[Dropped head syndrome as first manifestation of primary hyperparathyroid myopathy].

PubMed

Ota, Kiyobumi; Koseki, Sayo; Ikegami, Kenji; Onishi, Iichiroh; Tomimitsu, Hiyoryuki; Shintani, Shuzo

2018-03-28

75 years old woman presented with 6-month history of progressive dropped head syndrome. Neurological examination revealed moderate weakness of flexor and extensor of neck and mild weakness of proximal appendicular muscles with normal deep tendon reflexes. The needle electromyography showed short duration and low amplitude motor unit potential. No fibrillation potentials or positive sharp waves were seen. Biopsy of deltoid muscle was normal. Laboratory studies showed elevated levels of serum calcium (11.8 mg/dl, upper limit of normal 10.1) and intact parathyroid hormone (104 pg/ml, upper limit of normal 65), and decreased level of serum phosphorus (2.3 mg/dl, lower limit of normal 2.7). Ultrasonography and enhanced computed tomography revealed a parathyroid tumor. The tumor was removed surgically. Pathological examination proved tumor to be parathyroid adenoma. Dropped head and weakness of muscles were dramatically improved within a week after the operation. Although hyperparathyroidism is a rare cause of dropped head syndrome, neurologists must recognize hyperparathyroidism as a treatable cause of dropped head syndrome.

Genetics Home Reference: hyperkalemic periodic paralysis

MedlinePlus

... reduce the ability of skeletal muscles to contract, leading to episodes of muscle weakness or paralysis. In 30 to 40 percent of cases, the cause of hyperkalemic periodic paralysis is unknown. Changes in other genes, which have not been identified, ...

The value of multiple tests of respiratory muscle strength

PubMed Central

Steier, Joerg; Kaul, Sunny; Seymour, John; Jolley, Caroline; Rafferty, Gerrard; Man, William; Luo, Yuan M; Roughton, Michael; Polkey, Michael I; Moxham, John

2007-01-01

Background Respiratory muscle weakness is an important clinical problem. Tests of varying complexity and invasiveness are available to assess respiratory muscle strength. The relative precision of different tests in the detection of weakness is less clear, as is the value of multiple tests. Methods The respiratory muscle function tests of clinical referrals who had multiple tests assessed in our laboratories over a 6‐year period were analysed. Thresholds for weakness for each test were determined from published and in‐house laboratory data. The patients were divided into three groups: those who had all relevant measurements of global inspiratory muscle strength (group A, n = 182), those with full assessment of diaphragm strength (group B, n = 264) and those for whom expiratory muscle strength was fully evaluated (group C, n = 60). The diagnostic outcome of each inspiratory, diaphragm and expiratory muscle test, both singly and in combination, was studied and the impact of using more than one test to detect weakness was calculated. Results The clinical referrals were primarily for the evaluation of neuromuscular diseases and dyspnoea of unknown cause. A low maximal inspiratory mouth pressure (Pimax) was recorded in 40.1% of referrals in group A, while a low sniff nasal pressure (Sniff Pnasal) was recorded in 41.8% and a low sniff oesophageal pressure (Sniff Poes) in 37.9%. When assessing inspiratory strength with the combination of all three tests, 29.6% of patients had weakness. Using the two non‐invasive tests (Pimax and Sniff Pnasal) in combination, a similar result was obtained (low in 32.4%). Combining Sniff Pdi (low in 68.2%) and Twitch Pdi (low in 67.4%) reduced the diagnoses of patients with diaphragm weakness to 55.3% in group B. 38.3% of the patients in group C had expiratory muscle weakness as measured by maximum expiratory pressure (Pemax) compared with 36.7% when weakness was diagnosed by cough gastric pressure (Pgas), and 28.3% when assessed by Twitch T10. Combining all three expiratory muscle tests reduced the number of patients diagnosed as having expiratory muscle weakness to 16.7%. Conclusion The use of single tests such as Pimax, Pemax and other available individual tests of inspiratory, diaphragm and expiratory muscle strength tends to overdiagnose weakness. Combinations of tests increase diagnostic precision and, in the population studied, they reduced the diagnosis of inspiratory, specific diaphragm and expiratory muscle weakness by 19–56%. Measuring both Pimax and Sniff Pnasal resulted in a relative reduction of 19.2% of patients falsely diagnosed with inspiratory muscle weakness. The addition of Twitch Pdi to Sniff Pdi increased diagnostic precision by a smaller amount (18.9%). Having multiple tests of respiratory muscle function available both increases diagnostic precision and makes assessment possible in a range of clinical circumstances. PMID:17557772

Muscle hypertrophy and pseudohypertrophy.

PubMed

Walters, Jon

2017-10-01

The physical examination always begins with a thorough inspection and patients with potential neuromuscular weakness are no exception. One question neurologists routinely address during this early part of the assessment is whether or not there is muscle enlargement. This finding may reflect true muscle hypertrophy-myofibres enlarged from repetitive activity, for example, in myotonia congenita or neuromyotonia-or muscles enlarged by the infiltration of fat or other tissue termed pseudohypertrophy or false enlargement. Pseudohypertrophic muscles are frequently paradoxically weak. Recognising such a clinical clue at the bed side can facilitate a diagnosis or at least can narrow down the list of potential suspects. This paper outlines the conditions, both myopathic and neurogenic, that cause muscle enlargement. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Ca2+ sensitizers: An emerging class of agents for counterbalancing weakness in skeletal muscle diseases?

PubMed

Ochala, Julien

2010-02-01

Ca(2+) ions are key regulators of skeletal muscle contraction. By binding to contractile proteins, they initiate a cascade of molecular events leading to cross-bridge formation and ultimately, muscle shortening and force production. The ability of contractile proteins to respond to Ca(2+) attachment, also known as Ca(2+) sensitivity, is often compromised in acquired and congenital skeletal muscle disorders. It constitutes, undoubtedly, a major physiological cause of weakness for patients. In this review, we discuss recent studies giving strong molecular and cellular evidence that pharmacological modulators of some of the contractile proteins, also termed Ca(2+) sensitizers, are efficient agents to improve Ca(2+) sensitivity and function in diseased skeletal muscle cells. In fact, they compensate for the impaired contractile proteins response to Ca(2+) binding. Currently, such Ca(2+) sensitizing compounds are successfully used for reducing problems in cardiac disorders. Therefore, in the future, under certain conditions, these agents may represent an emerging class of agents to enhance the quality of life of patients suffering from skeletal muscle weakness. Copyright 2009 Elsevier B.V. All rights reserved.

Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type-dependent changes in trophicity: novel insights in nemaline myopathy

PubMed Central

Li, Frank; Buck, Danielle; De Winter, Josine; Kolb, Justin; Meng, Hui; Birch, Camille; Slater, Rebecca; Escobar, Yael Natelie; Smith, John E.; Yang, Lin; Konhilas, John; Lawlor, Michael W.; Ottenheijm, Coen; Granzier, Henk L.

2015-01-01

Nebulin is a giant filamentous protein that is coextensive with the actin filaments of the skeletal muscle sarcomere. Nebulin mutations are the main cause of nemaline myopathy (NEM), with typical adult patients having low expression of nebulin, yet the roles of nebulin in adult muscle remain poorly understood. To establish nebulin's functional roles in adult muscle, we studied a novel conditional nebulin KO (Neb cKO) mouse model in which nebulin deletion was driven by the muscle creatine kinase (MCK) promotor. Neb cKO mice are born with high nebulin levels in their skeletal muscles, but within weeks after birth nebulin expression rapidly falls to barely detectable levels Surprisingly, a large fraction of the mice survive to adulthood with low nebulin levels (<5% of control), contain nemaline rods and undergo fiber-type switching toward oxidative types. Nebulin deficiency causes a large deficit in specific force, and mechanistic studies provide evidence that a reduced fraction of force-generating cross-bridges and shortened thin filaments contribute to the force deficit. Muscles rich in glycolytic fibers upregulate proteolysis pathways (MuRF-1, Fbxo30/MUSA1, Gadd45a) and undergo hypotrophy with smaller cross-sectional areas (CSAs), worsening their force deficit. Muscles rich in oxidative fibers do not have smaller weights and can even have hypertrophy, offsetting their specific-force deficit. These studies reveal nebulin as critically important for force development and trophicity in adult muscle. The Neb cKO phenocopies important aspects of NEM (muscle weakness, oxidative fiber-type predominance, variable trophicity effects, nemaline rods) and will be highly useful to test therapeutic approaches to ameliorate muscle weakness. PMID:26123491

Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during Adulthood

PubMed Central

McDonald, Fiona B.; Dempsey, Eugene M.; O'Halloran, Ken D.

2016-01-01

Intermittent hypoxia is a feature of apnea of prematurity (AOP), chronic lung disease, and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH) during postnatal development (pCIH) causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 h of delivery, pups and their respective dams were exposed to CIH: 90 s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 h per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH), where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm) weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life. PMID:26973537

Hypoglycemia, hepatic dysfunction, muscle weakness, cardiomyopathy, free carnitine deficiency and long-chain acylcarnitine excess responsive to medium chain triglyceride diet.

PubMed

Glasgow, A M; Engel, A G; Bier, D M; Perry, L W; Dickie, M; Todaro, J; Brown, B I; Utter, M F

1983-05-01

Fraternal twins who had fasting hypoglycemia, hypoketonemia, muscle weakness, and hepatic dysfunction are reported. The hepatic dysfunction occurred only during periods of caloric deprivation. The surviving patient developed a cardiomyopathy. In this sibling, muscle weakness and cardiomyopathy were markedly improved by a diet high in medium chain triglycerides. There was a marked deficiency of muscle total carnitine and a mild deficiency of hepatic total carnitine. Unlike patients with systemic carnitine deficiency, serum and muscle long-chain acylcarnitine were elevated and renal reabsorption of carnitine was normal. It was postulated that the defect in long-chain fatty acid oxidation in this disorder is caused by an abnormality in the mitochondrial acylcarnitine transport. Detailed studies of the cause of the hypoglycemia revealed that insulin, growth hormone, cortisol, and glucagon secretion were appropriate and that it is unlikely that there was a major deficiency of a glycolytic or gluconeogenic enzyme. Glucose production and alanine conversion to glucose were in the low normal range when compared to normal children in the postabsorptive state. The hypoglycemia in our patients was probably due to a modest increase in glucose consumption, secondary to the decreased oxidation of fatty acids and ketones, alternate fuels which spare glucose utilization, plus a modest decrease in hepatic glucose production secondary to decreased available hepatic energy substrates.

A case report: a heterozygous deletion (2791_2805 del) in exon 18 of the filamin C gene causing filamin C-related myofibrillar myopathies in a Chinese family.

PubMed

Miao, Jing; Su, Fei-Fei; Liu, Xue-Mei; Wei, Xiao-Jing; Yuan, Yun; Yu, Xue-Fan

2018-06-04

Filamin C-related myofibrillar myopathies (MFM) are progressive skeletal myopathies with an autosomal dominant inheritance pattern. The conditions are caused by mutations of the filamin C gene (FLNC) located in the chromosome 7q32-q35 region. Genetic variations in the FLNC gene result in various clinical phenotypes. We describe a 43-year-old woman who suffered filamin C-related MFM, with symptoms first presenting in the proximal muscles of the lower limbs and eventually spreading to the upper limbs and distal muscles. The patient's serum level of creatine kinase was mildly increased. Mildy myopathic changes in the electromyographic exam and moderate lipomatous alterations in lower limb MRI were found. Histopathological examination revealed increased muscle fiber size variability, disturbances in oxidative enzyme activity, and the presence of abnormal protein aggregates and vacuoles in some muscle fibers. Ultrastructural analysis showed inclusions composed of thin filaments and interspersed granular densities. DNA sequencing analysis detected a novel 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the FLNC gene. The patient's father, sister, brother, three paternal aunts, one paternal uncle, and the uncle's son also had slowly progressive muscle weakness, and thus, we detected an autosomal dominant inheritance pattern of the disorder. A novel heterogeneous 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the Ig-like domain 7 of the FLNC gene was found to cause filamin C-related MFM. This deletion in the FLNC gene causes protein aggregation, abnormalities in muscle structure, and impairment in muscle fiber function, which leads to muscle weakness.

Co-activation: its association with weakness and specific neurological pathology

PubMed Central

Busse, Monica E; Wiles, Charles M; van Deursen, Robert WM

2006-01-01

Background Net agonist muscle strength is in part determined by the degree of antagonist co-activation. The level of co-activation might vary in different neurological disorders causing weakness or might vary with agonist strength. Aim This study investigated whether antagonist co-activation changed a) with the degree of muscle weakness and b) with the nature of the neurological lesion causing weakness. Methods Measures of isometric quadriceps and hamstrings strength were obtained. Antagonist (hamstring) co-activation during knee extension was calculated as a ratio of hamstrings over quadriceps activity both during an isometric and during a functional sit to stand (STS) task (using kinematics) in groups of patients with extrapyramidal (n = 15), upper motor neuron (UMN) (n = 12), lower motor neuron (LMN) with (n = 18) or without (n = 12) sensory loss, primary muscle or neuromuscular junction disorder (n = 17) and in healthy matched controls (n = 32). Independent t-tests or Mann Witney U tests were used to compare between the groups. Correlations between variables were also investigated. Results In healthy subjects mean (SD) co-activation of hamstrings during isometric knee extension was 11.8 (6.2)% and during STS was 20.5 (12.9)%. In patients, co-activation ranged from 7 to 17% during isometric knee extension and 15 to 25% during STS. Only the extrapyramidal group had lower co-activation levels than healthy matched controls (p < 0.05). Agonist isometric muscle strength and co-activation correlated only in muscle disease (r = -0.6, p < 0.05) and during STS in UMN disorders (r = -0.7, p < 0.5). Conclusion It is concluded that antagonist co-activation does not systematically vary with the site of neurological pathology when compared to healthy matched controls or, in most patient groups, with strength. The lower co-activation levels found in the extrapyramidal group require confirmation and further investigation. Co-activation may be relevant to individuals with muscle weakness. Within patient serial studies in the presence of changing muscle strength may help to understand these relationships more clearly. PMID:17116259

[Adverse muscle effects of a podofyllotoxin-containing cytotoxic drug product with simvastatin].

PubMed

Kaipiainen-Seppänen, Oili; Savolainen, Elina; Elfving, Pia; Kononoff, Aulikki

2009-01-01

With the ageing population, drug interactions pose an increasing challenge to health professionals. We describe four patients, for whom concurrent administration of a podofyllotoxin-containing cytotoxic drug product and simvastatin caused severe adverse effects on muscles, including muscle pain, soreness or fatigue or weakness, and in some patients also disintegration of muscle tissue, i.e. rhabdomyolysis. The metabolism of both drugs proceeds via the common CYP3A4 enzyme pathway.

Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

NASA Technical Reports Server (NTRS)

Young, R. B.; Bridge, K. Y.

2003-01-01

Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate CAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of CAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of CAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of CAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of CAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of CAMP by either epinephrine or isoproterenol.

Sex hormones and skeletal muscle weakness.

PubMed

Sipilä, Sarianna; Narici, Marco; Kjaer, Michael; Pöllänen, Eija; Atkinson, Ross A; Hansen, Mette; Kovanen, Vuokko

2013-06-01

Human ageing is accompanied with deterioration in endocrine functions the most notable and well characterized of which being the decrease in the production of sex hormones. Current research literature suggests that low sex hormone concentration may be among the key mechanism for sarcopenia and muscle weakness. Within the European large scale MYOAGE project, the role of sex hormones, estrogens and testosterone, in causing the aging-related loss of muscle mass and function was further investigated. Hormone replacement therapy (HRT) in women is shown to diminish age-associated muscle loss, loss in fast muscle function (power), and accumulation of fat in skeletal muscle. Further HRT raises the protein synthesis rate in skeletal muscle after resistance training, and has an anabolic effect upon connective tissue in both skeletal muscle and tendon, which influences matrix structure and mechanical properties. HRT influences gene expression in e.g. cytoskeletal and cell-matrix proteins, has a stimulating effect upon IGF-I, and a role in IL-6 and adipokine regulation. Despite low circulating steroid-hormone level, postmenopausal women have a high local concentration of steroidogenic enzymes in skeletal muscle.

The myasthenic patient in crisis: an update of the management in Neurointensive Care Unit.

PubMed

Godoy, Daniel Agustin; Mello, Leonardo Jardim Vaz de; Masotti, Luca; Di Napoli, Mario

2013-09-01

Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission leading to generalized or localized muscle weakness due most frequently to the presence of autoantibodies against acetylcholine receptors in the postsynaptic motor end-plate. Myasthenic crisis (MC) is a complication of MG characterized by worsening muscle weakness, resulting in respiratory failure that requires intubation and mechanical ventilation. It also includes postsurgical patients, in whom exacerbation of muscle weakness from MG causes a delay in extubation. MC is a very important, serious, and reversible neurological emergency that affects 20-30% of the myasthenic patients, usually within the first year of illness and maybe the debut form of the disease. Most patients have a predisposing factor that triggers the crisis, generally an infection of the respiratory tract. Immunoglobulins, plasma exchange, and steroids are the cornerstones of immunotherapy. Today with the modern neurocritical care, mortality rate of MC is less than 5%.

Effect of beta-ADrenergic Agonist on Cyclic AMP Synthesis in Chicken Skeletal Muscle Cells in Culture

NASA Technical Reports Server (NTRS)

Young, R. B.; Bridge, K. Y.; Rose, M. Franklin (Technical Monitor)

2000-01-01

Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Because it seems logical that these agonists exert their action on muscle through stimulation of cAMP synthesis, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax levels were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. In addition, the EC50 values for isoproterenol, cimaterol, clenbuterol, epinephrine, and albuterol were 360 nM, 630 nM, 900 nM, 2,470 nM, and 3,650 nM, respectively. Finally, dose response curves show that the concentrations of cimaterol and clenbuterol in culture media at concentrations known to cause significant muscle hypertrophy in animals had no detectable effect on stimulation of CAMP accumulation in chicken skeletal muscle cells.

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.

Health hazard evaluation report HETA 84-419-1697, USGS Laboratory, Doraville, Georgia. [Benzene, methylene chloride, hexane, and acetone

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

Rondinelli, R.; Wilcox, T.; Roper, P.

1986-05-01

The U.S. Geological Survey National Water Quality Laboratory, Doraville, Georgia requested an evaluation of physical complaints reported by employees to determine possible work related causes. Laboratory workers, in general, complained of physical symptoms which were irritative (rash, sore throat, nose or sinus irritation), neurological (numbness, muscle weakness) and nonspecific (dizziness, headache, emotional swings, insomnia, muscle aching, fatigue). Reported exposure to solvents such as benzene, methylene chloride, hexane and acetone were positively related with light headedness or dizziness, numbness, unexplained muscle weakness and muscle aching. Air sampling did not reveal any remarkable exposure to chemical contaminants. The authors conclude that nomore » relationship could be established between chemical exposures and antinuclear antibody positivity. Exposure to chemicals measured by air sampling were below occupational health exposure limits.« less

Diagnostic evaluation of rhabdomyolysis.

PubMed

Nance, Jessica R; Mammen, Andrew L

2015-06-01

Rhabdomyolysis is characterized by severe acute muscle injury resulting in muscle pain, weakness, and/or swelling with release of myofiber contents into the bloodstream. Symptoms develop over hours to days after an inciting factor and may be associated with dark pigmentation of the urine. Serum creatine kinase and urine myoglobin levels are markedly elevated. Clinical examination, history, laboratory studies, muscle biopsy, and genetic testing are useful tools for diagnosis of rhabdomyolysis, and they can help differentiate acquired from inherited causes of rhabdomyolysis. Acquired causes include substance abuse, medication or toxic exposures, electrolyte abnormalities, endocrine disturbances, and autoimmune myopathies. Inherited predisposition to rhabdomyolysis can occur with disorders of glycogen metabolism, fatty acid β-oxidation, and mitochondrial oxidative phosphorylation. Less common inherited causes of rhabdomyolysis include structural myopathies, channelopathies, and sickle-cell disease. This review focuses on the differentiation of acquired and inherited causes of rhabdomyolysis and proposes a practical diagnostic algorithm. Muscle Nerve 51: 793-810, 2015. © 2015 Wiley Periodicals, Inc.

Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

NASA Technical Reports Server (NTRS)

Young, R. B.; Bridge, K. Y.; Cureri, Peter A. (Technical Monitor)

2002-01-01

Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of cAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of cAMP by either epinephrine or isoproterenol.

Relationship Between Muscle Strength Asymmetry and Body Sway in Older Adults.

PubMed

Koda, Hitoshi; Kai, Yoshihiro; Murata, Shin; Osugi, Hironori; Anami, Kunihiko; Fukumoto, Takahiko; Imagita, Hidetaka

2018-05-31

The purpose of this study was to investigate the relationship between muscle strength asymmetry and body sway while walking. We studied 63 older adult women. Strong side and weak side of knee extension strength, toe grip strength, hand grip strength, and body sway while walking were measured. The relationship between muscle strength asymmetry for each muscle and body sway while walking was evaluated using Pearson's correlation coefficient. Regarding the muscles recognized to have significant correlation with body sway, the asymmetry cutoff value causing an increased sway was calculated. Toe grip strength asymmetry was significantly correlated with body sway. Toe grip strength asymmetry causing an increased body sway had a cutoff value of 23.5%. Our findings suggest toe grip strength asymmetry may be a target for improving gait stability.

Effect of temperature on residual force enhancement in single skeletal muscle fibers.

PubMed

Lee, Eun-Jeong; Herzog, Walter

2008-08-28

It is well accepted that the steady-state isometric force following active stretching of a muscle is greater than the steady-state isometric force obtained in a purely isometric contraction at the same length. This property of skeletal muscle has been called residual force enhancement (FE). Despite decades of research the mechanisms responsible for FE have remained largely unknown. Based on previous studies showing increases in FE in fibers in which cross-bridges were biased towards weakly bound states, we hypothesized that FE might be associated with a stretch-induced facilitation of transitioning from weakly to strongly bound cross-bridges. In order to test this hypothesis, single fibers (n=11) from the lumbrical muscles of frog (Rana pipiens) were used to determine FE at temperatures of 7 and 20 degrees C. At the cold temperature, cross-bridges are biased towards weakly bound states, therefore we expected FE to be greater at 7 degrees C compared to 20 degrees C. The average FE was significantly greater at 7 degrees C (11.5+/-1.1%) than at 20 degrees C (7.8+/-1.0%), as expected. The enhancement of force/stiffness was also significantly greater at the low (13.3+/-1.4%) compared to the high temperature (5.6+/-1.7%), indicating an increased conversion from weakly to strongly bound cross-bridges at the low temperature. We conclude from the results of this study that muscle preparations that are biased towards weakly bound cross-bridge states show increased FE for given stretch conditions, thereby supporting the idea that FE might be caused, in part, by a stretch-induced facilitation of the conversion of weakly to strongly bound cross-bridges.

Focal atrophy of the unilateral masticatory muscles caused by pure trigeminal motor neuropathy: case report.

PubMed

Kämppi, Antti; Kämppi, Leena; Kemppainen, Pentti; Kanerva, Mari; Toppila, Jussi; Auranen, Mari

2018-05-01

Patients with unknown clinical or radiological asymmetry in the face structures combined with atrophy and weakness of the masticatory muscles should be comprehensively examined clinically and with MRI, neurophysiological measurements, and serologically. Malignant lesions or benign idiopathic unilateral trigeminal motor neuropathy should be considered as an etiological explanation for the asymmetry.

Homozygous MYH7 R1820W mutation results in recessive myosin storage myopathy: scapuloperoneal and respiratory weakness with dilated cardiomyopathy.

PubMed

Yüceyar, Nur; Ayhan, Özgecan; Karasoy, Hatice; Tolun, Aslıhan

2015-04-01

Myosin storage myopathy (MSM) is a protein aggregate myopathy caused by the accumulation of myosin in muscle fibres and results from MYH7 mutation. Although MYH7 mutation is also an established cause of variable cardiomyopathy with or without skeletal myopathy, cardiomyopathy with MSM is a rare combination. Here, we update the clinical findings in the two brothers that we previously reported as having recessively inherited MSM characterized by scapuloperoneal distribution of weakness and typical hyaline-like bodies in type 1 muscle fibres. One of the patients, weak from childhood but not severely symptomatic until 28 years of age, had an unusual combination of MSM, severe dilated cardiomyopathy, and respiratory impairment at the age of 44 years. We identified homozygous missense mutation c.5458C>T (p.R1820W) in exon 37 in these patients as the second recessive MYH7 mutation reported to date. Copyright © 2015 Elsevier B.V. All rights reserved.

GFPT1 deficiency in muscle leads to myasthenia and myopathy in mice.

PubMed

Issop, Yasmin; Hathazi, Denisa; Khan, Muzamil Majid; Rudolf, Rüdiger; Weis, Joachim; Spendiff, Sally; Slater, Clarke R; Roos, Andreas; Lochmüller, Hanns

2018-06-14

Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the rate-limiting enzyme in the hexosamine biosynthetic pathway which yields precursors required for protein and lipid glycosylation. Mutations in GFPT1 and other genes downstream of this pathway cause congenital myasthenic syndrome (CMS) characterised by fatigable muscle weakness due to impaired neurotransmission. The precise pathomechanisms at the neuromuscular junction (NMJ) due to a deficiency in GFPT1 is yet to be discovered. One of the challenges we face is the viability of Gfpt1 -/- knockout mice. In this study, we use Cre/LoxP technology to generate a muscle-specific GFPT1 knockout mouse model, Gfpt1tm1d/tm1d, characteristic of the human CMS phenotype. Our data suggests a critical role for muscle derived GFPT1 in the development of the NMJ, neurotransmission, skeletal muscle integrity, and highlights that a deficiency in skeletal muscle alone is sufficient to cause morphological postsynaptic NMJ changes that are accompanied by presynaptic alterations despite the conservation of neuronal GFPT1 expression. In addition to the conventional morphological NMJ changes and fatigable muscle weakness, Gfpt1tm1d/tm1d mice display a progressive myopathic phenotype with the presence of tubular aggregates in muscle, characteristic of the GFPT1-CMS phenotype. We further identify an upregulation of skeletal muscle proteins glypican-1, farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha and Muscle-specific kinase which are known to be involved in the differentiation and maintenance of the NMJ. The Gfpt1tm1d/tm1d model allows for further investigation of pathophysiological consequences on genes and pathways downstream of GFPT1 likely to involve misglycosylation or hypoglycosylation of NMJs and muscle targets.

Hyperventilation of pregnancy presenting with flaccid quadriparesis due to hypokalaemia secondary to respiratory alkalosis.

PubMed

Santra, Gouranga; Paul, Rudrajit; Das, Shubhabrata; Pradhan, Sourav

2014-06-01

Hyperventilation in pregnancy is a cause of chronic respiratory alkalosis. Alkalosis either metabolic or respiratory may cause intracellular shift of potassium ions that may lead to hypokalaemia. However, the resultant hypokalaemia in respiratory alkalosis is usually mild and does not cause much clinical features. A five-months-pregnant female of the age 25 years presented with sudden onset flaccid weakness of both lower limbs associated with thigh muscle pain followed by weakness of both upper limbs within three days. Subsequent investigation revealed severe hypokalaemia due to acute exacerbation of chronic respiratory alkalosis secondary to hyperventilation of pregnancy, other causes of hypokalaemia being ruled out. Respiratory alkalosis causes tetany and other clinical manifestations. But hypokalaemia and such weakness is rarely found. Thisis probably the first report of this type from India.

Common Conditions in Newborns

MedlinePlus

... following in your baby, contact your pediatrician. Abdominal Distension Most babies’ bellies normally stick out, especially after ... new bone is forming to mend the injury. Muscle weakness is another common birth injury, caused during ...

Fatigue is associated with muscle weakness in Ehlers-Danlos syndrome: an explorative study.

PubMed

Voermans, N C; Knoop, H; Bleijenberg, G; van Engelen, B G

2011-06-01

Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of inherited connective tissue disorders characterised by joint hypermobility, skin hyperextensibility and tissue fragility. It has recently been shown that muscle weakness occurs frequently in EDS, and that fatigue is a common and clinically important symptom. The aim of this study was to investigate the relationship between fatigue severity and subjective and objective measures of muscle weakness. Furthermore, the predictive value of muscle weakness for fatigue severity was determined, together with that of pain and physical activity. An explorative, cross-sectional, observational study. Thirty EDS patients, recruited from the Dutch patient association, were investigated at the neuromuscular outpatient department of a tertiary referral centre in The Netherlands. Muscle strength measured with manual muscle strength testing and hand-held dynamometry. Self-reported muscle weakness, pain, physical activity levels and fatigue were assessed with standardised questionnaires. Fatigue severity in EDS was significantly correlated with measured and self-reported muscle weakness (r=-0.408 for manual muscle strength, r=0.461 for hand-held dynamometry and r=0.603 for self-reported muscle weakness). Both muscle weakness and pain severity were significant predictors of fatigue severity in a multiple regression analysis. The results suggest a positive and direct relationship between fatigue severity and muscle weakness in EDS. Future research should focus on the relationship between fatigue, muscle weakness and objectively measured physical activity, preferably in a larger cohort of EDS patients. Copyright © 2010 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

Bench-to-bedside review: Rhabdomyolysis – an overview for clinicians

PubMed Central

Huerta-Alardín, Ana L; Varon, Joseph; Marik, Paul E

2005-01-01

Rhabdomyolysis ranges from an asymptomatic illness with elevation in the creatine kinase level to a life-threatening condition associated with extreme elevations in creatine kinase, electrolyte imbalances, acute renal failure and disseminated intravascular coagulation. Muscular trauma is the most common cause of rhabdomyolysis. Less common causes include muscle enzyme deficiencies, electrolyte abnormalities, infectious causes, drugs, toxins and endocrinopathies. Weakness, myalgia and tea-colored urine are the main clinical manifestations. The most sensitive laboratory finding of muscle injury is an elevated plasma creatine kinase level. The management of patients with rhabdomyolysis includes early vigorous hydration. PMID:15774072

The role of MicroRNAs in COPD muscle dysfunction and mass loss: implications on the clinic.

PubMed

Barreiro, Esther

2016-09-01

Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable disease and a leading cause of morbidity and mortality worldwide. In COPD, comorbidities, acute exacerbations, and systemic manifestations negatively influence disease severity, prognosis, and progression regardless of the respiratory condition. Several factors and biological mechanisms are involved in the pathophysiology of COPD muscle dysfunction. The non-coding microRNAs were shown to be differentially expressed in the respiratory and limb muscles of patients with COPD. Moreover, a differential expression profile of muscle-specific microRNAs has also been demonstrated in the lower limb muscles of COPD patients with and without muscle mass loss and weakness. All these features are reviewed herein. The most relevant articles on the topic in question were selected from PubMed to write this review. Expert commentary: MicroRNAs are excellent targets for the design of specific therapeutic interventions in patients with muscle weakness. Selective enhancers of microRNAs that promote myogenesis (proliferation and differentiation of satellite cells) should be designed to alleviate the negative impact of skeletal muscle dysfunction and mass loss in COPD regardless of the degree of the airway obstruction.

Adult patient with Becker dystrophy undergoing orthopedic surgery: an anesthesia challenge.

PubMed

Parish, Masoud; Farzin, Haleh

2018-01-01

Muscular dystrophies are considered to be a series of neuromuscular diseases with genetic causes and are characterized by progressive muscle weakness and degeneration of the skeletal muscle. The case of an adult man with Becker dystrophy referred for repair of the patella tendon tearing and patella fracture is described. He underwent successful surgery using total intravenous anesthesia without any complications.

Medical Issues: Orthopedics

MedlinePlus

... Cure SMA Store Volunteer Donate Learn About SMA Research Support & Care Get Involved Donate About Us News www.curesma.org > support & care > living with sma > medical issues > orthopedics Orthopedics In SMA, muscle weakness can cause several ...

