a Cre-Lox system.

PubMed

Mu, Xiaodong; Peng, Hairong; Pan, Haiying; Huard, Johnny; Li, Yong

2011-02-03

Dedifferentiation of muscle cells in the tissue of mammals has yet to be observed. One of the challenges facing the study of skeletal muscle cell dedifferentiation is the availability of a reliable model that can confidentially distinguish differentiated cell populations of myotubes and non-fused mononuclear cells, including stem cells that can coexist within the population of cells being studied. In the current study, we created a Cre/Lox-β-galactosidase system, which can specifically tag differentiated multinuclear myotubes and myotube-generated mononuclear cells based on the activation of the marker gene, β-galactosidase. By using this system in an adult mouse model, we found that β-galactosidase positive mononuclear cells were generated from β-galactosidase positive multinuclear myofibers upon muscle injury. We also demonstrated that these mononuclear cells can develop into a variety of different muscle cell lineages, i.e., myoblasts, satellite cells, and muscle derived stem cells. These novel findings demonstrated, for the first time, that cellular dedifferentiation of skeletal muscle cells actually occurs in mammalian skeletal muscle following traumatic injury in vivo.

DNA methylation assessment from human slow- and fast-twitch skeletal muscle fibers

PubMed Central

Begue, Gwénaëlle; Raue, Ulrika; Jemiolo, Bozena

2017-01-01

A new application of the reduced representation bisulfite sequencing method was developed using low-DNA input to investigate the epigenetic profile of human slow- and fast-twitch skeletal muscle fibers. Successful library construction was completed with as little as 15 ng of DNA, and high-quality sequencing data were obtained with 32 ng of DNA. Analysis identified 143,160 differentially methylated CpG sites across 14,046 genes. In both fiber types, selected genes predominantly expressed in slow or fast fibers were hypomethylated, which was supported by the RNA-sequencing analysis. These are the first fiber type-specific methylation data from human skeletal muscle and provide a unique platform for future research. NEW & NOTEWORTHY This study validates a low-DNA input reduced representation bisulfite sequencing method for human muscle biopsy samples to investigate the methylation patterns at a fiber type-specific level. These are the first fiber type-specific methylation data reported from human skeletal muscle and thus provide initial insight into basal state differences in myosin heavy chain I and IIa muscle fibers among young, healthy men. PMID:28057818

Application of cellular mechanisms to growth and development of food producing animals.

PubMed

Chung, K Y; Johnson, B J

2008-04-01

Postnatal skeletal muscle growth is a result of hypertrophy of existing skeletal muscle fibers in food producing animals. Accumulation of additional nuclei, as a source of DNA, to the multinucleated skeletal muscle fiber aids in fiber hypertrophy during periods of rapid skeletal muscle growth. Muscle satellite cells are recognized as the source of nuclei to support muscle hypertrophy. Exogenous growth-enhancing compounds have been used to modulate growth rate and efficiency in meat animals for over a half century. In cattle, these compounds enhance efficiency of growth by preferentially stimulating skeletal muscle growth compared with adipose tissue. There are 2 main classes of compounds approved for use in cattle in the United States, anabolic steroids and beta-adrenergic agonists (beta-AA). Administration of both trenbolone acetate and estradiol-17beta, as implants, increased carcass protein accumulation 8 to 10% in yearling steers. Muscle satellite cells isolated from steers implanted with trenbolone acetate/ estradiol-17beta had a shorter lag phase in culture compared with satellite cells isolated from control steers. Collectively, these data indicate that activation, increased proliferation, and subsequent fusion of satellite cells in muscles of implanted cattle may be an important mechanism by which anabolic steroids enhance muscle hypertrophy. Oral administration of beta-AA to ruminants does not alter DNA accumulation in skeletal muscle over a typical feeding period (28 to 42 d). Enhanced muscle hypertrophy observed due to beta-AA feeding occurs by direct, receptor-mediated changes in protein synthesis and degradation rates of skeletal muscle tissue. Proper timing of anabolic steroid administration when coupled with beta-AA feeding could result in a synergistic response in skeletal muscle growth due to the effects of anabolic steroids at increasing satellite cell activity, which then can support the rapid hypertrophic changes of the muscle fiber when exposed to beta-AA. At the same time each of these classes of compounds are stimulating lean tissue deposition, they appear to repress adipogenesis in meat animals. Increased knowledge of the mechanism by which growth promoters regulate lean tissue deposition and adipogenesis in meat animals will allow for effective application of these techniques to optimize lean tissue growth and minimize the negative effects on meat quality.

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.

Distinct transcriptomic changes in E14.5 mouse skeletal muscle lacking RYR1 or Cav1.1 converge at E18.5

PubMed Central

Henry, Margit; Rotshteyn, Tamara; Brunn, Anna; Carstov, Mariana; Deckert, Martina; Hescheler, Jürgen; Sachinidis, Agapios; Pfitzer, Gabriele

2018-01-01

In skeletal muscle the coordinated actions of two mechanically coupled Ca2+ channels—the 1,4-dihydropyridine receptor (Cav1.1) and the type 1 ryanodine receptor (RYR1)–underlie the molecular mechanism of rapid cytosolic [Ca2+] increase leading to contraction. While both [Ca2+]i and contractile activity have been implicated in the regulation of myogenesis, less is known about potential specific roles of Cav1.1 and RYR1 in skeletal muscle development. In this study, we analyzed the histology and the transcriptomic changes occurring at E14.5 –the end of primary myogenesis and around the onset of intrauterine limb movement, and at E18.5 –the end of secondary myogenesis, in WT, RYR1-/-, and Cav1.1-/- murine limb skeletal muscle. At E14.5 the muscle histology of both mutants exhibited initial alterations, which became much more severe at E18.5. Immunohistological analysis also revealed higher levels of activated caspase-3 in the Cav1.1-/- muscles at E14.5, indicating an increase in apoptosis. With WT littermates as controls, microarray analyses identified 61 and 97 differentially regulated genes (DEGs) at E14.5, and 493 and 1047 DEGs at E18.5, in RYR1-/- and Cav1.1-/- samples, respectively. Gene enrichment analysis detected no overlap in the affected biological processes and pathways in the two mutants at E14.5, whereas at E18.5 there was a significant overlap of DEGs in both mutants, affecting predominantly processes linked to muscle contraction. Moreover, the E18.5 vs. E14.5 comparison revealed multiple genotype-specific DEGs involved in contraction, cell cycle and miRNA-mediated signaling in WT, neuronal and bone development in RYR1-/-, and lipid metabolism in Cav1.1-/- samples. Taken together, our study reveals discrete changes in the global transcriptome occurring in limb skeletal muscle from E14.5 to E18.5 in WT, RYR1-/- and Cav1.1-/- mice. Our results suggest distinct functional roles for RYR1 and Cav1.1 in skeletal primary and secondary myogenesis. PMID:29543863

Williams installs CBEF Cell Mechanosensing Humidifier

NASA Image and Video Library

2016-04-01

ISS047e032018 (04/01/2016) --- NASA astronaut Jeff Williams works to install the Cell Biology Experiment Facility (CBEF) Cell Mechanosensing Humidifier. Cell Mechanosensing is a Japan Aerospace Exploration Agency (JAXA) investigation that identifies gravity sensors in skeletal muscle cells to develop countermeasures to muscle atrophy, a key space health issue. Scientists believe that the lack of mechanical stress from gravity causes tension fluctuations in the plasma membrane of skeletal muscle cells which changes the expression of key proteins and genes, and allows muscles to atrophy.

Synovial osteochondromatosis in hereditary arthro-ophthalmopathy (Wagner-Stickler syndrome).

PubMed

Tins, Bernhard; Cassar-Pullicino, Victor

2003-05-01

A case of bilateral synovial osteochondromatosis in a patient with hereditary arthro-ophthalmopathy is presented. The osteochondral lesions were largely calcified in one joint and largely chondromatous in the other. Typical features of hereditary arthro-ophthalmopathy are reviewed and it is hypothesised that the abnormal collagen in this syndrome is responsible for the development of synovial osteochondromatosis. Synovial manifestations of skeletal dysplasias have to our knowledge not been described previously but we suggest that synovial osteochondromatosis can be the manifestation of an underlying skeletal dysplasia.

High skeletal muscle adenylate cyclase in malignant hyperthermia.

PubMed Central

Willner, J H; Cerri, C G; Wood, D S

1981-01-01

Malignant hyperthermia occurs in humans with several congenital myopathies, usually in response to general anesthesia. Commonly, individuals who develop this syndrome lack symptoms of muscle disease, and their muscle lacks specific pathological changes. A biochemical marker for this myopathy has not previously been available; we found activity of adenylate cyclase and content of cyclic AMP to be abnormally high in skeletal muscle. Secondary modification of protein phosphorylation could explain observed abnormalities of phosphorylase activation and sarcoplasmic reticulum function. PMID:6271806

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

Skeletal stem cell isolation: A review on the state-of-the-art microfluidic label-free sorting techniques.

PubMed

Xavier, Miguel; Oreffo, Richard O C; Morgan, Hywel

2016-01-01

Skeletal stem cells (SSC) are a sub-population of bone marrow stromal cells that reside in postnatal bone marrow with osteogenic, chondrogenic and adipogenic differentiation potential. SSCs reside only in the bone marrow and have organisational and regulatory functions in the bone marrow microenvironment and give rise to the haematopoiesis-supportive stroma. Their differentiation capacity is restricted to skeletal lineages and therefore the term SSC should be clearly distinguished from mesenchymal stem cells which are reported to exist in extra-skeletal tissues and, critically, do not contribute to skeletal development. SSCs are responsible for the unique regeneration capacity of bone and offer unlimited potential for application in bone regenerative therapies. A current unmet challenge is the isolation of homogeneous populations of SSCs, in vitro, with homogeneous regeneration and differentiation capacities. Challenges that limit SSC isolation include a) the scarcity of SSCs in bone marrow aspirates, estimated at between 1 in 10-100,000 mononuclear cells; b) the absence of specific markers and thus the phenotypic ambiguity of the SSC and c) the complexity of bone marrow tissue. Microfluidics provides innovative approaches for cell separation based on bio-physical features of single cells. Here we review the physical principles underlying label-free microfluidic sorting techniques and review their capacity for stem cell selection/sorting from complex (heterogeneous) samples. Copyright © 2016 Elsevier Inc. All rights reserved.

Skeletal Responses to Long-Duration Simulated Weightlessness in Rats

NASA Technical Reports Server (NTRS)

Adams, Julia; Torres, Samantha; Schreurs, Ann-Sofie; Alwood, Joshua S.; Shirazi-Fard, Yasaman; Tahimic, Candice; Globus, Ruth

2017-01-01

Damaging effects due to spaceflight and long-duration weightlessness are seen in the musculoskeletal system, specifically with regards to bone loss, bone resorption, and changes in overall bone structure. These adverse effects are all seen with indicators of oxidative stress and a variation in the levels of oxidative gene expression. Once gravity is restored, however, the recovery is slow and incomplete. Despite this, few reports have investigated the correlation between oxidative damage and general modifications within the bone. In this project, we will make use of a ground-based model of simulated weightlessness (hindlimb unloading, HU) in order to observe skeletal changes in response to induced microgravity due to changes in oxidative pressures. With this model we will analyze samples at 14-day and 90-day time points following HU for the determination of acute and chronic effects, each with corresponding controls. We hypothesize that simulated microgravity will lead to skeletal adaptations including time-dependent activation of pro-oxidative processes and pro-osteoclastogenic signals related to the progression, plateau, and recovery of the bone. Microcomputed tomography techniques will be utilized to measure skeletal changes in response to HU. With the results of this study, we hope to further the understanding of skeletal affects as a result of long-duration weightlessness and develop countermeasures to combat bone loss in spaceflight and osteoporosis on Earth.

An Antibody Blocking Activin Type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

PubMed Central

Minetti, Giulia C.; Sheppard, KellyAnn; Ibebunjo, Chikwendu; Feige, Jerome N.; Hartmann, Steffen; Brachat, Sophie; Rivet, Helene; Koelbing, Claudia; Morvan, Frederic; Hatakeyama, Shinji

2014-01-01

The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 prevents myostatin- or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings. PMID:24298022

A modern documented Italian identified skeletal collection of 2127 skeletons: the CAL Milano Cemetery Skeletal Collection.

PubMed

Cattaneo, Cristina; Mazzarelli, Debora; Cappella, Annalisa; Castoldi, Elisa; Mattia, Mirko; Poppa, Pasquale; De Angelis, Danilo; Vitello, Antonio; Biehler-Gomez, Lucie

2018-06-01

The CAL Milano Cemetery Skeletal Collection is a modern and continuously growing identified osteological collection of 2127 skeletons under study in the Laboratorio di Antropologia e Odontologia Forense (LABANOF) in the Department of Biomedical Sciences for Health of the University of Milan (Italy), and part of the Collezione Antropologica LABANOF (CAL). The collection presents individuals of both sexes and of all age groups with a high representation of the elderly and an interesting sample of infants. Each individual is associated with a documentation that includes sex, age-at-death, dates of birth and death, and a death certificate that specifies the exact cause of death and the chain of events that led to it (related pathological conditions or traumatic events). It was also possible to recover for several individuals the autopsy reports and antemortem photographs. This documented osteological collection is of crucial interest in physical and forensic anthropology: it provides unique teaching opportunities and more importantly considerable research possibilities to test and develop sex and age estimation methods, investigate key subjects of forensic relevance and discuss pathological markers, among others. The aim of this paper is to introduce the CAL Milano Cemetery Skeletal Collection as a new identified skeletal collection and present its research and teaching potential. Copyright © 2018 Elsevier B.V. All rights reserved.

Genetics Home Reference: osteoglophonic dysplasia

MedlinePlus

... as cell division, regulation of cell growth and maturation, formation of blood vessels, wound healing, and embryonic development. In particular, they play a major role in skeletal development. The FGFR1 protein spans the cell membrane, ...

Hox11 genes regulate postnatal longitudinal bone growth and growth plate proliferation.

PubMed

Pineault, Kyriel M; Swinehart, Ilea T; Garthus, Kayla N; Ho, Edward; Yao, Qing; Schipani, Ernestina; Kozloff, Kenneth M; Wellik, Deneen M

2015-10-23

Hox genes are critical regulators of skeletal development and Hox9-13 paralogs, specifically, are necessary for appendicular development along the proximal to distal axis. Loss of function of both Hoxa11 and Hoxd11 results in severe malformation of the forelimb zeugopod. In the radius and ulna of these mutants, chondrocyte development is perturbed, growth plates are not established, and skeletal growth and maturation fails. In compound mutants in which one of the four Hox11 alleles remains wild-type, establishment of a growth plate is preserved and embryos develop normally through newborn stages, however, skeletal phenotypes become evident postnatally. During postnatal development, the radial and ulnar growth rate slows compared to wild-type controls and terminal bone length is reduced. Growth plate height is decreased in mutants and premature growth plate senescence occurs along with abnormally high levels of chondrocyte proliferation in the reserve and proliferative zones. Compound mutants additionally develop an abnormal curvature of the radius, which causes significant distortion of the carpal elements. The progressive bowing of the radius appears to result from physical constraint caused by the disproportionately slower growth of the ulna than the radius. Collectively, these data are consistent with premature depletion of forelimb zeugopod progenitor cells in the growth plate of Hox11 compound mutants, and demonstrate a continued function for Hox genes in postnatal bone growth and patterning. © 2015. Published by The Company of Biologists Ltd.

Skeletal development of the glenoid and glenoid-coracoid interface in the pediatric population: MRI features.

PubMed

Kothary, Shefali; Rosenberg, Zehava Sadka; Poncinelli, Leonardo L; Kwong, Steven

2014-09-01

To assess the MRI appearance of normal skeletal development of the glenoid and glenoid-coracoid interface in the pediatric population. To the best of our knowledge, this has not yet been studied in detail in the literature. An IRB-approved, HIPAA-compliant retrospective review of 105 consecutive shoulder MRI studies in children, ages 2 months to 18 years was performed. The morphology, MR signal, and development of the following were assessed: (1) scapular-coracoid bipolar growth plate, (2) glenoid and glenoid-coracoid interface secondary ossification centers, (3) glenoid advancing osseous surface. The glenoid and glenoid-coracoid interface were identified in infancy as a contiguous, cartilaginous mass. A subcoracoid secondary ossification center in the superior glenoid was identified and fused in all by age 12 and 16, respectively. In ten studies, additional secondary ossification centers were identified in the inferior two-thirds of the glenoid. The initial concavity of the glenoid osseous surface gradually transformed to convexity, matching the convex glenoid articular surface. The glenoid growth plate fused by 16 years of age. Our study, based on MRI, demonstrated a similar pattern of development of the glenoid and glenoid coracoid interface to previously reported anatomic and radiographic studies, except for an earlier development and fusion of the secondary ossification centers of the inferior glenoid. The pattern of skeletal development of the glenoid and glenoid-coracoid interface follows a chronological order, which can serve as a guideline when interpreting MRI studies in children.