Dextromethorphan and Quinidine

MedlinePlus

... is in a class of medications called central nervous system agents. The way it works in the brain ... ever had myasthenia gravis (a disorder of the nervous system that causes muscle weakness), a history of street ...

Poison hemlock-induced respiratory failure in a toddler.

PubMed

West, Patrick L; Horowitz, B Zane; Montanaro, Marc T; Lindsay, James N

2009-11-01

The ingestion of poison hemlock, or Conium maculatum, is described in a 2-year-old boy. He had the onset of abdominal pain and weakness after being fed C. maculatum picked by his sister from the roadside 2 hours earlier. He had a rapidly progressive muscular weakness and was intubated for respiratory failure. His symptoms completely resolved within 24 hours of the ingestion. Conium maculatum is a common weed that causes toxicity by its primary toxin, coniine, which stimulates nicotinic receptors and causes a syndrome of rapidly progressive muscle weakness and paralysis. We describe the course of a benign-appearing plant ingestion resulting in respiratory failure.

The General Weakness Syndrome Therapy (GymNAST) study: protocol for a cohort study on recovery on walking function

PubMed Central

Mehrholz, Jan; Mückel, Simone; Oehmichen, Frank; Pohl, Marcus

2014-01-01

Introduction Critical illness myopathy (CIM) and polyneuropathy (CIP) are common complications of critical illness that frequently occur together. Both cause so called intensive care unit (ICU)-acquired muscle weakness. This weakness of limb muscles increases morbidity and delay rehabilitation and recovery of walking ability. Although full recovery has been reported people with severe weakness may take months to improve walking. Focused physical rehabilitation of people with ICU-acquired muscle weakness is therefore of great importance. However, although physical rehabilitation is common, detailed knowledge about the pattern and the time course of recovery of walking function are not well understood. Therefore, the aim of the General Weakness Syndrome Therapy (GymNAST) study is to describe the time course of recovery of walking function and other activities of daily living in these patients. Methods and analysis We conduct a prospective cohort study of people with ICU-acquired muscle weakness with defined diagnosis of CIM or CIP. Based on our sample size calculation, approximately 150 patients will be recruited from the ICU of our hospital in Germany. Amount and content of physical rehabilitation, clinical tests for example, muscle strength and motor function and neuropsychological assessments will be used as independent variables. The primary outcomes will include recovery of walking function and mobility. Secondary outcomes will include global motor function, activities in daily life and participation. Ethics and dissemination The study is being carried out in agreement with the Declaration of Helsinki and conducted with the approval of the local medical Ethics Committee (Landesärztekammer Sachsen, Germany, reference number EK-BR-32/13-1) and with the understanding and written consent of each patient's guardian. The results of this study will be published in peer-reviewed journals and disseminated to the medical society and general public. PMID:25344484

Prevalence of clinically relevant muscle weakness and its association with vitamin D status among older adults in Ecuador.

PubMed

Orces, Carlos H

2017-10-01

Muscle weakness and 25-hydroxyvitamin D (25(OH)D) deficiency have been associated with adverse outcomes among older adults. However, little is known about the relationship between clinically relevant muscle weakness and 25(OH)D levels in Ecuador. To examine the prevalence of muscle weakness and its association with 25(OH)D status among subjects aged 60 years and older in Ecuador. The present study was based on data from 2205 participants in the first National Survey of Health, Wellbeing, and Aging. The Foundation for the National Institute of Health Sarcopenia Project criteria was used to examine muscle weakness prevalence rates. Gender-specific general linear and logistic regression models adjusted for potential confounders were created to compare mean 25(OH)D concentrations and 25(OH)D deficiency across muscle strength categories, respectively. An estimated 32.2% of women and 33.4% of men had evidence of clinically relevant muscle weakness in Ecuador. In general, increased muscle weakness prevalence rates were present among Indigenous, residents in the rural Andes Mountains, underweight subjects, and those with a sedentary lifestyle. Muscle strength was significantly and directly correlated with mean 25(OH)D levels. After controlling for potential confounders, 25(OH)D deficiency prevalence rates were 31 and 43% higher among men and women with muscle weakness than those with normal strength, respectively. One-third of older adults nationwide had evidence of muscle weakness. While the present study found a significant correlation between muscle strength and 25(OH)D concentrations, further research is needed to examine whether optimizing 25(OH)D levels may improve muscle weakness among older adults.

Esophageal manometry

MedlinePlus

... have symptoms of: Heartburn or nausea after eating ( gastroesophageal reflux disease, or GERD ) Problems swallowing (feeling like food is stuck behind ... stomach ( achalasia ) A weak LES, which causes heartburn (GERD) Abnormal contractions of the esophagus muscles that do ...

Limb girdle muscular dystrophy type 2G with myopathic-neurogenic motor unit potentials and a novel muscle image pattern.

PubMed

Cotta, Ana; Paim, Julia Filardi; da-Cunha-Junior, Antonio Lopes; Neto, Rafael Xavier; Nunes, Simone Vilela; Navarro, Monica Magalhaes; Valicek, Jaquelin; Carvalho, Elmano; Yamamoto, Lydia U; Almeida, Camila F; Braz, Shelida Vasconcelos; Takata, Reinaldo Issao; Vainzof, Mariz

2014-01-01

Limb girdle muscular dystrophy type 2G (LGMD2G) is a subtype of autosomal recessive muscular dystrophy caused by mutations in the telethonin gene. There are few LGMD2G patients worldwide reported, and this is the first description associated with early tibialis anterior sparing on muscle image and myopathic-neurogenic motor unit potentials. Here we report a 31 years old caucasian male patient with progressive gait disturbance, and severe lower limb proximal weakness since the age of 20 years, associated with subtle facial muscle weakness. Computed tomography demonstrated soleus, medial gastrocnemius, and diffuse thigh muscles involvement with tibialis anterior sparing. Electromyography disclosed both neurogenic and myopathic motor unit potentials. Muscle biopsy demonstrated large groups of atrophic and hypertrophic fibers, frequent fibers with intracytoplasmic rimmed vacuoles full of autophagic membrane and sarcoplasmic debris, and a total deficiency of telethonin. Molecular investigation identified the common homozygous c.157C > T in the TCAP gene. This report expands the phenotypic variability of telethoninopathy/ LGMD2G, including: 1) mixed neurogenic and myopathic motor unit potentials, 2) facial weakness, and 3) tibialis anterior sparing. Appropriate diagnosis in these cases is important for genetic counseling and prognosis.

Distribution and severity of weakness among patients with polymyositis, dermatomyositis and juvenile dermatomyositis

PubMed Central

Harris-Love, M. O.; Shrader, J. A.; Koziol, D.; Pahlajani, N.; Jain, M.; Smith, M.; Cintas, H. L.; McGarvey, C. L.; James-Newton, L.; Pokrovnichka, A.; Moini, B.; Cabalar, I.; Lovell, D. J.; Wesley, R.; Plotz, P. H.; Miller, F. W.; Hicks, J. E.

2009-01-01

Objective. To describe the distribution and severity of muscle weakness using manual muscle testing (MMT) in 172 patients with PM, DM and juvenile DM (JDM). The secondary objectives included characterizing individual muscle group weakness and determining associations of weakness with functional status and myositis characteristics in this large cohort of patients with myositis. Methods. Strength was assessed for 13 muscle groups using the 10-point MMT and expressed as a total score, subscores based on functional and anatomical regions, and grades for individual muscle groups. Patient characteristics and secondary outcomes, such as clinical course, muscle enzymes, corticosteroid dosage and functional status were evaluated for association with strength using univariate and multivariate analyses. Results. A gradient of proximal weakness was seen, with PM weakest, DM intermediate and JDM strongest among the three myositis clinical groups (P ≤ 0.05). Hip flexors, hip extensors, hip abductors, neck flexors and shoulder abductors were the muscle groups with the greatest weakness among all three clinical groups. Muscle groups were affected symmetrically. Conclusions. Axial and proximal muscle impairment was reflected in the five weakest muscles shared by our cohort of myositis patients. However, differences in the pattern of weakness were observed among all three clinical groups. Our findings suggest a greater severity of proximal weakness in PM in comparison with DM. PMID:19074186

Facial-muscle weakness, speech disorders and dysphagia are common in patients with classic infantile Pompe disease treated with enzyme therapy.

PubMed

van Gelder, C M; van Capelle, C I; Ebbink, B J; Moor-van Nugteren, I; van den Hout, J M P; Hakkesteegt, M M; van Doorn, P A; de Coo, I F M; Reuser, A J J; de Gier, H H W; van der Ploeg, A T

2012-05-01

Classic infantile Pompe disease is an inherited generalized glycogen storage disorder caused by deficiency of lysosomal acid α-glucosidase. If left untreated, patients die before one year of age. Although enzyme-replacement therapy (ERT) has significantly prolonged lifespan, it has also revealed new aspects of the disease. For up to 11 years, we investigated the frequency and consequences of facial-muscle weakness, speech disorders and dysphagia in long-term survivors. Sequential photographs were used to determine the timing and severity of facial-muscle weakness. Using standardized articulation tests and fibreoptic endoscopic evaluation of swallowing, we investigated speech and swallowing function in a subset of patients. This study included 11 patients with classic infantile Pompe disease. Median age at the start of ERT was 2.4 months (range 0.1-8.3 months), and median age at the end of the study was 4.3 years (range 7.7 months -12.2 years). All patients developed facial-muscle weakness before the age of 15 months. Speech was studied in four patients. Articulation was disordered, with hypernasal resonance and reduced speech intelligibility in all four. Swallowing function was studied in six patients, the most important findings being ineffective swallowing with residues of food (5/6), penetration or aspiration (3/6), and reduced pharyngeal and/or laryngeal sensibility (2/6). We conclude that facial-muscle weakness, speech disorders and dysphagia are common in long-term survivors receiving ERT for classic infantile Pompe disease. To improve speech and reduce the risk for aspiration, early treatment by a speech therapist and regular swallowing assessments are recommended.

Becker muscular dystrophy due to an intronic splicing mutation inducing a dual dystrophin transcript.

PubMed

Todeschini, Alice; Gualandi, Francesca; Trabanelli, Cecilia; Armaroli, Annarita; Ravani, Anna; Fanin, Marina; Rota, Silvia; Bello, Luca; Ferlini, Alessandra; Pegoraro, Elena; Padovani, Alessandro; Filosto, Massimiliano

2016-10-01

We describe a 29-year-old patient who complained of left thigh muscle weakness since he was 23 and of moderate proximal weakness of both lower limbs with difficulty in climbing stairs and running since he was 27. Mild weakness of iliopsoas and quadriceps muscles and muscle atrophy of both the distal forearm and thigh were observed upon clinical examination. He harboured a novel c.1150-3C>G substitution in the DMD gene, affecting the intron 10 acceptor splice site and causing exon 11 skipping and an out-of-frame transcript. However, protein of normal molecular weight but in reduced amounts was observed on Western Blot analysis. Reverse transcription analysis on muscle RNA showed production, via alternative splicing, of a transcript missing exon 11 as well as a low abundant full-length transcript which is enough to avoid the severe Duchenne phenotype. Our study showed that a reduced amount of full length dystrophin leads to a mild form of Becker muscular dystrophy. These results confirm earlier findings that low amounts of dystrophin can be associated with a milder phenotype, which is promising for therapies aiming at dystrophin restoration. Copyright © 2016 Elsevier B.V. All rights reserved.

Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy

PubMed Central

Rocheteau, P.; Chatre, L.; Briand, D.; Mebarki, M.; Jouvion, G.; Bardon, J.; Crochemore, C.; Serrani, P.; Lecci, P. P.; Latil, M.; Matot, B.; Carlier, P. G.; Latronico, N.; Huchet, C.; Lafoux, A.; Sharshar, T.; Ricchetti, M.; Chrétien, F.

2015-01-01

Sepsis, or systemic inflammatory response syndrome, is the major cause of critical illness resulting in admission to intensive care units. Sepsis is caused by severe infection and is associated with mortality in 60% of cases. Morbidity due to sepsis is complicated by neuromyopathy, and patients face long-term disability due to muscle weakness, energetic dysfunction, proteolysis and muscle wasting. These processes are triggered by pro-inflammatory cytokines and metabolic imbalances and are aggravated by malnutrition and drugs. Skeletal muscle regeneration depends on stem (satellite) cells. Herein we show that mitochondrial and metabolic alterations underlie the sepsis-induced long-term impairment of satellite cells and lead to inefficient muscle regeneration. Engrafting mesenchymal stem cells improves the septic status by decreasing cytokine levels, restoring mitochondrial and metabolic function in satellite cells, and improving muscle strength. These findings indicate that sepsis affects quiescent muscle stem cells and that mesenchymal stem cells might act as a preventive therapeutic approach for sepsis-related morbidity. PMID:26666572

Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy.

PubMed

Rocheteau, P; Chatre, L; Briand, D; Mebarki, M; Jouvion, G; Bardon, J; Crochemore, C; Serrani, P; Lecci, P P; Latil, M; Matot, B; Carlier, P G; Latronico, N; Huchet, C; Lafoux, A; Sharshar, T; Ricchetti, M; Chrétien, F

2015-12-15

Sepsis, or systemic inflammatory response syndrome, is the major cause of critical illness resulting in admission to intensive care units. Sepsis is caused by severe infection and is associated with mortality in 60% of cases. Morbidity due to sepsis is complicated by neuromyopathy, and patients face long-term disability due to muscle weakness, energetic dysfunction, proteolysis and muscle wasting. These processes are triggered by pro-inflammatory cytokines and metabolic imbalances and are aggravated by malnutrition and drugs. Skeletal muscle regeneration depends on stem (satellite) cells. Herein we show that mitochondrial and metabolic alterations underlie the sepsis-induced long-term impairment of satellite cells and lead to inefficient muscle regeneration. Engrafting mesenchymal stem cells improves the septic status by decreasing cytokine levels, restoring mitochondrial and metabolic function in satellite cells, and improving muscle strength. These findings indicate that sepsis affects quiescent muscle stem cells and that mesenchymal stem cells might act as a preventive therapeutic approach for sepsis-related morbidity.

Manual muscle testing: a method of measuring extremity muscle strength applied to critically ill patients.

PubMed

Ciesla, Nancy; Dinglas, Victor; Fan, Eddy; Kho, Michelle; Kuramoto, Jill; Needham, Dale

2011-04-12

Survivors of acute respiratory distress syndrome (ARDS) and other causes of critical illness often have generalized weakness, reduced exercise tolerance, and persistent nerve and muscle impairments after hospital discharge. Using an explicit protocol with a structured approach to training and quality assurance of research staff, manual muscle testing (MMT) is a highly reliable method for assessing strength, using a standardized clinical examination, for patients following ARDS, and can be completed with mechanically ventilated patients who can tolerate sitting upright in bed and are able to follow two-step commands. (7, 8) This video demonstrates a protocol for MMT, which has been taught to ≥ 43 research staff who have performed >800 assessments on >280 ARDS survivors. Modifications for the bedridden patient are included. Each muscle is tested with specific techniques for positioning, stabilization, resistance, and palpation for each score of the 6-point ordinal Medical Research Council scale. Three upper and three lower extremity muscles are graded in this protocol: shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension, and ankle dorsiflexion. These muscles were chosen based on the standard approach for evaluating patients for ICU-acquired weakness used in prior publications. (1,2).

CuZnSOD gene deletion targeted to skeletal muscle leads to loss of contractile force but does not cause muscle atrophy in adult mice

PubMed Central

Zhang, Yiqiang; Davis, Carol; Sakellariou, George K.; Shi, Yun; Kayani, Anna C.; Pulliam, Daniel; Bhattacharya, Arunabh; Richardson, Arlan; Jackson, Malcolm J.; McArdle, Anne; Brooks, Susan V.; Van Remmen, Holly

2013-01-01

We have previously shown that deletion of CuZnSOD in mice (Sod1−/− mice) leads to accelerated loss of muscle mass and contractile force during aging. To dissect the relative roles of skeletal muscle and motor neurons in this process, we used a Cre-Lox targeted approach to establish a skeletal muscle-specific Sod1-knockout (mKO) mouse to determine whether muscle-specific CuZnSOD deletion is sufficient to cause muscle atrophy. Surprisingly, mKO mice maintain muscle masses at or above those of wild-type control mice up to 18 mo of age. In contrast, maximum isometric specific force measured in gastrocnemius muscle is significantly reduced in the mKO mice. We found no detectable increases in global measures of oxidative stress or ROS production, no reduction in mitochondrial ATP production, and no induction of adaptive stress responses in muscle from mKO mice. However, Akt-mTOR signaling is elevated and the number of muscle fibers with centrally located nuclei is increased in skeletal muscle from mKO mice, which suggests elevated regenerative pathways. Our data demonstrate that lack of CuZnSOD restricted to skeletal muscle does not lead to muscle atrophy but does cause muscle weakness in adult mice and suggest loss of CuZnSOD may potentiate muscle regenerative pathways.—Zhang, Y., Davis, C., Sakellariou, G.K., Shi, Y., Kayani, A.C., Pulliam, D., Bhattacharya, A., Richardson, A., Jackson, M.J., McArdle, A., Brooks, S.V., Van Remmen, H. CuZnSOD gene deletion targeted to skeletal muscle leads to loss of contractile force but does not cause muscle atrophy in adult mice. PMID:23729587

[Morphological signs of mitochondrial cytopathy in skeletal muscles and micro-vessel walls in a patient with cerebral artery dissection associated with MELAS syndrome].

PubMed

Sakharova, A V; Kalashnikova, L A; Chaĭkovskaia, R P; Mir-Kasimov, M F; Nazarova, M A; Pykhtina, T N; Dobrynina, L A; Patrusheva, N L; Patrushev, L I; Protskiĭ, S V

2012-01-01

Skin and muscles biopsy specimens of a patient harboring A3243G mutation in mitochondrial DNA, with dissection of internal carotid and vertebral arteries, associated with MELAS were studied using histochemical and electron-microscopy techniques. Ragged red fibers, regional variability of SDH histochemical reaction, two types of morphologically atypical mitochondria and their aggregation were found in muscle. There was correlation between SDH histochemical staining and number of mitochondria revealed by electron microscopy in muscle tissue. Similar mitochondrial abnormality, their distribution and cell lesions followed by extra-cellular matrix mineralization were found in the blood vessel walls. In line with generalization of cytopathy process caused by gene mutation it can be supposed that changes found in skin and muscle microvessels also exist in large cerebral vessels causing the vessel wall "weakness", predisposing them to dissection.

Quantification of Diaphragm Mechanics in Pompe Disease Using Dynamic 3D MRI

PubMed Central

Mogalle, Katja; Perez-Rovira, Adria; Ciet, Pierluigi; Wens, Stephan C. A.; van Doorn, Pieter A.; Tiddens, Harm A. W. M.; van der Ploeg, Ans T.; de Bruijne, Marleen

2016-01-01

Background Diaphragm weakness is the main reason for respiratory dysfunction in patients with Pompe disease, a progressive metabolic myopathy affecting respiratory and limb-girdle muscles. Since respiratory failure is the major cause of death among adult patients, early identification of respiratory muscle involvement is necessary to initiate treatment in time and possibly prevent irreversible damage. In this paper we investigate the suitability of dynamic MR imaging in combination with state-of-the-art image analysis methods to assess respiratory muscle weakness. Methods The proposed methodology relies on image registration and lung surface extraction to quantify lung kinematics during breathing. This allows for the extraction of geometry and motion features of the lung that characterize the independent contribution of the diaphragm and the thoracic muscles to the respiratory cycle. Results Results in 16 3D+t MRI scans (10 Pompe patients and 6 controls) of a slow expiratory maneuver show that kinematic analysis from dynamic 3D images reveals important additional information about diaphragm mechanics and respiratory muscle involvement when compared to conventional pulmonary function tests. Pompe patients with severely reduced pulmonary function showed severe diaphragm weakness presented by minimal motion of the diaphragm. In patients with moderately reduced pulmonary function, cranial displacement of posterior diaphragm parts was reduced and the diaphragm dome was oriented more horizontally at full inspiration compared to healthy controls. Conclusion Dynamic 3D MRI provides data for analyzing the contribution of both diaphragm and thoracic muscles independently. The proposed image analysis method has the potential to detect less severe diaphragm weakness and could thus be used to determine the optimal start of treatment in adult patients with Pompe disease in prospect of increased treatment response. PMID:27391236

Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells

PubMed Central

Fontes-Oliveira, Cibely C.; Steinz, Maarten; Schneiderat, Peter; Mulder, Hindrik; Durbeej, Madeleine

2017-01-01

Skeletal muscle has high energy requirement and alterations in metabolism are associated with pathological conditions causing muscle wasting and impaired regeneration. Congenital muscular dystrophy type 1A (MDC1A) is a severe muscle disorder caused by mutations in the LAMA2 gene. Leigh syndrome (LS) is a neurometabolic disease caused by mutations in genes related to mitochondrial function. Skeletal muscle is severely affected in both diseases and a common feature is muscle weakness that leads to hypotonia and respiratory problems. Here, we have investigated the bioenergetic profile in myogenic cells from MDC1A and LS patients. We found dysregulated expression of genes related to energy production, apoptosis and proteasome in myoblasts and myotubes. Moreover, impaired mitochondrial function and a compensatory upregulation of glycolysis were observed when monitored in real-time. Also, alterations in cell cycle populations in myoblasts and enhanced caspase-3 activity in myotubes were observed. Thus, we have for the first time demonstrated an impairment of the bioenergetic status in human MDC1A and LS muscle cells, which could contribute to cell cycle disturbance and increased apoptosis. Our findings suggest that skeletal muscle metabolism might be a promising pharmacological target in order to improve muscle function, energy efficiency and tissue maintenance of MDC1A and LS patients. PMID:28367954

Diagnostic Evaluation of Rhabdomyolysis

PubMed Central

Nance, Jessica R.; Mammen, Andrew L.

2015-01-01

Rhabdomyolysis is characterized by severe acute muscle injury resulting in muscle pain, weakness, and/or swelling with release of myofiber contents into the bloodstream. Symptoms develop over hours to days following an inciting factor and may be associated with dark pigmentation of the urine. Serum creatine kinase and urine myoglobin levels are markedly elevated. The clinical examination, history, laboratory studies, muscle biopsy, and genetic testing are useful tools for diagnosis of rhabdomyolysis, and they can help differentiate acquired from inherited causes of rhabdomyolysis. Acquired causes include substance abuse, medication or toxic exposures, electrolyte abnormalities, endocrine disturbance, and autoimmune myopathies. Inherited predisposition to rhabdomyolysis can occur with disorders of glycogen metabolism, fatty acid beta-oxidation, and mitochondrial oxidative phosphorylation. Less common inherited causes of rhabdomyolysis include structural myopathies, channelopathies, and sickle cell disease. This review focuses on the differentiation of acquired and inherited causes of rhabdomyolysis and proposes a practical diagnostic algorithm. PMID:25678154

Acute quadriplegic myopathy with myosin-deficient muscle fibres after liver transplantation: defining the clinical picture and delimiting the risk factors.

PubMed

Miró, O; Salmerón, J M; Masanés, F; Alonso, J R; Graus, F; Mas, A; Grau, J M

1999-04-27

In the last few years, rare cases of acute quadriplegic myopathy (AQM*) with myosin-deficient muscle fibres occurring after solid organ transplantation has been reported. The aim of the present study was to review all cases of AQM with myosin deficient fibres seen at our institution among a large series of patients after orthotopic liver transplants (OLT), with special attention to clinical aspects and associated risk factors. Additionally, an extensive review of all ultrastructurally demonstrated cases of AQM in transplant recipients is also included. Among patients involved in 281 consecutive liver transplant procedures performed in a 4-year period, 3 men and 1 woman developed an arreflexic, flaccid quadriplegia in the immediate postoperative period of OLT. After ruling out other causes of weakness, a muscle biopsy was performed and a loss of thick (myosin) filaments was confirmed by ultrastructural analysis in all cases. Accurate clinical, epidemiological, and evolutive data were recorded. Corticosteroids had been used at usual dosage given to liver transplant recipients; all four patients had several intra- and postoperative complications leading to receiving significantly higher amounts of hemoderivates, to develop renal failure in all cases, and to require a significantly higher number of reoperations within a few days after transplantation than our contemporaneous global series of liver transplant recipients. AQM patients required a significantly longer intensive care unit and hospital stay. Muscular recovery was the rule, but currently a mild myopathic gait remains in three patients. These and other reported cases of AQM do not histologically and clinically differ from AQM seen in other critically ill patients who have not had transplants. Patients with a complicated intra- and postoperative course of OLT who develop newly acquired acute muscle weakness should be suspected as having acute AQM with myosin-deficient muscle fibres. In this setting, differential diagnosis with other causes of weakness should be carried out, because the prognosis of this myopathy is good with early muscle rehabilitation therapy.

[Adult form of Pompe disease].

PubMed

Ziółkowska-Graca, Bozena; Kania, Aleksander; Zwolińska, Grazyna; Nizankowska-Mogilnicka, Ewa

2008-01-01

Pompe disease (glycogen-storage disease type II) is an autosomal recessive disorder caused by a deficiency of lysosomal acid alpha-glucosidase (GAA), leading to the accumulation of glycogen in the lysosomes primarily in muscle cells. In the adult form of the disease, proximal muscle weakness is noted and muscle volume is decreased. The infantile form is usually fatal. In the adult form of the disease the prognosis is relatively good. Muscle weakness may, however, interfere with normal daily activities, and respiratory insufficiency may be associated with obstructive sleep apnea. Death usually results from respiratory failure. Effective specific treatment is not available. Enzyme replacement therapy with recombinant human GAA (rh-GAA) still remains a research area. We report the case of a 24-year-old student admitted to the Department of Pulmonary Diseases because of severe respiratory insufficiency. Clinical symptoms such as dyspnea, muscular weakness and increased daytime sleepiness had been progressing for 2 years. Clinical examination and increased blood levels of CK suggested muscle pathology. Histopathological analysis of muscle biopsy, performed under electron microscope, confirmed the presence of vacuoles containing glycogen. Specific enzymatic activity of alpha-glucosidase was analyzed confirming Pompe disease. The only effective method to treat respiratory insufficiency was bi-level positive pressure ventilation. Respiratory rehabilitation was instituted and is still continued by the patient at home. A high-protein, low-sugar diet was proposed for the patient. Because of poliglobulia low molecular weight heparin was prescribed. The patient is eligible for experimental replacement therapy with rh-GAA.

CK (Creatine Kinase) Test

MedlinePlus

... you have muscle weakness, muscle aches, and/or dark urine and your healthcare practitioner suspects muscle damage; ... such as: Muscle pain or aches Muscle weakness Dark urine (The urine may be dark because of ...

Gene therapy for inherited muscle diseases: where genetics meets rehabilitation medicine.

PubMed

Braun, Robynne; Wang, Zejing; Mack, David L; Childers, Martin K

2014-11-01

The development of clinical vectors to correct genetic mutations that cause inherited myopathies and related disorders of skeletal muscle is advancing at an impressive rate. Adeno-associated virus vectors are attractive for clinical use because (1) adeno-associated viruses do not cause human disease and (2) these vectors are able to persist for years. New vectors are now becoming available as gene therapy delivery tools, and recent preclinical experiments have demonstrated the feasibility, safety, and efficacy of gene therapy with adeno-associated virus for long-term correction of muscle pathology and weakness in myotubularin-deficient canine and murine disease models. In this review, recent advances in the application of gene therapies to treat inherited muscle disorders are presented, including Duchenne muscular dystrophy and x-linked myotubular myopathy. Potential areas for therapeutic synergies between rehabilitation medicine and genetics are also discussed.

Hereditary motor and sensory neuropathy Lom type in a Serbian family.

PubMed

Dacković, J; Keckarević-Marković, M; Komazec, Z; Rakocević-Stojanović, V; Lavrnić, D; Stević, Z; Ribarić, K; Romac, S; Apostolski, S

2008-10-01

Hereditary motor and sensory neuropathy Lom type (HMSNL), also called CMT 4D, a hereditary autosomal recessive neuropathy, caused by mutation in N-Myc downstream regulated gene 1 (NDRG1 gene), was first described in a Bulgarian Gypsy population near Lom and later has been found in Gypsy communities in Italy, Spain, Slovenia and Hungary. We present two siblings with HMSNL, female and male, aged 30 and 26, respectively in a Serbian non-consanguineous family of Gypsy ethnic origin. They had normal developmental milestones. Both had symptoms of lower limb muscle weakness and walking difficulties with frequent falls, which began at the age of seven. At the age of 12, they developed hearing problems and at the age of 15 hand muscle weakness. Neurological examination revealed sensorineural hearing loss, dysarthria, severe distal and mild proximal muscle wasting and weakness, areflexia and impairment of all sensory modalities of distal distribution. Electrophysiological study revealed denervation with severe and early axonal loss. Sensorineural hearing loss was confirmed on electrocochleography and brainstem evoked potentials. Molecular genetic testing confirmed homozygote C564t (R148X) mutation in NDRG1 gene.

Eculizumab Injection

MedlinePlus

... myasthenia gravis (MG; a disorder of the nervous system that causes muscle weakness). Eculizumab injection is in a group of medications called monoclonal antibodies. It works by blocking the activity of the part of the immune system that may damage blood cells in people with ...

Haycocknema perplexum: an emerging cause of parasitic myositis in Australia.

PubMed

Vos, Luke J; Robertson, Thomas; Binotto, Enzo

2016-12-24

Haycocknema perplexum is a rare cause of parasitic myositis, with all cases of human infection reported from Australia. This case involved an 80-year-old Queensland wildlife carer, who presented with muscle weakness, mild eosinophilia and creatine kinase elevation. This case supports an association with native animal contact and highlights the debilitating nature of this infection.

Contribution of oxidative stress to pathology in diaphragm and limb muscles with Duchenne muscular dystrophy.

PubMed

Kim, Jong-Hee; Kwak, Hyo-Bum; Thompson, LaDora V; Lawler, John M

2013-02-01

Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease that makes walking and breathing difficult. DMD is caused by an X-linked (Xp21) mutation in the dystrophin gene. Dystrophin is a scaffolding protein located in the sarcolemmal cytoskeleton, important in maintaining structural integrity and regulating muscle cell (muscle fiber) growth and repair. Dystrophin deficiency in mouse models (e.g., mdx mouse) destabilizes the interface between muscle fibers and the extracellular matrix, resulting in profound damage, inflammation, and weakness in diaphragm and limb muscles. While the link between dystrophin deficiency with inflammation and pathology is multi-factorial, elevated oxidative stress has been proposed as a central mediator. Unfortunately, the use of non-specific antioxidant scavengers in mouse and human studies has led to inconsistent results, obscuring our understanding of the importance of redox signaling in pathology of muscular dystrophy. However, recent studies with more mechanistic approaches in mdx mice suggest that NAD(P)H oxidase and nuclear factor-kappaB are important in amplifying dystrophin-deficient muscle pathology. Therefore, more targeted antioxidant therapeutics may ameliorate damage and weakness in human population, thus promoting better muscle function and quality of life. This review will focus upon the pathobiology of dystrophin deficiency in diaphragm and limb muscle primarily in mouse models, with a rationale for development of targeted therapeutic antioxidants in DMD patients.

Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice

PubMed Central

Zou, Yaqun; Zwolanek, Daniela; Izu, Yayoi; Gandhy, Shreya; Schreiber, Gudrun; Brockmann, Knut; Devoto, Marcella; Tian, Zuozhen; Hu, Ying; Veit, Guido; Meier, Markus; Stetefeld, Jörg; Hicks, Debbie; Straub, Volker; Voermans, Nicol C.; Birk, David E.; Barton, Elisabeth R.; Koch, Manuel; Bönnemann, Carsten G.

2014-01-01

Collagen VI-related myopathies are disorders of connective tissue presenting with an overlap phenotype combining clinical involvement from the muscle and from the connective tissue. Not all patients displaying related overlap phenotypes between muscle and connective tissue have mutations in collagen VI. Here, we report a homozygous recessive loss of function mutation and a de novo dominant mutation in collagen XII (COL12A1) as underlying a novel overlap syndrome involving muscle and connective tissue. Two siblings homozygous for a loss of function mutation showed widespread joint hyperlaxity combined with weakness precluding independent ambulation, while the patient with the de novo missense mutation was more mildly affected, showing improvement including the acquisition of walking. A mouse model with inactivation of the Col12a1 gene showed decreased grip strength, a delay in fiber-type transition and a deficiency in passive force generation while the muscle seems more resistant to eccentric contraction induced force drop, indicating a role for a matrix-based passive force-transducing elastic element in the generation of the weakness. This new muscle connective tissue overlap syndrome expands on the emerging importance of the muscle extracellular matrix in the pathogenesis of muscle disease. PMID:24334604

Hyperthyroidism: an unusual case presentation.

PubMed

Scripture, D L

1998-02-01

Hyperthyroidism is the most common disorder of the thyroid. Patients typically present with complaints consistent with a hypermetabolic state, including nervousness, weight loss, heat intolerance, palpitations, irritability, and tremor. This case report reviews a 34-year-old woman who presented with unilateral upper extremity weakness, weight gain, and an episode of atrial fibrillation, the latter coinciding with a 36-hour lack of sleep and excess alcohol and caffeine intake. Although an extensive neurologic evaluation failed to identify any abnormality, the patient's laboratory analysis revealed elevations in thyroxine (T4) and triiodothyronine (T3) levels with unsuppressed thyroid-stimulating hormone levels. Subsequent treatment with the antithyroid drug methimazole (Tapazole) provided complete relief of symptoms. This case report illustrates how health care providers can be diverted to pursue a neurologic etiology when muscle weakness presents as a unilateral symptom. Plausible alternative causes for muscle weakness and other symptoms are presented.

Inhibition of Activin Receptor Type IIB Increases Strength and Lifespan in Myotubularin-Deficient Mice

PubMed Central

Lawlor, Michael W.; Read, Benjamin P.; Edelstein, Rachel; Yang, Nicole; Pierson, Christopher R.; Stein, Matthew J.; Wermer-Colan, Ariana; Buj-Bello, Anna; Lachey, Jennifer L.; Seehra, Jasbir S.; Beggs, Alan H.

2011-01-01

X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by deficiency of the lipid phosphatase, myotubularin. Patients with XLMTM often have severe perinatal weakness that requires mechanical ventilation to prevent death from respiratory failure. Muscle biopsy specimens from patients with XLMTM exhibit small myofibers with central nuclei and central aggregations of organelles in many cells. It was postulated that therapeutically increasing muscle fiber size would cause symptomatic improvement in myotubularin deficiency. Recent studies have elucidated an important role for the activin-receptor type IIB (ActRIIB) in regulation of muscle growth and have demonstrated that ActRIIB inhibition results in significant muscle hypertrophy. To evaluate whether promoting muscle hypertrophy can attenuate symptoms resulting from myotubularin deficiency, the effect of ActRIIB-mFC treatment was determined in myotubularin-deficient (Mtm1δ4) mice. Compared with wild-type mice, untreated Mtm1δ4 mice have decreased body weight, skeletal muscle hypotrophy, and reduced survival. Treatment of Mtm1δ4 mice with ActRIIB-mFC produced a 17% extension of lifespan, with transient increases in weight, forelimb grip strength, and myofiber size. Pathologic analysis of Mtm1δ4 mice during treatment revealed that ActRIIB-mFC produced marked hypertrophy restricted to type 2b myofibers, which suggests that oxidative fibers in Mtm1δ4 animals are incapable of a hypertrophic response in this setting. These results support ActRIIB-mFC as an effective treatment for the weakness observed in myotubularin deficiency. PMID:21281811

Congenital myasthenic syndromes due to mutations in ALG2 and ALG14.

PubMed

Cossins, Judith; Belaya, Katsiaryna; Hicks, Debbie; Salih, Mustafa A; Finlayson, Sarah; Carboni, Nicola; Liu, Wei Wei; Maxwell, Susan; Zoltowska, Katarzyna; Farsani, Golara Torabi; Laval, Steven; Seidhamed, Mohammed Zain; Donnelly, Peter; Bentley, David; McGowan, Simon J; Müller, Juliane; Palace, Jacqueline; Lochmüller, Hanns; Beeson, David

2013-03-01

Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed linkage analysis, whole-exome and whole-genome sequencing to determine the underlying defect in patients with an inherited limb-girdle pattern of myasthenic weakness. We identify ALG14 and ALG2 as novel genes in which mutations cause a congenital myasthenic syndrome. Through analogy with yeast, ALG14 is thought to form a multiglycosyltransferase complex with ALG13 and DPAGT1 that catalyses the first two committed steps of asparagine-linked protein glycosylation. We show that ALG14 is concentrated at the muscle motor endplates and small interfering RNA silencing of ALG14 results in reduced cell-surface expression of muscle acetylcholine receptor expressed in human embryonic kidney 293 cells. ALG2 is an alpha-1,3-mannosyltransferase that also catalyses early steps in the asparagine-linked glycosylation pathway. Mutations were identified in two kinships, with mutation ALG2p.Val68Gly found to severely reduce ALG2 expression both in patient muscle, and in cell cultures. Identification of DPAGT1, ALG14 and ALG2 mutations as a cause of congenital myasthenic syndrome underscores the importance of asparagine-linked protein glycosylation for proper functioning of the neuromuscular junction. These syndromes form part of the wider spectrum of congenital disorders of glycosylation caused by impaired asparagine-linked glycosylation. It is likely that further genes encoding components of this pathway will be associated with congenital myasthenic syndromes or impaired neuromuscular transmission as part of a more severe multisystem disorder. Our findings suggest that treatment with cholinesterase inhibitors may improve muscle function in many of the congenital disorders of glycosylation.

Morphological and ultrastructural evaluation of the golden retriever muscular dystrophy trachea, lungs, and diaphragm muscle.

PubMed

Lessa, Thais Borges; de Abreu, Dilayla Kelly; Rodrigues, Márcio Nogueira; Brólio, Marina Pandolphi; Miglino, Maria Angélica; Ambrósio, Carlos Eduardo

2014-11-01

Duchenne muscular dystrophy (DMD) is a genetic disease, characterized by atrophy and muscle weakness. The respiratory failure is a common cause of early death in patients with DMD. Golden retriever muscular dystrophy (GRMD) is a canine model which has been extensively used for many advances in therapeutics applications. As the patients with DMD, the GRMD frequently died from cardiac and respiratory failure. Observing the respiratory failure in DMD is one of the major causes of mortality we aimed to describe the morphological and ultrastructural data of trachea, lungs (conductive and respiratory portion of the system), and diaphragm muscle using histological and ultrastructural analysis. The diaphragm muscle showed discontinuous fibers architecture, with different diameter; a robust perimysium inflammatory infiltrate and some muscle cells displayed central nuclei. GRMD trachea and lungs presented collagen fibers and in addition, the GRMD lungs showed higher of levels collagen fibers that could limit the alveolar ducts and alveoli distension. Therefore, the most features observed were the collagen areas and fibrosis. We suggested in this study that the collagen remodeling in the trachea, lungs, and diaphragm muscle may increase fibrosis and affect the trachea, lungs, and diaphragm muscle function that can be a major cause of respiratory failure that occur in patients with DMD. © 2014 Wiley Periodicals, Inc.

Interbrachial Pinch by Trapezius Transfer in Amyoplasia Congenita: A Case Report

PubMed Central

Thione, Alessandro; Cavadas, Pedro C.; Rubi, Carlo G.

2017-01-01

Summary: Amyoplasia congenita, or “classic distal arthrogryposis,” is the most common disorder among the congenital, non-progressive, multiple joint contractural conditions named arthrogryposis. The cause remains unknown, and it occurs sporadically. Abnormal neurological examination indicates that movement in utero was diminished as a result of an abnormality of the central or peripheral nervous system, the motor end plate, or muscle. The absence of central neural pathology indicates the origin in akinetic fetal condition. Three weeks are enough to cause muscle weakness and joint fibrosis. Joint contractures in amyoplasia are often rigid and refractory to nonoperative treatment such as passive stretching. Surgery is focused on each patient's need respecting adaptive maneuvers to accomplish daily tasks. We present a case in which pectoral major muscle had no strength for pinching; a trapezius muscle transfer was planned to obtain an interbrachial pinch useful for grasping. PMID:28607845

Glutaric aciduria type 2, late onset type in Thai siblings with myopathy.

PubMed

Wasant, Pornswan; Kuptanon, Chulaluck; Vattanavicharn, Nithiwat; Liammongkolkul, Somporn; Ratanarak, Pisanu; Sangruchi, Tumtip; Yamaguchi, Seiji

2010-10-01

Reported here is a novel presentation of late onset glutaric aciduria type 2 in two Thai siblings. A 9-year-old boy presented with gradual onset of proximal muscle weakness for 6 weeks. The initial diagnosis was postviral myositis, and then polymyositis. Electromyography and nerve conduction velocity testing indicated a myopathic pattern. Muscle biopsy revealed excessive accumulation of fat. Acylcarnitine profiling led to the diagnosis of glutaric aciduria type 2. Immunoblot analysis of electron-transferring-flavoprotein and its dehydrogenase electron-transferring-flavoprotein dehydrogenase led to mutation analysis of the ETFDH gene, which revealed two different pathogenic mutations in both alleles and confirmed the diagnosis of glutaric aciduria type 2 caused by electron-transferring-flavoprotein dehydrogenase deficiency. The boy recovered completely after treatment. Later, his younger sibling became symptomatic; the same diagnosis was confirmed, and treatment was similarly effective. Acylcarnitine profiling was a crucial investigation in making this diagnosis in the presence of normal urine organic acid findings. Late onset glutaric aciduria type 2, a rare cause of muscle weakness in children, should be included in the differential diagnosis of myopathy. Copyright © 2010 Elsevier Inc. All rights reserved.

Intranuclear Aggregates Precede Clinical Onset in Oculopharyngeal Muscular Dystrophy.

PubMed

van der Sluijs, B M; Raz, V; Lammens, M; van den Heuvel, L P; Voermans, N C; van Engelen, B G M

2016-03-03

Oculopharyngeal muscular dystrophy (OPMD) has long been characterized by a combination of bilateral ptosis and dysphagia and subsequent limb girdle weakness. The role of the typical intranuclear inclusion in the pathophysiology is unresolved. The aim of this study was to describe the clinical and histopathological features of oculopharyngeal muscular dystrophy (OPMD). We examined this in a Dutch cohort including presymptomatic Ala-expanded-PABPN1 carriers and late symptomatic patients. We performed a prospective, observational study in OPMD patients and adult children of genetically confirmed OPMD patients. The study includes a structured history, a detailed neurological examination, muscle histology and biochemical analysis. Forty patients and 18 adult children participated in this study, among whom were six presymptomatic mutation carriers. One patient died during the study and had given permission to autopsy. In addition to the characteristic OPMD symptoms including ptosis and dysphagia, other symptoms such as limb girdle and axial weakness, and external ophthalmoplegia were frequently observed. Intranuclear aggregates were observed in the biopsies of presymptomatic carriers. Biochemical analysis of the biopsies of the presymptomatic carriers showed no mitochondrial dysfunction. The autopsy showed that muscle weakness correlated with histopathological findings in five different muscles in an individual patient. The main findings of this nationwide study are the presence of intranuclear aggregates before clinical onset and the absence of mitochondrial changes in Ala-expanded-PABPN1 carriers. This indicates that the expression of Ala-expanded-PABPN1 causes the formation of nuclear aggregates before the onset of muscle weakness. Normal results of biochemical analysis in presymptomatic carriers suggest that possible mitochondrial dysfunction occurs later. Furthermore we confirmed that limb girdle weakness occurs frequently in Dutch OPMD patients. This study thus expands the OPMD research towards characterization of presymptomatic carriers.

Characterization of Strength and Function in Ambulatory Adults With GNE Myopathy.

PubMed

Argov, Zohar; Bronstein, Faye; Esposito, Alicia; Feinsod-Meiri, Yael; Florence, Julaine M; Fowler, Eileen; Greenberg, Marcia B; Malkus, Elizabeth C; Rebibo, Odelia; Siener, Catherine S; Caraco, Yoseph; Kolodny, Edwin H; Lau, Heather A; Pestronk, Alan; Shieh, Perry; Skrinar, Alison M; Mayhew, Jill E

2017-09-01

To characterize the pattern and extent of muscle weakness and impact on physical functioning in adults with GNEM. Strength and function were assessed in GNEM subjects (n = 47) using hand-held dynamometry, manual muscle testing, upper and lower extremity functional capacity tests, and the GNEM-Functional Activity Scale (GNEM-FAS). Profound upper and lower muscle weakness was measured using hand-held dynamometry in a characteristic pattern, previously described. Functional tests and clinician-reported outcomes demonstrated the consequence of muscle weakness on physical functioning. The characteristic pattern of upper and lower muscle weakness associated with GNEM and the resulting functional limitations can be reliably measured using these clinical outcome assessments of muscle strength and function.

Pyridostigmine but not 3,4-diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle-specific kinase autoantibody

PubMed Central

Morsch, Marco; Reddel, Stephen W; Ghazanfari, Nazanin; Toyka, Klaus V; Phillips, William D

2013-01-01

In myasthenia gravis, the neuromuscular junction is impaired by the antibody-mediated loss of postsynaptic acetylcholine receptors (AChRs). Muscle weakness can be improved upon treatment with pyridostigmine, a cholinesterase inhibitor, or with 3,4-diaminopyridine, which increases the release of ACh quanta. The clinical efficacy of pyridostigmine is in doubt for certain forms of myasthenia. Here we formally examined the effects of these compounds in the antibody-induced mouse model of anti-muscle-specific kinase (MuSK) myasthenia gravis. Mice received 14 daily injections of IgG from patients with anti-MuSK myasthenia gravis. This caused reductions in postsynaptic AChR densities and in endplate potential amplitudes. Systemic delivery of pyridostigmine at therapeutically relevant levels from days 7 to 14 exacerbated the anti-MuSK-induced structural alterations and functional impairment at motor endplates in the diaphragm muscle. No such effect of pyridostigmine was found in mice receiving control human IgG. Mice receiving smaller amounts of MuSK autoantibodies did not display overt weakness, but 9 days of pyridostigmine treatment precipitated generalised muscle weakness. In contrast, one week of treatment with 3,4-diaminopyridine enhanced neuromuscular transmission in the diaphragm muscle. Both pyridostigmine and 3,4-diaminopyridine increase ACh in the synaptic cleft yet only pyridostigmine potentiated the anti-MuSK-induced decline in endplate ACh receptor density. These results thus suggest that ongoing pyridostigmine treatment potentiates anti-MuSK-induced AChR loss by prolonging the activity of ACh in the synaptic cleft. PMID:23440963

Pyridostigmine but not 3,4-diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle-specific kinase autoantibody.

PubMed

Morsch, Marco; Reddel, Stephen W; Ghazanfari, Nazanin; Toyka, Klaus V; Phillips, William D

2013-05-15

In myasthenia gravis, the neuromuscular junction is impaired by the antibody-mediated loss of postsynaptic acetylcholine receptors (AChRs). Muscle weakness can be improved upon treatment with pyridostigmine, a cholinesterase inhibitor, or with 3,4-diaminopyridine, which increases the release of ACh quanta. The clinical efficacy of pyridostigmine is in doubt for certain forms of myasthenia. Here we formally examined the effects of these compounds in the antibody-induced mouse model of anti-muscle-specific kinase (MuSK) myasthenia gravis. Mice received 14 daily injections of IgG from patients with anti-MuSK myasthenia gravis. This caused reductions in postsynaptic AChR densities and in endplate potential amplitudes. Systemic delivery of pyridostigmine at therapeutically relevant levels from days 7 to 14 exacerbated the anti-MuSK-induced structural alterations and functional impairment at motor endplates in the diaphragm muscle. No such effect of pyridostigmine was found in mice receiving control human IgG. Mice receiving smaller amounts of MuSK autoantibodies did not display overt weakness, but 9 days of pyridostigmine treatment precipitated generalised muscle weakness. In contrast, one week of treatment with 3,4-diaminopyridine enhanced neuromuscular transmission in the diaphragm muscle. Both pyridostigmine and 3,4-diaminopyridine increase ACh in the synaptic cleft yet only pyridostigmine potentiated the anti-MuSK-induced decline in endplate ACh receptor density. These results thus suggest that ongoing pyridostigmine treatment potentiates anti-MuSK-induced AChR loss by prolonging the activity of ACh in the synaptic cleft.

Becker muscular dystrophy with widespread muscle hypertrophy and a non-sense mutation of exon 2.

PubMed

Witting, N; Duno, M; Vissing, J

2013-01-01

Becker muscular dystrophy features progressive proximal weakness, wasting and often focal hypertrophy. We present a patient with pain and cramps from adolescence. Widespread muscle hypertrophy, preserved muscle strength and a 10-20-fold raised CPK were noted. Muscle biopsy was dystrophic, and Western blot showed a 95% reduction of dystrophin levels. Genetic analyses revealed a non-sense mutation in exon 2 of the dystrophin gene. This mutation is predicted to result in a Duchenne phenotype, but resulted in a mild Becker muscular dystrophy with widespread muscle hypertrophy. We suggest that this unusual phenotype is caused by translation re-initiation downstream from the mutation site. Copyright © 2012 Elsevier B.V. All rights reserved.

Progress on gene therapy, cell therapy, and pharmacological strategies toward the treatment of oculopharyngeal muscular dystrophy.

PubMed

Harish, Pradeep; Malerba, Alberto; Dickson, George; Bachtarzi, Houria

2015-05-01

Oculopharyngeal muscular dystrophy (OPMD) is a muscle-specific, late-onset degenerative disorder whereby muscles of the eyes (causing ptosis), throat (leading to dysphagia), and limbs (causing proximal limb weakness) are mostly affected. The disease is characterized by a mutation in the poly(A)-binding protein nuclear-1 (PABPN1) gene, resulting in a short GCG expansion in the polyalanine tract of PABPN1 protein. Accumulation of filamentous intranuclear inclusions in affected skeletal muscle cells constitutes the pathological hallmark of OPMD. This review highlights the current translational research advances in the treatment of OPMD. In vitro and in vivo disease models are described. Conventional and experimental therapeutic approaches are discussed with emphasis on novel molecular therapies including the use of intrabodies, gene therapy, and myoblast transfer therapy.

The Evolution of and Risk Factors for Neck Muscle Atrophy and Weakness in Nasopharyngeal Carcinoma Treated With Intensity-Modulated Radiotherapy

PubMed Central

Zhang, Lu-Lu; Mao, Yan-Ping; Zhou, Guan-Qun; Tang, Ling-Long; Qi, Zhen-Yu; Lin, Li; Yao, Ji-Jin; Ma, Jun; Lin, Ai-Hua; Sun, Ying

2015-01-01

Abstract The aim of this study was to investigate the evolution of sternocleidomastoid muscle (SCM) atrophy in nasopharyngeal carcinoma (NPC) patients following intensity-modulated radiotherapy (IMRT), and the relationship between SCM atrophy and neck weakness. Data were retrospectively analyzed from 223 biopsy-proven NPC patients with no distant metastasis who underwent IMRT with or without chemotherapy. The volume of SCM was measured on pretreatment magnetic resonance imaging (MRI), and MRIs were conducted 1, 2, and 3 years after the completion of IMRT. Change in SCM volume was calculated and classified using the late effects of normal tissues–subjective, objective, management, and analytic system. The grade of neck muscle weakness, classified by the Common Terminology Criteria for Adverse Events V 3.0, was measured 3 years after the completion of IMRT. The average SCM atrophy ratio was −10.97%, −18.65%, and −22.25% at 1, 2, and 3 years postirradiation, respectively. Multivariate analysis indicated N stage and the length of time after IMRT were independent prognostic variables. There were significant associations between the degree of SCM atrophy and neck weakness. Radical IMRT can cause significant SCM atrophy in NPC patients. A more advanced N stage was associated with more severe SCM atrophy, but no difference was observed between N2 and N3. SCM atrophy progresses over time during the 3 years following IMRT. Grade of SCM atrophy is significantly associated with neck weakness. PMID:26252307

The Evolution of and Risk Factors for Neck Muscle Atrophy and Weakness in Nasopharyngeal Carcinoma Treated With Intensity-Modulated Radiotherapy: A Retrospective Study in an Endemic Area.

PubMed

Zhang, Lu-Lu; Mao, Yan-Ping; Zhou, Guan-Qun; Tang, Ling-Long; Qi, Zhen-Yu; Lin, Li; Yao, Ji-Jin; Ma, Jun; Lin, Ai-Hua; Sun, Ying

2015-08-01

The aim of this study was to investigate the evolution of sternocleidomastoid muscle (SCM) atrophy in nasopharyngeal carcinoma (NPC) patients following intensity-modulated radiotherapy (IMRT), and the relationship between SCM atrophy and neck weakness.Data were retrospectively analyzed from 223 biopsy-proven NPC patients with no distant metastasis who underwent IMRT with or without chemotherapy. The volume of SCM was measured on pretreatment magnetic resonance imaging (MRI), and MRIs were conducted 1, 2, and 3 years after the completion of IMRT. Change in SCM volume was calculated and classified using the late effects of normal tissues-subjective, objective, management, and analytic system. The grade of neck muscle weakness, classified by the Common Terminology Criteria for Adverse Events V 3.0, was measured 3 years after the completion of IMRT.The average SCM atrophy ratio was -10.97%, -18.65%, and -22.25% at 1, 2, and 3 years postirradiation, respectively. Multivariate analysis indicated N stage and the length of time after IMRT were independent prognostic variables. There were significant associations between the degree of SCM atrophy and neck weakness.Radical IMRT can cause significant SCM atrophy in NPC patients. A more advanced N stage was associated with more severe SCM atrophy, but no difference was observed between N2 and N3. SCM atrophy progresses over time during the 3 years following IMRT. Grade of SCM atrophy is significantly associated with neck weakness.

Divergent clinical outcomes of alpha-glucosidase enzyme replacement therapy in two siblings with infantile-onset Pompe disease treated in the symptomatic or pre-symptomatic state.

PubMed

Matsuoka, Takashi; Miwa, Yoshiyuki; Tajika, Makiko; Sawada, Madoka; Fujimaki, Koichiro; Soga, Takashi; Tomita, Hideshi; Uemura, Shigeru; Nishino, Ichizo; Fukuda, Tokiko; Sugie, Hideo; Kosuga, Motomichi; Okuyama, Torayuki; Umeda, Yoh

2016-12-01

Pompe disease is an autosomal recessive, lysosomal glycogen storage disease caused by acid α-glucosidase deficiency. Infantile-onset Pompe disease (IOPD) is the most severe form and is characterized by cardiomyopathy, respiratory distress, hepatomegaly, and skeletal muscle weakness. Untreated, IOPD generally results in death within the first year of life. Enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has been shown to markedly improve the life expectancy of patients with IOPD. However, the efficacy of ERT in patients with IOPD is affected by the presence of symptoms and cross-reactive immunologic material (CRIM) status. We have treated two siblings with IOPD with ERT at different ages: the first was symptomatic and the second was asymptomatic. The female proband (Patient 1) was diagnosed with IOPD and initiated ERT at 4 months of age. Her younger sister (Patient 2) was diagnosed with IOPD at 10 days of age and initiated ERT at Day 12. Patient 1, now 6 years old, is alive but bedridden, and requires 24-hour invasive ventilation due to gradually progressive muscle weakness. In Patient 2, typical symptoms of IOPD, including cardiac failure, respiratory distress, progressive muscle weakness, hepatomegaly and myopathic facial features were largely absent during the first 12 months of ERT. Her cardiac function and mobility were well-maintained for the first 3 years, and she had normal motor development. However, she developed progressive hearing impairment and muscle weakness after 3 years of ERT. Both siblings have had low anti-rhGAA immunoglobulin G (IgG) antibody titers during ERT and have tolerated the treatment well. These results suggest that initiation of ERT during the pre-symptomatic period can prevent and/or attenuate the progression of IOPD, including cardiomyopathy, respiratory distress, and muscle weakness for first several years of ERT. However, to improve the long-term efficacy of ERT for IOPD, new strategies for ERT for IOPD, e.g. modifying the enzyme to enhance uptake into skeletal muscle and/or to cross the blood brain barrier (BBB), will be required.

Sarcoidosis presenting as granulomatous myositis in a 16-year-old adolescent.

PubMed

Orandi, Amir B; Eutsler, Eric; Ferguson, Cole; White, Andrew J; Kitcharoensakkul, Maleewan

2016-11-10

Sarcoidosis is a multi-system disease characterized by the presence of non-caseating epithelioid granulomas in affected tissues, including skeletal muscle. These organized collections of immune cells have important pathophysiologic action including cytokine production leading to inflammation as well as enzymatic conversion of cholecalciferol to calcitriol via 1-α hydroxylase. There are limited reports of isolated granulomatous myositis causing hypercalcemia in pediatric patients. Our patient uniquely presented with symptoms from hypercalcemia and renal insufficiency caused by an overwhelming burden of granulomatous myositis in her lower extremities, but was otherwise asymptomatic. A 16 year old Caucasian female presented with protracted symptoms of fatigue, nausea and prominent weight loss with laboratory evidence of hypercalcemia and renal insufficiency. She lacked clinical and physical findings of arthritis, weakness, rash, uveitis, fever, lymphadenopathy or respiratory symptoms. After extensive negative investigations, re-examination yielded subtle soft tissue changes in her lower extremities, with striking MRI findings of extensive myositis without correlative weakness or serum enzyme elevation. Biopsy showed the presence of non-caseating epithelioid granulomas and calcium oxalate crystals. The patient responded well to prednisone and methotrexate but relapsed with weaning of steroids. She reachieved remission with addition of adalimumab. Sarcoidosis should be considered in patients presenting with symptomatic hypercalcemia with no apparent causes and negative routine workup. The absences of decreased muscle strength or elevated muscle enzymes do not preclude the diagnosis of granulomatous myositis.

Characterization of Strength and Function in Ambulatory Adults With GNE Myopathy

PubMed Central

Argov, Zohar; Bronstein, Faye; Esposito, Alicia; Feinsod-Meiri, Yael; Florence, Julaine M.; Fowler, Eileen; Greenberg, Marcia B.; Malkus, Elizabeth C.; Rebibo, Odelia; Siener, Catherine S.; Caraco, Yoseph; Kolodny, Edwin H.; Lau, Heather A.; Pestronk, Alan; Shieh, Perry; Mayhew, Jill E.

2017-01-01

Abstract Objective: To characterize the pattern and extent of muscle weakness and impact on physical functioning in adults with GNEM. Methods: Strength and function were assessed in GNEM subjects (n = 47) using hand-held dynamometry, manual muscle testing, upper and lower extremity functional capacity tests, and the GNEM-Functional Activity Scale (GNEM-FAS). Results: Profound upper and lower muscle weakness was measured using hand-held dynamometry in a characteristic pattern, previously described. Functional tests and clinician-reported outcomes demonstrated the consequence of muscle weakness on physical functioning. Conclusions: The characteristic pattern of upper and lower muscle weakness associated with GNEM and the resulting functional limitations can be reliably measured using these clinical outcome assessments of muscle strength and function. PMID:28827485

FAT1 Gene Alteration in Facioscapulohumeral Muscular Dystrophy Type 1.

PubMed

Park, Hyung Jun; Lee, Wookjae; Kim, Se Hoon; Lee, Jung Hwan; Shin, Ha Young; Kim, Seung Min; Park, Kee Duk; Lee, Ji Hyun; Choi, Young Chul

2018-03-01

Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array. Recent studies revealed that the FAT1 expression is associated with disease activity of FSHD, and the FAT1 alterations result in myopathy with a FSHD-like phenotype. We describe a 59-year-old woman with both contracted D4Z4 repeat units and a FAT1 mutation. Shoulder girdle muscle weakness developed at the age of 56 years, and was followed by proximal leg weakness. When we examined her at 59 years of age, she displayed asymmetric and predominant weakness of facial and proximal muscles. Muscle biopsy showed increased variation in fiber size and multifocal degenerating fibers with lymphocytic infiltration. Southern blot analysis revealed 8 D4Z4 repeat units, and targeted sequencing of modifier genes demonstrated the c.10331 A>G variant in the FAT1 gene. This FAT1 variant has previously been reported as pathogenic variant in a patient with FSHD-like phenotype. Our study is the first report of a FAT1 mutation in a FSHD1 patient, and suggests that FAT1 alterations might work as a genetic modifier. © Copyright: Yonsei University College of Medicine 2018.

Are linear AChR epitopes the real culprit in ocular myasthenia gravis?

PubMed

Wu, Xiaorong; Tüzün, Erdem

2017-02-01

Extraocular muscle weakness occurs in most of the myasthenia gravis (MG) patients and it is often the initial complaint. Approximately 10-20% of MG patients with extraocular muscle weakness display only ocular symptoms and rest of the patients subsequently develop generalized muscle weakness. It is not entirely clear why some MG patients develop only ocular symptoms and why extraocular muscle weakness almost always precedes generalized muscle weakness. These facts are often explained by increased susceptibility of extraocular muscles due to their reduced endplate safety factor and lower complement inhibitor expression. Findings of a recently developed animal model of ocular MG suggest that additional factors might be in play. While immunization of HLA transgenic and wild-type (WT) mice with the native acetylcholine receptor (AChR) pentamer carrying conformational epitopes generates severe generalized muscle weakness, immunization of the same mouse strains with recombinant unfolded AChR subunits containing linear epitopes induces ptosis with or without mild generalized muscle weakness. Notably, immunization of mice with deficient T helper cell-mediated antigen presentation with recombinant AChR subunits or whole native AChR pentamer also induces ocular symptoms, AChR-reactive B cells and AChR antibodies. Based on these findings, we hypothesize that ocular symptoms observed in the earlier stages of MG might be triggered by linear and non-conformational AChR epitopes expressed by thymic cells or invading microorganisms. This initial AChR autoimmunity might be managed by T cell-independent and B cell mediated mechanisms yielding low affinity AChR antibodies. These antibodies are putatively capable of inducing muscle weakness only in extraocular muscles which have increased vulnerability due to their inherent biological properties. After this initial attack, as AChR bearing immune complexes form and the immune system gains access to the native AChR expressed by muscle and thymic myoid cells, a more robust anti-AChR autoimmunity develops giving way to high affinity AChR antibodies, thymic germinal center formation and severe generalized muscle weakness. Accurate characterization of chain if events leading to ocular and generalized symptoms in MG might enable development of novel therapeutics that might prevent the transition from mild ocular symptoms to severe generalized weakness in earlier stages of the disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dystrophin-deficient pigs provide new insights into the hierarchy of physiological derangements of dystrophic muscle.