Identification of specific malformations of sea urchin larvae for toxicity assessment: application to marine pisciculture effluents.

PubMed

Carballeira, C; Ramos-Gómez, J; Martín-Díaz, L; DelValls, T A

2012-06-01

Standard toxicity screening tests are useful tools in the management of impacted coastal ecosystems. To our knowledge, this is the first time that the sea urchin embryo development test has been used to evaluate the potential impact of effluents from land-based aquaculture farms in coastal areas. The toxicity of effluents from 8 land-based turbot farms was determined by calculating the percentage of abnormal larvae, according to two criteria: (a) standard, considering as normal pyramid-shaped larvae with differentiated components, and (b) skeletal, a new criterion that considers detailed skeletal characteristics. The skeletal criterion appeared to be more sensitive and enabled calculation of effective concentrations EC(5), EC(10), EC(20) and EC(50), unlike the classical criterion. Inclusion of the skeleton criterion in the sea urchin embryo development test may be useful for categorizing the relatively low toxicity of discharges from land-based marine fish farms. Further studies are encouraged to establish any causative relationships between pollutants and specific larval deformities. Copyright © 2012 Elsevier Ltd. All rights reserved.

Mest but Not MiR-335 Affects Skeletal Muscle Growth and Regeneration

PubMed Central

Hiramuki, Yosuke; Sato, Takahiko; Furuta, Yasuhide; Surani, M. Azim; Sehara-Fujisawa, Atsuko

2015-01-01

When skeletal muscle fibers are injured, they regenerate and grow until their sizes are adjusted to surrounding muscle fibers and other relevant organs. In this study, we examined whether Mest, one of paternally expressed imprinted genes that regulates body size during development, and miR-335 located in the second intron of the Mest gene play roles in muscle regeneration. We generated miR-335-deficient mice, and found that miR-335 is a paternally expressed imprinted microRNA. Although both Mest and miR-335 are highly expressed during muscle development and regeneration, only Mest+/- (maternal/paternal) mice show retardation of body growth. In addition to reduced body weight in Mest+/-; DMD-null mice, decreased muscle growth was observed in Mest+/- mice during cardiotoxin-induced regeneration, suggesting roles of Mest in muscle regeneration. Moreover, expressions of H19 and Igf2r, maternally expressed imprinted genes were affected in tibialis anterior muscle of Mest+/-; DMD-null mice compared to DMD-null mice. Thus, Mest likely mediates muscle regeneration through regulation of imprinted gene networks in skeletal muscle. PMID:26098312

Mest but Not MiR-335 Affects Skeletal Muscle Growth and Regeneration.

PubMed

Hiramuki, Yosuke; Sato, Takahiko; Furuta, Yasuhide; Surani, M Azim; Sehara-Fujisawa, Atsuko

2015-01-01

When skeletal muscle fibers are injured, they regenerate and grow until their sizes are adjusted to surrounding muscle fibers and other relevant organs. In this study, we examined whether Mest, one of paternally expressed imprinted genes that regulates body size during development, and miR-335 located in the second intron of the Mest gene play roles in muscle regeneration. We generated miR-335-deficient mice, and found that miR-335 is a paternally expressed imprinted microRNA. Although both Mest and miR-335 are highly expressed during muscle development and regeneration, only Mest+/- (maternal/paternal) mice show retardation of body growth. In addition to reduced body weight in Mest+/-; DMD-null mice, decreased muscle growth was observed in Mest+/- mice during cardiotoxin-induced regeneration, suggesting roles of Mest in muscle regeneration. Moreover, expressions of H19 and Igf2r, maternally expressed imprinted genes were affected in tibialis anterior muscle of Mest+/-; DMD-null mice compared to DMD-null mice. Thus, Mest likely mediates muscle regeneration through regulation of imprinted gene networks in skeletal muscle.

The effect of weather on morphometric traits of juvenile cliff swallows

USGS Publications Warehouse

Roche, Erin A.; Brown, Mary Bomberger; Brown, Charles R.

2015-01-01

Episodes of food deprivation may change how nestling birds allocate energy to the growth of skeletal and feather morphological traits during development. Cliff swallows (Petrochelidon pyrrhonota) are colonial, insectivorous birds that regularly experience brief periods of severe weather-induced food deprivation during the nesting season which may affect offspring development. We investigated how annual variation in timing of rearing and weather were associated with length of wing and tail, skeletal traits, and body mass in juvenile cliff swallows reared in southwestern Nebraska during 2001–2006. As predicted under conditions of food deprivation, nestling skeletal and feather measurements were generally smaller in cooler years. However, variability explained by weather was small, suggesting that morphometric traits of juvenile cliff swallows were not highly sensitive to weather conditions experienced during this study. Measurements of juvenile morphological traits were positively correlated with measurements taken as adults, meaning that any variation among juveniles in response to rearing conditions showed evidence of persisting into a bird’s first breeding season. Our results show that body size in this species is phenotypically plastic and influenced, in part, by weather variables.

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.

Imaging deep skeletal muscle structure using a high-sensitivity ultrathin side-viewing optical coherence tomography needle probe

PubMed Central

Yang, Xiaojie; Lorenser, Dirk; McLaughlin, Robert A.; Kirk, Rodney W.; Edmond, Matthew; Simpson, M. Cather; Grounds, Miranda D.; Sampson, David D.

2013-01-01

We have developed an extremely miniaturized optical coherence tomography (OCT) needle probe (outer diameter 310 µm) with high sensitivity (108 dB) to enable minimally invasive imaging of cellular structure deep within skeletal muscle. Three-dimensional volumetric images were acquired from ex vivo mouse tissue, examining both healthy and pathological dystrophic muscle. Individual myofibers were visualized as striations in the images. Degradation of cellular structure in necrotic regions was seen as a loss of these striations. Tendon and connective tissue were also visualized. The observed structures were validated against co-registered hematoxylin and eosin (H&E) histology sections. These images of internal cellular structure of skeletal muscle acquired with an OCT needle probe demonstrate the potential of this technique to visualize structure at the microscopic level deep in biological tissue in situ. PMID:24466482

[Contribution of the cervical vertebral maturation (CVM) method to dentofacial orthopedics: update].

PubMed

Elhaddaoui, R; Benyahia, H; Azaroual, F; Zaoui, F

2014-11-01

The successful orthopedic treatment of skeletal Class II malocclusions is closely related to the reasoned determination of the optimal time to initiate the treatment. This is why various methods have been proposed to assess skeletal maturation, such as a hand-wrist radiograph or the cervical vertebral maturation (CVM) method. The hand-wrist radiograph was up to now the most frequently used method to assess skeletal maturation. However, the clinical and biological limitations of this technique, as well as the need to perform an additional radiograph, were reasons to develop another method to explore the maturation stages of visible cervical vertebrae on a simple lateral cephalometric radiograph. The authors compare the 2 methods and prove the greater contribution of the CVM method compared to the hand-wrist radiograph. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

The skeletal consequences of thyrotoxicosis.

PubMed

Nicholls, Jonathan J; Brassill, Mary Jane; Williams, Graham R; Bassett, J H Duncan

2012-06-01

Euthyroid status is essential for normal skeletal development and the maintenance of adult bone structure and strength. Established thyrotoxicosis has long been recognised as a cause of high bone turnover osteoporosis and fracture but more recent studies have suggested that subclinical hyperthyroidism and long-term suppressive doses of thyroxine (T4) may also result in decreased bone mineral density (BMD) and an increased risk of fragility fracture, particularly in postmenopausal women. Furthermore, large population studies of euthyroid individuals have demonstrated that a hypothalamic-pituitary-thyroid axis set point at the upper end of the normal reference range is associated with reduced BMD and increased fracture susceptibility. Despite these findings, the cellular and molecular mechanisms of thyroid hormone action in bone remain controversial and incompletely understood. In this review, we discuss the role of thyroid hormones in bone and the skeletal consequences of hyperthyroidism.

Cross-sectional growth changes in skeletal and soft tissue cephalometric landmarks of children.

PubMed

Inada, Emi; Saitoh, Issei; Hayasaki, Haruaki; Yamada, Chiaki; Iwase, Yoko; Takemoto, Yoshihiko; Matsumoto, Yuko; Yamasaki, Youichi

2008-07-01

In order to provide standard values for craniofacial growth of normal children, we evaluated the growth changes of skeletal and soft tissue cephalometric landmarks from lateral cephalograms of 180 Japanese children. They were divided into three groups: primary dentition, mixed dentition, and permanent dentition. Specific skeletal angles and distances showed significant gender differences with increasing age. The only significant soft tissue gender difference was nose height in the oldest group. Upper pharynx dimension and nose height differed significantly among the groups in both genders. Positions of both the upper and lower lip changed significantly between the intermediate and oldest groups of both genders. Nasolabial angle did not change significantly with growth. The results of this study should be useful for predicting craniofacial growth and development or determining the effect of orthodontic treatment.

Cell Science and Cell Biology Research at MSFC: Summary

NASA Technical Reports Server (NTRS)

2003-01-01

The common theme of these research programs is that they investigate regulation of gene expression in cells, and ultimately gene expression is controlled by the macromolecular interactions between regulatory proteins and DNA. The NASA Critical Path Roadmap identifies Muscle Alterations and Atrophy and Radiation Effects as Very Serious Risks and Severe Risks, respectively, in long term space flights. The specific problem addressed by Dr. Young's research ("Skeletal Muscle Atrophy and Muscle Cell Signaling") is that skeletal muscle loss in space cannot be prevented by vigorous exercise. Aerobic skeletal muscles (i.e., red muscles) undergo the most extensive atrophy during long-term space flight. Of the many different potential avenues for preventing muscle atrophy, Dr. Young has chosen to study the beta-adrenergic receptor (betaAR) pathway. The reason for this choice is that a family of compounds called betaAR agonists will preferentially cause an increase in muscle mass of aerobic muscles (i.e., red muscle) in animals, potentially providing a specific pharmacological solution to muscle loss in microgravity. In addition, muscle atrophy is a widespread medical problem in neuromuscular diseases, spinal cord injury, lack of exercise, aging, and any disease requiring prolonged bedridden status. Skeletal muscle cells in cell culture are utilized as a model system to study this problem. Dr. Richmond's research ("Radiation & Cancer Biology of Mammary Cells in Culture") is directed toward developing a laboratory model for use in risk assessment of cancer caused by space radiation. This research is unique because a human model will be developed utilizing human mammary cells that are highly susceptible to tumor development. This approach is preferential over using animal cells because of problems in comparing radiation-induced cancers between humans and animals.

Downregulation of lipin-1 induces insulin resistance by increasing intracellular ceramide accumulation in C2C12 myotubes

PubMed Central

Huang, Shujuan; Huang, Suling; Wang, Xi; Zhang, Qingli; Liu, Jia; Leng, Ying

2017-01-01

Dysregulation of lipid metabolism in skeletal muscle is involved in the development of insulin resistance. Mutations in lipin-1, a key lipid metabolism regulator leads to significant systemic insulin resistance in fld mice. However, the function of lipin-1 on lipid metabolism and insulin sensitivity in skeletal muscle is still unclear. Herein we demonstrated that downregulation of lipin-1 in C2C12 myotubes by siRNA transfection suppressed insulin action, characterized by reduced insulin stimulated Akt phosphorylation and glucose uptake. Correspondingly, decreased lipin-1 expression was observed in palmitate-induced insulin resistance in C2C12 myotubes, suggested that lipin-1 might play a role in the etiology of insulin resistance in skeletal muscle. The insulin resistance induced by lipin-1 downregulation was related to the disturbance of lipid homeostasis. Lipin-1 silencing reduced intracellular DAG and TAG levels, but elevated ceramide accumulation in C2C12 myotubes. Moreover, the impaired insulin stimulated Akt phosphorylation and glucose uptake caused by lipin-1 silencing could be blocked by the pretreatment with SPT inhibitor myriocin, ceramide synthase inhibitor FB1, or PP2A inhibitor okadaic acid, suggested that the increased ceramide accumulation might be responsible for the development of insulin resistance induced by lipin-1 silencing in C2C12 myotubes. Meanwhile, decreased lipin-1 expression also impaired mitochondrial function in C2C12 myotubes. Therefore, our study suggests that lipin-1 plays an important role in lipid metabolism and downregulation of lipin-1 induces insulin resistance by increasing intracellular ceramide accumulation in C2C12 myotubes. These results offer a molecular insight into the role of lipin-1 in the development of insulin resistance in skeletal muscle. PMID:28123341

Downregulation of lipin-1 induces insulin resistance by increasing intracellular ceramide accumulation in C2C12 myotubes.

PubMed

Huang, Shujuan; Huang, Suling; Wang, Xi; Zhang, Qingli; Liu, Jia; Leng, Ying

2017-01-01

Dysregulation of lipid metabolism in skeletal muscle is involved in the development of insulin resistance. Mutations in lipin-1, a key lipid metabolism regulator leads to significant systemic insulin resistance in fld mice. However, the function of lipin-1 on lipid metabolism and insulin sensitivity in skeletal muscle is still unclear. Herein we demonstrated that downregulation of lipin-1 in C2C12 myotubes by siRNA transfection suppressed insulin action, characterized by reduced insulin stimulated Akt phosphorylation and glucose uptake. Correspondingly, decreased lipin-1 expression was observed in palmitate-induced insulin resistance in C2C12 myotubes, suggested that lipin-1 might play a role in the etiology of insulin resistance in skeletal muscle. The insulin resistance induced by lipin-1 downregulation was related to the disturbance of lipid homeostasis. Lipin-1 silencing reduced intracellular DAG and TAG levels, but elevated ceramide accumulation in C2C12 myotubes. Moreover, the impaired insulin stimulated Akt phosphorylation and glucose uptake caused by lipin-1 silencing could be blocked by the pretreatment with SPT inhibitor myriocin, ceramide synthase inhibitor FB1, or PP2A inhibitor okadaic acid, suggested that the increased ceramide accumulation might be responsible for the development of insulin resistance induced by lipin-1 silencing in C2C12 myotubes. Meanwhile, decreased lipin-1 expression also impaired mitochondrial function in C2C12 myotubes. Therefore, our study suggests that lipin-1 plays an important role in lipid metabolism and downregulation of lipin-1 induces insulin resistance by increasing intracellular ceramide accumulation in C2C12 myotubes. These results offer a molecular insight into the role of lipin-1 in the development of insulin resistance in skeletal muscle.