PubMed

Klymiuk, Nikolai; Blutke, Andreas; Graf, Alexander; Krause, Sabine; Burkhardt, Katinka; Wuensch, Annegret; Krebs, Stefan; Kessler, Barbara; Zakhartchenko, Valeri; Kurome, Mayuko; Kemter, Elisabeth; Nagashima, Hiroshi; Schoser, Benedikt; Herbach, Nadja; Blum, Helmut; Wanke, Rüdiger; Aartsma-Rus, Annemieke; Thirion, Christian; Lochmüller, Hanns; Walter, Maggie C; Wolf, Eckhard

2013-11-01

Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked dystrophin (DMD) gene. The absence of dystrophin protein leads to progressive muscle weakness and wasting, disability and death. To establish a tailored large animal model of DMD, we deleted DMD exon 52 in male pig cells by gene targeting and generated offspring by nuclear transfer. DMD pigs exhibit absence of dystrophin in skeletal muscles, increased serum creatine kinase levels, progressive dystrophic changes of skeletal muscles, impaired mobility, muscle weakness and a maximum life span of 3 months due to respiratory impairment. Unlike human DMD patients, some DMD pigs die shortly after birth. To address the accelerated development of muscular dystrophy in DMD pigs when compared with human patients, we performed a genome-wide transcriptome study of biceps femoris muscle specimens from 2-day-old and 3-month-old DMD and age-matched wild-type pigs. The transcriptome changes in 3-month-old DMD pigs were in good concordance with gene expression profiles in human DMD, reflecting the processes of degeneration, regeneration, inflammation, fibrosis and impaired metabolic activity. In contrast, the transcriptome profile of 2-day-old DMD pigs showed similarities with transcriptome changes induced by acute exercise muscle injury. Our studies provide new insights into early changes associated with dystrophin deficiency in a clinically severe animal model of DMD.

Channelopathies of skeletal muscle excitability

PubMed Central

Cannon, Stephen C.

2016-01-01

Familial disorders of skeletal muscle excitability were initially described early in the last century and are now known to be caused by mutations of voltage-gated ion channels. The clinical manifestations are often striking, with an inability to relax after voluntary contraction (myotonia) or transient attacks of severe weakness (periodic paralysis). An essential feature of these disorders is fluctuation of symptoms that are strongly impacted by environmental triggers such as exercise, temperature, or serum K+ levels. These phenomena have intrigued physiologists for decades, and in the past 25 years the molecular lesions underlying these disorders have been identified and mechanistic studies are providing insights for therapeutic strategies of disease modification. These familial disorders of muscle fiber excitability are “channelopathies” caused by mutations of a chloride channel (ClC-1), sodium channel (NaV1.4), calcium channel (CaV1.1) and several potassium channels (Kir2.1, Kir2.6, Kir3.4). This review provides a synthesis of the mechanistic connections between functional defects of mutant ion channels, their impact on muscle excitability, how these changes cause clinical phenotypes, and approaches toward therapeutics. PMID:25880512

EFFECTS OF 2,4-DITHIOBIURET ON SENSORY AND MOTOR FUNCTION

EPA Science Inventory

2,4-Dithiobiuret exposure causes a delayed onset muscle weakness in rats that has been attributed to depressed neuromuscular transmission. he present study compares the effects of DTB on sensory and motor function in rats. dult male Long-Evans hooded rats were exposed to saline, ...

Bell's Palsy (For Teens)

MedlinePlus

... español Parálisis de Bell What Is Bell's Palsy? Bell's palsy is a temporary weakness or paralysis of the muscles on one side of the ... of your body. Some other conditions can cause paralysis that's more serious than Bell's palsy. Tell the doctor if you are having ...

Sildenafil reduces respiratory muscle weakness and fibrosis in the mdx mouse model of Duchenne muscular dystrophy.

PubMed

Percival, Justin M; Whitehead, Nicholas P; Adams, Marvin E; Adamo, Candace M; Beavo, Joseph A; Froehner, Stanley C

2012-09-01

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy caused by mutations in the dystrophin gene. Loss of dystrophin initiates a progressive decline in skeletal muscle integrity and contractile capacity which weakens respiratory muscles including the diaphragm, culminating in respiratory failure, the leading cause of morbidity and mortality in DMD patients. At present, corticosteroid treatment is the primary pharmacological intervention in DMD, but has limited efficacy and adverse side effects. Thus, there is an urgent need for new safe, cost-effective, and rapidly implementable treatments that slow disease progression. One promising new approach is the amplification of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signalling pathways with phosphodiesterase 5 (PDE5) inhibitors. PDE5 inhibitors serve to amplify NO signalling that is attenuated in many neuromuscular diseases including DMD. We report here that a 14-week treatment of the mdx mouse model of DMD with the PDE5 inhibitor sildenafil (Viagra(®), Revatio(®)) significantly reduced mdx diaphragm muscle weakness without impacting fatigue resistance. In addition to enhancing respiratory muscle contractility, sildenafil also promoted normal extracellular matrix organization. PDE5 inhibition slowed the establishment of mdx diaphragm fibrosis and reduced matrix metalloproteinase-13 (MMP-13) expression. Sildenafil also normalized the expression of the pro-fibrotic (and pro-inflammatory) cytokine tumour necrosis factor α (TNFα). Sildenafil-treated mdx diaphragms accumulated significantly less Evans Blue tracer dye than untreated controls, which is also indicative of improved diaphragm muscle health. We conclude that sildenafil-mediated PDE5 inhibition significantly reduces diaphragm respiratory muscle dysfunction and pathology in the mdx mouse model of Duchenne muscular dystrophy. This study provides new insights into the therapeutic utility of targeting defects in NO-cGMP signalling with PDE5 inhibitors in dystrophin-deficient muscle. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Brillouin spectroscopy reveals changes in muscular viscoelasticity in Drosophila POMT mutants

NASA Astrophysics Data System (ADS)

Meng, Zhaokai; Baker, Ryan; Panin, Vladislav M.; Yakovlev, Vladislav V.

2015-03-01

Muscular dystrophy (MD) is a group of muscle diseases that induce weakness in skeletal muscle and cause progressive muscle degeneration. The muscular mechanical properties (i.e., viscoelasticity), however, have not been thoroughly examined before and after MD. On the other hand, Brillouin spectroscopy (BS) provides a non-invasive approach to probing the local sound speed within a small volume. Moreover, recent advances in background-free Brillouin spectroscopy enable investigators to imaging not only transparent samples, but also turbid ones. In this study, we investigated the mechanical properties of muscles while employing Drosophila model of dystroglycanopathies, human congenital muscular dystrophies resulting from abnormal glycosylation of alphadystroglycan. Specifically, we analyzed larval abdominal muscles of Drosophila with mutations in protein Omannosyltransferase (POMT) genes. As a comparison, we have also examined muscular tissues dissected from wildtype Drosophila. The Brillouin spectra were obtained by a background free VIPA (virtually imaged phased array) spectrometer described in the previous report. As a reference, the Raman spectra were also acquired for each test. Our current results indicated that POMT defects cause changes in muscle elasticity, which suggests that muscular dystrophy conditions may be also associated with abnormalities in muscle elastic properties.

A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis

PubMed Central

Wu, Fenfen; Mi, Wentao; Burns, Dennis K.; Fu, Yu; Gray, Hillery F.; Struyk, Arie F.; Cannon, Stephen C.

2011-01-01

Hypokalemic periodic paralysis (HypoPP) is an ion channelopathy of skeletal muscle characterized by attacks of muscle weakness associated with low serum K+. HypoPP results from a transient failure of muscle fiber excitability. Mutations in the genes encoding a calcium channel (CaV1.1) and a sodium channel (NaV1.4) have been identified in HypoPP families. Mutations of NaV1.4 give rise to a heterogeneous group of muscle disorders, with gain-of-function defects causing myotonia or hyperkalemic periodic paralysis. To address the question of specificity for the allele encoding the NaV1.4-R669H variant as a cause of HypoPP and to produce a model system in which to characterize functional defects of the mutant channel and susceptibility to paralysis, we generated knockin mice carrying the ortholog of the gene encoding the NaV1.4-R669H variant (referred to herein as R669H mice). Homozygous R669H mice had a robust HypoPP phenotype, with transient loss of muscle excitability and weakness in low-K+ challenge, insensitivity to high-K+ challenge, dominant inheritance, and absence of myotonia. Recovery was sensitive to the Na+/K+-ATPase pump inhibitor ouabain. Affected fibers had an anomalous inward current at hyperpolarized potentials, consistent with the proposal that a leaky gating pore in R669H channels triggers attacks, whereas a reduction in the amplitude of action potentials implies additional loss-of-function changes for the mutant NaV1.4 channels. PMID:21881211

Disorders of lipid metabolism in muscle.

PubMed

Di Mauro, S; Trevisan, C; Hays, A

1980-01-01

At rest and during sustained exercise, lipids are the main source of energy for muscle. Free fatty acids become available to muscle from plasma free fatty acids and triglycerides, and from intracellular triglycride lipid droplets. Transport of long-chain fatty acyl groups into the mitochondria requires esterification and de-esterification with carnitine by the "twin" enzymes carnitine palmityltransferase (CPT) I and II, bound to the outer and inner faces of the inner mitochondrial membrane. Carnitine deficiency occurs in two clinical syndromes. (1) In the myopathic form, there is weakness; muscle biopsy shows excessive accumulation of lipid droplets; and the carnitine concentration is markedly decreased in muscle but normal in plasma. (2) In the systemic form, there are weakness and recurrent episodes of hepatic encephalopathy; muscle biopsy shows lipid storage; and the carnitine concentration is decreased in muscle, liver, and plasma. The etiology of carnitine deficiency is not known in either the myopathic or the systemic form, but administration of carnitine or corticosteroids has been beneficial in some patients. "Secondary" carnitine deficiency may occur in patients with malnutrition, liver disease, chronic hemodialysis, and, possibly, mitochondrial disorders. CPT deficiency causes recurrent myoglobinuria, usually precipitated by prolonged exercise or fasting. Muscle biopsy may be normal or show varying degrees of lipid storage. Genetic transmission is probably autosomal recessive, but the great male predominance (20/21) remains unexplained. In many cases, lipid storage myopathy is not accompanied by carnitine or CPT deficiency, and the biochemical error remains to be identified.

Lateral Pectoral Nerve Injury Mimicking Cervical Radiculopathy.

PubMed

Aktas, Ilknur; Palamar, Deniz; Akgun, Kenan

2015-07-01

The lateral pectoral nerve (LPN) is commonly injured along with the brachial plexus, but its isolated lesions are rare. Here, we present a case of an isolated LPN lesion confused with cervical radiculopathy. A 41-year-old man was admitted to our clinic because of weakness in his right arm. Previous magnetic resonance imaging (MRI) examination revealed right posterolateral protrusion at the C6-7 level. At the initial assessment, atrophy of the right pectoralis major muscle was evident, and mild weakness of the right shoulder adductor, internal rotator, and flexor muscles was observed. Therefore, electrodiagnostic evaluation was performed, and a diagnosis of isolated LPN injury was made. Nerve injury was thought to have been caused by weightlifting exercises and traction injury. Lateral pectoral nerve injury can mimic cervical radiculopathy, and MRI examination alone may lead to misdiagnosis. Repeated physical examinations during the evaluation and treatment phase will identify the muscle atrophy that occurs 1 or more months after the injury.

Dropped-head in recessive oculopharyngeal muscular dystrophy.

PubMed

Garibaldi, Matteo; Pennisi, Elena Maria; Bruttini, Mirella; Bizzarri, Veronica; Bucci, Elisabetta; Morino, Stefania; Talerico, Caterina; Stoppacciaro, Antonella; Renieri, Alessandra; Antonini, Giovanni

2015-11-01

A 69-year-old woman presented a dropped head, caused by severe neck extensor weakness that had started two years before. She had also developed a mild degree of dysphagia, rhinolalia, eyelid ptosis and proximal limb weakness during the last months. EMG revealed myopathic changes. Muscle MRI detected fatty infiltration in the posterior neck muscles and tongue. Muscle biopsy revealed fiber size variations, sporadic rimmed vacuoles, small scattered angulated fibers and a patchy myofibrillar network. Genetic analysis revealed homozygous (GCN)11 expansions in the PABPN1 gene that were consistent with recessive oculopharyngeal muscular dystrophy (OPMD). There are a few reports of the recessive form, which has a later disease onset with milder symptoms and higher clinical variability than the typical dominantly inherited form. This patient, who is the first Italian and the eighth worldwide reported case of recessive OPMD, is also the first case of OPMD with dropped-head syndrome, which thus expands the clinical phenotype of recessive OPMD. Copyright © 2015 Elsevier B.V. All rights reserved.

Approach to critical illness polyneuropathy and myopathy.

PubMed

Pati, S; Goodfellow, J A; Iyadurai, S; Hilton-Jones, D

2008-07-01

A newly acquired neuromuscular cause of weakness has been found in 25-85% of critically ill patients. Three distinct entities have been identified: (1) critical illness polyneuropathy (CIP); (2) acute myopathy of intensive care (itself with three subtypes); and (3) a syndrome with features of both 1 and 2 (called critical illness myopathy and/or neuropathy or CRIMYNE). CIP is primarily a distal axonopathy involving both sensory and motor nerves. Electroneurography and electromyography (ENG-EMG) is the gold standard for diagnosis. CIM is a proximal as well as distal muscle weakness affecting both types of muscle fibres. It is associated with high use of non-depolarising muscle blockers and corticosteroids. Avoidance of systemic inflammatory response syndrome (SIRS) is the most effective way to reduce the likelihood of developing CIP or CIM. Outcome is variable and depends largely on the underlying illness. Detailed history, careful physical examination, review of medication chart and analysis of initial investigations provides invaluable clues towards the diagnosis.

Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy*

PubMed Central

Ebert, Scott M.; Dyle, Michael C.; Bullard, Steven A.; Dierdorff, Jason M.; Murry, Daryl J.; Fox, Daniel K.; Bongers, Kale S.; Lira, Vitor A.; Meyerholz, David K.; Talley, John J.; Adams, Christopher M.

2015-01-01

Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle. PMID:26338703

Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy.

PubMed

Ebert, Scott M; Dyle, Michael C; Bullard, Steven A; Dierdorff, Jason M; Murry, Daryl J; Fox, Daniel K; Bongers, Kale S; Lira, Vitor A; Meyerholz, David K; Talley, John J; Adams, Christopher M

2015-10-16

Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The relationship between hamstring length and gluteal muscle strength in individuals with sacroiliac joint dysfunction

PubMed Central

Massoud Arab, Amir; Reza Nourbakhsh, Mohammad; Mohammadifar, Ali

2011-01-01

It has been suggested that tight hamstring muscle, due to its anatomical connections, could be a compensatory mechanism for providing sacroiliac (SI) joint stability in patients with gluteal muscle weakness and SIJ dysfunction. The purpose of this study was to determine the relationship between hamstring muscle length and gluteal muscle strength in subjects with sacroiliac joint dysfunction. A total of 159 subjects with and without low back pain (LBP) between the ages of 20 and 65 years participate in the study. Subjects were categorized into three groups: LBP without SIJ involvement (n = 53); back pain with SIJ dysfunction (n = 53); and no low back pain (n = 53). Hamstring muscle length and gluteal muscle strength were measured in all subjects. The number of individuals with gluteal weakness was significantly (P = 0.02) higher in subjects with SI joint dysfunction (66%) compared to those with LBP without SI joint dysfunctions (34%). In pooled data, there was no significant difference (P = 0.31) in hamstring muscle length between subjects with SI joint dysfunction and those with back pain without SI involvement. In subjects with SI joint dysfunction, however, those with gluteal muscle weakness had significantly (P = 0.02) shorter hamstring muscle length (mean = 158±11°) compared to individuals without gluteal weakness (mean = 165±10°). There was no statistically significant difference (P>0.05) in hamstring muscle length between individuals with and without gluteal muscle weakness in other groups. In conclusion, hamstring tightness in subjects with SI joint dysfunction could be related to gluteal muscle weakness. The slight difference in hamstring muscle length found in this study, although statistically significant, was not sufficient for making any definite conclusions. Further studies are needed to establish the role of hamstring muscle in SI joint stability. PMID:22294848

The relationship between hamstring length and gluteal muscle strength in individuals with sacroiliac joint dysfunction.

PubMed

Massoud Arab, Amir; Reza Nourbakhsh, Mohammad; Mohammadifar, Ali

2011-02-01

It has been suggested that tight hamstring muscle, due to its anatomical connections, could be a compensatory mechanism for providing sacroiliac (SI) joint stability in patients with gluteal muscle weakness and SIJ dysfunction. The purpose of this study was to determine the relationship between hamstring muscle length and gluteal muscle strength in subjects with sacroiliac joint dysfunction. A total of 159 subjects with and without low back pain (LBP) between the ages of 20 and 65 years participate in the study. Subjects were categorized into three groups: LBP without SIJ involvement (n = 53); back pain with SIJ dysfunction (n = 53); and no low back pain (n = 53). Hamstring muscle length and gluteal muscle strength were measured in all subjects. The number of individuals with gluteal weakness was significantly (P = 0.02) higher in subjects with SI joint dysfunction (66%) compared to those with LBP without SI joint dysfunctions (34%). In pooled data, there was no significant difference (P = 0.31) in hamstring muscle length between subjects with SI joint dysfunction and those with back pain without SI involvement. In subjects with SI joint dysfunction, however, those with gluteal muscle weakness had significantly (P = 0.02) shorter hamstring muscle length (mean = 158±11°) compared to individuals without gluteal weakness (mean = 165±10°). There was no statistically significant difference (P>0.05) in hamstring muscle length between individuals with and without gluteal muscle weakness in other groups. In conclusion, hamstring tightness in subjects with SI joint dysfunction could be related to gluteal muscle weakness. The slight difference in hamstring muscle length found in this study, although statistically significant, was not sufficient for making any definite conclusions. Further studies are needed to establish the role of hamstring muscle in SI joint stability.

Late-onset Pompe disease: what is the prevalence of limb-girdle muscular weakness presentation?

PubMed

Lorenzoni, Paulo José; Kay, Cláudia Suemi Kamoi; Higashi, Nádia Sugano; D'Almeida, Vânia; Werneck, Lineu Cesar; Scola, Rosana Herminia

2018-04-01

Pompe disease is an inherited disease caused by acid alpha-glucosidase (GAA) deficiency. A single center observational study aimed at assessing the prevalence of late-onset Pompe disease in a high-risk Brazilian population, using the dried blood spot test to detect GAA deficiency as a main screening tool. Dried blood spots were collected for GAA activity assay from 24 patients with "unexplained" limb-girdle muscular weakness without vacuolar myopathy in their muscle biopsy. Samples with reduced enzyme activity were also investigated for GAA gene mutations. Of the 24 patients with dried blood spots, one patient (4.2%) showed low GAA enzyme activity (NaG/AaGIA: 40.42; %INH: 87.22%). In this patient, genetic analysis confirmed two heterozygous mutations in the GAA gene (c.-32-13T>G/p.Arg854Ter). Our data confirm that clinicians should look for late-onset Pompe disease in patients whose clinical manifestation is an "unexplained" limb-girdle weakness even without vacuolar myopathy in muscle biopsy.

Pharmacotherapy to protect the neuromuscular junction after acute organophosphorus pesticide poisoning.

PubMed

Bird, Steven B; Krajacic, Predrag; Sawamoto, Keigo; Bunya, Naofumi; Loro, Emanuele; Khurana, Tejvir S

2016-06-01

Organophosphorus (OP) pesticide poisoning is a leading cause of morbidity and mortality in the developing world, affecting an estimated three million people annually. Much of the morbidity is directly related to muscle weakness, which develops 1-4 days after poisoning. This muscle weakness, termed the intermediate syndrome (IMS), leads to respiratory, bulbar, and proximal limb weakness and frequently necessitates the use of mechanical ventilation. While not entirely understood, the IMS is most likely due to persistently elevated acetylcholine (ACh), which activates nicotinic ACh receptors at the neuromuscular junction (NMJ). Thus, the NMJ is potentially a target-rich area for the development of new therapies for acute OP poisoning. In this manuscript, we discuss what is known about the IMS and studies investigating the use of nicotinic ACh receptor antagonists to prevent or mitigate NMJ dysfunction after acute OP poisoning. © 2016 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.

Simulating the effect of muscle weakness and contracture on neuromuscular control of normal gait in children.

PubMed

Fox, Aaron S; Carty, Christopher P; Modenese, Luca; Barber, Lee A; Lichtwark, Glen A

2018-03-01

Altered neural control of movement and musculoskeletal deficiencies are common in children with spastic cerebral palsy (SCP), with muscle weakness and contracture commonly experienced. Both neural and musculoskeletal deficiencies are likely to contribute to abnormal gait, such as equinus gait (toe-walking), in children with SCP. However, it is not known whether the musculoskeletal deficiencies prevent normal gait or if neural control could be altered to achieve normal gait. This study examined the effect of simulated muscle weakness and contracture of the major plantarflexor/dorsiflexor muscles on the neuromuscular requirements for achieving normal walking gait in children. Initial muscle-driven simulations of walking with normal musculoskeletal properties by typically developing children were undertaken. Additional simulations with altered musculoskeletal properties were then undertaken; with muscle weakness and contracture simulated by reducing the maximum isometric force and tendon slack length, respectively, of selected muscles. Muscle activations and forces required across all simulations were then compared via waveform analysis. Maintenance of normal gait appeared robust to muscle weakness in isolation, with increased activation of weakened muscles the major compensatory strategy. With muscle contracture, reduced activation of the plantarflexors was required across the mid-portion of stance suggesting a greater contribution from passive forces. Increased activation and force during swing was also required from the tibialis anterior to counteract the increased passive forces from the simulated dorsiflexor muscle contracture. Improvements in plantarflexor and dorsiflexor motor function and muscle strength, concomitant with reductions in plantarflexor muscle stiffness may target the deficits associated with SCP that limit normal gait. Copyright © 2018 Elsevier B.V. All rights reserved.

Assignment of the creatine transporter gene (SLC6A8) to human chromosome Xq28 telomeric to G6PD

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

Gregor, P.; Nash, S.R.; Caron, M.G.

1995-01-01

The creatine-phosphocreatine shuttle has important functions in the temporal and spatial maintenance of the energy supply to skeletal and cardiac muscle. Muscle cells do not synthesize creatine, but take it up via a specific sodium-dependent transporter - the creatine transporter. Thus, the creatine transporter has an important role in muscular physiology. Furthermore, inhibition of creatine transport in experimental animals causes muscle weakness. Recently, creatine transporter cDNAs have been isolated and characterized from rabbit and human. In this communication we report mapping of the creatine transporter gene to human chromosome Xq28. 12 refs., 1 fig.

Excess TGF-β mediates muscle weakness associated with bone metastases in mice

PubMed Central

Reiken, Steven; Xie, Wenjun; Andersson, Daniel C.; John, Sutha; Chiechi, Antonella; Wright, Laura E.; Umanskaya, Alisa; Niewolna, Maria; Trivedi, Trupti; Charkhzarrin, Sahba; Khatiwada, Pooja; Wronska, Anetta; Haynes, Ashley; Benassi, Maria Serena; Witzmann, Frank A.; Zhen, Gehua; Wang, Xiao; Cao, Xu; Roodman, G. David; Marks, Andrew R.; Guise, Theresa A.

2015-01-01

Cancer-associated muscle weakness is poorly understood and there is no effective treatment. Here, we find that seven different mouse models of human osteolytic bone metastases, representing breast, lung and prostate cancers, as well as multiple myeloma exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that TGF-β, released from the bone surface as a result of metastasis-induced bone destruction upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor/calcium (Ca2+) release channel (RyR1). The oxidized RyR1 channels leaked Ca2+, resulting in lower intracellular signaling required for proper muscle contraction. We found that inhibiting RyR1 leak, TGF-β signaling, TGF-β release from bone or Nox4 all improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast cancer- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, higher levels of Nox4 protein and Nox4 binding to RyR1, and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a non-malignant metabolic bone disorder associated with increased TGF-β activity. Thus, metastasis-induced TGF-β release from bone contributes to muscle weakness by decreasing Ca2+-induced muscle force production. PMID:26457758

Behavioral and histological changes in the Formosan subterranean termite (Isoptera: Rhinotermitidae) induced by the chitin synthesis inhibitor noviflumuron.

PubMed

Xing, Lin; Chouvenc, Thomas; Su, Nan-Yao

2014-04-01

This study describes the behavioral and histological changes of the molting process in Coptotermes formosanus Shiraki caused by the chitin synthesis inhibitor noviflumuron. Termites exposed to noviflumuron initiated ecdysis as untreated individuals did; however, peristalsis contractions were weak and the expansion of the dorsal breach of the exoskeleton did not occur. Treated termites could not complete their molting process and died after the initiation of the ecdysis. Histological observations showed that the process of voiding the gut protozoa during premolting was not affected by the noviflumuron treatment. However, the formation of the new cuticle was disrupted resulting in the loss of integrity of the cuticle. The alteration of the cuticle was visible in the gizzard (foregut), the thoracic pleurons, and most of the exoskeleton. Muscles were partially able to reattach to the incompletely formed new cuticle, and muscle contractions resulted in tearing off the cuticle. Because the integrity of the newly formed cuticle was compromised by the noviflumuron treatment, we concluded that termites' death was caused primarily by the loss of hemolymph as a result of the damage done by the muscle contractions on the exoskeleton during the peristalsis. As the physiological homeostasis was disrupted, termites were too weak to shed their old cuticle, ultimately resulting in termite dying during the molting process.

Mitochondrial Function in an In Vitro Model of Skeletal Muscle of Patients With Protracted Critical Illness and Intensive Care Unit-Acquired Weakness.

PubMed

Jiroutková, Kateřina; Krajčová, Adéla; Žiak, Jakub; Fric, Michal; Gojda, Jan; Džupa, Valér; Kalous, Martin; Tůmová, Jana; Trnka, Jan; Duška, František

2017-09-01

Functional mitochondria in skeletal muscle of patients with protracted critical illness and intensive care unit-acquired weakness are depleted, but remaining mitochondria have increased functional capacities of respiratory complexes II and III. This can be an adaptation to relative abundancy of fatty acid over glucose caused by insulin resistance. We hypothesized that the capacity of muscle mitochondria to oxidize fatty acid is increased in protracted critical illness. We assessed fatty acid oxidation (FAO) and mitochondrial functional indices in vitro by using extracellular flux analysis in cultured myotubes obtained by isolating and culturing satellite cells from vastus lateralis muscle biopsy samples from patients with ICU-acquired weakness (n = 6) and age-matched healthy controls (n = 7). Bioenergetic measurements were performed at baseline and after 6 days of exposure to free fatty acids (FFAs). Mitochondrial density in myotubes from ICU patients was 69% of healthy controls ( P = .051). After adjustment to mitochondrial content, there were no differences in adenosine triphosphate (ATP) synthesis or the capacity and coupling of the respiratory chain. FAO capacity in ICU patients was 157% of FAO capacity in controls ( P = .015). In myotubes of ICU patients, unlike healthy controls, the exposure to FFA significantly ( P = .009) increased maximum respiratory chain capacity. In an in vitro model of skeletal muscle of patients with protracted critical illness, we have shown signs of adaptation to increased FAO. Even in the presence of glucose and insulin, elevation of FFAs in the extracellular environment increased maximal capacity of the respiratory chain.

Objective Evaluation of Muscle Strength in Infants with Hypotonia and Muscle Weakness

ERIC Educational Resources Information Center

Reus, Linda; van Vlimmeren, Leo A.; Staal, J. Bart; Janssen, Anjo J. W. M.; Otten, Barto J.; Pelzer, Ben J.; Nijhuis-van der Sanden, Maria W. G.

2013-01-01

The clinical evaluation of an infant with motor delay, muscle weakness, and/or hypotonia would improve considerably if muscle strength could be measured objectively and normal reference values were available. The authors developed a method to measure muscle strength in infants and tested 81 typically developing infants, 6-36 months of age, and 17…

Skeletal muscle weakness in osteogenesis imperfecta mice.

PubMed

Gentry, Bettina A; Ferreira, J Andries; McCambridge, Amanda J; Brown, Marybeth; Phillips, Charlotte L

2010-09-01

Exercise intolerance, muscle fatigue and weakness are often-reported, little-investigated concerns of patients with osteogenesis imperfecta (OI). OI is a heritable connective tissue disorder hallmarked by bone fragility resulting primarily from dominant mutations in the proα1(I) or proα2(I) collagen genes and the recently discovered recessive mutations in post-translational modifying proteins of type I collagen. In this study we examined the soleus (S), plantaris (P), gastrocnemius (G), tibialis anterior (TA) and quadriceps (Q) muscles of mice expressing mild (+/oim) and moderately severe (oim/oim) OI for evidence of inherent muscle pathology. In particular, muscle weight, fiber cross-sectional area (CSA), fiber type, fiber histomorphology, fibrillar collagen content, absolute, relative and specific peak tetanic force (P(o), P(o)/mg and P(o)/CSA respectively) of individual muscles were evaluated. Oim/oim mouse muscles were generally smaller, contained less fibrillar collagen, had decreased P(o) and an inability to sustain P(o) for the 300-ms testing duration for specific muscles; +/oim mice had a similar but milder skeletal muscle phenotype. +/oim mice had mild weakness of specific muscles but were less affected than their oim/oim counterparts which demonstrated readily apparent skeletal muscle pathology. Therefore muscle weakness in oim mice reflects inherent skeletal muscle pathology. Copyright © 2010 Elsevier B.V. All rights reserved.

Restricting calcium currents is required for correct fiber type specification in skeletal muscle

PubMed Central

Sultana, Nasreen; Dienes, Beatrix; Benedetti, Ariane; Tuluc, Petronel; Szentesi, Peter; Sztretye, Monika; Rainer, Johannes; Hess, Michael W.; Schwarzer, Christoph; Obermair, Gerald J.; Csernoch, Laszlo

2016-01-01

ABSTRACT Skeletal muscle excitation-contraction (EC) coupling is independent of calcium influx. In fact, alternative splicing of the voltage-gated calcium channel CaV1.1 actively suppresses calcium currents in mature muscle. Whether this is necessary for normal development and function of muscle is not known. However, splicing defects that cause aberrant expression of the calcium-conducting developmental CaV1.1e splice variant correlate with muscle weakness in myotonic dystrophy. Here, we deleted CaV1.1 (Cacna1s) exon 29 in mice. These mice displayed normal overall motor performance, although grip force and voluntary running were reduced. Continued expression of the developmental CaV1.1e splice variant in adult mice caused increased calcium influx during EC coupling, altered calcium homeostasis, and spontaneous calcium sparklets in isolated muscle fibers. Contractile force was reduced and endurance enhanced. Key regulators of fiber type specification were dysregulated and the fiber type composition was shifted toward slower fibers. However, oxidative enzyme activity and mitochondrial content declined. These findings indicate that limiting calcium influx during skeletal muscle EC coupling is important for the secondary function of the calcium signal in the activity-dependent regulation of fiber type composition and to prevent muscle disease. PMID:26965373

Protocol for diaphragm pacing in patients with respiratory muscle weakness due to motor neurone disease (DiPALS): a randomised controlled trial

PubMed Central

2012-01-01

Background Motor neurone disease (MND) is a devastating illness which leads to muscle weakness and death, usually within 2-3 years of symptom onset. Respiratory insufficiency is a common cause of morbidity, particularly in later stages of MND and respiratory complications are the leading cause of mortality in MND patients. Non Invasive Ventilation (NIV) is the current standard therapy to manage respiratory insufficiency. Some MND patients however do not tolerate NIV due to a number of issues including mask interface problems and claustrophobia. In those that do tolerate NIV, eventually respiratory muscle weakness will progress to a point at which intermittent/overnight NIV is ineffective. The NeuRx RA/4 Diaphragm Pacing System was originally developed for patients with respiratory insufficiency and diaphragm paralysis secondary to stable high spinal cord injuries. The DiPALS study will assess the effect of diaphragm pacing (DP) when used to treat patients with MND and respiratory insufficiency. Method/Design 108 patients will be recruited to the study at 5 sites in the UK. Patients will be randomised to either receive NIV (current standard care) or receive DP in addition to NIV. Study participants will be required to complete outcome measures at 5 follow up time points (2, 3, 6, 9 and 12 months) plus an additional surgery and 1 week post operative visit for those in the DP group. 12 patients (and their carers) from the DP group will also be asked to complete 2 qualitative interviews. Discussion The primary objective of this trial will be to evaluate the effect of Diaphragm Pacing (DP) on survival over the study duration in patients with MND with respiratory muscle weakness. The project is funded by the National Institute for Health Research, Health Technology Assessment (HTA) Programme (project number 09/55/33) and the Motor Neurone Disease Association and the Henry Smith Charity. Trial Registration: Current controlled trials ISRCTN53817913. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health. PMID:22897892

Rhabdomyolysis After LSD Ingestion.

PubMed

Berrens, Zachary; Lammers, Jessica; White, Christopher

2010-01-01

Rhabdomyolysis involves the release of intracellular contents secondary to muscle cell injury; it generally presents with muscle pain and weakness. Illicit drugs, including phencyclidine, MDMA ("ecstasy"), and cocaine, are frequently documented as a cause of rhabdomyolysis. The authors review the literature on LSD-associated rhabdomyolysis. The authors provide a new case report of a previously health patient who suffered rhabdomyolysis after LSD ingestion. Although frequently listed as a cause of rhabdomyolysis, there are only limited reports of rhabdomyolysis in patients who have ingested LSD. The discussion outlines potential mechanisms and management of LSD-associated rhabdomyolysis. Consultation psychiatrists may be called to assist in management of acute mental-status changes or agitation associated with LSD intoxication in addition to facilitating subsequent chemical-dependency treatment.

Influence of vision on masticatory muscles function: surface electromyographic evaluation

PubMed Central

Ciavarella, Domenico; Palazzo, Antonio; De Lillo, Alfredo; Lo Russo, Lucio; Paduano, Sergio; Laino, Luigi; Chimenti, Claudio; Frezza, Federica; Lo Muzio, Lorenzo

2014-01-01

Summary The role of the ocular disorders (OD) in pathogenesis of MMp is still a controversal issue. Ocular arc reflexes (OAR) may involve changes in head and neck posture and generate modifications of contraction resulting in muscle contraction and finally weakness. sEMG tests were performed on 28 patients (13 with masticatory muscles pain and myopia/15 healthy) in rest position with eyes open and eyes closed. Patients group control (healthy patients) showed no significance difference in sEMG record in open/close test. In non healthy patients there were great differences between the sEMG recordings with eyes closed and open. Temporalis and masseters showed a statistical difference of means activation in two tests (temporalis p = 0.0010; masseters = 0.0006). Great difference there was in means muscles activation between open eyes healthy test and non healthy. No difference in close eyes test was evaluated in temporalis and masseters close test in the two groups. The exact causes of MMp are still unknown. The role how ocular disorders (OD) may play an important role in pathogenesis of MMp is still a controversal issue. Ocular arc reflexes (OAR) may involve changes in head and neck posture and generate modifications of contraction resulting in muscle contraction and finally weakness. PMID:25002919

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

Role of Oxidative Stress as Key Regulator of Muscle Wasting during Cachexia.

PubMed

Ábrigo, Johanna; Elorza, Alvaro A; Riedel, Claudia A; Vilos, Cristian; Simon, Felipe; Cabrera, Daniel; Estrada, Lisbell; Cabello-Verrugio, Claudio

2018-01-01

Skeletal muscle atrophy is a pathological condition mainly characterized by a loss of muscular mass and the contractile capacity of the skeletal muscle as a consequence of muscular weakness and decreased force generation. Cachexia is defined as a pathological condition secondary to illness characterized by the progressive loss of muscle mass with or without loss of fat mass and with concomitant diminution of muscle strength. The molecular mechanisms involved in cachexia include oxidative stress, protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction. Oxidative stress is one of the most common mechanisms of cachexia caused by different factors. It results in increased ROS levels, increased oxidation-dependent protein modification, and decreased antioxidant system functions. In this review, we will describe the importance of oxidative stress in skeletal muscles, its sources, and how it can regulate protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction involved in cachexia.

PABPN1 gene therapy for oculopharyngeal muscular dystrophy

PubMed Central

Malerba, A.; Klein, P.; Bachtarzi, H.; Jarmin, S. A.; Cordova, G.; Ferry, A.; Strings, V.; Espinoza, M. Polay; Mamchaoui, K.; Blumen, S. C.; St Guily, J. Lacau; Mouly, V.; Graham, M.; Butler-Browne, G.; Suhy, D. A.; Trollet, C.; Dickson, G.

2017-01-01

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by ptosis, swallowing difficulties, proximal limb weakness and nuclear aggregates in skeletal muscles. OPMD is caused by a trinucleotide repeat expansion in the PABPN1 gene that results in an N-terminal expanded polyalanine tract in polyA-binding protein nuclear 1 (PABPN1). Here we show that the treatment of a mouse model of OPMD with an adeno-associated virus-based gene therapy combining complete knockdown of endogenous PABPN1 and its replacement by a wild-type PABPN1 substantially reduces the amount of insoluble aggregates, decreases muscle fibrosis, reverts muscle strength to the level of healthy muscles and normalizes the muscle transcriptome. The efficacy of the combined treatment is further confirmed in cells derived from OPMD patients. These results pave the way towards a gene replacement approach for OPMD treatment. PMID:28361972

Ethanol Exposure Causes Muscle Degeneration in Zebrafish

PubMed Central

Coffey, Elizabeth C.; Pasquarella, Maggie E.; Goody, Michelle F.

2018-01-01

Alcoholic myopathies are characterized by neuromusculoskeletal symptoms such as compromised movement and weakness. Although these symptoms have been attributed to neurological damage, EtOH may also target skeletal muscle. EtOH exposure during zebrafish primary muscle development or adulthood results in smaller muscle fibers. However, the effects of EtOH exposure on skeletal muscle during the growth period that follows primary muscle development are not well understood. We determined the effects of EtOH exposure on muscle during this phase of development. Strikingly, muscle fibers at this stage are acutely sensitive to EtOH treatment: EtOH induces muscle degeneration. The severity of EtOH-induced muscle damage varies but muscle becomes more refractory to EtOH as muscle develops. NF-kB induction in muscle indicates that EtOH triggers a pro-inflammatory response. EtOH-induced muscle damage is p53-independent. Uptake of Evans blue dye shows that EtOH treatment causes sarcolemmal instability before muscle fiber detachment. Dystrophin-null sapje mutant zebrafish also exhibit sarcolemmal instability. We tested whether Trichostatin A (TSA), which reduces muscle degeneration in sapje mutants, would affect EtOH-treated zebrafish. We found that TSA and EtOH are a lethal combination. EtOH does, however, exacerbate muscle degeneration in sapje mutants. EtOH also disrupts adhesion of muscle fibers to their extracellular matrix at the myotendinous junction: some detached muscle fibers retain beta-Dystroglycan indicating failure of muscle end attachments. Overexpression of Paxillin, which reduces muscle degeneration in zebrafish deficient for beta-Dystroglycan, is not sufficient to rescue degeneration. Taken together, our results suggest that EtOH exposure has pleiotropic deleterious effects on skeletal muscle. PMID:29615556

Early Exercise Rehabilitation of Muscle Weakness in Acute Respiratory Failure Patients

PubMed Central

Berry, Michael J.; Morris, Peter E.

2013-01-01

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

Distinct distal myopathy phenotype caused by VCP gene mutation in a Finnish family.

PubMed

Palmio, Johanna; Sandell, Satu; Suominen, Tiina; Penttilä, Sini; Raheem, Olayinka; Hackman, Peter; Huovinen, Sanna; Haapasalo, Hannu; Udd, Bjarne

2011-08-01

Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) is caused by mutations in the valosin-containing protein (VCP) gene. We report a new distal phenotype caused by VCP gene mutation in a Finnish family with nine affected members in three generations. Patients had onset of distal leg muscle weakness and atrophy in the anterior compartment muscles after age 35, which caused a foot drop at age 50. None of the siblings had scapular winging, proximal myopathy, cardiomyopathy or respiratory problems during long-term follow-up. Three distal myopathy patients developed rapidly progressive dementia, became bedridden and died of cachexia and pneumonia and VCP gene mutation P137L (c.410C>T) was then identified in the family. Late onset autosomal dominant distal myopathy with rimmed vacuolar muscle pathology was not sufficient for exact diagnosis in this family until late-occurring dementia provided the clue for molecular diagnosis. VCP needs to be considered in the differential diagnostic work-up in patients with distal myopathy phenotype. Copyright © 2011 Elsevier B.V. All rights reserved.

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.

[Overactive muscles: it can be more serious than common myalgia or cramp].

PubMed

Molenaar, Joery P F; Snoeck, Marc M J; Voermans, Nicol C; van Engelen, Baziel G M

2016-01-01

Positive muscle phenomena are due to muscle overactivity. Examples are cramp, myalgia, and stiffness. These manifestations have mostly acquired causes, e.g. side-effects of medication, metabolic disorders, vitamin deficiency, excessive caffeine intake or neurogenic disorders. We report on three patients with various positive muscle phenomena, to illustrate the clinical signs that indicate an underlying myopathy. Patient A, a 56-year-old man, was diagnosed with muscle cramp in the context of excessive coffee use and previous lumbosacral radiculopathy. Patient B, a 71-year-old man, was shown to have RYR1-related myopathy. Patient C, a 42-year-old man, suffered from Brody myopathy. We propose for clinicians to look out for a number of 'red flags' that can point to an underlying myopathy, and call for referral to neurology if indicated. Red flags include second wind phenomenon, familial occurrence of similar complaints, marked muscle stiffness, myotonia, muscle weakness, muscle hypertrophy, and myoglobinuria. Establishing a correct diagnosis is important for proper treatment. Certain myopathies call for cardiac or respiratory screening.

Contractile dysfunction in muscle may underlie androgen-dependent motor dysfunction in spinal bulbar muscular atrophy

PubMed Central

Oki, Kentaro; Halievski, Katherine; Vicente, Laura; Xu, Youfen; Zeolla, Donald; Poort, Jessica; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Wiseman, Robert W.; Breedlove, S. Marc

2015-01-01

Spinal and bulbar muscular atrophy (SBMA) is characterized by progressive muscle weakness linked to a polyglutamine expansion in the androgen receptor (AR). Current evidence indicates that mutant AR causes SBMA by acting in muscle to perturb its function. However, information about how muscle function is impaired is scant. One fundamental question is whether the intrinsic strength of muscles, an attribute of muscle independent of its mass, is affected. In the current study, we assess the contractile properties of hindlimb muscles in vitro from chronically diseased males of three different SBMA mouse models: a transgenic (Tg) model that broadly expresses a full-length human AR with 97 CAGs (97Q), a knock-in (KI) model that expresses a humanized AR containing a CAG expansion in the first exon, and a Tg myogenic model that overexpresses wild-type AR only in skeletal muscle fibers. We found that hindlimb muscles in the two Tg models (97Q and myogenic) showed marked losses in their intrinsic strength and resistance to fatigue, but were minimally affected in KI males. However, diseased muscles of all three models showed symptoms consistent with myotonic dystrophy type 1, namely, reduced resting membrane potential and deficits in chloride channel mRNA. These data indicate that muscle dysfunction is a core feature of SBMA caused by at least some of the same pathogenic mechanisms as myotonic dystrophy. Thus mechanisms controlling muscle function per se independent of mass are prime targets for SBMA therapeutics. PMID:25663674

Hypophosphatemia promotes lower rates of muscle ATP synthesis.

PubMed

Pesta, Dominik H; Tsirigotis, Dimitrios N; Befroy, Douglas E; Caballero, Daniel; Jurczak, Michael J; Rahimi, Yasmeen; Cline, Gary W; Dufour, Sylvie; Birkenfeld, Andreas L; Rothman, Douglas L; Carpenter, Thomas O; Insogna, Karl; Petersen, Kitt Falk; Bergwitz, Clemens; Shulman, Gerald I

2016-10-01

Hypophosphatemia can lead to muscle weakness and respiratory and heart failure, but the mechanism is unknown. To address this question, we noninvasively assessed rates of muscle ATP synthesis in hypophosphatemic mice by using in vivo saturation transfer [ 31 P]-magnetic resonance spectroscopy. By using this approach, we found that basal and insulin-stimulated rates of muscle ATP synthetic flux (V ATP ) and plasma inorganic phosphate (P i ) were reduced by 50% in mice with diet-induced hypophosphatemia as well as in sodium-dependent P i transporter solute carrier family 34, member 1 (NaPi2a)-knockout (NaPi2a -/- ) mice compared with their wild-type littermate controls. Rates of V ATP normalized in both hypophosphatemic groups after restoring plasma P i concentrations. Furthermore, V ATP was directly related to cellular and mitochondrial P i uptake in L6 and RC13 rodent myocytes and isolated muscle mitochondria. Similar findings were observed in a patient with chronic hypophosphatemia as a result of a mutation in SLC34A3 who had a 50% reduction in both serum P i content and muscle V ATP After oral P i repletion and normalization of serum P i levels, muscle V ATP completely normalized in the patient. Taken together, these data support the hypothesis that decreased muscle ATP synthesis, in part, may be caused by low blood P i concentrations, which may explain some aspects of muscle weakness observed in patients with hypophosphatemia.-Pesta, D. H., Tsirigotis, D. N., Befroy, D. E., Caballero, D., Jurczak, M. J., Rahimi, Y., Cline, G. W., Dufour, S., Birkenfeld, A. L., Rothman, D. L., Carpenter, T. O., Insogna, K., Petersen, K. F., Bergwitz, C., Shulman, G. I. Hypophosphatemia promotes lower rates of muscle ATP synthesis. © The Author(s).

Hypophosphatemia promotes lower rates of muscle ATP synthesis

PubMed Central

Pesta, Dominik H.; Tsirigotis, Dimitrios N.; Befroy, Douglas E.; Caballero, Daniel; Jurczak, Michael J.; Rahimi, Yasmeen; Cline, Gary W.; Dufour, Sylvie; Birkenfeld, Andreas L.; Rothman, Douglas L.; Carpenter, Thomas O.; Insogna, Karl; Petersen, Kitt Falk; Bergwitz, Clemens; Shulman, Gerald I.

2016-01-01

Hypophosphatemia can lead to muscle weakness and respiratory and heart failure, but the mechanism is unknown. To address this question, we noninvasively assessed rates of muscle ATP synthesis in hypophosphatemic mice by using in vivo saturation transfer [31P]-magnetic resonance spectroscopy. By using this approach, we found that basal and insulin-stimulated rates of muscle ATP synthetic flux (VATP) and plasma inorganic phosphate (Pi) were reduced by 50% in mice with diet-induced hypophosphatemia as well as in sodium-dependent Pi transporter solute carrier family 34, member 1 (NaPi2a)-knockout (NaPi2a−/−) mice compared with their wild-type littermate controls. Rates of VATP normalized in both hypophosphatemic groups after restoring plasma Pi concentrations. Furthermore, VATP was directly related to cellular and mitochondrial Pi uptake in L6 and RC13 rodent myocytes and isolated muscle mitochondria. Similar findings were observed in a patient with chronic hypophosphatemia as a result of a mutation in SLC34A3 who had a 50% reduction in both serum Pi content and muscle VATP. After oral Pi repletion and normalization of serum Pi levels, muscle VATP completely normalized in the patient. Taken together, these data support the hypothesis that decreased muscle ATP synthesis, in part, may be caused by low blood Pi concentrations, which may explain some aspects of muscle weakness observed in patients with hypophosphatemia.—Pesta, D. H., Tsirigotis, D. N., Befroy, D. E., Caballero, D., Jurczak, M. J., Rahimi, Y., Cline, G. W., Dufour, S., Birkenfeld, A. L., Rothman, D. L., Carpenter, T. O., Insogna, K., Petersen, K. F., Bergwitz, C., Shulman, G. I. Hypophosphatemia promotes lower rates of muscle ATP synthesis. PMID:27338702

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs.

PubMed

Barreto, Rafael; Waning, David L; Gao, Hongyu; Liu, Yunlong; Zimmers, Teresa A; Bonetto, Andrea

2016-07-12

Cachexia affects the majority of cancer patients, with currently no effective treatments. Cachexia is defined by increased fatigue and loss of muscle function resulting from muscle and fat depletion. Previous studies suggest that chemotherapy may contribute to cachexia, although the causes responsible for this association are not clear. The purpose of this study was to investigate the mechanism(s) associated with chemotherapy-related effects on body composition and muscle function. Normal mice were administered chemotherapy regimens used for the treatment of colorectal cancer, such as Folfox (5-FU, leucovorin, oxaliplatin) or Folfiri (5-FU, leucovorin, irinotecan) for 5 weeks. The animals that received chemotherapy exhibited concurrent loss of muscle mass and muscle weakness. Consistently with previous findings, muscle wasting was associated with up-regulation of ERK1/2 and p38 MAPKs. No changes in ubiquitin-dependent proteolysis or in the expression of TGFβ-family members were detected. Further, marked decreases in mitochondrial content, associated with abnormalities at the sarcomeric level and with increase in the number of glycolytic fibers were observed in the muscle of mice receiving chemotherapy. Finally, ACVR2B/Fc or PD98059 prevented Folfiri-associated ERK1/2 activation and myofiber atrophy in C2C12 cultures. Our findings demonstrate that chemotherapy promotes MAPK-dependent muscle atrophy as well as mitochondrial depletion and alterations of the sarcomeric units. Therefore, these findings suggest that chemotherapy potentially plays a causative role in the occurrence of muscle loss and weakness. Moreover, the present observations provide a strong rationale for testing ACVR2B/Fc or MEK1 inhibitors in combination with anticancer drugs as novel strategies aimed at preventing chemotherapy-associated muscle atrophy.

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs

PubMed Central

Barreto, Rafael; Waning, David L.; Gao, Hongyu; Liu, Yunlong; Zimmers, Teresa A.; Bonetto, Andrea

2016-01-01

Cachexia affects the majority of cancer patients, with currently no effective treatments. Cachexia is defined by increased fatigue and loss of muscle function resulting from muscle and fat depletion. Previous studies suggest that chemotherapy may contribute to cachexia, although the causes responsible for this association are not clear. The purpose of this study was to investigate the mechanism(s) associated with chemotherapy-related effects on body composition and muscle function. Normal mice were administered chemotherapy regimens used for the treatment of colorectal cancer, such as Folfox (5-FU, leucovorin, oxaliplatin) or Folfiri (5-FU, leucovorin, irinotecan) for 5 weeks. The animals that received chemotherapy exhibited concurrent loss of muscle mass and muscle weakness. Consistently with previous findings, muscle wasting was associated with up-regulation of ERK1/2 and p38 MAPKs. No changes in ubiquitin-dependent proteolysis or in the expression of TGFβ-family members were detected. Further, marked decreases in mitochondrial content, associated with abnormalities at the sarcomeric level and with increase in the number of glycolytic fibers were observed in the muscle of mice receiving chemotherapy. Finally, ACVR2B/Fc or PD98059 prevented Folfiri-associated ERK1/2 activation and myofiber atrophy in C2C12 cultures. Our findings demonstrate that chemotherapy promotes MAPK-dependent muscle atrophy as well as mitochondrial depletion and alterations of the sarcomeric units. Therefore, these findings suggest that chemotherapy potentially plays a causative role in the occurrence of muscle loss and weakness. Moreover, the present observations provide a strong rationale for testing ACVR2B/Fc or MEK1 inhibitors in combination with anticancer drugs as novel strategies aimed at preventing chemotherapy-associated muscle atrophy. PMID:27259276

Cardiac cycle-synchronized electrical muscle stimulator for lower limb training with the potential to reduce the heart's pumping workload

PubMed Central

Matsuse, Hiroo; Akimoto, Ryuji; Kamiya, Shiro; Moritani, Toshio; Sasaki, Motoki; Ishizaki, Yuta; Ohtsuka, Masanori; Nakayoshi, Takaharu; Ueno, Takafumi; Shiba, Naoto; Fukumoto, Yoshihiro

2017-01-01

Background The lower limb muscle may play an important role in decreasing the heart’s pumping workload. Aging and inactivity cause atrophy and weakness of the muscle, leading to a loss of the heart-assisting role. An electrical lower limb muscle stimulator can prevent atrophy and weakness more effectively than conventional resistance training; however, it has been reported to increase the heart’s pumping workload in some situations. Therefore, more effective tools should be developed. Methods We newly developed a cardiac cycle-synchronized electrical lower limb muscle stimulator by combining a commercially available electrocardiogram monitor and belt electrode skeletal muscle electrical stimulator, making it possible to achieve strong and wide but not painful muscle contractions. Then, we tested the stimulator in 11 healthy volunteers to determine whether the special equipment enabled lower limb muscle training without harming the hemodynamics using plethysmography and a percutaneous cardiac output analyzer. Results In 9 of 11 subjects, the stimulator generated diastolic augmentation waves on the dicrotic notches and end-diastolic pressure reduction waves on the plethysmogram waveforms of the brachial artery, showing analogous waveforms in the intra-aortic balloon pumping heart-assisting therapy. The heart rate, stroke volume, and cardiac output significantly increased during the stimulation. There was no change in the systolic or diastolic blood pressure during the stimulation. Conclusion Cardiac cycle-synchronized electrical muscle stimulation for the lower limbs may enable muscle training without harmfully influencing the hemodynamics and with a potential to reduce the heart’s pumping workload, suggesting a promising tool for effectively treating both locomotor and cardiovascular disorders. PMID:29117189

Sporadic inclusion body myositis: the genetic contributions to the pathogenesis

PubMed Central

2014-01-01

Sporadic inclusion body myositis (sIBM) is the commonest idiopathic inflammatory muscle disease in people over 50 years old. It is characterized by slowly progressive muscle weakness and atrophy, with typical pathological changes of inflammation, degeneration and mitochondrial abnormality in affected muscle fibres. The cause(s) of sIBM are still unknown, but are considered complex, with the contribution of multiple factors such as environmental triggers, ageing and genetic susceptibility. This review summarizes the current understanding of the genetic contributions to sIBM and provides some insights for future research in this mysterious disease with the advantage of the rapid development of advanced genetic technology. An international sIBM genetic study is ongoing and whole-exome sequencing will be applied in a large cohort of sIBM patients with the aim of unravelling important genetic risk factors for sIBM. PMID:24948216

Effects of Inspiratory Muscle Training and Calisthenics-and-Breathing Exercises in COPD With and Without Respiratory Muscle Weakness.

PubMed

Basso-Vanelli, Renata P; Di Lorenzo, Valéria A Pires; Labadessa, Ivana G; Regueiro, Eloisa M G; Jamami, Mauricio; Gomes, Evelim L F D; Costa, Dirceu

2016-01-01

Patients with COPD may experience respiratory muscle weakness. Two therapeutic approaches to the respiratory muscles are inspiratory muscle training and calisthenics-and-breathing exercises. The aims of the study are to compare the effects of inspiratory muscle training and calisthenics-and-breathing exercises associated with physical training in subjects with COPD as an additional benefit of strength and endurance of the inspiratory muscles, thoracoabdominal mobility, physical exercise capacity, and reduction in dyspnea on exertion. In addition, these gains were compared between subjects with and without respiratory muscle weakness. 25 subjects completed the study: 13 composed the inspiratory muscle training group, and 12 composed the calisthenics-and-breathing exercises group. Subjects were assessed before and after training by spirometry, measurements of respiratory muscle strength and test of inspiratory muscle endurance, thoracoabdominal excursion measurements, and the 6-min walk test. Moreover, scores for the Modified Medical Research Council dyspnea scale were reported. After intervention, there was a significant improvement in both groups of respiratory muscle strength and endurance, thoracoabdominal mobility, and walking distance in the 6-min walk test. Additionally, there was a decrease of dyspnea in the 6-min walk test peak. A difference was found between groups, with higher values of respiratory muscle strength and thoracoabdominal mobility and lower values of dyspnea in the 6-min walk test peak and the Modified Medical Research Council dyspnea scale in the inspiratory muscle training group. In the inspiratory muscle training group, subjects with respiratory muscle weakness had greater gains in inspiratory muscle strength and endurance. Both interventions increased exercise capacity and decreased dyspnea during physical effort. However, inspiratory muscle training was more effective in increasing inspiratory muscle strength and endurance, which could result in a decreased sensation of dyspnea. In addition, subjects with respiratory muscle weakness that performed inspiratory muscle training had higher gains in inspiratory muscle strength and endurance but not of dyspnea and submaximal exercise capacity. (ClinicalTrials.gov registration NCT01510041.). Copyright © 2016 by Daedalus Enterprises.

Skeletal muscle disorders of glycogenolysis and glycolysis.

PubMed

Godfrey, Richard; Quinlivan, Ros

2016-07-01

Skeletal muscle disorders of glycogenolysis and glycolysis account for most of the conditions collectively termed glycogen storage diseases (GSDs). These disorders are rare (incidence 1 in 20,000-43,000 live births), and are caused by autosomal or X-linked recessive mutations that result in a specific enzyme deficiency, leading to the inability to utilize muscle glycogen as an energy substrate. McArdle disease (GSD V) is the most common of these disorders, and is caused by mutations in the gene encoding muscle glycogen phosphorylase. Symptoms of McArdle disease and most other related GSDs include exercise intolerance, muscle contracture, acute rhabdomyolysis, and risk of acute renal failure. Older patients may exhibit muscle wasting and weakness involving the paraspinal muscles and shoulder girdle. For patients with these conditions, engaging with exercise is likely to be beneficial. Diagnosis is frequently delayed owing to the rarity of the conditions and lack of access to appropriate investigations. A few randomized clinical trials have been conducted, some focusing on dietary modification, although the quality of the evidence is low and no specific recommendations can yet be made. The development of EUROMAC, an international registry for these disorders, should improve our knowledge of their natural histories and provide a platform for future clinical trials.

Surgical Removal of Circumferentially Leaked Polymethyl Methacrylate in the Epidural Space of the Thoracic Spine after Percutaneous Vertebroplasty

PubMed Central

Kita, Kenichiro; Takata, Yoichiro; Higashino, Kosaku; Yamashita, Kazuta; Tezuka, Fumitake; Sakai, Toshinori; Nagamachi, Akihiro; Sairyo, Koichi

2017-01-01

Background  The major complication of percutaneous vertebroplasty (PVP) using polymethyl methacrylate (PMMA) is epidural leakage of PMMA that damages the spinal cord. Methods  This is a case report. Result  A 77-year-old man presented to our institution with a 6-month history of muscle weakness and an intolerable burning sensation of both lower limbs after PVP with PMMA for thoracic compression fracture at T7 at another hospital. His past medical history was significant for hypertension. He had no history of smoking and alcohol. Computed tomography revealed massive leakage of PMMA into the T6 and T7 spinal canal circumferentially surrounding the spinal cord that caused marked encroachment of the thecal sac. Magnetic resonance images revealed cord compression and intramedullary signal change from T6 to T7 level. After we verified that the leaked PMMA could be easily detached from the dura mater in the cadaveric lumbar spine, surgical decompression and removal of epidural PMMA was performed. The leaked PMMA was carefully thinned down with a high-speed diamond burr. Eight pieces of PMMA were detached from the dura mater easily without causing a dural tear. No neurologic deterioration was observed in the postoperative period. The burning sensation resolved, but the muscle weakness remained unchanged. One and a half years postoperatively, the muscle weakness has improved to ⅘ on the manual muscle strength test, but he could not walk without an aid because of spasticity. Conclusion  This report demonstrates the catastrophic epidural extrusion of PMMA following PVP. Extravasated PMMA can be removed through a working space created by means of laminectomy and subtraction of the affected pedicle. Spine surgeons should recognize the possible neurologic complications of PVP and be prepared to treat them using suitable approaches. PMID:28825011

Relative contribution of different altered motor unit control to muscle weakness in stroke: a simulation study

NASA Astrophysics Data System (ADS)

Shin, Henry; Suresh, Nina L.; Zev Rymer, William; Hu, Xiaogang

2018-02-01

Objective. Chronic muscle weakness impacts the majority of individuals after a stroke. The origins of this hemiparesis is multifaceted, and an altered spinal control of the motor unit (MU) pool can lead to muscle weakness. However, the relative contribution of different MU recruitment and discharge organization is not well understood. In this study, we sought to examine these different effects by utilizing a MU simulation with variations set to mimic the changes of MU control in stroke. Approach. Using a well-established model of the MU pool, this study quantified the changes in force output caused by changes in MU recruitment range and recruitment order, as well as MU firing rate organization at the population level. We additionally expanded the original model to include a fatigue component, which variably decreased the output force with increasing length of contraction. Differences in the force output at both the peak and fatigued time points across different excitation levels were quantified and compared across different sets of MU parameters. Main results. Across the different simulation parameters, we found that the main driving factor of the reduced force output was due to the compressed range of MU recruitment. Recruitment compression caused a decrease in total force across all excitation levels. Additionally, a compression of the range of MU firing rates also demonstrated a decrease in the force output mainly at the higher excitation levels. Lastly, changes to the recruitment order of MUs appeared to minimally impact the force output. Significance. We found that altered control of MUs alone, as simulated in this study, can lead to a substantial reduction in muscle force generation in stroke survivors. These findings may provide valuable insight for both clinicians and researchers in prescribing and developing different types of therapies for the rehabilitation and restoration of lost strength after stroke.

The Influence of Muscle Weakness on the Association Between Obesity and Inpatient Recovery From Total Hip Arthroplasty.

PubMed

Oosting, Ellen; Hoogeboom, Thomas J; Dronkers, Jaap J; Visser, Marlieke; Akkermans, Reinier P; van Meeteren, Nico L U

2017-06-01

There is ongoing discussion about whether preoperative obesity is negatively associated with inpatient outcomes of total hip arthroplasty (THA). The aim was to investigate the interaction between obesity and muscle strength and the association with postoperative inpatient recovery after THA. Preoperative obesity (body mass index [BMI] >30 kg/m 2 ) and muscle weakness (hand grip strength <20 kg for woman and <30 kg for men) were measured about 6 weeks before THA. Patients with a BMI <18.5 kg/m 2 were excluded. Outcomes were delayed inpatient recovery of activities (>2 days to reach independence of walking) and prolonged length of hospital stay (LOS, >4 days and/or discharge to extended rehabilitation). Univariate and multivariable regression analyses with the independent variables muscle weakness and obesity, and the interaction between obesity and muscle weakness, were performed and corrected for possible confounders. Two hundred and ninety-seven patients were included, 54 (18%) of whom were obese and 21 (7%) who also had muscle weakness. Obesity was not significantly associated with prolonged LOS (odds ratio [OR] 1.36, 95% confidence interval [CI] 0.75-2.47) or prolonged recovery of activities (OR 1.77, 95% CI 0.98-3.22), but the combination of obesity and weakness was significantly associated with prolonged LOS (OR 3.59, 95% CI 1.09-11.89) and prolonged recovery of activities (OR 6.21, 95% CI 1.64-23.65). Obesity is associated with inpatient recovery after THA only in patients with muscle weakness. The results of this study suggest that we should measure muscle strength in addition to BMI (or body composition) to identify patients at risk of prolonged LOS. Copyright © 2017 Elsevier Inc. All rights reserved.

Peripheral facial weakness (Bell's palsy).

PubMed

Basić-Kes, Vanja; Dobrota, Vesna Dermanović; Cesarik, Marijan; Matovina, Lucija Zadro; Madzar, Zrinko; Zavoreo, Iris; Demarin, Vida

2013-06-01

Peripheral facial weakness is a facial nerve damage that results in muscle weakness on one side of the face. It may be idiopathic (Bell's palsy) or may have a detectable cause. Almost 80% of peripheral facial weakness cases are primary and the rest of them are secondary. The most frequent causes of secondary peripheral facial weakness are systemic viral infections, trauma, surgery, diabetes, local infections, tumor, immune disorders, drugs, degenerative diseases of the central nervous system, etc. The diagnosis relies upon the presence of typical signs and symptoms, blood chemistry tests, cerebrospinal fluid investigations, nerve conduction studies and neuroimaging methods (cerebral MRI, x-ray of the skull and mastoid). Treatment of secondary peripheral facial weakness is based on therapy for the underlying disorder, unlike the treatment of Bell's palsy that is controversial due to the lack of large, randomized, controlled, prospective studies. There are some indications that steroids or antiviral agents are beneficial but there are also studies that show no beneficial effect. Additional treatments include eye protection, physiotherapy, acupuncture, botulinum toxin, or surgery. Bell's palsy has a benign prognosis with complete recovery in about 80% of patients, 15% experience some mode of permanent nerve damage and severe consequences remain in 5% of patients.