Follistatin in chondrocytes: the link between TRPV4 channelopathies and skeletal malformations

PubMed Central

Leddy, Holly A.; McNulty, Amy L.; Lee, Suk Hee; Rothfusz, Nicole E.; Gloss, Bernd; Kirby, Margaret L.; Hutson, Mary R.; Cohn, Daniel H.; Guilak, Farshid; Liedtke, Wolfgang

2014-01-01

Point mutations in the calcium-permeable TRPV4 ion channel have been identified as the cause of autosomal-dominant human motor neuropathies, arthropathies, and skeletal malformations of varying severity. The objective of this study was to determine the mechanism by which TRPV4 channelopathy mutations cause skeletal dysplasia. The human TRPV4V620I channelopathy mutation was transfected into primary porcine chondrocytes and caused significant (2.6-fold) up-regulation of follistatin (FST) expression levels. Pore altering mutations that prevent calcium influx through the channel prevented significant FST up-regulation (1.1-fold). We generated a mouse model of theTRPV4V620I mutation, and found significant skeletal deformities (e.g., shortening of tibiae and digits, similar to the human disease brachyolmia) and increases in Fst/TRPV4 mRNA levels (2.8-fold). FST was significantly up-regulated in primary chondrocytes transfected with 3 different dysplasia-causing TRPV4 mutations (2- to 2.3-fold), but was not affected by an arthropathy mutation (1.1-fold). Furthermore, FST-loaded microbeads decreased bone ossification in developing chick femora (6%) and tibiae (11%). FST gene and protein levels were also increased 4-fold in human chondrocytes from an individual natively expressing the TRPV4T89I mutation. Taken together, these data strongly support that up-regulation of FST in chondrocytes by skeletal dysplasia-inducing TRPV4 mutations contributes to disease pathogenesis.—Leddy, H. A., McNulty, A. L., Lee, S. H., Rothfusz, N. E., Gloss, B., Kirby, M. L., Hutson, M. R., Cohn, D. H., Guilak, F., Liedtke, W. Follistatin in chondrocytes: the link between TRPV4 channelopathies and skeletal malformations. PMID:24577120

Considerations in high resolution skeletal muscle DTI using single-shot EPI with stimulated echo preparation and SENSE

PubMed Central

Karampinos, Dimitrios C.; Banerjee, Suchandrima; King, Kevin F.; Link, Thomas M.; Majumdar, Sharmila

2011-01-01

Previous studies have shown that skeletal muscle diffusion tensor imaging (DTI) can non-invasively probe changes in the muscle fiber architecture and microstructure in diseased and damaged muscles. However, DTI fiber reconstruction in small muscles and in muscle regions close to aponeuroses and tendons remains challenging because of partial volume effects. Increasing the spatial resolution of skeletal muscle single-shot diffusion weighted (DW)-EPI can be hindered by the inherently low SNR of muscle DW-EPI due to the short muscle T2 and the high sensitivity of single-shot EPI to off-resonance effects and T2* blurring. In the present work, eddy-current compensated diffusion-weighted stimulated echo preparation is combined with sensitivity encoding (SENSE) to maintain good SNR properties and reduce the sensitivity to distortions and T2* blurring in high resolution skeletal muscle single-shot DW-EPI. An analytical framework is developed for optimizing the reduction factor and diffusion weighting time to achieve maximum SNR. Arguments for the selection of the experimental parameters are then presented considering the compromise between SNR, B0-induced distortions, T2* blurring effects and tissue incoherent motion effects. Based on the selected parameters in a high resolution skeletal muscle single-shot DW-EPI protocol, imaging protocols at lower acquisition matrix sizes are defined with matched bandwidth in the phase-encoding direction and SNR. In vivo results show that high resolution skeletal muscle DTI with minimized sensitivity to geometric distortions and T2* blurring is feasible using the proposed methodology. In particular, a significant benefit is demonstrated from reducing partial volume effects on resolving multi-pennate muscles and muscles with small cross sections in calf muscle DTI. PMID:22081519

Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction

PubMed Central

Zizola, Cynthia; Kennel, Peter J.; Akashi, Hirokazu; Ji, Ruiping; Castillero, Estibaliz; George, Isaac; Homma, Shunichi

2015-01-01

Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF. PMID:25713305

Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction.

PubMed

Zizola, Cynthia; Kennel, Peter J; Akashi, Hirokazu; Ji, Ruiping; Castillero, Estibaliz; George, Isaac; Homma, Shunichi; Schulze, P Christian

2015-05-01

Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF. Copyright © 2015 the American Physiological Society.

Biomineralization in Newly Settled Recruits of the Scleractinian Coral Pocillopora damicornis

NASA Astrophysics Data System (ADS)

Meibom, A.; Gilis, M.; Domart-Coulon, I.; Grauby, O.; Stolarski, J.; Baronnet, A.

2014-12-01

Calcium carbonate biomineralization of scleractinian coral recruits is fundamental to the construction of reefs and their survival under stress from global and local environmental change. Establishing a baseline for how normal, healthy coral recruits initiate skeletal formation is therefore warranted. We present a multiscale, microscopic and spectroscopic investigation of skeletal elements deposited by Pocillopora damicornis recruits, from 12 h to 22 days after settlement in aquarium on a flat substrate. Six growth stages are defined, primarily based on appearance and morphology of successively deposited skeletal structures, with the following average formation timescales: A (<24 h), B (24-36 h), C (36-48 h), D (48- 72 h), E (72-96 h), and F (>10 days). Raman and energy dispersive X-ray spectroscopy indicate the presence of calcite among the earliest components of the basal plate, which consist of micrometer-sized, rod-shaped crystals with rhom- boidal habit. All later CaCO3 skeletal structures are composed exclusively of aragonite. High-resolution scanning electron microscopy reveals that, externally, all CaCO3 deposits consist of <100 nm granular units. Fusiform, dumbbell-like, and semispherulitic structures, 25-35 mm in longest dimension, occur only during the earliest stages (Stages A-C), with morphologies similar to structures formed abiotically or induced by organics in in vitro carbonate crystallization experiments. All other skeletal structures of the basal plate are composed of vertically extending lamellar bundles of granules. From Stage D, straight fibrils, 40-45 nm in width and presumably of organic composition, form bridges between these aragonitic bundles emerging from the growing front of fusing skeletal structures. Our results show a clear evolution in the coral polyp biomineralization process as the carbonate structures develop toward those characterizing the adult skeleton.

Biomineralization in newly settled recruits of the scleractinian coral Pocillopora damicornis.

PubMed

Gilis, Melany; Meibom, Anders; Domart-Coulon, Isabelle; Grauby, Olivier; Stolarski, Jarosław; Baronnet, Alain

2014-12-01

Calcium carbonate biomineralization of scleractinian coral recruits is fundamental to the construction of reefs and their survival under stress from global and local environmental change. Establishing a baseline for how normal, healthy coral recruits initiate skeletal formation is, therefore, warranted. Here, we present a thorough, multiscale, microscopic and spectroscopic investigation of skeletal elements deposited by Pocillopora damicornis recruits, from 12 h to 22 days after settlement in aquarium on a flat substrate. Six growth stages are defined, primarily based on appearance and morphology of successively deposited skeletal structures, with the following average formation time-scales: A (<24 h), B (24-36 h), C (36-48 h), D (48-72 h), E (72-96 h), and F (>10 days). Raman and energy dispersive X-ray spectroscopy indicate the presence of calcite among the earliest components of the basal plate, which consist of micrometer-sized, rod-shaped crystals with rhomboidal habit. All later CaCO3 skeletal structures are composed exclusively of aragonite. High-resolution scanning electron microscopy reveals that, externally, all CaCO3 deposits consist of <100 nm granular units. Fusiform, dumbbell-like, and semispherulitic structures, 25-35 µm in longest dimension, occur only during the earliest stages (Stages A-C), with morphologies similar to structures formed abiotically or induced by organics in in vitro carbonate crystallization experiments. All other skeletal structures of the basal plate are composed of vertically extending lamellar bundles of granules. From Stage D, straight fibrils, 40-45 nm in width and presumably of organic composition, form bridges between these aragonitic bundles emerging from the growing front of fusing skeletal structures. Our results show a clear evolution in the coral polyp biomineralization process as the carbonate structures develop toward those characterizing the adult skeleton. © 2014 Wiley Periodicals, Inc.

Muscle-specific inflammation induced by MCP-1 overexpression does not affect whole-body insulin sensitivity in mice.

PubMed

Evers-van Gogh, Inkie J A; Oteng, Antwi-Boasiako; Alex, Sheril; Hamers, Nicole; Catoire, Milene; Stienstra, Rinke; Kalkhoven, Eric; Kersten, Sander

2016-03-01

Obesity is associated with a state of chronic low-grade inflammation that is believed to contribute to the development of skeletal muscle insulin resistance. However, the extent to which local and systemic elevation of cytokines, such as monocyte chemoattractant protein 1 (MCP-1), interferes with the action of insulin and promotes insulin resistance and glucose intolerance in muscle remains unclear. Here, we aim to investigate the effect of muscle-specific overexpression of MCP-1 on insulin sensitivity and glucose tolerance in lean and obese mice. We used Mck-Mcp-1 transgenic (Tg) mice characterised by muscle-specific overexpression of Mcp-1 (also known as Ccl2) and elevated plasma MCP-1 levels. Mice were fed either chow or high-fat diet for 10 weeks. Numerous metabolic variables were measured, including glucose and insulin tolerance tests, muscle insulin signalling and plasma NEFA, triacylglycerol, cholesterol, glucose and insulin. Despite clearly promoting skeletal muscle inflammation, muscle-specific overexpression of Mcp-1 did not influence glucose tolerance or insulin sensitivity in either lean chow-fed or diet-induced obese mice. In addition, plasma NEFA, triacylglycerol, cholesterol, glucose and insulin were not affected by MCP-1 overexpression. Finally, in vivo insulin-induced Akt phosphorylation in skeletal muscle did not differ between Mcp-1-Tg and wild-type mice. We show that increased MCP-1 production in skeletal muscle and concomitant elevated MCP-1 levels in plasma promote inflammation in skeletal muscle but do not influence insulin signalling and have no effect on insulin resistance and glucose tolerance in lean and obese mice. Overall, our data argue against MCP-1 promoting insulin resistance in skeletal muscle and raise questions about the impact of inflammation on insulin sensitivity in muscle.

Development and evaluation of a musculoskeletal model of the elbow joint complex

NASA Technical Reports Server (NTRS)

Gonzalez, Roger V.; Hutchins, E. L.; Barr, Ronald E.; Abraham, Lawrence D.

1993-01-01

This paper describes the development and evaluation of a musculoskeletal model that represents human elbow flexion-extension and forearm pronation-supination. The length, velocity, and moment arm for each of the eight musculotendon actuators were based on skeletal anatomy and position. Musculotendon parameters were determined for each actuator and verified by comparing analytical torque-angle curves with experimental joint torque data. The parameters and skeletal geometry were also utilized in the musculoskeletal model for the analysis of ballistic elbow joint complex movements. The key objective was to develop a computational model, guided by parameterized optimal control, to investigate the relationship among patterns of muscle excitation, individual muscle forces, and movement kinematics. The model was verified using experimental kinematic, torque, and electromyographic data from volunteer subjects performing ballistic elbow joint complex movements.

Human skeletal muscle responses to spaceflight and possible countermeasures

NASA Technical Reports Server (NTRS)

Gollnick, Philip D.; Edgerton, V. Reggie; Saltin, Bengt

1990-01-01

The current status of knowledge concerning the effects of unweighting skeletal muscle is summarized. The results of both ground-based and space-based animal studies are reviewed which show that there is rapid loss in muscle mass, primarily in slow-twitch muscle, of the rat during unweighting of muscle. There is also a shift in the myosin isoforms with muscles such that slow-twitch muscles take on many of the characteristics of fast-twitch muscles. Ground-based studies in human suggest that programs of electrical stimulation can be developed to simulate normal muscular contractions. Attempts to develop countermeasures to the adverse effects of space travel on muscular functions in humans have not been successful to date.

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.

Autonomic dysfunction in muscular dystrophy: a theoretical framework for muscle reflex involvement

PubMed Central

Smith, Scott A.; Downey, Ryan M.; Williamson, Jon W.; Mizuno, Masaki

2014-01-01

Muscular dystrophies are a heterogeneous group of genetically inherited disorders whose most prominent clinical feature is progressive degeneration of skeletal muscle. In several forms of the disease, the function of cardiac muscle is likewise affected. The primary defect in this group of diseases is caused by mutations in myocyte proteins important to cellular structure and/or performance. That being stated, a growing body of evidence suggests that the development of autonomic dysfunction may secondarily contribute to the generation of skeletal and cardio-myopathy in muscular dystrophy. Indeed, abnormalities in the regulation of both sympathetic and parasympathetic nerve activity have been reported in a number of muscular dystrophy variants. However, the mechanisms mediating this autonomic dysfunction remain relatively unknown. An autonomic reflex originating in skeletal muscle, the exercise pressor reflex, is known to contribute significantly to the control of sympathetic and parasympathetic activity when stimulated. Given the skeletal myopathy that develops with muscular dystrophy, it is logical to suggest that the function of this reflex might also be abnormal with the pathogenesis of disease. As such, it may contribute to or exacerbate the autonomic dysfunction that manifests. This possibility along with a basic description of exercise pressor reflex function in health and disease are reviewed. A better understanding of the mechanisms that possibly underlie autonomic dysfunction in muscular dystrophy may not only facilitate further research but could also lead to the identification of new therapeutic targets for the treatment of muscular dystrophy. PMID:24600397

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.

Connective tissue growth factor is required for skeletal development and postnatal skeletal homeostasis in male mice.

PubMed

Canalis, Ernesto; Zanotti, Stefano; Beamer, Wesley G; Economides, Aris N; Smerdel-Ramoya, Anna

2010-08-01

Connective tissue growth factor (CTGF), a member of the cysteine-rich 61 (Cyr 61), CTGF, nephroblastoma overexpressed (NOV) (CCN) family of proteins, is synthesized by osteoblasts, and its overexpression inhibits osteoblastogenesis and causes osteopenia. The global inactivation of Ctgf leads to defective endochondral bone formation and perinatal lethality; therefore, the consequences of Ctgf inactivation on the postnatal skeleton are not known. To study the function of CTGF, we generated Ctgf(+/LacZ) heterozygous null mice and tissue-specific null Ctgf mice by mating Ctgf conditional mice, where Ctgf is flanked by lox sequences with mice expressing the Cre recombinase under the control of the paired-related homeobox gene 1 (Prx1) enhancer (Prx1-Cre) or the osteocalcin promoter (Oc-Cre). Ctgf(+/LacZ) heterozygous mice exhibited transient osteopenia at 1 month of age secondary to decreased trabecular number. A similar osteopenic phenotype was observed in 1-month-old Ctgf conditional null male mice generated with Prx1-Cre, suggesting that the decreased trabecular number was secondary to impaired endochondral bone formation. In contrast, when the conditional deletion of Ctgf was achieved by Oc-Cre, an osteopenic phenotype was observed only in 6-month-old male mice. Osteoblast and osteoclast number, bone formation, and eroded surface were not affected in Ctgf heterozygous or conditional null mice. In conclusion, CTGF is necessary for normal skeletal development but to a lesser extent for postnatal skeletal homeostasis.

Secreted Protein Acidic and Rich in Cysteine (SPARC) in Human Skeletal Muscle

PubMed Central

Jørgensen, Louise H.; Petersson, Stine J.; Sellathurai, Jeeva; Andersen, Ditte C.; Thayssen, Susanne; Sant, Dorte J.; Jensen, Charlotte H.; Schrøder, Henrik D.

2009-01-01

Secreted protein acidic and rich in cysteine (SPARC)/osteonectin is expressed in different tissues during remodeling and repair, suggesting a function in regeneration. Several gene expression studies indicated that SPARC was expressed in response to muscle damage. Studies on myoblasts further indicated a function of SPARC in skeletal muscle. We therefore found it of interest to study SPARC expression in human skeletal muscle during development and in biopsies from Duchenne and Becker muscular dystrophy and congenital muscular dystrophy, congenital myopathy, inclusion body myositis, and polymyositis patients to analyze SPARC expression in a selected range of inherited and idiopathic muscle wasting diseases. SPARC-positive cells were observed both in fetal and neonatal muscle, and in addition, fetal myofibers were observed to express SPARC at the age of 15–16 weeks. SPARC protein was detected in the majority of analyzed muscle biopsies (23 of 24), mainly in mononuclear cells of which few were pax7 positive. Myotubes and regenerating myofibers also expressed SPARC. The expression-degree seemed to reflect the severity of the lesion. In accordance with these in vivo findings, primary human-derived satellite cells were found to express SPARC both during proliferation and differentiation in vitro. In conclusion, this study shows SPARC expression both during muscle development and in regenerating muscle. The expression is detected both in satellite cells/myoblasts and in myotubes and muscle fibers, indicating a role for SPARC in the skeletal muscle compartment. (J Histochem Cytochem 57:29–39, 2009) PMID:18796407

Correlation between three-dimensional morphological changes of the hyoid bone with other skeletal maturation methods in adolescents.