Finger extension weakness and downbeat nystagmus motor neuron disease syndrome: A novel motor neuron disorder?

PubMed

Delva, Aline; Thakore, Nimish; Pioro, Erik P; Poesen, Koen; Saunders-Pullman, Rachel; Meijer, Inge A; Rucker, Janet C; Kissel, John T; Van Damme, Philip

2017-12-01

Disturbances of eye movements are infrequently encountered in motor neuron diseases (MNDs) or motor neuropathies, and there is no known syndrome that combines progressive muscle weakness with downbeat nystagmus. To describe the core clinical features of a syndrome of MND associated with downbeat nystagmus, clinical features were collected from 6 patients. All patients had slowly progressive muscle weakness and wasting in combination with downbeat nystagmus, which was clinically most obvious in downward and lateral gaze. Onset was in the second to fourth decade with finger extension weakness, progressing to other distal and sometimes more proximal muscles. Visual complaints were not always present. Electrodiagnostic testing showed signs of regional motor axonal loss in all patients. The etiology of this syndrome remains elusive. Because finger extension weakness and downbeat nystagmus are the discriminating clinical features of this MND, we propose the name FEWDON-MND syndrome. Muscle Nerve 56: 1164-1168, 2017. © 2017 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc.

Prevalence of adult Pompe disease in patients with proximal myopathic syndrome and undiagnosed muscle biopsy.

PubMed

Golsari, Amir; Nasimzadah, Arzoo; Thomalla, Götz; Keller, Sarah; Gerloff, Christian; Magnus, Tim

2018-03-01

We examined patients with limb-girdle muscle weakness and/or hyper-CKaemia and undiagnosed muscle biopsy for late onset Pompe disease (LOPD). Patients with an inconclusive limb-girdle muscle weakness who presented at our neuromuscular centre between 2005 and 2015 with undiagnosed muscle biopsies were examined by dry blood spot testing (DBS) including determination of the enzyme activity of acid alpha-glucosidase (GAA). In the case of depressed enzyme activity, additional gene testing of the GAA gene was carried out. Of the 340 evaluated muscle biopsies, 69 patients fulfilled the inclusion criteria and were examined with DBS. Among those patients, 76% showed a limb-girdle muscle weakness and 14% showed a hyper-CKaemia. A diagnosis of LOPD could be established in the case of two patients (2.9%) with reduced GAA enzyme activity and proof of mutations in the GAA gene. One of the two patients presents in the muscle biopsy suggestive features of Pompe disease including vacuoles with positive acid phosphatase reaction. In summary, our results show that a muscle biopsy can be helpful in identifying LOPD patients, but vacuolation with glycogen storage can also be absent. An inconspicuous muscle biopsy does not rule out Pompe disease. Consequently, all patients with limb-girdle muscle weakness should be examined by DBS before conducting a muscle biopsy. Copyright © 2017 Elsevier B.V. All rights reserved.

Elderly persons with ICU-acquired weakness: the potential role for β-hydroxy-β-methylbutyrate (HMB) supplementation?

PubMed

Rahman, Adam; Wilund, Kenneth; Fitschen, Peter J; Jeejeebhoy, Khursheed; Agarwala, Ravi; Drover, John W; Mourtzakis, Marina

2014-07-01

Intensive care unit (ICU)-acquired weakness is common and characterized by muscle loss, weakness, and paralysis. It is associated with poor short-term outcomes, including increased mortality, but the consequences of reduced long-term outcomes, including decreased physical function and quality of life, can be just as devastating. ICU-acquired weakness is particularly relevant to elderly patients who are increasingly consuming ICU resources and are at increased risk for ICU-acquired weakness and complications, including mortality. Elderly patients often enter critical illness with reduced muscle mass and function and are also at increased risk for accelerated disuse atrophy with acute illness. Increasingly, intensivists and researchers are focusing on strategies and therapies aimed at improving long-term neuromuscular function. β-Hydroxy-β-methylbutyrate (HMB), an ergogenic supplement, has shown efficacy in elderly patients and certain clinical populations in counteracting muscle loss. The present review discusses ICU-acquired weakness, as well as the unique physiology of muscle loss and skeletal muscle function in elderly patients, and then summarizes the evidence for HMB in elderly patients and in clinical populations. We subsequently postulate on the potential role and strategies in studying HMB in elderly ICU patients to improve muscle mass and function. © 2013 American Society for Parenteral and Enteral Nutrition.

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

Reductions in muscle quality and quantity in CIDP patients assessed by magnetic resonance imaging.

PubMed

Gilmore, Kevin J; Doherty, Timothy J; Kimpinski, Kurt; Rice, Charles L

2018-05-09

Weakness in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) may be caused by decreases in muscle quantity and quality, but these have not been explored. Twelve patients with CIDP (mean 61 years) and ten age- matched (mean 59 years) control subjects were assessed for ankle dorsiflexion strength, and two different MRI scans (T1 and T2) of leg musculature. Isometric strength was lower in CIDP patients by 36% compared with controls. Tibialis anterior muscle volumes of CIDP patients were smaller by ∼17% than controls, and non-contractile tissue volume was ∼58% greater in CIDP patients. When normalized to total muscle or corrected contractile volume, strength was ∼ 29% and ∼18% lower, respectively in CIDP patients DISCUSSION: These results provide insight into structural integrity of muscle contractile proteins and pathological changes to whole-muscle tissue composition that contribute to impaired muscle function in CIDP. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Ultrasound Imaging of Muscle Contraction of the Tibialis Anterior in Patients with Facioscapulohumeral Dystrophy.

PubMed

Gijsbertse, Kaj; Goselink, Rianne; Lassche, Saskia; Nillesen, Maartje; Sprengers, André; Verdonschot, Nico; van Alfen, Nens; de Korte, Chris

2017-11-01

A need exists for biomarkers to diagnose, quantify and longitudinally follow facioscapulohumeral muscular dystrophy (FSHD) and many other neuromuscular disorders. Furthermore, the pathophysiological mechanisms leading to muscle weakness in most neuromuscular disorders are not completely understood. Dynamic ultrasound imaging (B-mode image sequences) in combination with speckle tracking is an easy, applicable and patient-friendly imaging tool to visualize and quantify muscle deformation. This dynamic information provides insight in the pathophysiological mechanisms and may help to distinguish the various stages of diseased muscle in FSHD. In this proof-of-principle study, we applied a speckle tracking technique to 2-D ultrasound image sequences to quantify the deformation of the tibialis anterior muscle in patients with FSHD and in healthy controls. The resulting deformation patterns were compared with muscle ultrasound echo intensity analysis (a measure of fat infiltration and dystrophy) and clinical outcome measures. Of the four FSHD patients, two patients had severe peroneal weakness and two patients had mild peroneal weakness on clinical examination. We found a markedly varied muscle deformation pattern between these groups: patients with severe peroneal weakness showed a different motion pattern of the tibialis anterior, with overall less displacement of the central tendon region, while healthy patients showed a non-uniform displacement pattern, with the central aponeurosis showing the largest displacement. Hence, dynamic muscle ultrasound of the tibialis anterior muscle in patients with FSHD revealed a distinctively different tissue deformation pattern among persons with and without tibialis anterior weakness. These findings could clarify the understanding of the pathophysiology of muscle weakness in FSHD patients. In addition, the change in muscle deformation shows good correlation with clinical measures and quantitative muscle ultrasound measurements. In conclusion, dynamic ultrasound in combination with speckle tracking allows the study of the effects of muscle pathology in relation to strength, force transmission and movement generation. Although further research is required, this technique can develop into a biomarker to quantify muscle disease severity. Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Sex, stress and sleep apnoea: Decreased susceptibility to upper airway muscle dysfunction following intermittent hypoxia in females.

PubMed

O'Halloran, Ken D; Lewis, Philip; McDonald, Fiona

2017-11-01

Obstructive sleep apnoea syndrome (OSAS) is a devastating respiratory control disorder more common in men than women. The reasons for the sex difference in prevalence are multifactorial, but are partly attributable to protective effects of oestrogen. Indeed, OSAS prevalence increases in post-menopausal women. OSAS is characterized by repeated occlusions of the pharyngeal airway during sleep. Dysfunction of the upper airway muscles controlling airway calibre and collapsibility is implicated in the pathophysiology of OSAS, and sex differences in the neuro-mechanical control of upper airway patency are described. It is widely recognized that chronic intermittent hypoxia (CIH), a cardinal feature of OSAS due to recurrent apnoea, drives many of the morbid consequences characteristic of the disorder. In rodents, exposure to CIH-related redox stress causes upper airway muscle weakness and fatigue, associated with mitochondrial dysfunction. Of interest, in adults, there is female resilience to CIH-induced muscle dysfunction. Conversely, exposure to CIH in early life, results in upper airway muscle weakness equivalent between the two sexes at 3 and 6 weeks of age. Ovariectomy exacerbates the deleterious effects of exposure to CIH in adult female upper airway muscle, an effect partially restored by oestrogen replacement therapy. Intriguingly, female advantage intrinsic to upper airway muscle exists with evidence of substantially greater loss of performance in male muscle during acute exposure to severe hypoxic stress. Sex differences in upper airway muscle physiology may have relevance to human OSAS. The oestrogen-oestrogen receptor α axis represents a potential therapeutic target in OSAS, particularly in post-menopausal women. Copyright © 2016 Elsevier B.V. All rights reserved.

A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy.

PubMed

Vissing, John; Barresi, Rita; Witting, Nanna; Van Ghelue, Marijke; Gammelgaard, Lise; Bindoff, Laurence A; Straub, Volker; Lochmüller, Hanns; Hudson, Judith; Wahl, Christoph M; Arnardottir, Snjolaug; Dahlbom, Kathe; Jonsrud, Christoffer; Duno, Morten

2016-08-01

Limb girdle muscular dystrophy type 2A is the most common limb girdle muscular dystrophy form worldwide. Although strict recessive inheritance is assumed, patients carrying a single mutation in the calpain 3 gene (CAPN3) are reported. Such findings are commonly attributed to incomplete mutation screening. In this investigation, we report 37 individuals (age range: 21-85 years, 21 females and 16 males) from 10 families in whom only one mutation in CAPN3 could be identified; a 21-bp, in-frame deletion (c.643_663del21). This mutation co-segregated with evidence of muscle disease and autosomal dominant transmission in several generations. Evidence of muscle disease was indicated by muscle pain, muscle weakness and wasting, significant fat replacement of muscles on imaging, myopathic changes on muscle biopsy and loss of calpain 3 protein on western blotting. Thirty-one of 34 patients had elevated creatine kinase or myoglobin. Muscle weakness was generally milder than observed in limb girdle muscular dystrophy type 2A, but affected the same muscle groups (proximal leg, lumbar paraspinal and medial gastrocnemius muscles). In some cases, the weakness was severely disabling. The 21-bp deletion did not affect mRNA maturation. Calpain 3 expression in muscle, assessed by western blot, was below 15% of normal levels in the nine mutation carriers in whom this could be tested. Haplotype analysis in four families from three different countries suggests that the 21-bp deletion is a founder mutation. This study provides strong evidence that heterozygosity for the c.643_663del21 deletion in CAPN3 results in a dominantly inherited muscle disease. The normal expression of mutated mRNA and the severe loss of calpain 3 on western blotting, suggest a dominant negative effect with a loss-of-function mechanism affecting the calpain 3 homodimer. This renders patients deficient in calpain 3 as in limb girdle muscular dystrophy type 2A, albeit in a milder form in most cases. Based on findings in 10 families, our study indicates that a dominantly inherited pattern of calpainopathy exists, and should be considered in the diagnostic work-up and genetic counselling of patients with calpainopathy and single-allele aberrations in CAPN3. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Muscle stem cell dysfunction impairs muscle regeneration in a mouse model of Down syndrome.

PubMed

Pawlikowski, Bradley; Betta, Nicole Dalla; Elston, Tiffany; Williams, Darian A; Olwin, Bradley B

2018-03-09

Down syndrome, caused by trisomy 21, is characterized by a variety of medical conditions including intellectual impairments, cardiovascular defects, blood cell disorders and pre-mature aging phenotypes. Several somatic stem cell populations are dysfunctional in Down syndrome and their deficiencies may contribute to multiple Down syndrome phenotypes. Down syndrome is associated with muscle weakness but skeletal muscle stem cells or satellite cells in Down syndrome have not been investigated. We find that a failure in satellite cell expansion impairs muscle regeneration in the Ts65Dn mouse model of Down syndrome. Ts65Dn satellite cells accumulate DNA damage and over express Usp16, a histone de-ubiquitinating enzyme that regulates the DNA damage response. Impairment of satellite cell function, which further declines as Ts65Dn mice age, underscores stem cell deficiencies as an important contributor to Down syndrome pathologies.

Compensatory strategies during manual wheelchair propulsion in response to weakness in individual muscle groups: A simulation study.

PubMed

Slowik, Jonathan S; McNitt-Gray, Jill L; Requejo, Philip S; Mulroy, Sara J; Neptune, Richard R

2016-03-01

The considerable physical demand placed on the upper extremity during manual wheelchair propulsion is distributed among individual muscles. The strategy used to distribute the workload is likely influenced by the relative force-generating capacities of individual muscles, and some strategies may be associated with a higher injury risk than others. The objective of this study was to use forward dynamics simulations of manual wheelchair propulsion to identify compensatory strategies that can be used to overcome weakness in individual muscle groups and identify specific strategies that may increase injury risk. Identifying these strategies can provide rationale for the design of targeted rehabilitation programs aimed at preventing the development of pain and injury in manual wheelchair users. Muscle-actuated forward dynamics simulations of manual wheelchair propulsion were analyzed to identify compensatory strategies in response to individual muscle group weakness using individual muscle mechanical power and stress as measures of upper extremity demand. The simulation analyses found the upper extremity to be robust to weakness in any single muscle group as the remaining groups were able to compensate and restore normal propulsion mechanics. The rotator cuff muscles experienced relatively high muscle stress levels and exhibited compensatory relationships with the deltoid muscles. These results underline the importance of strengthening the rotator cuff muscles and supporting muscles whose contributions do not increase the potential for impingement (i.e., the thoracohumeral depressors) and minimize the risk of upper extremity injury in manual wheelchair users. Copyright © 2016 Elsevier Ltd. All rights reserved.

Compensatory Strategies during Manual Wheelchair Propulsion in Response to Weakness in Individual Muscle Groups: A Simulation Study

PubMed Central

Slowik, Jonathan S.; McNitt-Gray, Jill L.; Requejo, Philip S.; Mulroy, Sara J.; Neptune, Richard R.

2016-01-01

Background The considerable physical demand placed on the upper extremity during manual wheelchair propulsion is distributed among the individual muscles. The strategy used to distribute the workload is likely influenced by the relative force-generating capacities of individual muscles, and some strategies may be associated with a higher injury risk than others. The objective of this study was to use forward dynamics simulations of manual wheelchair propulsion to identify compensatory strategies that can be used to overcome weakness in individual muscle groups and identify specific strategies that may increase injury risk. Identifying these strategies can provide rationale for the design of targeted rehabilitation programs aimed at preventing the development of pain and injury in manual wheelchair users. Methods Muscle-actuated forward dynamics simulations of manual wheelchair propulsion were analyzed to identify compensatory strategies in response to individual muscle group weakness, using individual muscle mechanical power and stress as measures of upper extremity demand. Findings The simulation analyses found the upper extremity to be robust to weakness in any single muscle group as the remaining groups were able to compensate and restore normal propulsion mechanics. The rotator cuff muscles experienced relatively high muscle stress levels and exhibited compensatory relationships with the deltoid muscles. Interpretation These results underline the importance of strengthening the rotator cuff muscles and supporting muscles whose contributions do not increase the potential for impingement (i.e., the thoracohumeral depressors) and minimize the risk of upper extremity injury in manual wheelchair users. PMID:26945719

Investigation of the activation of the temporalis and masseter muscles in voluntary and spontaneous smile production.

PubMed

Steele, Jessica E; Woodcock, Ian R; Murphy, Adrian D; Ryan, Monique M; Penington, Tony J; Coombs, Christopher J

2018-07-01

Masticatory muscles or their nerve supply are options for facial reanimation surgery, but their ability to create spontaneous smile has been questioned. This study assessed the percentage of healthy adults who activate the temporalis and masseter muscles during voluntary and spontaneous smile. Healthy volunteer adults underwent electromyography (EMG) studies of the temporalis and masseter muscles during voluntary and spontaneous smile. Responses were repeated three times and recorded as negative, weakly positive, or strongly positive according to the activity observed. The best response was used for analysis. Thirty healthy adults (median age: 34 years, range: 25-69 years) participated. Overall, 92% of the masseter muscles were activated during voluntary smile (22% strong, 70% weak). Seventy-seven percent of the masseter muscles were activated in spontaneous smile (12% strong, 65% weak). The temporalis muscle was activated in 62% of responses in voluntary smile (15% strong, 47% weak) and in 45% of responses in spontaneous smile (13% strong, 32% weak). No significant difference was found for males vs females or closed vs open mouth smiles. There was no significant difference in responses between voluntary and spontaneous smiles for the temporalis and masseter muscles, and their use in voluntary smile did not predict activity in spontaneous smile. Our study has shown that masseter and temporalis are active in a high proportion of healthy adults during voluntary and spontaneous smiles. Further work is required to determine the relationship between preoperative donor muscle activation and postoperative spontaneous smile, and whether masticatory muscle activity can be upregulated with appropriate training. Copyright © 2018. Published by Elsevier Ltd.

Facioscapulohumeral muscular dystrophy

MedlinePlus

... due to weakness of the cheek muscles Decreased facial expression due to weakness of facial muscles Depressed or angry facial expression Difficulty pronouncing words Difficulty reaching above the shoulder ...

History-dependence of muscle slack length following contraction and stretch in the human vastus lateralis.

PubMed

Stubbs, Peter W; Walsh, Lee D; D'Souza, Arkiev; Héroux, Martin E; Bolsterlee, Bart; Gandevia, Simon C; Herbert, Robert D

2018-06-01

In reduced muscle preparations, the slack length and passive stiffness of muscle fibres have been shown to be influenced by previous muscle contraction or stretch. In human muscles, such behaviours have been inferred from measures of muscle force, joint stiffness and reflex magnitudes and latencies. Using ultrasound imaging, we directly observed that isometric contraction of the vastus lateralis muscle at short lengths reduces the slack lengths of the muscle-tendon unit and muscle fascicles. The effect is apparent 60 s after the contraction. These observations imply that muscle contraction at short lengths causes the formation of bonds which reduce the effective length of structures that generate passive tension in muscles. In reduced muscle preparations, stretch and muscle contraction change the properties of relaxed muscle fibres. In humans, effects of stretch and contraction on properties of relaxed muscles have been inferred from measurements of time taken to develop force, joint stiffness and reflex latencies. The current study used ultrasound imaging to directly observe the effects of stretch and contraction on muscle-tendon slack length and fascicle slack length of the human vastus lateralis muscle in vivo. The muscle was conditioned by (a) strong isometric contractions at long muscle-tendon lengths, (b) strong isometric contractions at short muscle-tendon lengths, (c) weak isometric contractions at long muscle-tendon lengths and (d) slow stretches. One minute after conditioning, ultrasound images were acquired from the relaxed muscle as it was slowly lengthened through its physiological range. The ultrasound image sequences were used to identify muscle-tendon slack angles and fascicle slack lengths. Contraction at short muscle-tendon lengths caused a mean 13.5 degree (95% CI 11.8-15.0 degree) shift in the muscle-tendon slack angle towards shorter muscle-tendon lengths, and a mean 5 mm (95% CI 2-8 mm) reduction in fascicle slack length, compared to the other conditions. A supplementary experiment showed the effect could be demonstrated if the muscle was conditioned by contraction at short lengths but not if the relaxed muscle was held at short lengths, confirming the role of muscle contraction. These observations imply that muscle contraction at short lengths causes the formation of bonds which reduce the effective length of structures that generate passive tension in muscles. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Na+,K+-pump stimulation improves contractility in isolated muscles of mice with hyperkalemic periodic paralysis

PubMed Central

Nielsen, Ole Bækgaard; Clausen, Johannes D.; Pedersen, Thomas Holm; Hayward, Lawrence J.

2011-01-01

In patients with hyperkalemic periodic paralysis (HyperKPP), attacks of muscle weakness or paralysis are triggered by K+ ingestion or rest after exercise. Force can be restored by muscle work or treatment with β2-adrenoceptor agonists. A missense substitution corresponding to a mutation in the skeletal muscle voltage-gated Na+ channel (Nav1.4, Met1592Val) causing human HyperKPP was targeted into the mouse SCN4A gene (mutants). In soleus muscles prepared from these mutant mice, twitch, tetanic force, and endurance were markedly reduced compared with soleus from wild type (WT), reflecting impaired excitability. In mutant soleus, contractility was considerably more sensitive than WT soleus to inhibition by elevated [K+]o. In resting mutant soleus, tetrodotoxin (TTX)-suppressible 22Na uptake and [Na+]i were increased by 470 and 58%, respectively, and membrane potential was depolarized (by 16 mV, P < 0.0001) and repolarized by TTX. Na+,K+ pump–mediated 86Rb uptake was 83% larger than in WT. Salbutamol stimulated 86Rb uptake and reduced [Na+]i both in mutant and WT soleus. Stimulating Na+,K+ pumps with salbutamol restored force in mutant soleus and extensor digitorum longus (EDL). Increasing [Na+]i with monensin also restored force in soleus. In soleus, EDL, and tibialis anterior muscles of mutant mice, the content of Na+,K+ pumps was 28, 62, and 33% higher than in WT, respectively, possibly reflecting the stimulating effect of elevated [Na+]i on the synthesis of Na+,K+ pumps. The results confirm that the functional disorders of skeletal muscles in HyperKPP are secondary to increased Na+ influx and show that contractility can be restored by acute stimulation of the Na+,K+ pumps. Calcitonin gene-related peptide (CGRP) restored force in mutant soleus but caused no detectable increase in 86Rb uptake. Repeated excitation and capsaicin also restored contractility, possibly because of the release of endogenous CGRP from nerve endings in the isolated muscles. These observations may explain how mild exercise helps locally to prevent severe weakness during an attack of HyperKPP. PMID:21708955

The effect of malaria and anti-malarial drugs on skeletal and cardiac muscles.

PubMed

Marrelli, Mauro Toledo; Brotto, Marco

2016-11-02

Malaria remains one of the most important infectious diseases in the world, being a significant public health problem associated with poverty and it is one of the main obstacles to the economy of an endemic country. Among the several complications, the effects of malaria seem to target the skeletal muscle system, leading to symptoms, such as muscle aches, muscle contractures, muscle fatigue, muscle pain, and muscle weakness. Malaria cause also parasitic coronary artery occlusion. This article reviews the current knowledge regarding the effect of malaria disease and the anti-malarial drugs on skeletal and cardiac muscles. Research articles and case report publications that addressed aspects that are important for understanding the involvement of malaria parasites and anti-malarial therapies affecting skeletal and cardiac muscles were analysed and their findings summarized. Sequestration of red blood cells, increased levels of serum creatine kinase and reduced muscle content of essential contractile proteins are some of the potential biomarkers of the damage levels of skeletal and cardiac muscles. These biomarkers might be useful for prevention of complications and determining the effectiveness of interventions designed to protect cardiac and skeletal muscles from malaria-induced damage.

Evolving paradigms in clinical pharmacology and therapeutics for the treatment of Duchenne muscular dystrophy.

PubMed

Huard, J; Mu, X; Lu, A

2016-08-01

Progressive muscle weakness and degeneration due to the lack of dystrophin eventually leads to the loss of independent ambulation by the middle of the patient's second decade, and a fatal outcome due to cardiac or respiratory failure by the third decade. More specifically, loss of sarcolemmal dystrophin and the dystrophin-associated glycoprotein (DAG) complex promotes muscle fiber damage during muscle contraction. This process results in an efflux of creatine kinase (CK), an influx of calcium ions, and the recruitment of T cells, macrophages, and mast cells to the damaged muscle, causing progressive myofiber necrosis. For the last 20 years, the major goal in the development of therapeutic approaches to alleviate muscle weakness in DMD has been centered on the restoration of dystrophin or proteins that are analogous to dystrophin, such as utrophin, through a variety of modalities including cell therapy, gene therapy, gene correction, and the highly promising techniques utilizing CRISPR/Cas9 technology. Despite the development of new therapeutic options, there still exist numerous challenges that we must face with regard to these new strategies and, consequently, we still do not have any feasible options available to ultimately slow the progression of this devastating disease. The purpose of this article is to highlight the current knowledge and advancements in the evolving paradigms in clinical pharmacology and therapeutics for this devastating musculoskeletal disease. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Rickets: case series and diagnostic review of hypovitaminosis D in swine.

PubMed

Madson, Darin M; Ensley, Steve M; Gauger, Phil C; Schwartz, Kent J; Stevenson, Greg W; Cooper, Vickie L; Janke, Bruce H; Burrough, Eric R; Goff, Jesse P; Horst, Ronald L

2012-11-01

Rickets can be attributed to nutritional, genetic, hormonal, or toxic disturbances and is classified as a metabolic bone disease. Rickets is most often associated with inappropriate dietary levels of calcium, phosphorus, and/or vitamin D. During a 27-month period (January 2010 through March 2012), the Iowa State University Veterinary Diagnostic Laboratory investigated causes of sudden, unexpected death and lameness in growing pigs throughout the Midwestern United States. Clinical observations from 17 growing pig cases included weakness, lameness, reluctance to move, muscle fasciculations and/or tremors, tetany, and death. Ribs were weak, soft, and bent prior to breaking; rachitic lesions were apparent at costochondral junctions in multiple cases. Acute and/or chronic bone fractures were also noted in multiple bones. Failure of endochondral ossification, expanded physes, infractions, thin trabeculae, and increased osteoclasts were noted microscopically. Decreased bone ash and serum 25(OH)D(3), combined with clinical and microscopic evaluation, confirmed a diagnosis of vitamin D-dependent rickets in all cases. In 3 cases, disease was linked to a specific nutrient supplier that ultimately resulted in a voluntary feed recall; however, most cases in the current investigation were not associated with a particular feed company. The present report describes vitamin D-associated rickets and its importance as a potential cause of weakness, lameness, muscle fasciculations, recumbency or sudden unexpected death in swine, and describes appropriate samples and tests for disease diagnosis.

Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral muscular dystrophy 2.

PubMed

Mitsuhashi, Satomi; Boyden, Steven E; Estrella, Elicia A; Jones, Takako I; Rahimov, Fedik; Yu, Timothy W; Darras, Basil T; Amato, Anthony A; Folkerth, Rebecca D; Jones, Peter L; Kunkel, Louis M; Kang, Peter B

2013-12-01

FSHD2 is a rare form of facioscapulohumeral muscular dystrophy (FSHD) characterized by the absence of a contraction in the D4Z4 macrosatellite repeat region on chromosome 4q35 that is the hallmark of FSHD1. However, hypomethylation of this region is common to both subtypes. Recently, mutations in SMCHD1 combined with a permissive 4q35 allele were reported to cause FSHD2. We identified a novel p.Lys275del SMCHD1 mutation in a family affected with FSHD2 using whole-exome sequencing and linkage analysis. This mutation alters a highly conserved amino acid in the ATPase domain of SMCHD1. Subject III-11 is a male who developed asymmetrical muscle weakness characteristic of FSHD at 13 years. Physical examination revealed marked bilateral atrophy at biceps brachii, bilateral scapular winging, some asymmetrical weakness at tibialis anterior and peroneal muscles, and mild lower facial weakness. Biopsy of biceps brachii in subject II-5, the father of III-11, demonstrated lobulated fibers and dystrophic changes. Endomysial and perivascular inflammation was found, which has been reported in FSHD1 but not FSHD2. Given the previous report of SMCHD1 mutations in FSHD2 and the clinical presentations consistent with the FSHD phenotype, we conclude that the SMCHD1 mutation is the likely cause of the disease in this family. Copyright © 2013 Elsevier B.V. All rights reserved.

Guidelines for pre-clinical assessment of the acetylcholine receptor-specific passive transfer myasthenia gravis model - recommendations for methods and experimental designs

PubMed Central

Kusner, Linda L.; Losen, Mario; Vincent, Angela; Lindstrom, Jon; Tzartos, Socrates; Lazaridis, Konstantinos; Martinez-Martinez, Pilar

2015-01-01

Antibodies against the muscle acetylcholine receptor (AChR) are the most common cause of myasthenia gravis (MG). Passive transfer of AChR antibodies from MG patients into animals reproduces key features of human disease, including antigenic modulation of the AChR, complement-mediated damage of the neuromuscular junction, and muscle weakness. Similarly, AChR antibodies generated by active immunization in experimental autoimmune MG models can subsequently be passively transferred to other animals and induce weakness. The passive transfer model is useful to test therapeutic strategies aimed at the effector mechanism of the autoantibodies. Here we summarize published and unpublished experience using the AChR passive transfer MG model in mice, rats and rhesus monkeys, and give recommendations for the design of preclinical studies in order to facilitate translation of positive and negative results to improve MG therapies. PMID:25743217

Investigation of Poor Academic Achievement in Children with Duchenne Muscular Dystrophy

ERIC Educational Resources Information Center

Hinton, V. J.; De Vivo, D. C.; Fee, R.; Goldstein, E.; Stern, Y.

2004-01-01

Duchenne Muscular Dystrophy (DMD) is a neurogenetic developmental disorder that presents with progressive muscular weakness. It is caused by a mutation in a gene that results in the absence of specific products that normally localize to muscle cells and the central nervous system (CNS). The majority of affected individuals have IQs within the…

Weaning failure and respiratory muscle function: What has been done and what can be improved?

PubMed

Magalhães, Paulo A F; Camillo, Carlos A; Langer, Daniel; Andrade, Lívia B; Duarte, Maria do Carmo M B; Gosselink, Rik

2018-01-01

Respiratory muscle dysfunction, being a common cause of weaning failure, is strongly associated with prolonged mechanical ventilation (MV) and prolonged stay in intensive care units. Inspiratory muscle training (IMT) has been described as an important contributor to the treatment of respiratory muscle dysfunction in critically ill patients. Its effectiveness is however yet controversial. To discuss evidence for assessment of readiness and the effectiveness of interventions for liberation from MV, with special attention to the role of IMT. PubMed, LILACS, PEDro and Web of Science were searched for papers of assessment and treatment of patients who failed liberation from MV after at least one attempt published in English or Portuguese until June 2016. Weaning predictors are related to weaning success (86%-100% for sensitivity and 7%-69% for specificity) and work of breathing (73%-100% for sensitivity and 56%-100% for specificity). Spontaneous breathing trials (SBT), noninvasive MV and early mobilization have been reported to improve weaning outcomes. Two modalities of IMT were identified in five selected studies: 1) adjustment of ventilator trigger sensitivity 2) inspiratory threshold loading. Both IMT training modalities promoted significant increases in respiratory muscle strength. IMT with threshold loading showed positive effect on endurance compared to control. Methods to indentify respiratory muscle weakness in critically ill patients are feasible and described as indexes that show good accuracy. Individualized and supervised rehabilitation programs including IMT, SBT, noninvasive MV and early mobilization should be encouraged in patients with inspiratory muscle weakness. Copyright © 2017 Elsevier Ltd. All rights reserved.

Relationship between muscle mass and physical performance: is it the same in older adults with weak muscle strength?