PubMed

Shim, Jocelyne; Heo, Giseon; Lagravère, Manuel O

2013-10-01

The study compares growth changes of hyoid bone in cone-beam computed tomography (CBCT) with conventional skeletal maturation methods to examine their potential implications in the development of a three-dimensional method. Subjects (n = 62, 11-17 years of age) were exposed to CBCT at a six-month interval (T1/T2/T3). Ten-hyoid distances were compared with age, hand wrist skeletal maturation index (SMI), and cervical vertebral maturation stage (CS). The length of greater cornua (GC) was most frequently, moderate to highly correlated with age (right: 0.57/0.53/0.58; left: 0.45/0.50/0.48), SMI (right: 0.52/0.40/0.45; left: 0.42 at T3), and CS (right: 0.52 at T1), followed by the length of the hyoid bone with age (right: 0.50/0.49/0.47; left: 0.44/0.47 at T1/T2), SMI (right: 0.45/0.41 at T1/T2), and CS (right: 0.48 at T1). The width of body of the hyoid (HB) width was correlated with age (0.43/0.44/0.44). The GC-HB gap was correlated with age (right: -0.41 at T3) and SMI (right: -0.42 at T1). Peripubertal hyoid maturation did not yield sufficient diagnostic information for considerations in the development of a 3D-skeletal maturation method. Copyright © 2013 Elsevier Inc. All rights reserved.

Advanced age-related denervation and fiber-type grouping in skeletal muscle of SOD1 knockout mice.

PubMed

Kostrominova, Tatiana Y

2010-11-30

In this study skeletal muscles from 1.5- and 10-month-old Cu/Zn superoxide dismutase (SOD1) homozygous knockout (JLSod1(-/-)) mice obtained from The Jackson Laboratory (C57Bl6/129SvEv background) were compared with muscles from age- and sex-matched heterozygous (JLSod1(+/-)) littermates. The results of this study were compared with previously published data on two different strains of Sod1(-/-) mice: one from Dr. Epstein's laboratory (ELSod1(-/-); C57Bl6 background) and the other from Cephalon, Inc. (CSod1(-/-); 129/CD-1 background). Grouping of succinate dehydrogenase-positive fibers characterized muscles of Sod1(-/-) mice from all three strains. The 10-month-old Sod1(-/-)C and JL mice displayed pronounced denervation of the gastrocnemius muscle, whereas the ELSod1(-/-) mice displayed a small degree of denervation at this age, but developed accelerated age-related denervation later on. Denervation markers were up-regulated in skeletal muscle of 10-month-old JLSod1(-/-) mice. This study is the first to show that metallothionein mRNA and protein expression was up-regulated in the skeletal muscle of 10-month-old JLSod1(-/-) mice and was mostly localized to the small atrophic muscle fibers. In conclusion, all three strains of Sod1(-/-) mice develop accelerated age-related muscle denervation, but the genetic background has significant influence on the progress of denervation. Copyright © 2010 Elsevier Inc. All rights reserved.

Skeletal effects in Angle Class II/1 patients treated with the functional regulator type II : Cephalometric and tensor analysis.

PubMed

Schulz, Simone; Koos, Bernd; Duske, Kathrin; Stahl, Franka

2016-11-01

The purpose of this work was to employ both cephalometric and tensor analysis in characterizing the skeletal changes experienced by patients with Angle Class II/1 malocclusion during functional orthodontic treatment with the functional regulator type II. A total of 23 patients with Class II/1 malocclusion based on lateral cephalograms obtained before and after treatment with the functional regulator type II were analyzed. Another 23 patients with Angle Class II/1 malocclusion who had not undergone treatment were included as controls. Our cephalometric data attest to significant therapeutic effects of the functional regulator type II on the skeletal mandibular system, including significant advancement of the mandible, increases in effective mandibular length with enhancement of the chin profile, and reduction of growth-related bite deepening. No treatment-related effects were observed at the cranial-base and midface levels. In addition, tensor analysis revealed significant stimulation of mandibular growth in sagittal directions, without indications of growth effects on the maxilla. Its growth-pattern findings differed from those of cephalometric analysis by indicating that the appliance did promote horizontal development, which supports the functional orthodontic treatment effect in Angle Class II/1 cases. Tensor analysis yielded additional insights into sagittal and vertical growth changes not identifiable by strictly cephalometric means. The functional regulator type II was an effective treatment modality for Angle Class II/1 malocclusion and influenced the skeletal development of these patients in favorable ways.

Cerebro-Oculo-Facio-Skeletal Syndrome (COFS)

MedlinePlus

... clenched fists, wide-set nipples, vision impairments, involuntary eye movements, and impaired cognitive development, which can be moderate ... clenched fists, wide-set nipples, vision impairments, involuntary eye movements, and impaired cognitive development, which can be moderate ...

Identification of mechanosensitive genes during skeletal development: alteration of genes associated with cytoskeletal rearrangement and cell signalling pathways.

PubMed

Rolfe, Rebecca A; Nowlan, Niamh C; Kenny, Elaine M; Cormican, Paul; Morris, Derek W; Prendergast, Patrick J; Kelly, Daniel; Murphy, Paula

2014-01-20

Mechanical stimulation is necessary for regulating correct formation of the skeleton. Here we test the hypothesis that mechanical stimulation of the embryonic skeletal system impacts expression levels of genes implicated in developmentally important signalling pathways in a genome wide approach. We use a mutant mouse model with altered mechanical stimulation due to the absence of limb skeletal muscle (Splotch-delayed) where muscle-less embryos show specific defects in skeletal elements including delayed ossification, changes in the size and shape of cartilage rudiments and joint fusion. We used Microarray and RNA sequencing analysis tools to identify differentially expressed genes between muscle-less and control embryonic (TS23) humerus tissue. We found that 680 independent genes were down-regulated and 452 genes up-regulated in humeri from muscle-less Spd embryos compared to littermate controls (at least 2-fold; corrected p-value ≤0.05). We analysed the resulting differentially expressed gene sets using Gene Ontology annotations to identify significant enrichment of genes associated with particular biological processes, showing that removal of mechanical stimuli from muscle contractions affected genes associated with development and differentiation, cytoskeletal architecture and cell signalling. Among cell signalling pathways, the most strongly disturbed was Wnt signalling, with 34 genes including 19 pathway target genes affected. Spatial gene expression analysis showed that both a Wnt ligand encoding gene (Wnt4) and a pathway antagonist (Sfrp2) are up-regulated specifically in the developing joint line, while the expression of a Wnt target gene, Cd44, is no longer detectable in muscle-less embryos. The identification of 84 genes associated with the cytoskeleton that are down-regulated in the absence of muscle indicates a number of candidate genes that are both mechanoresponsive and potentially involved in mechanotransduction, converting a mechanical stimulus into a transcriptional response. This work identifies key developmental regulatory genes impacted by altered mechanical stimulation, sheds light on the molecular mechanisms that interpret mechanical stimulation during skeletal development and provides valuable resources for further investigation of the mechanistic basis of mechanoregulation. In particular it highlights the Wnt signalling pathway as a potential point of integration of mechanical and molecular signalling and cytoskeletal components as mediators of the response.

Identification of mechanosensitive genes during skeletal development: alteration of genes associated with cytoskeletal rearrangement and cell signalling pathways

PubMed Central

2014-01-01

Background Mechanical stimulation is necessary for regulating correct formation of the skeleton. Here we test the hypothesis that mechanical stimulation of the embryonic skeletal system impacts expression levels of genes implicated in developmentally important signalling pathways in a genome wide approach. We use a mutant mouse model with altered mechanical stimulation due to the absence of limb skeletal muscle (Splotch-delayed) where muscle-less embryos show specific defects in skeletal elements including delayed ossification, changes in the size and shape of cartilage rudiments and joint fusion. We used Microarray and RNA sequencing analysis tools to identify differentially expressed genes between muscle-less and control embryonic (TS23) humerus tissue. Results We found that 680 independent genes were down-regulated and 452 genes up-regulated in humeri from muscle-less Spd embryos compared to littermate controls (at least 2-fold; corrected p-value ≤0.05). We analysed the resulting differentially expressed gene sets using Gene Ontology annotations to identify significant enrichment of genes associated with particular biological processes, showing that removal of mechanical stimuli from muscle contractions affected genes associated with development and differentiation, cytoskeletal architecture and cell signalling. Among cell signalling pathways, the most strongly disturbed was Wnt signalling, with 34 genes including 19 pathway target genes affected. Spatial gene expression analysis showed that both a Wnt ligand encoding gene (Wnt4) and a pathway antagonist (Sfrp2) are up-regulated specifically in the developing joint line, while the expression of a Wnt target gene, Cd44, is no longer detectable in muscle-less embryos. The identification of 84 genes associated with the cytoskeleton that are down-regulated in the absence of muscle indicates a number of candidate genes that are both mechanoresponsive and potentially involved in mechanotransduction, converting a mechanical stimulus into a transcriptional response. Conclusions This work identifies key developmental regulatory genes impacted by altered mechanical stimulation, sheds light on the molecular mechanisms that interpret mechanical stimulation during skeletal development and provides valuable resources for further investigation of the mechanistic basis of mechanoregulation. In particular it highlights the Wnt signalling pathway as a potential point of integration of mechanical and molecular signalling and cytoskeletal components as mediators of the response. PMID:24443808

Store-Operated Ca2+ Entry (SOCE) Contributes to Normal Skeletal Muscle Contractility in young but not in aged skeletal muscle

PubMed Central

Brotto, Leticia S.; Bougoin, Sylvain; Nosek, Thomas M.; Reid, Michael; Hardin, Brian; Pan, Zui; Ma, Jianjie; Parness, Jerome

2011-01-01

Muscle atrophy alone is insufficient to explain the significant decline in contractile force of skeletal muscle during normal aging. One contributing factor to decreased contractile force in aging skeletal muscle could be compromised excitation-contraction (E-C) coupling, without sufficient available Ca2+ to allow for repetitive muscle contractility, skeletal muscles naturally become weaker. Using biophysical approaches, we previously showed that store-operated Ca2+ entry (SOCE) is compromised in aged skeletal muscle but not in young ones. While important, a missing component from previous studies is whether or not SOCE function correlates with contractile function during aging. Here we test the contribution of extracellular Ca2+ to contractile function of skeletal muscle during aging. First, we demonstrate graded coupling between SR Ca2+ release channel-mediated Ca2+ release and activation of SOCE. Inhibition of SOCE produced significant reduction of contractile force in young skeletal muscle, particularly at high frequency stimulation, and such effects were completely absent in aged skeletal muscle. Our data indicate that SOCE contributes to the normal physiological contractile response of young healthy skeletal muscle and that defective extracellular Ca2+ entry through SOCE contributes to the reduced contractile force characteristic of aged skeletal muscle. PMID:21666285

Store-operated Ca(2+) entry (SOCE) contributes to normal skeletal muscle contractility in young but not in aged skeletal muscle.

PubMed

Thornton, Angela M; Zhao, Xiaoli; Weisleder, Noah; Brotto, Leticia S; Bougoin, Sylvain; Nosek, Thomas M; Reid, Michael; Hardin, Brian; Pan, Zui; Ma, Jianjie; Parness, Jerome; Brotto, Marco

2011-06-01

Muscle atrophy alone is insufficient to explain the significant decline in contractile force of skeletal muscle during normal aging. One contributing factor to decreased contractile force in aging skeletal muscle could be compromised excitation-contraction (E-C) coupling, without sufficient available Ca(2+) to allow for repetitive muscle contractility, skeletal muscles naturally become weaker. Using biophysical approaches, we previously showed that store-operated Ca(2+) entry (SOCE) is compromised in aged skeletal muscle but not in young ones. While important, a missing component from previous studies is whether or not SOCE function correlates with contractile function during aging. Here we test the contribution of extracellular Ca(2+) to contractile function of skeletal muscle during aging. First, we demonstrate graded coupling between SR Ca(2+) release channel-mediated Ca(2+) release and activation of SOCE. Inhibition of SOCE produced significant reduction of contractile force in young skeletal muscle, particularly at high frequency stimulation, and such effects were completely absent in aged skeletal muscle. Our data indicate that SOCE contributes to the normal physiological contractile response of young healthy skeletal muscle and that defective extracellular Ca(2+) entry through SOCE contributes to the reduced contractile force characteristic of aged skeletal muscle.

Automated bone age assessment of older children using the radius

NASA Astrophysics Data System (ADS)

Tsao, Sinchai; Gertych, Arkadiusz; Zhang, Aifeng; Liu, Brent J.; Huang, Han K.

2008-03-01

The Digital Hand Atlas in Assessment of Skeletal Development is a large-scale Computer Aided Diagnosis (CAD) project for automating the process of grading Skeletal Development of children from 0-18 years of age. It includes a complete collection of 1,400 normal hand X-rays of children between the ages of 0-18 years of age. Bone Age Assessment is used as an index of skeletal development for detection of growth pathologies that can be related to endocrine, malnutrition and other disease types. Previous work at the Image Processing and Informatics Lab (IPILab) allowed the bone age CAD algorithm to accurately assess bone age of children from 1 to 16 (male) or 14 (female) years of age using the Phalanges as well as the Carpal Bones. At the older ages (16(male) or 14(female) -19 years of age) the Phalanges as well as the Carpal Bones are fully developed and do not provide well-defined features for accurate bone age assessment. Therefore integration of the Radius Bone as a region of interest (ROI) is greatly needed and will significantly improve the ability to accurately assess the bone age of older children. Preliminary studies show that an integrated Bone Age CAD that utilizes the Phalanges, Carpal Bones and Radius forms a robust method for automatic bone age assessment throughout the entire age range (1-19 years of age).

STIM1 as a key regulator for Ca2+ homeostasis in skeletal-muscle development and function

PubMed Central

2011-01-01

Stromal interaction molecules (STIM) were identified as the endoplasmic-reticulum (ER) Ca2+ sensor controlling store-operated Ca2+ entry (SOCE) and Ca2+-release-activated Ca2+ (CRAC) channels in non-excitable cells. STIM proteins target Orai1-3, tetrameric Ca2+-permeable channels in the plasma membrane. Structure-function analysis revealed the molecular determinants and the key steps in the activation process of Orai by STIM. Recently, STIM1 was found to be expressed at high levels in skeletal muscle controlling muscle function and properties. Novel STIM targets besides Orai channels are emerging. Here, we will focus on the role of STIM1 in skeletal-muscle structure, development and function. The molecular mechanism underpinning skeletal-muscle physiology points toward an essential role for STIM1-controlled SOCE to drive Ca2+/calcineurin/nuclear factor of activated T cells (NFAT)-dependent morphogenetic remodeling programs and to support adequate sarcoplasmic-reticulum (SR) Ca2+-store filling. Also in our hands, STIM1 is transiently up-regulated during the initial phase of in vitro myogenesis of C2C12 cells. The molecular targets of STIM1 in these cells likely involve Orai channels and canonical transient receptor potential (TRPC) channels TRPC1 and TRPC3. The fast kinetics of SOCE activation in skeletal muscle seem to depend on the triad-junction formation, favoring a pre-localization and/or pre-formation of STIM1-protein complexes with the plasma-membrane Ca2+-influx channels. Moreover, Orai1-mediated Ca2+ influx seems to be essential for controlling the resting Ca2+ concentration and for proper SR Ca2+ filling. Hence, Ca2+ influx through STIM1-dependent activation of SOCE from the T-tubule system may recycle extracellular Ca2+ losses during muscle stimulation, thereby maintaining proper filling of the SR Ca2+ stores and muscle function. Importantly, mouse models for dystrophic pathologies, like Duchenne muscular dystrophy, point towards an enhanced Ca2+ influx through Orai1 and/or TRPC channels, leading to Ca2+-dependent apoptosis and muscle degeneration. In addition, human myopathies have been associated with dysfunctional SOCE. Immunodeficient patients harboring loss-of-function Orai1 mutations develop myopathies, while patients suffering from Duchenne muscular dystrophy display alterations in their Ca2+-handling proteins, including STIM proteins. In any case, the molecular determinants responsible for SOCE in human skeletal muscle and for dysregulated SOCE in patients of muscular dystrophy require further examination. PMID:21798093

Development and refinement of computer-assisted planning and execution system for use in face-jaw-teeth transplantation to improve skeletal and dento-occlusal outcomes.