PubMed

Kim, Kyoung-Eun; Jang, Soong-Nang; Lim, Soo; Park, Young Joo; Paik, Nam-Jong; Kim, Ki Woong; Jang, Hak Chul; Lim, Jae-Young

2012-11-01

the relationship between muscle mass and physical performance has not been consistent among studies. to clarify the relationship between muscle mass and physical performance in older adults with weak muscle strength. cross-sectional analysis using the baseline data of 542 older men and women from the Korean Longitudinal Study on Health and Aging. dual X-ray absorptiometry, isokinetic dynamometer and the Short Physical Performance Battery (SPPB) were performed. Two muscle mass parameters, appendicular skeletal mass divided by weight (ASM/Wt) and by height squared (ASM/Ht(2)), were measured. We divided the participants into a lower-quartile (L25) group and an upper-three-quartiles (H75) group based on the knee-extensor peak torque. Correlation analysis and logistic regression models were used to assess the association between muscle mass and low physical performance, defined as SPPB scores <9, after controlling for confounders. in the L25 group, no correlation between mass and SPPB was detected, whereas the correlation between peak torque and SPPB was significant and higher than that in the H75 group. Results from the logistic models also showed no association between muscle mass and SPPB in the L25 group, whereas muscle mass was associated with SPPB in the H75 group. muscle mass was not associated with physical performance in weak older adults. Measures of muscle strength may be of greater clinical importance in weak older adults than is muscle mass per se.

Myasthenia and related disorders of the neuromuscular junction.

PubMed

Spillane, Jennifer; Beeson, David J; Kullmann, Dimitri M

2010-08-01

Our understanding of transmission at the neuromuscular junction has increased greatly in recent years. We now recognise a wide variety of autoimmune and genetic diseases that affect this specialised synapse, causing muscle weakness and fatigue. These disorders greatly affect quality of life and rarely can be fatal. Myasthenia gravis is the most common disorder and is most commonly caused by autoantibodies targeting postsynaptic acetylcholine receptors. Antibodies to muscle-specific kinase (MuSK) are detected in a variable proportion of the remainder. Treatment is symptomatic and immunomodulatory. Lambert-Eaton myasthenic syndrome is caused by antibodies to presynaptic calcium channels, and approximately 50% of cases are paraneoplastic, most often related to small cell carcinoma of the lung. Botulism is an acquired disorder caused by neurotoxins produced by Clostridium botulinum, impairing acetylcholine release into the synaptic cleft. In addition, several rare congenital myasthenic syndromes have been identified, caused by inherited defects in presynaptic, synaptic basal lamina and postsynaptic proteins necessary for neuromuscular transmission. This review focuses on recent advances in the diagnosis and treatment of these disorders.

Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres

PubMed Central

Yuen, Michaela; Cooper, Sandra T.; Marston, Steve B.; Nowak, Kristen J.; McNamara, Elyshia; Mokbel, Nancy; Ilkovski, Biljana; Ravenscroft, Gianina; Rendu, John; de Winter, Josine M.; Klinge, Lars; Beggs, Alan H.; North, Kathryn N.; Ottenheijm, Coen A.C.; Clarke, Nigel F.

2015-01-01

Dominant mutations in TPM3, encoding α-tropomyosinslow, cause a congenital myopathy characterized by generalized muscle weakness. Here, we used a multidisciplinary approach to investigate the mechanism of muscle dysfunction in 12 TPM3-myopathy patients. We confirm that slow myofibre hypotrophy is a diagnostic hallmark of TPM3-myopathy, and is commonly accompanied by skewing of fibre-type ratios (either slow or fast fibre predominance). Patient muscle contained normal ratios of the three tropomyosin isoforms and normal fibre-type expression of myosins and troponins. Using 2D-PAGE, we demonstrate that mutant α-tropomyosinslow was expressed, suggesting muscle dysfunction is due to a dominant-negative effect of mutant protein on muscle contraction. Molecular modelling suggested mutant α-tropomyosinslow likely impacts actin–tropomyosin interactions and, indeed, co-sedimentation assays showed reduced binding of mutant α-tropomyosinslow (R168C) to filamentous actin. Single fibre contractility studies of patient myofibres revealed marked slow myofibre specific abnormalities. At saturating [Ca2+] (pCa 4.5), patient slow fibres produced only 63% of the contractile force produced in control slow fibres and had reduced acto-myosin cross-bridge cycling kinetics. Importantly, due to reduced Ca2+-sensitivity, at sub-saturating [Ca2+] (pCa 6, levels typically released during in vivo contraction) patient slow fibres produced only 26% of the force generated by control slow fibres. Thus, weakness in TPM3-myopathy patients can be directly attributed to reduced slow fibre force at physiological [Ca2+], and impaired acto-myosin cross-bridge cycling kinetics. Fast myofibres are spared; however, they appear to be unable to compensate for slow fibre dysfunction. Abnormal Ca2+-sensitivity in TPM3-myopathy patients suggests Ca2+-sensitizing drugs may represent a useful treatment for this condition. PMID:26307083

Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres.

PubMed

Yuen, Michaela; Cooper, Sandra T; Marston, Steve B; Nowak, Kristen J; McNamara, Elyshia; Mokbel, Nancy; Ilkovski, Biljana; Ravenscroft, Gianina; Rendu, John; de Winter, Josine M; Klinge, Lars; Beggs, Alan H; North, Kathryn N; Ottenheijm, Coen A C; Clarke, Nigel F

2015-11-15

Dominant mutations in TPM3, encoding α-tropomyosinslow, cause a congenital myopathy characterized by generalized muscle weakness. Here, we used a multidisciplinary approach to investigate the mechanism of muscle dysfunction in 12 TPM3-myopathy patients. We confirm that slow myofibre hypotrophy is a diagnostic hallmark of TPM3-myopathy, and is commonly accompanied by skewing of fibre-type ratios (either slow or fast fibre predominance). Patient muscle contained normal ratios of the three tropomyosin isoforms and normal fibre-type expression of myosins and troponins. Using 2D-PAGE, we demonstrate that mutant α-tropomyosinslow was expressed, suggesting muscle dysfunction is due to a dominant-negative effect of mutant protein on muscle contraction. Molecular modelling suggested mutant α-tropomyosinslow likely impacts actin-tropomyosin interactions and, indeed, co-sedimentation assays showed reduced binding of mutant α-tropomyosinslow (R168C) to filamentous actin. Single fibre contractility studies of patient myofibres revealed marked slow myofibre specific abnormalities. At saturating [Ca(2+)] (pCa 4.5), patient slow fibres produced only 63% of the contractile force produced in control slow fibres and had reduced acto-myosin cross-bridge cycling kinetics. Importantly, due to reduced Ca(2+)-sensitivity, at sub-saturating [Ca(2+)] (pCa 6, levels typically released during in vivo contraction) patient slow fibres produced only 26% of the force generated by control slow fibres. Thus, weakness in TPM3-myopathy patients can be directly attributed to reduced slow fibre force at physiological [Ca(2+)], and impaired acto-myosin cross-bridge cycling kinetics. Fast myofibres are spared; however, they appear to be unable to compensate for slow fibre dysfunction. Abnormal Ca(2+)-sensitivity in TPM3-myopathy patients suggests Ca(2+)-sensitizing drugs may represent a useful treatment for this condition. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Mitochondrial myopathies.

PubMed

DiMauro, Salvatore

2006-11-01

Our understanding of mitochondrial diseases (defined restrictively as defects of the mitochondrial respiratory chain) is expanding rapidly. In this review, I will give the latest information on disorders affecting predominantly or exclusively skeletal muscle. The most recently described mitochondrial myopathies are due to defects in nuclear DNA, including coenzyme Q10 deficiency and mutations in genes controlling mitochondrial DNA abundance and structure, such as POLG, TK2, and MPV17. Barth syndrome, an X-linked recessive mitochondrial myopathy/cardiopathy, is associated with decreased amount and altered structure of cardiolipin, the main phospholipid of the inner mitochondrial membrane, but a secondary impairment of respiratory chain function is plausible. The role of mutations in protein-coding genes of mitochondrial DNA in causing isolated myopathies has been confirmed. Mutations in tRNA genes of mitochondrial DNA can also cause predominantly myopathic syndromes and--contrary to conventional wisdom--these mutations can be homoplasmic. Defects in the mitochondrial respiratory chain impair energy production and almost invariably involve skeletal muscle, causing exercise intolerance, cramps, recurrent myoglobinuria, or fixed weakness, which often affects extraocular muscles and results in droopy eyelids (ptosis) and progressive external ophthalmoplegia.

Nonpharmacologic Pain Management and Muscle Strengthening following Total Knee Arthroplasty.

PubMed

Chughtai, Morad; Elmallah, Randa D K; Mistry, Jaydev B; Bhave, Anil; Cherian, Jeffrey Jai; McGinn, Tanner L; Harwin, Steven F; Mont, Michael A

2016-04-01

Despite technological advances in total knee arthroplasty (TKA), management of postoperative muscle weakness and pain continue to pose challenges for both patients and health care providers. Nonpharmacologic therapies, such as neuromodulation in the form of neuromuscular electrical stimulation (NMES) and transcutaneous electrical nerve stimulation (TENS), and other modalities, such as cryotherapy and prehabilitation, have been highlighted as possible adjuncts to standard-of-care pharmacologic management to treat postoperative pain and muscle weakness. The aim of this review was to discuss existing evidence for neuromodulation in the treatment of pain and muscular weakness following TKA, and to shed light on other noninvasive and potential future modalities. Our review of the literature demonstrated that NMES, prehabilitation, and some specialized exercises are beneficial for postoperative muscle weakness, and TENS, cooling therapies, and compression may help to alleviate post-TKA pain. However, there are no clear guidelines for the use of these modalities. Further studies should be aimed at developing guidelines or delineating indications for neuromodulation and other nonpharmacologic therapies in the management of post-TKA pain and muscle weakness. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Inhibition of the renin-angiotensin system improves physiological outcomes in mice with mild or severe cancer cachexia.

PubMed

Murphy, Kate T; Chee, Annabel; Trieu, Jennifer; Naim, Timur; Lynch, Gordon S

2013-09-01

Cancer cachexia describes the progressive skeletal muscle wasting and weakness associated with many cancers. Cachexia reduces mobility and quality of life and accounts for 20-30% of all cancer-related deaths. Activation of the renin-angiotensin system causes skeletal muscle wasting and weakness. We tested the hypothesis that treatment with the angiotensin converting enzyme (ACE) inhibitor, perindopril, would enhance whole body and skeletal muscle function in cachectic mice bearing Colon-26 (C-26) tumors. CD2F1 mice received a subcutaneous injection of phosphate buffered saline or C-26 tumor cells inducing either a mild or severe cachexia. The following day, one cohort of C-26 mice began receiving perindopril in their drinking water (4 mg kg(-1) day(-1) ) for 21 days. In mild and severe cachexia, perindopril increased measures of whole body function (grip strength and rotarod) and reduced fatigue in isolated contracting diaphragm muscle strips (p < 0.05). In severely cachectic mice, perindopril reduced tumor growth, improved locomotor activity and reduced fatigue of tibialis anterior muscles in situ (p < 0.05), which was associated with increased oxidative enzyme capacity (succinate deyhydrogenase, p < 0.05). Perindopril attenuated the increase in MuRF-1 and IL-6 mRNA expression and enhanced Akt phosphorylation in severely cachectic mice but neither body nor muscle mass was increased. These findings support the therapeutic potential of ACE inhibition for enhancing whole body function and reducing fatigue of respiratory muscles in early and late stage cancer cachexia and should be confirmed in future clinical trials. Since ACE inhibition alone did not enhance body or muscle mass, co-treatment with an anabolic agent may be required to address these aspects of cancer cachexia. Copyright © 2013 UICC.

Peri-partum and pelvic floor dysfunction.

PubMed

McClurg, Doreen

2014-01-01

Pelvic floor muscles (PFM) are the layer of muscles that support the pelvic organs and span the bottom of the pelvis. Weakened PFM mean the internal organs are not fully supported and can lead to difficulties controlling the release of urine, faeces or flatus. Pregnancy and vaginal birth are a recognised cause of PFM weakness; however it has been shown that PFM exercises, if carried out correctly and routinely, can reduce the severity of symptoms. Midwives need to be pro-active in teaching PFM exercises and identifying women who may need to be referred on for more specialist treatment.

Familial Periodic Paralyses

MedlinePlus

... by episodes in which the affected muscles become slack, weak, and unable to contract. Between attacks, the ... by episodes in which the affected muscles become slack, weak, and unable to contract. Between attacks, the ...

Influence of weak hip abductor muscles on joint contact forces during normal walking: probabilistic modeling analysis.

PubMed

Valente, Giordano; Taddei, Fulvia; Jonkers, Ilse

2013-09-03

The weakness of hip abductor muscles is related to lower-limb joint osteoarthritis, and joint overloading may increase the risk for disease progression. The relationship between muscle strength, structural joint deterioration and joint loading makes the latter an important parameter in the study of onset and follow-up of the disease. Since the relationship between hip abductor weakness and joint loading still remains an open question, the purpose of this study was to adopt a probabilistic modeling approach to give insights into how the weakness of hip abductor muscles, in the extent to which normal gait could be unaltered, affects ipsilateral joint contact forces. A generic musculoskeletal model was scaled to each healthy subject included in the study, and the maximum force-generating capacity of each hip abductor muscle in the model was perturbed to evaluate how all physiologically possible configurations of hip abductor weakness affected the joint contact forces during walking. In general, the muscular system was able to compensate for abductor weakness. The reduced force-generating capacity of the abductor muscles affected joint contact forces to a mild extent, with 50th percentile mean differences up to 0.5 BW (maximum 1.7 BW). There were greater increases in the peak knee joint loads than in loads at the hip or ankle. Gluteus medius, particularly the anterior compartment, was the abductor muscle with the most influence on hip and knee loads. Further studies should assess if these increases in joint loading may affect initiation and progression of osteoarthritis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Exacerbation of pathology by oxidative stress in respiratory and locomotor muscles with Duchenne muscular dystrophy.

PubMed

Lawler, John M

2011-05-01

Duchenne muscular dystrophy (DMD) is the most devastating type of muscular dystrophy, leading to progressive weakness of respiratory (e.g. diaphragm) and locomotor muscles (e.g. gastrocnemius). DMD is caused by X-linked defects in the gene that encodes for dystrophin, a key scaffolding protein of the dystroglycan complex (DCG) within the sarcolemmal cytoskeleton. As a result of a compromised dystroglycan complex, mechanical integrity is impaired and important signalling proteins (e.g. nNOS, caveolin-3) and pathways are disrupted. Disruption of the dystroglycan complex leads to high susceptibility to injury with repeated, eccentric contractions as well as inflammation, resulting in significant damage and necrosis. Chronic damage and repair cycling leads to fibrosis and weakness. While the link between inflammation with damage and weakness in the DMD diaphragm is unresolved, elevated oxidative stress may contribute to damage, weakness and possibly fibrosis. While utilization of non-specific antioxidant interventions has yielded inconsistent results, recent data suggest that NAD(P)H oxidase could play a pivotal role in elevating oxidative stress via integrated changes in caveolin-3 and stretch-activated channels (SACs). Oxidative stress may act as an amplifier, exacerbating disruption of the dystroglycan complex, upregulation of the inflammatory transcription factor NF-B, and thus functional impairment of force-generating capacity.

Muscle torque of healthy individuals and individuals with spastic hemiparesis after passive static streching.

PubMed

Tatsukawa DE Freitas, Sérgio Takeshi; DE Carvalho Abreu, Elizângela Márcia; Dos Reis, Mariane Cecilia; DE Souza Cunha, Bruna; Souza Moreira Prianti, Tamires; Pupio Silva Lima, Fernanda; Oliveira Lima, Mário

2016-01-01

Spasticity is one of the main causes of contracture, muscle weakness and subsequent functional incapacity. The passive static stretching can be included as having the purpose of increasing musculoskeletal flexibility, however, it also can influence the muscle torque. The objective is to verify the immediate effect of passive static stretching in the muscle strength of healthy and those who present spastic hemiparesis. There were assessed 20 subjects, 10 spastic hemiparetic (EG) and 10 healthy individuals (CG), including both sexes, aged between 22 and 78 years. The torque of extensor muscles of the knee was analyzed using isokinetic dynamometer. Results have shown that EG has less muscle torque compared to CG ( p < 0.01). In addition, EG presented a decrease in significance of muscle torque after stretching ( p < 0.05), however, it has not shown significant alteration in muscle torque of CG after performing the program that was prescribed. Immediately after the passive stretch, a significant torque decrease can be seen in hypertonic muscle; it is believed that this reduction may be associated with the physiological overlap between actin and myosin filaments and so preventing the muscle to develop a maximum contraction.

Primary adenosine monophosphate (AMP) deaminase deficiency in a hypotonic infant.

PubMed

Castro-Gago, Manuel; Gómez-Lado, Carmen; Pérez-Gay, Laura; Eirís-Puñal, Jesús; Martínez, Elena Pintos; García-Consuegra, Inés; Martín, Miguel Angel

2011-06-01

The spectrum of the adenosine monophosphate (AMP) deaminase deficiency ranges from asymptomatic carriers to patients who manifest exercise-induced muscle pain, occasionally rhabdomyolysis, and idiopathic hyperCKemia. However, previous to the introduction of molecular techniques, rare cases with congenital weakness and hypotonia have also been reported. We report a 6-month-old girl with the association of congenital muscle weakness and hypotonia, muscle deficiency of adenosine monophosphate deaminase, and the homozygous C to T mutation at nucleotide 34 of the adenosine monophosphate deaminase-1 gene. This observation indicates the possible existence of a primary adenosine monophosphate deaminase deficiency manifested by congenital muscle weakness and hypotonia.

An elderly-onset limb girdle muscular dystrophy type 1B (LGMD1B) with pseudo-hypertrophy of paraspinal muscles.

PubMed

Furuta, Mitsuru; Sumi-Akamaru, Hisae; Takahashi, Masanori P; Hayashi, Yukiko K; Nishino, Ichizo; Mochizuki, Hideki

2016-09-01

Mutations in LMNA, encoding A-type lamins, lead to diverse disorders, collectively called "laminopathies," which affect the striated muscle, cardiac muscle, adipose tissue, skin, peripheral nerve, and premature aging. We describe a patient with limb-girdle muscular dystrophy type 1B (LGMD1B) carrying a heterozygous p.Arg377His mutation in LMNA, in whom skeletal muscle symptom onset was at the age of 65 years. Her weakness started at the erector spinae muscles, which showed marked pseudo-hypertrophy even at the age of 72 years. Her first episode of syncope was at 44 years; however, aberrant cardiac conduction was not revealed until 60 years. The p.Arg377His mutation has been previously reported in several familial LMNA-associated myopathies, most of which showed muscle weakness before the 6th decade. This is the first report of pseudo-hypertrophy of paravertebral muscles in LMNA-associated myopathies. The pseudo-hypertrophy of paravertebral muscles and the elderly-onset of muscle weakness make this case unique and reportable. Copyright © 2016 Elsevier B.V. All rights reserved.

Strengthening the Gluteus Medius Using Various Bodyweight and Resistance Exercises

PubMed Central

Tufano, James J.; Golas, Artur; Petr, Miroslav

2016-01-01

ABSTRACT THE GLUTEUS MEDIUS (Gmed) IS AN IMPORTANT MUSCLE AND, IF WEAK, CAN CAUSE KNEE, HIP, OR LOWER-BACK PATHOLOGIES. THIS ARTICLE REVIEWS METHODS OF Gmed STRENGTH ASSESSMENT, PROVIDES EXERCISES THAT TARGET THE Gmed BASED ON ELECTROMYOGRAPHY, PRESENTS HOW TO IMPLEMENT Gmed STRENGTHENING IN HEAVY RESISTANCE TRAINING PROGRAMS, AND EXPLAINS THE IMPORTANCE OF INCLUDING THESE EXERCISES IN THESE PROGRAMS. PMID:27340373

BAG3 myofibrillar myopathy presenting with cardiomyopathy.

PubMed

Konersman, Chamindra G; Bordini, Brett J; Scharer, Gunter; Lawlor, Michael W; Zangwill, Steven; Southern, James F; Amos, Louella; Geddes, Gabrielle C; Kliegman, Robert; Collins, Michael P

2015-05-01

Myofibrillar myopathies (MFMs) are a heterogeneous group of neuromuscular disorders distinguished by the pathological hallmark of myofibrillar dissolution. Most patients present in adulthood, but mutations in several genes including BCL2-associated athanogene 3 (BAG3) cause predominantly childhood-onset disease. BAG3-related MFM is particularly severe, featuring weakness, cardiomyopathy, neuropathy, and early lethality. While prior cases reported either neuromuscular weakness or concurrent weakness and cardiomyopathy at onset, we describe the first case in which cardiomyopathy and cardiac transplantation (age eight) preceded neuromuscular weakness by several years (age 12). The phenotype comprised distal weakness and severe sensorimotor neuropathy. Nerve biopsy was primarily axonal with secondary demyelinating/remyelinating changes without "giant axons." Muscle biopsy showed extensive neuropathic changes that made myopathic changes difficult to interpret. Similar to previous cases, a p.Pro209Leu mutation in exon 3 of BAG3 was found. This case underlines the importance of evaluating for MFMs in patients with combined neuromuscular weakness and cardiomyopathy. Copyright © 2015 Elsevier B.V. All rights reserved.

Physiology of respiratory disturbances in muscular dystrophies

PubMed Central

Lo Mauro, Antonella

2016-01-01

Muscular dystrophy is a group of inherited myopathies characterised by progressive skeletal muscle wasting, including of the respiratory muscles. Respiratory failure, i.e. when the respiratory system fails in its gas exchange functions, is a common feature in muscular dystrophy, being the main cause of death, and it is a consequence of lung failure, pump failure or a combination of the two. The former is due to recurrent aspiration, the latter to progressive weakness of respiratory muscles and an increase in the load against which they must contract. In fact, both the resistive and elastic components of the work of breathing increase due to airway obstruction and chest wall and lung stiffening, respectively. The respiratory disturbances in muscular dystrophy are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. They can be present at different rates according to the type of muscular dystrophy and its progression, leading to different onset of each symptom, prognosis and degree of respiratory involvement. Key points A common feature of muscular dystrophy is respiratory failure, i.e. the inability of the respiratory system to provide proper oxygenation and carbon dioxide elimination. In the lung, respiratory failure is caused by recurrent aspiration, and leads to hypoxaemia and hypercarbia. Ventilatory failure in muscular dystrophy is caused by increased respiratory load and respiratory muscles weakness. Respiratory load increases in muscular dystrophy because scoliosis makes chest wall compliance decrease, atelectasis and fibrosis make lung compliance decrease, and airway obstruction makes airway resistance increase. The consequences of respiratory pump failure are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. Educational aims To understand the mechanisms leading to respiratory disturbances in patients with muscular dystrophy. To understand the impact of respiratory disturbances in patients with muscular dystrophy. To provide a brief description of the main forms of muscular dystrophy with their respiratory implications. PMID:28210319

Physiology of respiratory disturbances in muscular dystrophies.

PubMed

Lo Mauro, Antonella; Aliverti, Andrea

2016-12-01

Muscular dystrophy is a group of inherited myopathies characterised by progressive skeletal muscle wasting, including of the respiratory muscles. Respiratory failure, i.e . when the respiratory system fails in its gas exchange functions, is a common feature in muscular dystrophy, being the main cause of death, and it is a consequence of lung failure, pump failure or a combination of the two. The former is due to recurrent aspiration, the latter to progressive weakness of respiratory muscles and an increase in the load against which they must contract. In fact, both the resistive and elastic components of the work of breathing increase due to airway obstruction and chest wall and lung stiffening, respectively. The respiratory disturbances in muscular dystrophy are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. They can be present at different rates according to the type of muscular dystrophy and its progression, leading to different onset of each symptom, prognosis and degree of respiratory involvement. A common feature of muscular dystrophy is respiratory failure, i.e. the inability of the respiratory system to provide proper oxygenation and carbon dioxide elimination.In the lung, respiratory failure is caused by recurrent aspiration, and leads to hypoxaemia and hypercarbia.Ventilatory failure in muscular dystrophy is caused by increased respiratory load and respiratory muscles weakness.Respiratory load increases in muscular dystrophy because scoliosis makes chest wall compliance decrease, atelectasis and fibrosis make lung compliance decrease, and airway obstruction makes airway resistance increase.The consequences of respiratory pump failure are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. To understand the mechanisms leading to respiratory disturbances in patients with muscular dystrophy.To understand the impact of respiratory disturbances in patients with muscular dystrophy.To provide a brief description of the main forms of muscular dystrophy with their respiratory implications.

Grave's Disease with Severe Hepatic Dysfunction: A Diagnostic and Therapeutic Challenge.

PubMed

Bhuyan, Ashok Krishna; Sarma, Dipti; Kaimal Saikia, Uma; Choudhury, Bipul Kumar

2014-01-01

Hepatic dysfunction in a patient with thyrotoxicosis may result from hyperthyroidism per se, as a side effect of antithyroid drugs, and causes unrelated to hyperthyroidism which sometimes causes diagnostic and therapeutic difficulties. A young female patient was admitted to our hospital with symptoms of thyrotoxicosis, diffuse goiter and ophthalmopathy along with cholestatic pattern of jaundice, and proximal muscle weakness. She was treated with propylthiouracil with gradual recovery. She was continuing her antithyroid medication with regular follow-up. The patient was readmitted a few months later with worsening thyrotoxicosis, proximal muscle weakness, fever, and a hepatocellular pattern of jaundice with sepsis. Propylthiouracil was stopped and lithium along with steroid coverage was given to control her thyrotoxicosis which was later changed to methimazole. Broad spectrum antibiotic therapy was also started but without any response. During her hospital stay, the patient also developed a flaccid paraplegia resembling Guillain-Barre syndrome. IV steroid was started for the neuropathy but meanwhile the patient succumbed to her illness. So in centers where facility for radioiodine therapy is not readily available, some definite well-tested protocols should be formulated to address such common but complicated clinical situations.

Grave's Disease with Severe Hepatic Dysfunction: A Diagnostic and Therapeutic Challenge

PubMed Central

Sarma, Dipti; Kaimal Saikia, Uma; Choudhury, Bipul Kumar

2014-01-01

Hepatic dysfunction in a patient with thyrotoxicosis may result from hyperthyroidism per se, as a side effect of antithyroid drugs, and causes unrelated to hyperthyroidism which sometimes causes diagnostic and therapeutic difficulties. A young female patient was admitted to our hospital with symptoms of thyrotoxicosis, diffuse goiter and ophthalmopathy along with cholestatic pattern of jaundice, and proximal muscle weakness. She was treated with propylthiouracil with gradual recovery. She was continuing her antithyroid medication with regular follow-up. The patient was readmitted a few months later with worsening thyrotoxicosis, proximal muscle weakness, fever, and a hepatocellular pattern of jaundice with sepsis. Propylthiouracil was stopped and lithium along with steroid coverage was given to control her thyrotoxicosis which was later changed to methimazole. Broad spectrum antibiotic therapy was also started but without any response. During her hospital stay, the patient also developed a flaccid paraplegia resembling Guillain-Barre syndrome. IV steroid was started for the neuropathy but meanwhile the patient succumbed to her illness. So in centers where facility for radioiodine therapy is not readily available, some definite well-tested protocols should be formulated to address such common but complicated clinical situations. PMID:25317178

[An autopsy case of progressive generalized muscle atrophy over 14 years due to post-polio syndrome].

PubMed

Oki, Ryosuke; Uchino, Akiko; Izumi, Yuishin; Ogawa, Hirohisa; Murayama, Shigeo; Kaji, Ryuji

2016-01-01

We report the case of a 72-year-old man who had contracted acute paralytic poliomyelitis in his childhood. Thereafter, he had suffered from paresis involving the left lower limb, with no relapse or progression of the disease. He began noticing slowly progressive muscle weakness and atrophy in the upper and lower extremities in his 60s. At the age of 72, muscle weakness developed rapidly, and he demonstrated dyspnea on exertion and dysphagia. He died after about 14 years from the onset of muscle weakness symptoms. Autopsy findings demonstrated motoneuron loss and glial scars not only in the plaque-like lesions in the anterior horns, which were sequelae of old poliomyelitis, but also throughout the spine. No Bunina bodies, TDP-43, and ubiquitin inclusions were found. Post-polio syndrome is rarely fatal due to rapid progressive dyspnea and dysphagia. Thus, the pathological findings in the patient are considered to be related to the development of muscle weakness.

Finger extension weakness and downbeat nystagmus motor neuron disease syndrome: A novel motor neuron disorder?

PubMed Central

Delva, Aline; Thakore, Nimish; Pioro, Erik P.; Poesen, Koen; Saunders‐Pullman, Rachel; Meijer, Inge A.; Rucker, Janet C.; Kissel, John T.

2017-01-01

ABSTACT Introduction: Disturbances of eye movements are infrequently encountered in motor neuron diseases (MNDs) or motor neuropathies, and there is no known syndrome that combines progressive muscle weakness with downbeat nystagmus. Methods: To describe the core clinical features of a syndrome of MND associated with downbeat nystagmus, clinical features were collected from 6 patients. Results: All patients had slowly progressive muscle weakness and wasting in combination with downbeat nystagmus, which was clinically most obvious in downward and lateral gaze. Onset was in the second to fourth decade with finger extension weakness, progressing to other distal and sometimes more proximal muscles. Visual complaints were not always present. Electrodiagnostic testing showed signs of regional motor axonal loss in all patients. Discussion: The etiology of this syndrome remains elusive. Because finger extension weakness and downbeat nystagmus are the discriminating clinical features of this MND, we propose the name FEWDON‐MND syndrome. Muscle Nerve 56: 1164–1168, 2017 PMID:28440863

[Prevalence and symptoms of vitamin D deficiency in general practices].

PubMed

Merlo, C; Ross, C; Trummler, M; Zeller, A

2012-10-31

In 776 primary care patients serum vitamin D level was measured in month of september showing deficiency (<50 nmol/l) in 45,1%, severe deficiency (<30 nmol/l) in 9,8% and serum levels below the recommended target level of 75 nmol/l in 88,9% of cases. Three possible symptoms of vitamin D deficiency were assessed by a visual analogue scale (0-10): fatigue, muscle weakness, and muscle and joint pain. A significant correlation between muscle weakness and degree of vitamin D deficiency was shown (p=0,04), whereas there was no correlation in the two other symptoms. However, patients with vitamin D deficiency more frequently reported fatigue (p=0,02) and muscle weakness (p=0,009) than patients without deficiency did, and no difference was seen concerning muscle and joint pain.

The effect of muscle weakness on the capability gap during gross motor function: a simulation study supporting design criteria for exoskeletons of the lower limb.

PubMed

Afschrift, Maarten; De Groote, Friedl; De Schutter, Joris; Jonkers, Ilse

2014-08-04

Enabling persons with functional weaknesses to perform activities of daily living (ADL) is one of the main challenges for the aging society. Powered orthoses, or exoskeletons, have the potential to support ADL while promoting active participation of the user. For this purpose, assistive devices should be designed and controlled to deliver assistance as needed (AAN). This means that the level of assistance should bridge the capability gap, i.e. the gap between the capabilities of the subjects and the task requirements. However, currently the actuators of exoskeletons are mainly designed using inverse dynamics (ID) based calculations of joint moments. The goal of the present study is to calculate the capability gap for the lower limb during ADL when muscle weakness is present, which is needed for appropriate selection of actuators to be integrated in exoskeletons. A musculoskeletal model (MM) is used to calculate the joint kinematics, joint kinetics and muscle forces of eight healthy subjects during ADL (gait, sit-to-stand, stand-to-sit, stair ascent, stair descent). Muscle weakness was imposed to the MM by a stepwise decrease in maximal isometric force imposed to all muscles. Muscle forces were calculated using static optimization. In order to compensate for muscle weakness, ideal moment actuators that represent the motors of an exoskeleton in the simulation were added to deliver AAN required to perform the task. The ID approach overestimates the required assistance since it relies solely on the demands of the task, whereas the AAN approach incorporates the capabilities of the subject. Furthermore, the ID approach delivers continuous support whereas the AAN approach targets the period where a capability gap occurs. The level of muscle weakness for which the external demands imposed by ADL can no longer be met by active muscle force production, is respectively 40%, 70%, 80% and 30%. The present workflow allows estimating the AAN during ADL for different levels of muscle weakness, which can be used in the mechatronic design and control of powered exoskeletons. The AAN approach is a more physiological approach than the ID approach, since the MM accounts for the subject-specific capabilities of the user.