PubMed

Hashemi, Sepehr; Armand, Mehran; Gordon, Chad R

2016-10-01

To describe the development and refinement of the computer-assisted planning and execution (CAPE) system for use in face-jaw-teeth transplants (FJTTs). Although successful, some maxillofacial transplants result in suboptimal hybrid occlusion and may require subsequent surgical orthognathic revisions. Unfortunately, the use of traditional dental casts and splints pose several compromising shortcomings in the context of FJTT and hybrid occlusion. Computer-assisted surgery may overcome these challenges. Therefore, the use of computer-assisted orthognathic techniques and functional planning may prevent the need for such revisions and improve facial-skeletal outcomes. A comprehensive CAPE system for use in FJTT was developed through a multicenter collaboration and refined using plastic models, live miniature swine surgery, and human cadaver models. The system marries preoperative surgical planning and intraoperative execution by allowing on-table navigation of the donor fragment relative to recipient cranium, and real-time reporting of patient's cephalometric measurements relative to a desired dental-skeletal outcome. FJTTs using live-animal and cadaveric models demonstrate the CAPE system to be accurate in navigation and beneficial in improving hybrid occlusion and other craniofacial outcomes. Future refinement of the CAPE system includes integration of more commonly performed orthognathic/maxillofacial procedures.

FDG-PET response of skeletal (bone marrow and bone) involvement after induction chemotherapy in pediatric Hodgkin lymphoma - Are specific response criteria required?

PubMed

Georgi, Thomas Walter; Kluge, Regine; Kurch, Lars; Chavdarova, Lidia; Hasenclever, Dirk; Stoevesandt, Dietrich; Pelz, Tanja; Landman-Parker, Judith; Wallace, Hamish; Karlen, Jonas; Fernandez-Teijeiro, Ana; Cepelova, Michaela; Fossa, Alexander; Balwierz, Walentyna; Attarbaschi, Andishe; Ammann, Roland A; Pears, Jane; Hraskova, Andrea; Uyttebroeck, Anne; Beishuizen, Auke; Dieckmann, Karin; Leblanc, Thierry; Daw, Stephen; Baumann, Julia; Körholz, Dieter; Sabri, Osama; Mauz-Körholz, Christine

2018-04-13

Purpose: This study focused on skeletal involvement in FDG-PET (PET) in Hodgkin lymphoma (HL). We aimed at a systematic evaluation of the different types of skeletal involvement and their PET response after two cycles of chemotherapy (PET-2), to answer the question whether the current PET response criterion for skeletal involvement is suitable. A secondary objective was to observe the influence of initial uptake intensity and metabolic tumor volume (MTV) of skeletal lesions on the PET-2 response. Methods: Initial PET scans (PET-0) of 1068 pediatric HL patients from the EuroNet-PHL-C1 (C1) trial were evaluated by central review for skeletal involvement. Three types of skeletal lesions were distinguished: skeletal lesions detected only in PET (PETonly), bone marrow (BM) lesions confirmed by MRI or BM biopsy and bone lesions. Uptake intensity (measured as qPET value) and MTV were calculated for each skeletal lesion. All PET-2 scans were assessed for residual tumor activity. The rates of complete metabolic response in PET-2 of skeletal and nodal involvement were compared. Results: 139/1068 (13%) C1 patients showed skeletal involvement (44/139 PETonly patients, 32/139 BM patients and 63/139 bone patients). 101/139 (73%) patients became PET-2 negative in the skeleton while lymph node involvement was PET-2 negative in 94/139 (68%) patients. Highest skeletal PET-2 negative rate was seen in 42/44 (95%) PETonly patients, followed by 22/32 (69%) BM patients and 37/63 (59%) bone patients. Skeletal lesions who became PET-2 negative showed lower median values for initial qPET (2.74) and MTV (2ml) than lesions who remained PET-2 positive (3.84; 7ml). Conclusion: In this study with pediatric HL patients, the complete response rate in PET-2 of skeletal and nodal involvement was similar. Bone flare seemed to be irrelevant. Overall, the current skeletal PET response criterion - comparison with the local skeletal background - is well suited. Initial uptake intensity and MTV of skeletal lesions were predictive for the PET-2 result. Higher values for both parameters were associated with a worse PET-2 response. Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Oncological outcomes of patients with Ewing's sarcoma: is there a difference between skeletal and extra-skeletal Ewing's sarcoma?

PubMed

Pradhan, A; Grimer, R J; Spooner, D; Peake, D; Carter, S R; Tillman, R M; Abudu, A; Jeys, L

2011-04-01

The aim of this study was to identify whether there was any difference in patient, tumour, treatment or outcome characteristics between patients with skeletal or extra-skeletal Ewing's sarcoma. We identified 300 patients with new primary Ewing's sarcoma diagnosed between 1980 and 2005 from the centres' local database. There were 253 (84%) with skeletal and 47 (16%) with extra-skeletal Ewing's sarcomas. Although patients with skeletal Ewing's were younger (mean age 16.8 years) than those with extra-skeletal Ewing's sarcoma (mean age 27.5 years), there was little difference between the groups in terms of tumour stage or treatment. Nearly all the patients were treated with chemotherapy and most had surgery. There was no difference in the overall survival of patients with skeletal (64%) and extra-skeletal Ewing's sarcoma (61%) (p = 0.85), and this was also the case when both groups were split by whether they had metastases or not. This large series has shown that the oncological outcomes of Ewing's sarcoma are related to tumour characteristics and patient age, and not determined by whether they arise in bone or soft tissue.

Application of skeletal age based on x-ray in selecting sports talents

NASA Astrophysics Data System (ADS)

Mao, Zongzhen; Xu, Guodong; Song, Tao

2012-01-01

Skeletal age has been studied and proved that for most elite athletes, it was coincident with the chronological ages when they were young. In order to explore the application of skeletal age in selecting sports talent, 32 athletes (female, chronological age 5-12 y) were chosen from the Gymnastics Training Base in this study. Their left hand-wrists were photographed with X-rays, and then the skeletal ages were estimated by Chinese version of the Tanner-Whitehouse Skeletal Maturity Assessment System. At the same time, their body shapes, functions, and sports ability were also measured. Results showed that 71.88% of the skeletal age was proportional to their chronological age (+/- 1 y); while 18.75% of the skeletal maturity was retarded by 1- 2 year, 9.37% of those was advanced more than 1 year. On the other hand, the body shape, functions and sports ability of the athletes were positively related with their skeletal maturity. This study proved that the determination of skeletal maturity is a reliable evaluation for selecting sports talent. A further study on the influence of gymnastics on the skeletal age is of great significance.

Skeletal stigmata as keys to access to the composite and ancient Gorlin-Goltz syndrome history: The Egypt, Pompeii and Herculaneum lessons.

PubMed

Ponti, Giovanni; Pellacani, Giovanni; Tomasi, Aldo; Sammaria, Giuliano; Manfredini, Marco

2016-09-10

There are several genetic diseases with a wide spectrum of congenital bone stigmata in association to cutaneous and visceral benign and malignant neoplasms. Gorlin-Goltz syndrome, also named nevoid basal cell carcinoma syndrome, is an autosomal dominant systemic disease with almost complete penetrance and high intra-familial phenotypic variability, caused by germline mutations of the gene PTCH1. The syndrome is characterized by unusual skeletal changes and high predisposition to the development of multiple basal cell carcinomas, odontogenic keratocysts tumors and other visceral tumors. The Gorlin syndrome, clinically defined as distinct syndrome in 1963, existed during Dynastic Egyptian times, as revealed by a costellation of skeletal findings compatible with the syndrome in mummies dating back to 3000years ago and, most likely, in the ancient population of Pompeii. These paleogenetic and historical evidences, together with the clinical and biomolecular modern evidences, confirm the quite benign behavior of the syndrome and the critical value of the multiple and synchronous skeletal anomalies in the recognition of these rare and complex genetic disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Treatment of class ii in adulthood by forsus frd device.

PubMed

DE Nuccio, F; D'Emidio, M M; DE Nuccio, F

2016-01-01

Scientific research data show that the Forsus FRD seems to have a great potential in the correction of Class II in childhood. The conclusions reached by the various Authors seem to support the hypothesis of an exclusively or mainly dentoalveolar correction, as the skeletal correction seems to have no - or little - appreciable results. In the light of such provided by different Authors, the potential of dentoalveolar compensation in adult patients with mild skeletal class II was investigated. At the UOC (Complex Operative Unit) of Orthodontics at "G. Eastman" Hospital Rome, 3 cases of skeletal class II mild (ANB <5 °) in adult patients were selected. They were treated with fixed multibracket appliance and Forsus EZ2 module. Cephalometric tracings were compared at the beginning and at the end of the treatment in order to assess the skeletal and dentoalveolar changes. The occlusal correction was achieved through a dentoalveolar compensation characterized by the flaring of the lower teeth. Forsus FRD equipment is an excellent compromise for the correction of mild Class II, even during the post development age. The resulting correction is appreciated at dental alveolar level with a mesial movement of the incisors and molars.

Interpreting environmental signals from the coralline sponge Astrosclera willeyana

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

Fallon, S J; McCulloch, M T; Guilderson, T P

2004-06-30

Coralline sponges (sclerosponges) have been proposed as a new source for paleo subsurface temperature reconstructions by utilizing methods developed for reef-building corals. However unlike corals, coralline sponges do not have density variations making age determination difficult. In this study we examined multiple elemental rations (B, Mg, Sr, Ba, U) in the coralline sponge Astrosclera willeyana. We also measured skeletal density profiles along the outer ''living'' edge of the sponges and this data indicates significant thickening of skeletal material over intervals of 2-3 mm or 2-3 years. This suggests that any skeletal recovered environmental record from Astrosclera willeyana is an integrationmore » of signals over a 2-3 year period. Sponge Sr/Ca seemed to hold the most promise as a recorder of water temperature and we compared Sr/Ca from 2 sponges in the Great Barrier Reef and one from Truk in Micronesia to their respective sea surface temperature record. The correlations were not that strong ({approx} r=-0.5) but they were significant. It appears that the signal smoothing due to thickening or perhaps even some biologic control on Sr skeletal partitioning limits the use of Sr/Ca as an indicator of water temperature in Astrosclera willeyana.« less

Matrix metalloproteinase-2 plays a critical role in overload induced skeletal muscle hypertrophy.

PubMed

Zhang, Qia; Joshi, Sunil K; Lovett, David H; Zhang, Bryon; Bodine, Sue; Kim, Hubert T; Liu, Xuhui

2014-01-01

extracellular matrix (ECM) components are instrumental in maintaining homeostasis and muscle fiber functional integrity. Skeletal muscle hypertrophy is associated with ECM remodeling. Specifically, recent studies have reported the involvement of matrix metalloproteinases (MMPs) in muscle ECM remodeling. However, the functional role of MMPs in muscle hypertrophy remains largely unknown. in this study, we examined the role of MMP-2 in skeletal muscle hypertrophy using a previously validated method where the plantaris muscle of mice were subjected to mechanical overload due to the surgical removal of synergist muscles (gastrocnemius and soleus). following two weeks of overload, we observed a significant increase in MMP-2 activity and up-regulation of ECM components and remodeling enzymes in the plantaris muscles of wild-type mice. However, MMP-2 knockout mice developed significantly less hypertrophy and ECM remodeling in response to overload compared to their wild-type littermates. Investigation of protein synthesis rate and Akt/mTOR signaling revealed no difference between wild-type and MMP-2 knockout mice, suggesting that a difference in hypertrophy was independent of protein synthesis. taken together, our results suggest that MMP-2 is a key mediator of ECM remodeling in the setting of skeletal muscle hypertrophy.

Matrix metalloproteinase-2 plays a critical role in overload induced skeletal muscle hypertrophy.

PubMed

Zhang, Qia; Joshi, Sunil K; Lovett, David H; Zhang, Bryon; Bodine, Sue; Kim, Hubert; Liu, Xuhui

2014-07-01

extracellular matrix (ECM) components are instrumental in maintaining homeostasis and muscle fiber functional integrity. Skeletal muscle hypertrophy is associated with ECM remodeling. Specifically, recent studies have reported the involvement of matrix metalloproteinases (MMPs) in muscle ECM remodeling. However, the functional role of MMPs in muscle hypertrophy remains largely unknown. in this study, we examined the role of MMP-2 in skeletal muscle hypertrophy using a previously validated method where the plantaris muscle of mice were subjected to mechanical overload due to the surgical removal of synergist muscles (gastrocnemius and soleus). following two weeks of overload, we observed a significant increase in MMP-2 activity and up-regulation of ECM components and remodeling enzymes in the plantaris muscles of wild-type mice. However, MMP-2 knockout mice developed significantly less hypertrophy and ECM remodeling in response to overload compared to their wild-type littermates. Investigation of protein synthesis rate and Akt/mTOR signaling revealed no difference between wild-type and MMP-2 knockout mice, suggesting that a difference in hypertrophy was independent of protein synthesis. taken together, our results suggest that MMP-2 is a key mediator of ECM remodeling in the setting of skeletal muscle hypertrophy.

Temperature and CO2 additively regulate physiology, morphology and genomic responses of larval sea urchins, Strongylocentrotus purpuratus

PubMed Central

Padilla-Gamiño, Jacqueline L.; Kelly, Morgan W.; Evans, Tyler G.; Hofmann, Gretchen E.

2013-01-01

Ocean warming and ocean acidification, both consequences of anthropogenic production of CO2, will combine to influence the physiological performance of many species in the marine environment. In this study, we used an integrative approach to forecast the impact of future ocean conditions on larval purple sea urchins (Strongylocentrotus purpuratus) from the northeast Pacific Ocean. In laboratory experiments that simulated ocean warming and ocean acidification, we examined larval development, skeletal growth, metabolism and patterns of gene expression using an orthogonal comparison of two temperature (13°C and 18°C) and pCO2 (400 and 1100 μatm) conditions. Simultaneous exposure to increased temperature and pCO2 significantly reduced larval metabolism and triggered a widespread downregulation of histone encoding genes. pCO2 but not temperature impaired skeletal growth and reduced the expression of a major spicule matrix protein, suggesting that skeletal growth will not be further inhibited by ocean warming. Importantly, shifts in skeletal growth were not associated with developmental delay. Collectively, our results indicate that global change variables will have additive effects that exceed thresholds for optimized physiological performance in this keystone marine species. PMID:23536595

The Role of Skeletal Muscle Glycogen Breakdown for Regulation of Insulin Sensitivity by Exercise

PubMed Central

Jensen, Jørgen; Rustad, Per Inge; Kolnes, Anders Jensen; Lai, Yu-Chiang

2011-01-01

Glycogen is the storage form of carbohydrates in mammals. In humans the majority of glycogen is stored in skeletal muscles (∼500 g) and the liver (∼100 g). Food is supplied in larger meals, but the blood glucose concentration has to be kept within narrow limits to survive and stay healthy. Therefore, the body has to cope with periods of excess carbohydrates and periods without supplementation. Healthy persons remove blood glucose rapidly when glucose is in excess, but insulin-stimulated glucose disposal is reduced in insulin resistant and type 2 diabetic subjects. During a hyperinsulinemic euglycemic clamp, 70–90% of glucose disposal will be stored as muscle glycogen in healthy subjects. The glycogen stores in skeletal muscles are limited because an efficient feedback-mediated inhibition of glycogen synthase prevents accumulation. De novo lipid synthesis can contribute to glucose disposal when glycogen stores are filled. Exercise physiologists normally consider glycogen’s main function as energy substrate. Glycogen is the main energy substrate during exercise intensity above 70% of maximal oxygen uptake (Vo2max⁡) and fatigue develops when the glycogen stores are depleted in the active muscles. After exercise, the rate of glycogen synthesis is increased to replete glycogen stores, and blood glucose is the substrate. Indeed insulin-stimulated glucose uptake and glycogen synthesis is elevated after exercise, which, from an evolutional point of view, will favor glycogen repletion and preparation for new “fight or flight” events. In the modern society, the reduced glycogen stores in skeletal muscles after exercise allows carbohydrates to be stored as muscle glycogen and prevents that glucose is channeled to de novo lipid synthesis, which over time will causes ectopic fat accumulation and insulin resistance. The reduction of skeletal muscle glycogen after exercise allows a healthy storage of carbohydrates after meals and prevents development of type 2 diabetes. PMID:22232606

Phenotypic characterization of Grm1crv4 mice reveals a functional role for the type 1 metabotropic glutamate receptor in bone mineralization.

PubMed

Musante, Ilaria; Mattinzoli, Deborah; Otescu, Lavinia Alexandra; Bossi, Simone; Ikehata, Masami; Gentili, Chiara; Cangemi, Giuliana; Gatti, Cinzia; Emionite, Laura; Messa, Piergiorgio; Ravazzolo, Roberto; Rastaldi, Maria Pia; Riccardi, Daniela; Puliti, Aldamaria

2017-01-01

Recent increasing evidence supports a role for neuronal type signaling in bone. Specifically glutamate receptors have been found in cells responsible for bone remodeling, namely the osteoblasts and the osteoclasts. While most studies have focused on ionotropic glutamate receptors, the relevance of the metabotropic glutamate signaling in bone is poorly understood. Specifically type 1 metabotropic glutamate (mGlu1) receptors are expressed in bone, but the effect of its ablation on skeletal development has never been investigated. Here we report that Grm1 crv4/crv4 mice, homozygous for an inactivating mutation of the mGlu1 receptor, and mainly characterized by ataxia and renal dysfunction, exhibit decreased body weight, bone length and bone mineral density compared to wild type (WT) animals. Blood analyses of the affected mice demonstrate the absence of changes in circulating factors, such as vitamin D and PTH, suggesting renal damage is not the main culprit of the skeletal phenotype. Cultures of osteoblasts lacking functional mGlu1 receptors exhibit less homogeneous collagen deposition than WT cells, and present increased expression of osteocalcin, a marker of osteoblast maturation. These data suggest that the skeletal damage is directly linked to the absence of the receptor, which in turn leads to osteoblasts dysfunction and earlier maturation. Accordingly, skeletal histomorphology suggests that Grm1 crv4/crv4 mice exhibit enhanced bone maturation, resulting in premature fusion of the growth plate and shortened long bones, and further slowdown of bone apposition rate compared to the WT animals. In summary, this work reveals novel functions of mGlu1 receptors in the bone and indicates that in osteoblasts mGlu1 receptors are necessary for production of normal bone matrix, longitudinal bone growth, and normal skeletal development. Copyright © 2016 Elsevier Inc. All rights reserved.

The role of skeletal muscle glycogen breakdown for regulation of insulin sensitivity by exercise.

PubMed

Jensen, Jørgen; Rustad, Per Inge; Kolnes, Anders Jensen; Lai, Yu-Chiang

2011-01-01

Glycogen is the storage form of carbohydrates in mammals. In humans the majority of glycogen is stored in skeletal muscles (∼500 g) and the liver (∼100 g). Food is supplied in larger meals, but the blood glucose concentration has to be kept within narrow limits to survive and stay healthy. Therefore, the body has to cope with periods of excess carbohydrates and periods without supplementation. Healthy persons remove blood glucose rapidly when glucose is in excess, but insulin-stimulated glucose disposal is reduced in insulin resistant and type 2 diabetic subjects. During a hyperinsulinemic euglycemic clamp, 70-90% of glucose disposal will be stored as muscle glycogen in healthy subjects. The glycogen stores in skeletal muscles are limited because an efficient feedback-mediated inhibition of glycogen synthase prevents accumulation. De novo lipid synthesis can contribute to glucose disposal when glycogen stores are filled. Exercise physiologists normally consider glycogen's main function as energy substrate. Glycogen is the main energy substrate during exercise intensity above 70% of maximal oxygen uptake ([Formula: see text]) and fatigue develops when the glycogen stores are depleted in the active muscles. After exercise, the rate of glycogen synthesis is increased to replete glycogen stores, and blood glucose is the substrate. Indeed insulin-stimulated glucose uptake and glycogen synthesis is elevated after exercise, which, from an evolutional point of view, will favor glycogen repletion and preparation for new "fight or flight" events. In the modern society, the reduced glycogen stores in skeletal muscles after exercise allows carbohydrates to be stored as muscle glycogen and prevents that glucose is channeled to de novo lipid synthesis, which over time will causes ectopic fat accumulation and insulin resistance. The reduction of skeletal muscle glycogen after exercise allows a healthy storage of carbohydrates after meals and prevents development of type 2 diabetes.

A multiplexed chip-based assay system for investigating the functional development of human skeletal myotubes in vitro.

PubMed

Smith, A S T; Long, C J; Pirozzi, K; Najjar, S; McAleer, C; Vandenburgh, H H; Hickman, J J

2014-09-20

This report details the development of a non-invasive in vitro assay system for investigating the functional maturation and performance of human skeletal myotubes. Data is presented demonstrating the survival and differentiation of human myotubes on microscale silicon cantilevers in a defined, serum-free system. These cultures can be stimulated electrically and the resulting contraction quantified using modified atomic force microscopy technology. This system provides a higher degree of sensitivity for investigating contractile waveforms than video-based analysis, and represents the first system capable of measuring the contractile activity of individual human muscle myotubes in a reliable, high-throughput and non-invasive manner. The development of such a technique is critical for the advancement of body-on-a-chip platforms toward application in pre-clinical drug development screens. Copyright © 2014 Elsevier B.V. All rights reserved.

Membrane traffic and muscle: lessons from human disease.

PubMed

Dowling, James J; Gibbs, Elizabeth M; Feldman, Eva L

2008-07-01

Like all mammalian tissues, skeletal muscle is dependent on membrane traffic for proper development and homeostasis. This fact is underscored by the observation that several human diseases of the skeletal muscle are caused by mutations in gene products of the membrane trafficking machinery. An examination of these diseases and the proteins that underlie them is instructive both in terms of determining disease pathogenesis and of understanding the normal aspects of muscle biology regulated by membrane traffic. This review highlights our current understanding of the trafficking genes responsible for human myopathies.

Skeletal effects of megavoltage irradiation in survivors of Wilms' tumor

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

Heaston, D.K.; Libshitz, H.I.; Chan, R.C.

1979-09-01

The skeletal effects of megavoltage irradiation (/sup 60/Co) in 25 long term survivors of Wilms' tumor are described. In general, the changes seen with megavoltage irradiation are as frequent but not as severe as those previously reported after orthovoltage irradiation. Vertebral body changes generally occur within 5 years after irradiation. Scoliosis and/or kyphosis do not usually develop until after five years postirradiation. Kyphotic curves tend to progress after the adolescent growth spurt while scoliotic curves do not. Other bony and nonosseous changes are detailed.

Twente spine model: A complete and coherent dataset for musculo-skeletal modeling of the thoracic and cervical regions of the human spine.

PubMed

Bayoglu, Riza; Geeraedts, Leo; Groenen, Karlijn H J; Verdonschot, Nico; Koopman, Bart; Homminga, Jasper

2017-06-14

Musculo-skeletal modeling could play a key role in advancing our understanding of the healthy and pathological spine, but the credibility of such models are strictly dependent on the accuracy of the anatomical data incorporated. In this study, we present a complete and coherent musculo-skeletal dataset for the thoracic and cervical regions of the human spine, obtained through detailed dissection of an embalmed male cadaver. We divided the muscles into a number of muscle-tendon elements, digitized their attachments at the bones, and measured morphological muscle parameters. In total, 225 muscle elements were measured over 39 muscles. For every muscle element, we provide the coordinates of its attachments, fiber length, tendon length, sarcomere length, optimal fiber length, pennation angle, mass, and physiological cross-sectional area together with the skeletal geometry of the cadaver. Results were consistent with similar anatomical studies. Furthermore, we report new data for several muscles such as rotatores, multifidus, levatores costarum, spinalis, semispinalis, subcostales, transversus thoracis, and intercostales muscles. This dataset complements our previous study where we presented a consistent dataset for the lumbar region of the spine (Bayoglu et al., 2017). Therefore, when used together, these datasets enable a complete and coherent dataset for the entire spine. The complete dataset will be used to develop a musculo-skeletal model for the entire human spine to study clinical and ergonomic applications. Copyright © 2017 Elsevier Ltd. All rights reserved.

Troponin T3 expression in skeletal and smooth muscle is required for growth and postnatal survival: characterization of Tnnt3(tm2a(KOMP)Wtsi) mice.

PubMed

Ju, Yawen; Li, Jie; Xie, Chao; Ritchlin, Christopher T; Xing, Lianping; Hilton, Matthew J; Schwarz, Edward M

2013-09-01

The troponin complex, which consists of three regulatory proteins (troponin C, troponin I, and troponin T), is known to regulate muscle contraction in skeletal and cardiac muscle, but its role in smooth muscle remains controversial. Troponin T3 (TnnT3) is a fast skeletal muscle troponin believed to be expressed only in skeletal muscle cells. To determine the in vivo function and tissue-specific expression of Tnnt3, we obtained the heterozygous Tnnt3+/flox/lacZ mice from Knockout Mouse Project (KOMP) Repository. Tnnt3(lacZ/+) mice are smaller than their WT littermates throughout development but do not display any gross phenotypes. Tnnt3(lacZ/lacZ) embryos are smaller than heterozygotes and die shortly after birth. Histology revealed hemorrhagic tissue in Tnnt3(lacZ/lacZ) liver and kidney, which was not present in Tnnt3(lacZ/+) or WT, but no other gross tissue abnormalities. X-gal staining for Tnnt3 promoter-driven lacZ transgene expression revealed positive staining in skeletal muscle and diaphragm and smooth muscle cells located in the aorta, bladder, and bronchus. Collectively, these findings suggest that troponins are expressed in smooth muscle and are required for normal growth and breathing for postnatal survival. Moreover, future studies with this mouse model can explore TnnT3 function in adult muscle function using the conditional-inducible gene deletion approach Copyright © 2013 Wiley Periodicals, Inc.

Brachymesomelic dysplasia with Peters anomaly of the eye results from disruptions of the X chromosome near the SHOX and SOX3 genes.

PubMed

Bleyl, Steven B; Byrne, Janice L B; South, Sarah T; Dries, David C; Stevenson, David A; Rope, Alan F; Vianna-Morgante, Angela M; Schoenwolf, Gary C; Kivlin, Jane D; Brothman, Arthur; Carey, John C

2007-12-01

We report on a mother and son affected with an unusual skeletal dysplasia and anterior segment eye abnormalities. Their skeletal phenotype overlaps with the SHOX-related skeletal dysplasias and is intermediate between Leri-Weill dyschondrosteosis (LWD) and Langer Mesomelic dysplasia (LMD). The mother has bilateral Peters anomaly of the eye and was reported as having a new syndrome; the son had severe bilateral sclerocornea. Chromosome analysis showed that the mother has a pericentric inversion of the X chromosome [46,X,inv(X)(p22.3q27)] and the son, a resultant recombinant X chromosome [46,Y,rec(X)dup(Xq)inv(X)(p22.3q27)]. The observed skeletal and ophthalmologic abnormalities in both patients were similar in severity. The additional features of developmental delay, growth retardation, agenesis of the corpus callosum, cryptorchidism and hypoplastic scrotum in the son are consistent with Xq28 duplication. Analysis of the son's recombinant X chromosome showed that the Xp22.33 breakpoint lies 30-68 kb 5' of the SHOX gene. This finding suggests that the skeletal dysplasia in both mother and son is allelic with LWD and LMD and results from a novel misexpression of SHOX. Analysis of the Xq27.1 breakpoint localized it to a 90 kb interval 3' of the SOX3 gene, supporting a novel role of SOX3 misexpression in the development of Peters anomaly of the eye. (c) 2007 Wiley-Liss, Inc.

A comparison of hand wrist bone analysis with two different cervical vertebral analysis in measuring skeletal maturation.

PubMed

Pichai, Saravanan; Rajesh, M; Reddy, Naveen; Adusumilli, Gopinath; Reddy, Jayaprakash; Joshi, Bhavana

2014-09-01

Skeletal maturation is an integral part of individual pattern of growth and development and is a continuous process. Peak growth velocity in standing height is the most valid representation of the rate of overall skeletal growth. Ossification changes of hand wrist and cervical vertebrae are the reliable indicators of growth status of individual. The objective of this study was to compare skeletal maturation as measured by hand wrist bone analysis and cervical vertebral analysis. Hand wrist radiographs and lateral cephalograms of 72 subjects aged between 7 and 16 years both male and female from the patients visiting Department of Orthodontics and Dentofacial Orthopedics, R.V. Dental College and Hospital. The 9 stages were reduced to 5 stages to compare with cervical vertebral maturation stage by Baccetti et al. The Bjork, Grave and Brown stages were reduced to six intervals to compare with cervical vertebral maturational index (CVMI) staging by Hassel and Farman. These measurements were then compared with the hand wrist bone analysis, and the results were statistically analyzed using the Mann-Whitney test. There was no significant difference between the hand wrist analysis and the two different cervical vertebral analyses for assessing skeletal maturation. There was no significant difference between the two cervical vertebral analyses, but the CVMI method, which is visual method is less time consuming. Vertebral analysis on a lateral cephalogram is as valid as the hand wrist bone analysis with the advantage of reducing the radiation exposure of growing subjects.

Opioid receptor agonists may favorably affect bone mechanical properties in rats with estrogen deficiency-induced osteoporosis.

PubMed

Janas, Aleksandra; Folwarczna, Joanna

2017-02-01

The results of epidemiological, clinical, and in vivo and in vitro experimental studies on the effect of opioid analgesics on bone are inconsistent. The aim of the present study was to investigate the effect of morphine (an agonist of opioid receptors), buprenorphine (a partial μ opioid receptor agonist and κ opioid receptor antagonist), and naloxone (an antagonist of opioid receptors) on the skeletal system of female rats in vivo. The experiments were carried out on 3-month-old Wistar rats, divided into two groups: nonovariectomized (intact; NOVX) rats and ovariectomized (OVX) rats. The bilateral ovariectomy was performed 7 days before the start of drug administration. Morphine hydrochloride (20 mg/kg/day s.c.), buprenorphine (0.05 mg/kg/day s.c.), or naloxone hydrochloride dihydrate (2 mg/kg/day s.c.) were administered for 4 weeks to NOVX and OVX rats. In OVX rats, the use of morphine and buprenorphine counteracted the development of osteoporotic changes in the skeletal system induced by estrogen deficiency. Morphine and buprenorphine beneficially affected also the skeletal system of NOVX rats, but the effects were much weaker than those in OVX rats. Naloxone generally did not affect the rat skeletal system. The results confirmed the role of opioid receptors in the regulation of bone remodeling processes and demonstrated, in experimental conditions, that the use of opioid analgesics at moderate doses may exert beneficial effects on the skeletal system, especially in estrogen deficiency.

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

Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells.

PubMed

Fletcher, Rachel S; Ratajczak, Joanna; Doig, Craig L; Oakey, Lucy A; Callingham, Rebecca; Da Silva Xavier, Gabriella; Garten, Antje; Elhassan, Yasir S; Redpath, Philip; Migaud, Marie E; Philp, Andrew; Brenner, Charles; Canto, Carles; Lavery, Gareth G

2017-08-01

Augmenting nicotinamide adenine dinucleotide (NAD + ) availability may protect skeletal muscle from age-related metabolic decline. Dietary supplementation of NAD + precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) appear efficacious in elevating muscle NAD + . Here we sought to identify the pathways skeletal muscle cells utilize to synthesize NAD + from NMN and NR and provide insight into mechanisms of muscle metabolic homeostasis. We exploited expression profiling of muscle NAD + biosynthetic pathways, single and double nicotinamide riboside kinase 1/2 (NRK1/2) loss-of-function mice, and pharmacological inhibition of muscle NAD + recycling to evaluate NMN and NR utilization. Skeletal muscle cells primarily rely on nicotinamide phosphoribosyltransferase (NAMPT), NRK1, and NRK2 for salvage biosynthesis of NAD + . NAMPT inhibition depletes muscle NAD + availability and can be rescued by NR and NMN as the preferred precursors for elevating muscle cell NAD + in a pathway that depends on NRK1 and NRK2. Nrk2 knockout mice develop normally and show subtle alterations to their NAD+ metabolome and expression of related genes. NRK1, NRK2, and double KO myotubes revealed redundancy in the NRK dependent metabolism of NR to NAD + . Significantly, these models revealed that NMN supplementation is also dependent upon NRK activity to enhance NAD + availability. These results identify skeletal muscle cells as requiring NAMPT to maintain NAD + availability and reveal that NRK1 and 2 display overlapping function in salvage of exogenous NR and NMN to augment intracellular NAD + availability.

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.

Discontinuous Skeletal Gradient Discretisation methods on polytopal meshes

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

Di Pietro, Daniele A.; Droniou, Jérôme; Manzini, Gianmarco

Here, in this work we develop arbitrary-order Discontinuous Skeletal Gradient Discretisations (DSGD) on general polytopal meshes. Discontinuous Skeletal refers to the fact that the globally coupled unknowns are broken polynomials on the mesh skeleton. The key ingredient is a high-order gradient reconstruction composed of two terms: (i) a consistent contribution obtained mimicking an integration by parts formula inside each element and (ii) a stabilising term for which sufficient design conditions are provided. An example of stabilisation that satisfies the design conditions is proposed based on a local lifting of high-order residuals on a Raviart–Thomas–Nédélec subspace. We prove that the novelmore » DSGDs satisfy coercivity, consistency, limit-conformity, and compactness requirements that ensure convergence for a variety of elliptic and parabolic problems. Lastly, links with Hybrid High-Order, non-conforming Mimetic Finite Difference and non-conforming Virtual Element methods are also studied. Numerical examples complete the exposition.« less

Biogenetically inspired synthesis and skeletal diversification of indole alkaloids.

PubMed

Mizoguchi, Haruki; Oikawa, Hideaki; Oguri, Hiroki

2014-01-01

To access architecturally complex natural products, chemists usually devise a customized synthetic strategy for constructing a single target skeleton. In contrast, biosynthetic assembly lines often employ divergent intramolecular cyclizations of a polyunsaturated common intermediate to produce diverse arrays of scaffolds. With the aim of integrating such biogenetic strategies, we show the development of an artificial divergent assembly line generating unprecedented numbers of scaffold variations of terpenoid indole alkaloids. This approach not only allows practical access to multipotent intermediates, but also enables systematic diversification of skeletal, stereochemical and functional group properties without structural simplification of naturally occurring alkaloids. Three distinct modes of [4+2] cyclizations and two types of redox-mediated annulations provided divergent access to five skeletally distinct scaffolds involving iboga-, aspidosperma-, andranginine- and ngouniensine-type skeletons and a non-natural variant within six to nine steps from tryptamine. The efficiency of our approach was demonstrated by successful total syntheses of (±)-vincadifformine, (±)-andranginine and (-)-catharanthine.

An Ethyl-Nitrosourea-Induced Point Mutation in Phex Causes Exon Skipping, X-Linked Hypophosphatemia, and Rickets

PubMed Central

Carpinelli, Marina R.; Wicks, Ian P.; Sims, Natalie A.; O’Donnell, Kristy; Hanzinikolas, Katherine; Burt, Rachel; Foote, Simon J.; Bahlo, Melanie; Alexander, Warren S.; Hilton, Douglas J.

2002-01-01

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G1) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease. PMID:12414538

An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x-linked hypophosphatemia, and rickets.

PubMed

Carpinelli, Marina R; Wicks, Ian P; Sims, Natalie A; O'Donnell, Kristy; Hanzinikolas, Katherine; Burt, Rachel; Foote, Simon J; Bahlo, Melanie; Alexander, Warren S; Hilton, Douglas J

2002-11-01

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G(1)) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease.

Discontinuous Skeletal Gradient Discretisation methods on polytopal meshes

DOE PAGES

Di Pietro, Daniele A.; Droniou, Jérôme; Manzini, Gianmarco

2017-11-21

Here, in this work we develop arbitrary-order Discontinuous Skeletal Gradient Discretisations (DSGD) on general polytopal meshes. Discontinuous Skeletal refers to the fact that the globally coupled unknowns are broken polynomials on the mesh skeleton. The key ingredient is a high-order gradient reconstruction composed of two terms: (i) a consistent contribution obtained mimicking an integration by parts formula inside each element and (ii) a stabilising term for which sufficient design conditions are provided. An example of stabilisation that satisfies the design conditions is proposed based on a local lifting of high-order residuals on a Raviart–Thomas–Nédélec subspace. We prove that the novelmore » DSGDs satisfy coercivity, consistency, limit-conformity, and compactness requirements that ensure convergence for a variety of elliptic and parabolic problems. Lastly, links with Hybrid High-Order, non-conforming Mimetic Finite Difference and non-conforming Virtual Element methods are also studied. Numerical examples complete the exposition.« less

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

Historical Overview of the Effect of β-Adrenergic Agonists on Beef Cattle Production

PubMed Central

Johnson, Bradley J.; Smith, Stephen B.; Chung, Ki Yong

2014-01-01

Postnatal muscle hypertrophy of beef cattle is the result of enhanced myofibrillar protein synthesis and reduced protein turnover. Skeletal muscle hypertrophy has been studied in cattle fed β-adrenergic agonists (β-AA), which are receptor-mediated enhancers of protein synthesis and inhibitors of protein degradation. Feeding β-AA to beef cattle increases longissimus muscle cross-sectional area 6% to 40% compared to non-treated cattle. The β-AA have been reported to improve live animal performance, including average daily gain, feed efficiency, hot carcass weight, and dressing percentage. Treatment with β-AA increased mRNA concentration of the β2 or β1-adrenergic receptor and myosin heavy chain IIX in bovine skeletal muscle tissue. This review will examine the effects of skeletal muscle and adipose development with β-AA, and will interpret how the use of β-AA affects performance, body composition, and growth in beef cattle. PMID:25050012

Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis.

PubMed

Goldring, Mary B; Goldring, Steven R

2010-03-01

The articular surface plays an essential role in load transfer across the joint, and conditions that produce increased load transfer or altered patterns of load distribution accelerate the development of osteoarthritis (OA). Current knowledge segregates the risk factors into two fundamental mechanisms related to the adverse effects of "abnormal" loading on normal cartilage or "normal" loading on abnormal cartilage. Although chondrocytes can modulate their functional state in response to loading, their capacity to repair and modify the surrounding extracellular matrix is limited in comparison to skeletal cells in bone. This differential adaptive capacity underlies the more rapid appearance of detectable skeletal changes, especially after acute injuries that alter joint mechanics. The imbalance in the adaptation of the cartilage and bone disrupts the physiological relationship between these tissues and further contributes to OA pathology. This review focuses on the specific articular cartilage and skeletal features of OA and the putative mechanisms involved in their pathogenesis.

In vivo monitoring of Ca2+ uptake into mitochondria of mouse skeletal muscle during contraction

PubMed Central

Rudolf, Rüdiger; Mongillo, Marco; Magalhães, Paulo J.; Pozzan, Tullio

2004-01-01

Although the importance of mitochondria in patho-physiology has become increasingly evident, it remains unclear whether these organelles play a role in Ca2+ handling by skeletal muscle. This undefined situation is mainly due to technical limitations in measuring Ca2+ transients reliably during the contraction–relaxation cycle. Using two-photon microscopy and genetically expressed “cameleon” Ca2+ sensors, we developed a robust system that enables the measurement of both cytoplasmic and mitochondrial Ca2+ transients in vivo. We show here for the first time that, in vivo and under highly physiological conditions, mitochondria in mammalian skeletal muscle take up Ca2+ during contraction induced by motor nerve stimulation and rapidly release it during relaxation. The mitochondrial Ca2+ increase is delayed by a few milliseconds compared with the cytosolic Ca2+ rise and occurs both during a single twitch and upon tetanic contraction. PMID:15314066

The Ca2+ sensitizer CK‐2066260 increases myofibrillar Ca2+ sensitivity and submaximal force selectively in fast skeletal muscle

PubMed Central

Cheng, Arthur J.; Hartman, James J.; Hinken, Aaron C.; Lee, Ken; Durham, Nickie; Russell, Alan J.; Malik, Fady I.; Westerblad, Håkan; Jasper, Jeffrey R.

2017-01-01

Key points We report that the small molecule CK‐2066260 selectively slows the off‐rate of Ca2 + from fast skeletal muscle troponin, leading to increased myofibrillar Ca2 + sensitivity in fast skeletal muscle.Rodents dosed with CK‐2066260 show increased hindlimb muscle force and power in response to submaximal rates of nerve stimulation in situ.CK‐2066260 has no effect on free cytosolic [Ca2 +] during contractions of isolated muscle fibres.We conclude that fast skeletal muscle troponin sensitizers constitute a potential therapy to address an unmet need of improving muscle function in conditions of weakness and premature muscle fatigue. Abstract Skeletal muscle dysfunction occurs in many diseases and can lead to muscle weakness and premature muscle fatigue. Here we show that the fast skeletal troponin activator, CK‐2066260, counteracts muscle weakness by increasing troponin Ca2+ affinity, thereby increasing myofibrillar Ca2+ sensitivity. Exposure to CK‐2066260 resulted in a concentration‐dependent increase in the Ca2+ sensitivity of ATPase activity in isolated myofibrils and reconstituted hybrid sarcomeres containing fast skeletal muscle troponin C. Stopped‐flow experiments revealed a ∼2.7‐fold decrease in the Ca2+ off‐rate of isolated troponin complexes in the presence of CK‐2066260 (6 vs. 17 s−1 under control conditions). Isolated mouse flexor digitorum brevis fibres showed a rapidly developing, reversible and concentration‐dependent force increase at submaximal stimulation frequencies. This force increase was not accompanied by any changes in the free cytosolic [Ca2+] or its kinetics. CK‐2066260 induced a slowing of relaxation, which was markedly larger at 26°C than at 31°C and could be linked to the decreased Ca2+ off‐rate of troponin C. Rats dosed with CK‐2066260 showed increased hindlimb isometric and isokinetic force in response to submaximal rates of nerve stimulation in situ producing significantly higher absolute forces at low isokinetic velocities, whereas there was no difference in force at the highest velocities. Overall muscle power was increased and the findings are consistent with a lack of effect on crossbridge kinetics. In conclusion, CK‐2066260 acts as a fast skeletal troponin activator that may be used to increase muscle force and power in conditions of muscle weakness. PMID:27869319

Skeletal maturation in Indonesian and white children assessed with hand-wrist and cervical vertebrae methods.

PubMed

Soegiharto, Benny M; Cunningham, Susan J; Moles, David R

2008-08-01

The purpose of this study was to describe the stages of skeletal maturity of Deutero-Malay Indonesian children according to the hand-wrist and cervical vertebrae methods and to compare them with white children. The study included 2167 patients with hand-wrist radiographs and lateral cephalometric radiographs. Of these, there were 648 Indonesian boys, 303 white boys (age range of boys, 10-17 years), 774 Indonesian girls, and 442 white girls (age range of girls, 8-15 years). The skeletal maturation index (SMI) was used to evaluate the stages of skeletal maturity from hand-wrist radiographs, and the cervical vertebrae maturation (CVM) index was used to evaluate the stages of skeletal maturity from lateral cephalometric radiographs. One observer made all observations, and a repeatability study was undertaken. Box-and-whisker plots were used to show the age distribution on attainment of each maturation stage based on the SMI and CVM. On average, both the SMI and the CVM showed that white children attained each maturation stage about 0.5 to 1 year earlier than their Indonesian peers, although the differences were less obvious in girls than in boys. Multiple regression analysis was used to predict the SMI from the chronologic age. Both the Indonesian and the white boys groups showed a good relationship between predicted SMI and chronologic age (R(2) = 0.728 and 0.739, respectively), as did the Indonesian and white girls groups (R(2) = 0.755 and 0.748, respectively). Further multiple regression analyses used to investigate the differences in the ages of attainment of skeletal development between Indonesian and white subjects indicated that, across the age ranges investigated, on average for a particular age, the white boys were 1 SMI stage ahead of the Indonesian boys, and the white girls were about 0.5 SMI stage ahead of their Indonesian peers. Because the CVM has only 5 categories, it was not considered appropriate to use this form of multiple regression analysis. The findings confirmed marked variations in the chronologic ages for each skeletal maturity stage and also showed differences between the timing of skeletal maturity with both the SMI and the CVM between the sexes and the ethnic groups. These differences should be considered during orthodontic diagnosis and treatment planning.

[Study on the difference of corresponding age at cervical vertebral maturation stages among different skeletal malocclusions].

PubMed

Zuo, Changyan; Cong, Chao; Wang, Shihui; Gu, Yan

2015-10-01

To compare the difference of corresponding age at cervical vertebral maturation (CVM) stages among different skeletal malocclusions and provide clinic guideline on optimal treatment timing for skeletal malocclusion. Based on ANB angle, 2 575 cephalograms collected from Department of Orthodontics, Peking University School and Hospital of Stomatology from May, 2006 to November, 2014 were classified into skeletal Class I (ANB 0°~5°, 1 317 subjects), Class II (ANB > 5°, 685 subjects) and Class III (ANB < 0°, 573 subjects) groups. CVM stages were evaluated with the modified version of CVM method. Independent sample t test was performed to analyze the difference of age at different CVM stages among various skeletal groups. Significant gender difference of age was found at CS3 to CS6 for skeletal Class I group (P < 0.05), at CS5 and CS6 for skeletal Class II group (P < 0.05), and at CS3 and CS5 for skeletal Class III group (P < 0.05). At CS3 stage, the average age of male in skeletal Class II and skeletal Class III groups was (11.6 ± 1.5) years old and (10.3 ± 1.9) years old, respectively; the average age of females in those two groups was (11.7 ± 1.3) years old and (9.3 ± 1.5) years old, respectively, and significant difference was found in both comparisons (P < 0.05). Compared average age at CS5 and CS6 between skeletal Class II and skeletal Class III groups [the ages of male was (15.1 ± 1.7) and (16.8 ± 1.6) years old, the ages of male was (14.6 ± 1.2) and (15.7 ± 2.5) years old], significant difference was also found (P < 0.05). Significant gender differences were found when evaluated CVM stage and age in skeletal Class I, II and III groups. Significant differences of age at different CVM stage was noted when skeletal Class II was compared with skeletal Class III groups.

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.

Irxl1 mutant mice show reduced tendon differentiation and no patterning defects in musculoskeletal system development.

PubMed

Kimura, Wataru; Machii, Masashi; Xue, XiaoDong; Sultana, Nishat; Hikosaka, Keisuke; Sharkar, Mohammad T K; Uezato, Tadayoshi; Matsuda, Masashi; Koseki, Haruhiko; Miura, Naoyuki

2011-01-01

Irxl1 (Iroquois-related homeobox like-1) is a newly identified three amino-acid loop extension (TALE) homeobox gene, which is expressed in various mesoderm-derived tissues, particularly in the progenitors of the musculoskeletal system. To analyze the roles of Irxl1 during embryonic development, we generated mice carrying a null allele of Irxl1. Mice homozygous for the targeted allele were viable, fertile, and showed reduced tendon differentiation. Skeletal morphology and skeletal muscle weight in Irxl1-knockout mice appeared normal. Expression patterns of several marker genes for cartilage, tendon, and muscle progenitors in homozygous mutant embryos were unchanged. These results suggest that Irxl1 is required for the tendon differentiation but dispensable for the patterning of the musculoskeletal system in development. Copyright © 2010 Wiley-Liss, Inc.

Skeletal injuries in small mammals: a multispecies assessment of prevalence and location

USGS Publications Warehouse

Stephens, Ryan B.; Burke, Christopher B.; Woodman, Neal; Poland, Lily B.; Rowe, Rebecca J.

2018-01-01

Wild mammals are known to survive injuries that result in skeletal abnormalities. Quantifying and comparing skeletal injuries among species can provide insight into the factors that cause skeletal injuries and enable survival following an injury. We documented the prevalence and location of structural bone abnormalities in a community of 7 small mammal species inhabiting the White Mountains of New Hampshire. These species differ in locomotion type and levels of intraspecific aggression. Overall, the majority of injuries were to the ribs or caudal vertebrae. Incidence of skeletal injuries was highest in older animals, indicating that injuries accumulate over a lifetime. Compared to species with ambulatory locomotion, those with more specialized (semi-fossorial, saltatorial, and scansorial) locomotion exhibited fewer skeletal abnormalities in the arms and legs, which we hypothesize is a result of a lesser ability to survive limb injuries. Patterns of skeletal injuries in shrews (Soricidae) were consistent with intraspecific aggression, particularly in males, whereas skeletal injuries in rodents (Rodentia) were more likely accidental or resulting from interactions with predators. Our results demonstrate that both the incidence and pattern of skeletal injuries vary by species and suggest that the ability of an individual to survive a specific skeletal injury depends on its severity and location as well as the locomotor mode of the species involved.

Skeletal and chronological ages in American adolescents: current findings in skeletal maturation.

PubMed

Calfee, Ryan P; Sutter, Melanie; Steffen, Jennifer A; Goldfarb, Charles A

2010-10-01

This study was designed to assess the relationship between skeletal and chronological ages among current American adolescents using the Greulich and Pyle atlas for skeletal age determination. We used the Greulich and Pyle atlas to prospectively determine skeletal age in a group of 138 otherwise healthy American adolescents from 12 to 18 years of age. 62 males and 76 females were enrolled in this cohort. Paired Student t-tests were used to statistically compare the skeletal and chronological ages in this population. Subgroup analysis examined the effect of gender on differences between chronologic age and skeletal age. For the entire cohort, mean skeletal age was significantly greater than chronological age (mean 0.80 years, P < 0.01). In 29 cases (21%) the skeletal age was at least 2 years greater than the chronologic age. Among females, such cases with marked discrepancy occurred exclusively in those chronologically between 12 and 15 years of age (P < 0.01). Males demonstrated a 2-year or greater discrepancy more commonly than females (26 vs. 17%). In males, 2-year discrepancies were equally likely across chronologic ages (P = 0.82). Current American adolescents are significantly more mature by skeletal age, as determined by the Greulich and Pyle method, than their chronological age would suggest. The skeletal ages of females are most likely to markedly exceed chronologic age between the ages of 12-15 years.

Differentiation of original and regenerated skeletal muscle fibres in mdx dystrophic muscles.

PubMed

Earnshaw, John C; Kyprianou, Phillip; Krishan, Kewal; Dhoot, Gurtej K

2002-07-01

The differentiation of both original muscle fibres and the regenerated muscle fibres following necrosis in mdx muscles was investigated using immunoblotting and immunocytochemical procedures. Before the onset of necrosis, postnatal skeletal muscles in mdx mouse differentiated well with only a slight delay in differentiation indicated by the level of developmental isoforms of troponin T. Prior to the onset of apparent myopathic change, both fast and slow skeletal muscle fibre types in mdx leg muscles also differentiated well when investigated by analysis of specific myosin heavy chain expression pattern. While the original muscle fibres in mdx leg muscles developed well, the differentiation of regenerated myotubes into both slow and distinct fast muscle fibre types, however, was markedly delayed or inhibited as indicated by several clusters of homogeneously staining fibres even at 14 weeks of age. The number of slow myosin heavy chain-positive myotubes amongst the regenerated muscle clusters was quite small even in soleus. This study thus established that while muscle fibres initially develop normally with only a slight delay in the differentiation process, the differentiation of regenerated myotubes in mdx muscles is markedly compromised and consequently delayed.

Fetal programming of fat and collagen in porcine skeletal muscles

PubMed Central

Karunaratne, JF; Ashton, CJ; Stickland, NC

2005-01-01

Connective tissue plays a key role in the scaffolding and development of skeletal muscle. Pilot studies carried out in our laboratory have shown that the smallest porcine littermate has a higher content of connective tissue within skeletal muscle compared with its largest littermate. The present study investigated the prenatal development of intralitter variation in terms of collagen content within connective tissue and intramuscular fat of the M. semitendinosus. Twenty-three pairs of porcine fetuses from a Large White–Landrace origin were used aged from 36 to 86 days of gestation. The largest and smallest littermates were chosen by weight and the M. semitendinosus was removed from each. Complete transverse muscle sections were stained with Oil Red O (detection of lipids) and immunocytochemistry was performed using an antibody to collagen I. Slides were analysed and paired t-Tests revealed the smallest littermate contained a significantly higher proportion of fat deposits and collagen I content compared with the largest littermate. Recent postnatal studies showing elevated levels of intramuscular lipids and low scores for meat tenderness in the smallest littermate corroborate our investigations. It can be concluded that the differences seen in connective tissue elements have a fetal origin that may continue postnatally. PMID:16367803

Development of Sensory Receptors in Skeletal Muscle

NASA Technical Reports Server (NTRS)

DeSantis, Mark

2000-01-01

There were two major goals for my project. One was to 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. This initial goal was subsequently modified so that additional developmental measures were taken (e.g. body weight, eye opening) as the progeny developed, and the study period was lengthened to eighty days. Also videotapes taken shortly after the pregnant Flight dams returned to Earth were scored for locomotor activity and compared to those for the Synchronous control dams at the same stage of pregnancy. The second goal was to examine skeletal muscle. Selected hindlimb skeletal muscles were to be identified, weighed, and examined for the presence and integrity of muscle receptors, (both muscle spindles and tendon organs), at the level of the light and electron microscope. Muscles were examined from rats that were at fetal (G20), newborn (postnatal day 1 or P1, where P1 = day of birth), and young adult (approx. P100) stages. At the present time data from only the last group of rats (i.e. P100) has been completely examined.

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

Impact of skeletal unloading on bone formation: Role of systemic and local factors

NASA Astrophysics Data System (ADS)

Bikle, Daniel D.; Halloran, Bernard P.; Morey-Holton, Emily

We have developed a model of skeletal unloading using growing rats whose hindlimbs are unweighted by tail suspension. The bones in the hindlimbs undergo a transient cessation of bone growth; when reloaded bone formation is accelerated until bone mass is restored. These changes do not occur in the normally loaded bones of the forelimbs. Associated with the fall in bone formation is a fall in 1,25(OH) 2D 3 production and osteocalcin levels. In contrast, no changes in parathyroid hormone, calcium, or corticosterone levels are seen. To examine the role of locally produced growth factors, we have measured the mRNA and protein levels of insulin like growth factor-1 (IGF-1) in bone during tail suspension. Surprisingly, both the mRNA and protein levels of IGF-1 increase during tail suspension as bone formation is reduced. Furthermore, the bones in the hindlimbs of the suspended animals develop a resistance to the growth promoting effects of both growth hormone and IGF-1 when given parenterally. Thus, the cessation of bone growth with skeletal unloading is apparently associated with a resistance to rather than failure to produce local growth factors. The cause of this resistance remains under active investigation.

Sex discrimination from the acetabulum in a twentieth-century skeletal sample from France using digital photogrammetry.

PubMed

Macaluso, P J

2011-02-01

Digital photogrammetric methods were used to collect diameter, area, and perimeter data of the acetabulum for a twentieth-century skeletal sample from France (Georges Olivier Collection, Musée de l'Homme, Paris) consisting of 46 males and 36 females. The measurements were then subjected to both discriminant function and logistic regression analyses in order to develop osteometric standards for sex assessment. Univariate discriminant functions and logistic regression equations yielded overall correct classification accuracy rates for both the left and the right acetabula ranging from 84.1% to 89.6%. The multivariate models developed in this study did not provide increased accuracy over those using only a single variable. Classification sex bias ratios ranged between 1.1% and 7.3% for the majority of models. The results of this study, therefore, demonstrate that metric analysis of acetabular size provides a highly accurate, and easily replicable, method of discriminating sex in this documented skeletal collection. The results further suggest that the addition of area and perimeter data derived from digital images may provide a more effective method of sex assessment than that offered by traditional linear measurements alone. Copyright © 2010 Elsevier GmbH. All rights reserved.

Time-dependent behavior of passive skeletal muscle

NASA Astrophysics Data System (ADS)

Ahamed, T.; Rubin, M. B.; Trimmer, B. A.; Dorfmann, L.

2016-03-01

An isotropic three-dimensional nonlinear viscoelastic model is developed to simulate the time-dependent behavior of passive skeletal muscle. The development of the model is stimulated by experimental data that characterize the response during simple uniaxial stress cyclic loading and unloading. Of particular interest is the rate-dependent response, the recovery of muscle properties from the preconditioned to the unconditioned state and stress relaxation at constant stretch during loading and unloading. The model considers the material to be a composite of a nonlinear hyperelastic component in parallel with a nonlinear dissipative component. The strain energy and the corresponding stress measures are separated additively into hyperelastic and dissipative parts. In contrast to standard nonlinear inelastic models, here the dissipative component is modeled using an evolution equation that combines rate-independent and rate-dependent responses smoothly with no finite elastic range. Large deformation evolution equations for the distortional deformations in the elastic and in the dissipative component are presented. A robust, strongly objective numerical integration algorithm is used to model rate-dependent and rate-independent inelastic responses. The constitutive formulation is specialized to simulate the experimental data. The nonlinear viscoelastic model accurately represents the time-dependent passive response of skeletal muscle.

A Noninvasive In Vitro Monitoring System Reporting Skeletal Muscle Differentiation.

PubMed

Öztürk-Kaloglu, Deniz; Hercher, David; Heher, Philipp; Posa-Markaryan, Katja; Sperger, Simon; Zimmermann, Alice; Wolbank, Susanne; Redl, Heinz; Hacobian, Ara

2017-01-01

Monitoring of cell differentiation is a crucial aspect of cell-based therapeutic strategies depending on tissue maturation. In this study, we have developed a noninvasive reporter system to trace murine skeletal muscle differentiation. Either a secreted bioluminescent reporter (Metridia luciferase) or a fluorescent reporter (green fluorescent protein [GFP]) was placed under the control of the truncated muscle creatine kinase (MCK) basal promoter enhanced by variable numbers of upstream MCK E-boxes. The engineered pE3MCK vector, coding a triple tandem of E-Boxes and the truncated MCK promoter, showed twentyfold higher levels of luciferase activation compared with a Cytomegalovirus (CMV) promoter. This newly developed reporter system allowed noninvasive monitoring of myogenic differentiation in a straining bioreactor. Additionally, binding sequences of endogenous microRNAs (miRNAs; seed sequences) that are known to be downregulated in myogenesis were ligated as complementary seed sequences into the reporter vector to reduce nonspecific signal background. The insertion of seed sequences improved the signal-to-noise ratio up to 25% compared with pE3MCK. Due to the highly specific, fast, and convenient expression analysis for cells undergoing myogenic differentiation, this reporter system provides a powerful tool for application in skeletal muscle tissue engineering.

Testing of therapies in a novel nebulin nemaline myopathy model demonstrate a lack of efficacy.

PubMed

Sztal, Tamar E; McKaige, Emily A; Williams, Caitlin; Oorschot, Viola; Ramm, Georg; Bryson-Richardson, Robert J

2018-05-30

Nemaline myopathies are heterogeneous congenital muscle disorders causing skeletal muscle weakness and, in some cases, death soon after birth. Mutations in nebulin, encoding a large sarcomeric protein required for thin filament function, are responsible for approximately 50% of nemaline myopathy cases. Despite the severity of the disease there is no effective treatment for nemaline myopathy with limited research to develop potential therapies. Several supplements, including L-tyrosine, have been suggested to be beneficial and consequently self-administered by nemaline myopathy patients without any knowledge of their efficacy. We have characterized a zebrafish model for nemaline myopathy caused by a mutation in nebulin. These fish form electron-dense nemaline bodies and display reduced muscle function akin to the phenotypes observed in nemaline myopathy patients. We have utilized our zebrafish model to test and evaluate four treatments currently self-administered by nemaline myopathy patients to determine their ability to increase skeletal muscle function. Analysis of muscle pathology and locomotion following treatment with L-tyrosine, L-carnitine, taurine, or creatine revealed no significant improvement in skeletal muscle function emphasizing the urgency to develop effective therapies for nemaline myopathy.

Unlocking the coral calcification process: Insights from boron isotope measurements and a skeletal growth model

NASA Astrophysics Data System (ADS)

Mollica, N. R.; Guo, W.; Cohen, A. L.; Huang, K. F.; Foster, G. L.; Donald, H.; Solow, A.

2017-12-01

Carbonate skeletons of scleractinian corals are important archives of ocean climate and environmental change. However, corals don't accrete their skeletons directly from ambient seawater, but from a calcifying fluid whose composition is strongly regulated. There is mounting evidence that the carbonate chemistry of this calcifying fluid significantly impacts the amount of carbonate the coral can precipitate, which in turn affects the geochemical composition of the skeleton produced. However the mechanistic link between calcifying fluid (cf) chemistry, particularly the up-regulation of pHcf and thereby aragonite saturation state (Ωcf), and coral calcification is not well understood. We explored this link by combining boron isotope measurements with in situ measurements of seawater temperature, salinity, and DIC to estimate Ωcf of nine Porites corals from four Pacific reefs. Associated calcification rates were quantified for each core via CT scanning. We do not observe a relationship between calcification rates and Ωcf or Ωsw. Instead, when we deconvolve calcification into linear extension and skeletal density, a significant correlation is observed between density and Ωcf, and also Ωsw while extension does not correlate with either. These observations are consistent with the two-step model of coral calcification, in which skeleton is secreted in two distinct phases: vertical extension creating new skeletal elements, followed by lateral thickening of existing elements that are covered by living tissue. We developed a numerical model of Porites skeletal growth that builds on this two-step model and links skeletal density with the external seawater environment via its influence on the chemistry of coral calcifying fluid. We validated the model using existing coral skeletal datasets from six Porites species collected across five reef sites, and quantified the effects of each seawater parameter (e.g. temperature, pH, DIC) on skeletal density. Our findings illustrate the sensitivity of the second phase of coral calcification to the carbonate chemistry of the calcifying fluid, and support previous coral proxy system modelling efforts by validating the two-step growth model on annual and seasonal scales.

Factors Associated with the Serum Myostatin Level in Patients Undergoing Peritoneal Dialysis: Potential Effects of Skeletal Muscle Mass and Vitamin D Receptor Activator Use.

PubMed

Yamada, Shunsuke; Tsuruya, Kazuhiko; Yoshida, Hisako; Tokumoto, Masanori; Ueki, Kenji; Ooboshi, Hiroaki; Kitazono, Takanari

2016-07-01

Myostatin is a member of the transforming growth factor-β family, which regulates synthesis and degradation of skeletal muscle proteins and is associated with the development of sarcopenia. It is up-regulated in the skeletal muscle of chronic kidney disease patients and is considered to be involved in the development of uremic sarcopenia. However, serum myostatin levels have rarely been determined, and the relationship between serum myostatin levels with clinical and metabolic factors remains unknown. This cross-sectional study investigated the association between serum myostatin level and clinical factors in 69 outpatients undergoing peritoneal dialysis. Serum myostatin level was determined by commercially available enzyme-linked immunosorbent assay (ELISA). Univariable and multivariable analysis were conducted to determine factors associated with serum myostatin levels. The factors included age, sex, diabetes mellitus, dialysis history, body mass index, residual kidney function, peritoneal dialysate volume, serum biochemistries, and the use of vitamin D receptor activators (VDRAs). Mean serum myostatin level was 7.59 ± 3.37 ng/mL. There was no association between serum myostatin level and residual kidney function. Serum myostatin levels were significantly and positively associated with lean body mass measured by the creatinine kinetic method and negatively associated with the use of VDRAs after adjustment for potential confounding factors. Our study indicated that serum myostatin levels are associated with skeletal muscle mass and are lower in patients treated with VDRAs. Further studies are necessary to determine the significance of measuring serum myostatin level in patients undergoing peritoneal dialysis.

Passive stiffness of rat skeletal muscle undernourished during fetal development

PubMed Central

Toscano, Ana Elisa; Ferraz, Karla Mônica; de Castro, Raul Manhães; Canon, Francis

2010-01-01

OBJECTIVES: The aim of the study was to investigate the effect of fetal undernutrition on the passive mechanical properties of skeletal muscle of weaned and young adult rats. INTRODUCTION: A poor nutrition supply during fetal development affects physiological functions of the fetus. From a mechanical point of view, skeletal muscle can be also characterized by its resistance to passive stretch. METHODS: Male Wistar rats were divided into two groups according to their mother's diet during pregnancy: a control group (mothers fed a 17% protein diet) and an isocaloric low‐protein group (mothers fed a 7.8% protein diet). At birth, all mothers received a standardized meal ad libitum. At the age of 25 and 90 days, the soleus muscle and extensor digitorum longus (EDL) muscles were removed in order to test the passive mechanical properties. A first mechanical test consisted of an incremental stepwise extension test using fast velocity stretching (500 mm/s) enabling us to measure, for each extension stepwise, the dynamic stress (σd) and the steady stress (σs). A second test consisted of a slow velocity stretch in order to calculate normalized stiffness and tangent modulus from the stress–strain relationship. RESULTS: The results for the mechanical properties showed an important increase in passive stiffness in both the soleus and EDL muscles in weaned rat. In contrast, no modification was observed in young adult rats. CONCLUSIONS: The increase in passive stiffness in skeletal muscle of weaned rat submitted to intrauterine undernutrition it is most likely due to changes in muscle passive stiffness. PMID:21340228