Non-traumatic rhabdomyolysis: Background, laboratory features, and acute clinical management.

PubMed

Cervellin, Gianfranco; Comelli, Ivan; Benatti, Mario; Sanchis-Gomar, Fabian; Bassi, Antonella; Lippi, Giuseppe

2017-08-01

Rhabdomyolysis is a relatively rare condition, but its clinical consequences are frequently dramatic in terms of both morbidity and mortality. Although no consensus has been reached so far about the precise definition of this condition, the term rhabdomyolysis describes a rapid breakdown of striated, or skeletal, muscle. It is hence characterized by the rupture and necrosis of muscle fibers, resulting in release of cell degradation products and intracellular elements within the bloodstream and extracellular space. Notably, the percentage of patients with rhabdomyolysis who develop acute kidney injury, the most dramatic consequence, varies from 13% to over 50% according to both the cause and the clinical and organizational setting where they are diagnosed. Despite direct muscle injury (i.e., traumatic rhabdomyolysis) remains the most common cause, additional causes, frequently overlapping, include hypoxic, physical, chemical or biological factors. The conventional triad of symptoms includes muscle pain, weakness and dark urine. The laboratory diagnosis is essentially based on the measurement of biomarkers of muscle injury, being creatine kinase (CK) the biochemical "gold standard" for diagnosis, and myoglobin the "gold standard" for prognostication, especially in patients with non-traumatic rhabdomyolysis. The essential clinical management in the emergency department is based on a targeted intervention to manage the underlying cause, combined with infusion of fluids and eventually sodium bicarbonate. We will present and discuss in this article the pathophysiological and clinical features of non-traumatic rhabdomyolysis, focusing specifically on Emergency Department (ED) management. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Fatigue of muscles weakened by death of motoneurons.

PubMed

Thomas, Christine K; Zijdewind, Inge

2006-01-01

Weakness is a characteristic of muscles influenced by the postpolio syndrome (PPS), amyotrophic lateral sclerosis (ALS), and spinal cord injury (SCI). The strength deficits relate to changes in muscle use and to the chronic denervation that can follow the spinal motoneuron death common to these disorders. PPS, ALS, and SCI also involve variable amounts of supraspinal neuron death, the effects of which on muscle weakness remains unclear. Nevertheless, weakness of muscle itself defines the functional consequences of these disorders. A weaker muscle requires an individual to work that muscle at higher than usual intensities relative to its maximal capacity, inducing progressive fatigue and an increased sense of effort. Little evidence is available to suggest that the fatigue commonly experienced by individuals with these disorders relates to an increase in the intrinsic fatigability of the muscle fibers. The only exception is when SCI induces chronic muscle paralysis. To reduce long-term functional deficits in these disorders, studies must identify the signaling pathways that influence neuron survival and determine the factors that encourage and limit sprouting of motor axons. This may ensure that a greater proportion of the fibers in each muscle remain innervated and available for use.

The impact of obesity on skeletal muscle strength and structure through adolescence to old age.

PubMed

Tomlinson, D J; Erskine, R M; Morse, C I; Winwood, K; Onambélé-Pearson, Gladys

2016-06-01

Obesity is associated with functional limitations in muscle performance and increased likelihood of developing a functional disability such as mobility, strength, postural and dynamic balance limitations. The consensus is that obese individuals, regardless of age, have a greater absolute maximum muscle strength compared to non-obese persons, suggesting that increased adiposity acts as a chronic overload stimulus on the antigravity muscles (e.g., quadriceps and calf), thus increasing muscle size and strength. However, when maximum muscular strength is normalised to body mass, obese individuals appear weaker. This relative weakness may be caused by reduced mobility, neural adaptations and changes in muscle morphology. Discrepancies in the literature remain for maximal strength normalised to muscle mass (muscle quality) and can potentially be explained through accounting for the measurement protocol contributing to muscle strength capacity that need to be explored in more depth such as antagonist muscle co-activation, muscle architecture, a criterion valid measurement of muscle size and an accurate measurement of physical activity levels. Current evidence demonstrating the effect of obesity on muscle quality is limited. These factors not being recorded in some of the existing literature suggest a potential underestimation of muscle force either in terms of absolute force production or relative to muscle mass; thus the true effect of obesity upon skeletal muscle size, structure and function, including any interactions with ageing effects, remains to be elucidated.

Influence of Anterior Cruciate Ligament Tear on Thigh Muscle Strength and Hamstring-to-Quadriceps Ratio: A Meta-Analysis.

PubMed

Kim, Hyun-Jung; Lee, Jin-Hyuck; Ahn, Sung-Eun; Park, Min-Ji; Lee, Dae-Hee

2016-01-01

Theoretical compensation after anterior cruciate ligament (ACL) tear could cause quadriceps weakness and hamstring activation, preventing anterior tibial subluxation and affecting the expected hamstring-to-quadriceps ratio. Although quadriceps weakness often occurs after ACL tears, it remains unclear whether hamstring strength and hamstring-to-quadriceps ratio increase in ACL deficient knees. This meta-analysis compared the isokinetic muscle strength of quadriceps and hamstring muscles, and the hamstring-to-quadriceps ratio, of the injured and injured limbs of patients with ACL tears. This meta-analysis included all studies comparing isokinetic thigh muscle strengths and hamstring-to-quadriceps ratio in the injured and uninjured legs of patients with ACL tear, without or before surgery. Thirteen studies were included in the meta-analysis. Quadriceps and hamstring strengths were 22.3 N∙m (95% CI: 15.2 to 29.3 N∙m; P<0.001) and 7.4 N∙m (95% CI: 4.3 to 10.5 N∙m; P<0.001) lower, respectively, on the injured than on the uninjured side. The mean hamstring-to-quadriceps ratio was 4% greater in ACL deficient than in uninjured limbs (95% CI: 1.7% to 6.3%; P<0.001). Conclusively, Decreases were observed in both the quadriceps and hamstring muscles of patients with ACL tear, with the decrease in quadriceps strength being 3-fold greater. These uneven reductions slightly increase the hamstring-to-quadriceps ratio in ACL deficient knees.

Influence of Anterior Cruciate Ligament Tear on Thigh Muscle Strength and Hamstring-to-Quadriceps Ratio: A Meta-Analysis

PubMed Central

Ahn, Sung-Eun; Park, Min-Ji; Lee, Dae-Hee

2016-01-01

Theoretical compensation after anterior cruciate ligament (ACL) tear could cause quadriceps weakness and hamstring activation, preventing anterior tibial subluxation and affecting the expected hamstring-to-quadriceps ratio. Although quadriceps weakness often occurs after ACL tears, it remains unclear whether hamstring strength and hamstring-to-quadriceps ratio increase in ACL deficient knees. This meta-analysis compared the isokinetic muscle strength of quadriceps and hamstring muscles, and the hamstring-to-quadriceps ratio, of the injured and injured limbs of patients with ACL tears. This meta-analysis included all studies comparing isokinetic thigh muscle strengths and hamstring-to-quadriceps ratio in the injured and uninjured legs of patients with ACL tear, without or before surgery. Thirteen studies were included in the meta-analysis. Quadriceps and hamstring strengths were 22.3 N∙m (95% CI: 15.2 to 29.3 N∙m; P<0.001) and 7.4 N∙m (95% CI: 4.3 to 10.5 N∙m; P<0.001) lower, respectively, on the injured than on the uninjured side. The mean hamstring-to-quadriceps ratio was 4% greater in ACL deficient than in uninjured limbs (95% CI: 1.7% to 6.3%; P<0.001). Conclusively, Decreases were observed in both the quadriceps and hamstring muscles of patients with ACL tear, with the decrease in quadriceps strength being 3-fold greater. These uneven reductions slightly increase the hamstring-to-quadriceps ratio in ACL deficient knees. PMID:26745808

Use of capillary Western immunoassay (Wes) for quantification of dystrophin levels in skeletal muscle of healthy controls and individuals with Becker and Duchenne muscular dystrophy.

PubMed

Beekman, Chantal; Janson, Anneke A; Baghat, Aabed; van Deutekom, Judith C; Datson, Nicole A

2018-01-01

Duchenne muscular dystrophy (DMD) is a neuromuscular disease characterized by progressive weakness of the skeletal and cardiac muscles. This X-linked disorder is caused by open reading frame disrupting mutations in the DMD gene, resulting in strong reduction or complete absence of dystrophin protein. In order to use dystrophin as a supportive or even surrogate biomarker in clinical studies on investigational drugs aiming at correcting the primary cause of the disease, the ability to reliably quantify dystrophin expression in muscle biopsies of DMD patients pre- and post-treatment is essential. Here we demonstrate the application of the ProteinSimple capillary immunoassay (Wes) method, a gel- and blot-free method requiring less sample, antibody and time to run than conventional Western blot assay. We optimized dystrophin quantification by Wes using 2 different antibodies and found it to be highly sensitive, reproducible and quantitative over a large dynamic range. Using a healthy control muscle sample as a reference and α-actinin as a protein loading/muscle content control, a panel of skeletal muscle samples consisting of 31 healthy controls, 25 Becker Muscle dystrophy (BMD) and 17 DMD samples was subjected to Wes analysis. In healthy controls dystrophin levels varied 3 to 5-fold between the highest and lowest muscle samples, with the reference sample representing the average of all 31 samples. In BMD muscle samples dystrophin levels ranged from 10% to 90%, with an average of 33% of the healthy muscle average, while for the DMD samples the average dystrophin level was 1.3%, ranging from 0.7% to 7% of the healthy muscle average. In conclusion, Wes is a suitable, efficient and reliable method for quantification of dystrophin expression as a biomarker in DMD clinical drug development.

A Review of the Surgical Management of Perineal Hernias in Dogs.

PubMed

Gill, Sukhjit Singh; Barstad, Robert D

2018-05-14

Perineal hernia refers to the failure of the muscular pelvic diaphragm to support the rectal wall, resulting in herniation of pelvic and, occasionally, abdominal viscera into the subcutaneous perineal region. The proposed causes of pelvic diaphragm weakness include tenesmus associated with chronic prostatic disease or constipation, myopathy, rectal abnormalities, and gonadal hormonal imbalances. The most common presentation of perineal hernia in dogs is a unilateral or bilateral nonpainful swelling of the perineum. Clinical signs do occur, but not always. Clinical signs may include constipation, obstipation, dyschezia, tenesmus, rectal prolapse, stranguria, or anuria. The definitive diagnosis of perineal hernia is based on clinical signs and findings of weak pelvic diaphragm musculature during a digital rectal examination. In dogs, perineal hernias are mostly treated by surgical intervention. Appositional herniorrhaphy is sometimes difficult to perform as the levator ani and coccygeus muscles are atrophied and unsuitable for use. Internal obturator muscle transposition is the most commonly used technique. Additional techniques include superficial gluteal and semitendinosus muscle transposition, in addition to the use of synthetic implants and biomaterials. Pexy techniques may be used to prevent rectal prolapse and bladder and prostate gland displacement. Postoperative care involves analgesics, antibiotics, a low-residue diet, and stool softeners.

A further patient with parasitic myositis due to Haycocknema perplexum, a rare entity.

PubMed

McKelvie, Penelope; Reardon, Katrina; Bond, Katherine; Spratt, David M; Gangell, Andrew; Zochling, Jane; Daffy, John

2013-07-01

A new genus of nematode, Haycocknema perplexum, causing polymyositis in humans, was first described in two Australian patients from Tasmania in 1998. Three patients with myositis due to the same nematode were reported from northern Queensland in 2008. We report the sixth case from Australia, a 50-year-old man, also from Tasmania. He had a 2-year history of progressive weakness, weight loss of 10 kg and dysphagia. Muscle biopsy was initially interpreted as polymyositis with eosinophils. Maximum creatine kinase (CK) level was 5700 U/L and full blood examination was normal. He deteriorated after several months of treatment with prednisolone and methotrexate and review of the muscle biopsy showed intramyofibre parasites of H. perplexum. After 3 months of treatment with albendazole therapy, he made a very good clinical recovery and his CK decreased to 470 U/L. This uniquely Australian parasite can mimic polymyositis and leads to significant irreversible morbidity (two of the previous patients still have weakness and elevated CK after years) and even mortality (one died), if diagnosed late or after corticosteroids. Diagnosis can only be made by histopathology of muscle biopsy. Copyright © 2012 Elsevier Ltd. All rights reserved.

A rare subclinical or mild type of Becker muscular dystrophy caused by a single exon 48 deletion of the dystrophin gene.

PubMed

Zimowski, Janusz G; Pilch, Jacek; Pawelec, Magdalena; Purzycka, Joanna K; Kubalska, Jolanta; Ziora-Jakutowicz, Karolina; Dudzińska, Magdalena; Zaremba, Jacek

2017-08-01

In the material of 227 families with Becker muscular dystrophy (BMD), we found nine non-consanguineous families with 17 male individuals carrying a rare mutation-a single exon 48 deletion of the dystrophin gene-who were affected with a very mild or subclinical form of BMD. They were usually detected thanks to accidental findings of elevated serum creatine phosphokinase (sCPK). A thorough clinical analysis of the carriers, both children (12) and adults (5), revealed in some of them muscle hypotonia (10/17) and/or very mild muscle weakness (9/17), as well as decreased tendon reflexes (6/17). Adults, apart from very mild muscle weakness and calf hypertrophy in some, had no significant abnormalities on neurological assessments and had good exercise tolerance. Parents of the children carriers of the exon 48 deletion are usually unaware of their children being affected, and possibly at risk of developing life-threatening cardiomyopathy. The same concerns the adult male carriers. Therefore, the authors postulate undertaking preventive measures such as cascade screening of the relatives of the probands. Newborn screening programmes of Duchenne muscular dystrophy (DMD)/BMD based on sCPK marked increase may be considered.

Effects of respiratory muscle training (RMT) in children with infantile-onset Pompe disease and respiratory muscle weakness.

PubMed

Jones, Harrison N; Crisp, Kelly D; Moss, Tronda; Strollo, Katherine; Robey, Randy; Sank, Jeffrey; Canfield, Michelle; Case, Laura E; Mahler, Leslie; Kravitz, Richard M; Kishnani, Priya S

2014-01-01

Respiratory muscle weakness is a primary therapeutic challenge for patients with infantile Pompe disease. We previously described the clinical implementation of a respiratory muscle training (RMT) regimen in two adults with late-onset Pompe disease; both demonstrated marked increases in inspiratory and expiratory muscle strength in response to RMT. However, the use of RMT in pediatric survivors of infantile Pompe disease has not been previously reported. We report the effects of an intensive RMT program on maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) using A-B-A (baseline-treatment-posttest) single subject experimental design in two pediatric survivors of infantile Pompe disease. Both subjects had persistent respiratory muscle weakness despite long-term treatment with alglucosidase alfa. Subject 1 demonstrated negligible to modest increases in MIP/MEP (6% increase in MIP, d=0.25; 19% increase in MEP, d=0.87), while Subject 2 demonstrated very large increases in MIP/MEP (45% increase in MIP, d=2.38; 81% increase in MEP, d=4.31). Following three-month RMT withdrawal, both subjects maintained these strength increases and demonstrated maximal MIP and MEP values at follow-up. Intensive RMT may be a beneficial treatment for respiratory muscle weakness in pediatric survivors of infantile Pompe disease.

Long-term effects of systemic gene therapy in a canine model of myotubular myopathy.

PubMed

Elverman, Matthew; Goddard, Melissa A; Mack, David; Snyder, Jessica M; Lawlor, Michael W; Meng, Hui; Beggs, Alan H; Buj-Bello, Ana; Poulard, Karine; Marsh, Anthony P; Grange, Robert W; Kelly, Valerie E; Childers, Martin K

2017-11-01

X-linked myotubular myopathy (XLMTM), a devastating pediatric disease caused by the absence of the protein myotubularin, results from mutations in the MTM1 gene. While there is no cure for XLMTM, we previously reported effects of MTM1 gene therapy using adeno-associated virus (AAV) vector on muscle weakness and pathology in MTM1-mutant dogs. Here, we followed 2 AAV-infused dogs over 4 years. We evaluated gait, strength, respiration, neurological function, muscle pathology, AAV vector copy number (VCN), and transgene expression. Four years following AAV-mediated gene therapy, gait, respiratory performance, neurological function and pathology in AAV-infused XLMTM dogs remained comparable to their healthy littermate controls despite a decline in VCN and muscle strength. AAV-mediated gene transfer of MTM1 in young XLMTM dogs results in long-term expression of myotubularin transgene with normal muscular performance and neurological function in the absence of muscle pathology. These findings support a clinical trial in patients. Muscle Nerve 56: 943-953, 2017. © 2017 Wiley Periodicals, Inc.

Phenotypic and immunohistochemical characterization of sarcoglycanopathies

PubMed Central

Ferreira, Ana F. B.; Carvalho, Mary S.; Resende, Maria Bernadete D.; Wakamatsu, Alda; Reed, Umbertina Conti; Marie, Suely Kazue Nagahashi

2011-01-01

INTRODUCTION: Limb-girdle muscular dystrophy presents with heterogeneous clinical and molecular features. The primary characteristic of this disorder is proximal muscular weakness with variable age of onset, speed of progression, and intensity of symptoms. Sarcoglycanopathies, which are a subgroup of the limb-girdle muscular dystrophies, are caused by mutations in sarcoglycan genes. Mutations in these genes cause secondary deficiencies in other proteins, due to the instability of the dystrophin-glycoprotein complex. Therefore, determining the etiology of a given sarcoglycanopathy requires costly and occasionally inaccessible molecular methods. OBJECTIVE: The aim of this study was to identify phenotypic differences among limb-girdle muscular dystrophy patients who were grouped according to the immunohistochemical phenotypes for the four sarcoglycans. METHODS: To identify phenotypic differences among patients with different types of sarcoglycanopathies, a questionnaire was used and the muscle strength and range of motion of nine joints in 45 patients recruited from the Department of Neurology – HC-FMUSP (Clinics Hospital of the Faculty of Medicine of the University of São Paulo) were evaluated. The findings obtained from these analyses were compared with the results of the immunohistochemical findings. RESULTS: The patients were divided into the following groups based on the immunohistochemical findings: α-sarcoglycanopathies (16 patients), β-sarcoglycanopathies (1 patient), γ-sarcoglycanopathies (5 patients), and non-sarcoglycanopathies (23 patients). The muscle strength analysis revealed significant differences for both upper and lower limb muscles, particularly the shoulder and hip muscles, as expected. No pattern of joint contractures was found among the four groups analyzed, even within the same family. However, a high frequency of tiptoe gait was observed in patients with α-sarcoglycanopathies, while calf pseudo-hypertrophy was most common in patients with non-sarcoglycanopathies. The α-sarcoglycanopathy patients presented with more severe muscle weakness than did γ-sarcoglycanopathy patients. CONCLUSION: The clinical differences observed in this study, which were associated with the immunohistochemical findings, may help to prioritize the mutational investigation of sarcoglycan genes. PMID:22012042

Diospyros rhodocalyx (Tako-Na), a Thai folk medicine, associated with hypokalemia and generalized muscle weakness: a case series.

PubMed

Othong, Rittirak; Trakulsrichai, Satariya; Wananukul, Winai

2017-11-01

Diospyros rhodocalyx (Tako-Na) is a Thai folk medicine purported to promote longevity, treat impotence, etc. We present patients with hypokalemia, weakness and hypertension after consuming Tako-Na tea. Case 1: A 61-year-old man was brought in nine hours after drinking 400-500 mL of Tako-Na tea. One handful of Tako-Na bark was boiled in water to make tea. He had vomiting and watery diarrhea six hours after drinking it. He took no medications and had no history of hypertension. The only remarkable vital sign was BP 167/90 mmHg. Physical examination revealed generalized muscle weakness. Laboratory findings were potassium 2.7 mmol/L, bicarbonate 24 mmol/L, and transtubular potassium gradient (TTKG) 5.6. He was discharged the next day with a BP 140/90 mmHg and potassium 4.2 mmol/L. Case 2: A 78-year-old man, a friend of case 1, also drank Tako-Na tea from the same pot at the same time as case 1. He also had vomiting and diarrhea six hours later. He took no medications despite past history of hypertension (baseline SBP 140-160). Initial BP was 230/70 mmHg. He also had muscle weakness. Laboratory findings were potassium 3.3 mmol/L, bicarbonate 24 mmol/L, TTKG 7.37 and normal thyroid function. He was also discharged the next day with a BP 148/70 mmHg and potassium 4.2 mmol/L. Case 3-7: These were patients reported to a poison center and their potassium concentrations were 1.4, 1.4, 3.3, 1.3 and 1.2 mmol/L, respectively. Three of them were intubated and case 3 died. Tako-Na contains betulin, betulinic acid, taraxerone, lupeol, and lupenone. Their structures are similar to glycyrrhetic acid, the active metabolite of glycyrrhizic acid found in licorice which is well known to cause pseudoaldosteronism. Glycyrrhetic acid is potent in inhibiting 11-beta-hydroxysteroid dehydrogenase, and causes pseudoaldosteronism. We hypothesize that the compounds in Tako-Na act in the same way as glycyrrhetic acid in producing pseudoaldosteronism.

Myasthenia Gravis: A Review

PubMed Central

Jayam Trouth, Annapurni; Dabi, Alok; Solieman, Noha; Kurukumbi, Mohankumar; Kalyanam, Janaki

2012-01-01

Acquired myasthenia gravis is a relatively uncommon disorder, with prevalence rates that have increased to about 20 per 100,000 in the US population. This autoimmune disease is characterized by muscle weakness that fluctuates, worsening with exertion, and improving with rest. In about two-thirds of the patients, the involvement of extrinsic ocular muscle presents as the initial symptom, usually progressing to involve other bulbar muscles and limb musculature, resulting in generalized myasthenia gravis. Although the cause of the disorder is unknown, the role of circulating antibodies directed against the nicotinic acetylcholine receptor in its pathogenesis is well established. As this disorder is highly treatable, prompt recognition is crucial. During the past decade, significant progress has been made in our understanding of the disease, leading to new treatment modalities and a significant reduction in morbidity and mortality. PMID:23193443

Muscle wasting in myotonic dystrophies: a model of premature aging.

PubMed

Mateos-Aierdi, Alba Judith; Goicoechea, Maria; Aiastui, Ana; Fernández-Torrón, Roberto; Garcia-Puga, Mikel; Matheu, Ander; López de Munain, Adolfo

2015-01-01

Myotonic dystrophy type 1 (DM1 or Steinert's disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG) triplet expansion in the 3' untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9 (CNBP/ZNF9) gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular degeneration seen in DM patients, highlighting the similarities found with muscle aging.

Muscle Weakness Is Associated With an Increase of Left Ventricular Mass Through Excessive Blood Pressure Elevation During Exercise in Patients With Hypertension.

PubMed

Kamada, Yumi; Masuda, Takashi; Tanaka, Shinya; Akiyama, Ayako; Nakamura, Takeshi; Hamazaki, Nobuaki; Okubo, Michihito; Kobayashi, Naoyuki; Ako, Junya

2017-08-03

Autonomic imbalance in hypertension induces excessive blood pressure (BP) elevation during exercise, thereby increasing left ventricular mass (LVM). Although muscle weakness enhances autonomic imbalance by stimulating muscle sympathetic activity during exercise, it is unclear whether muscle weakness is associated with an increase of LVM in patients with hypertension. This study aimed to investigate the relationships between muscle weakness, BP elevation during exercise, and LVM in these patients. Eighty-six hypertensive patients aged 69 ± 8 years with controlled resting BP (ie, < 140/90 mmHg) were recruited. Plasma brain natriuretic peptide (BNP), left ventricular mass index (LVMI), and knee extension muscle strength were measured. Changes in plasma noradrenaline (NORA) and brachial-ankle pulse wave velocity (ba-PWV) were assessed before and after an ergometer exercise test performed at moderate intensity (ΔNORA and ΔPWV, respectively). A difference between baseline and peak systolic BP during the exercise test was defined as BP elevation during exercise (ΔSBP). Relationships between muscle strength, ΔNORA, ΔPWV, ΔSBP, BNP, and LVMI were analyzed, and significant factors increasing LVM were identified using univariate and multivariate regression analyses. Muscle strength was negatively correlated with ΔNORA (r = -0.202, P = 0.048), ΔPWV (r = -0.328, P = 0.002), ΔSBP (r = -0.230, P = 0.033), BNP (r = -0.265, P = 0.014), and LVMI (r = -0.233, P = 0.031). LVMI was positively correlated with ΔPWV (r = 0.246, P = 0.023) and ΔSBP (r = 0.307, P = 0.004). Muscle strength was a significant independent factor associated with LVMI (β = -0.331, P = 0.010). Our findings suggest that muscle weakness is associated with an increase of LVM through excessive BP elevation during exercise in patients with hypertension.

Black Tar Heroin Skin Popping as a Cause of Wound Botulism.

PubMed

Qureshi, Ihtesham A; Qureshi, Mohtashim A; Rauf Afzal, Mohammad; Maud, Alberto; Rodriguez, Gustavo J; Cruz-Flores, Salvador; Kassar, Darine

2017-12-01

Botulism is a rare potentially fatal and treatable disorder caused by a bacteria-produced toxin that affects the presynaptic synaptic membrane resulting in a characteristic neuromuscular dysfunction. It is caused by either the ingestion of the toxin or the bacteria, inhalation, or wound infection. We present our observations with a descriptive case series of wound botulism secondary to black tar heroin (BTH) injection. We report a retrospective single-center case series of 15 consecutive cases of wound botulism presenting to University Medical Center of El Paso. Medical records where reviewed to obtain demographic information, clinical presentation, treatment, and outcome. We identified fifteen patients with mean age of 47 years: twelve men, and three women. All had administered BTH through skin popping and had abscesses in the administration areas. By history, the most common symptoms were dysphagia (66%), proximal muscle weakness of upper and lower extremity (60%), neck flexor muscle weakness (33%), ophthalmoplegia (53%), bilateral ptosis (46%), dysarthria (53%), double vision (40%), blurred vision (33%), and dry mouth (20%). During the examination, the most common features noted were: proximal muscle weakness of upper and lower extremities (73%), ophthalmoplegia (53%), ptosis (46%). In patients with documented wound botulism, the pupils were reactive in 46%. All patients required mechanical ventilation and were treated with the trivalent antitoxin. Eleven patients (73.3%) were discharged home, two were transferred to a skill nursing facility, and two were transferred to long-term acute care facility. In our patients, BTH injection, involving the action of injecting under the skin acetylated morphine derivatives (mostly 6-monoacetylmorphine and 3-monoacetylmorphine), was associated with the development of botulism. The availability of BTH at the US-Mexican border is not surprising since it is frequently produced in Latin America. Its association with the development of botulism should be recognized early to allow a prompt diagnosis and treatment with the antitoxin. A clinical feature worth noting is the presence of normal pupillary light reflex in nearly half of patients. Therefore, the presence of a normal pupillary response does not exclude the presence of wound botulism.

Patient-specific fibre-based models of muscle wrapping

PubMed Central

Kohout, J.; Clapworthy, G. J.; Zhao, Y.; Tao, Y.; Gonzalez-Garcia, G.; Dong, F.; Wei, H.; Kohoutová, E.

2013-01-01

In many biomechanical problems, the availability of a suitable model for the wrapping of muscles when undergoing movement is essential for the estimation of forces produced on and by the body during motion. This is an important factor in the Osteoporotic Virtual Physiological Human project which is investigating the likelihood of fracture for osteoporotic patients undertaking a variety of movements. The weakening of their skeletons makes them particularly vulnerable to bone fracture caused by excessive loading being placed on the bones, even in simple everyday tasks. This paper provides an overview of a novel volumetric model that describes muscle wrapping around bones and other muscles during movement, and which includes a consideration of how the orientations of the muscle fibres change during the motion. The method can calculate the form of wrapping of a muscle of medium size and visualize the outcome within tenths of seconds on commodity hardware, while conserving muscle volume. This makes the method suitable not only for educational biomedical software, but also for clinical applications used to identify weak muscles that should be strengthened during rehabilitation or to identify bone stresses in order to estimate the risk of fractures. PMID:24427519

Protein turnover and cellular stress in mildly and severely affected muscles from patients with limb girdle muscular dystrophy type 2I.

PubMed

Hauerslev, Simon; Sveen, Marie L; Vissing, John; Krag, Thomas O

2013-01-01

Patients with Limb girdle muscular dystrophy type 2I (LGMD2I) are characterized by progressive muscle weakness and wasting primarily in the proximal muscles, while distal muscles often are spared. Our aim was to investigate if wasting could be caused by impaired regeneration in the proximal compared to distal muscles. Biopsies were simultaneously obtained from proximal and distal muscles of the same patients with LGMD2I (n = 4) and healthy subjects (n = 4). The level of past muscle regeneration was evaluated by counting internally nucleated fibers and determining actively regenerating fibers by using the developmental markers embryonic myosin heavy chain (eMHC) and neural cell adhesion molecule (NCAM) and also assessing satellite cell activation status by myogenin positivity. Severe muscle histopathology was occasionally observed in the proximal muscles of patients with LGMD2I whereas distal muscles were always relatively spared. No difference was found in the regeneration markers internally nucleated fibers, actively regenerating fibers or activation status of satellite cells between proximal and distal muscles. Protein turnover, both synthesis and breakdown, as well as cellular stress were highly increased in severely affected muscles compared to mildly affected muscles. Our results indicate that alterations in the protein turnover and myostatin levels could progressively impair the muscle mass maintenance and/or regeneration resulting in gradual muscular atrophy.

Hypermagnesemia disturbances in rats, NO-related: pentadecapeptide BPC 157 abrogates, L-NAME and L-arginine worsen.

PubMed

Medvidovic-Grubisic, Maria; Stambolija, Vasilije; Kolenc, Danijela; Katancic, Jadranka; Murselovic, Tamara; Plestina-Borjan, Ivna; Strbe, Sanja; Drmic, Domagoj; Barisic, Ivan; Sindic, Aleksandra; Seiwerth, Sven; Sikiric, Predrag

2017-08-01

Stable gastric pentadecapeptide BPC 157, administered before a high-dose magnesium injection in rats, might be a useful peptide therapy against magnesium toxicity and the magnesium-induced effect on cell depolarization. Moreover, this might be an NO-system-related effect. Previously, BPC 157 counteracts paralysis, arrhythmias and hyperkalaemia, extreme muscle weakness; parasympathetic and neuromuscular blockade; injured muscle healing and interacts with the NOS-blocker and NOS-substrate effects. Assessment included magnesium sulfate (560 mg/kg intraperitoneally)-induced muscle weakness, muscle and brain lesions, hypermagnesemia, hyperkalaemia, increased serum enzyme values assessed in rats during and at the end of a 30-min period and medication (given intraperitoneally/kg at 15 min before magnesium) [BPC 157 (10 µg, 10 ng), L-NAME (5 mg), L-arginine (100 mg), alone and/or together]. In HEK293 cells, the increasing magnesium concentration from 1 to 5 mM could depolarize the cells at 1.75 ± 0.44 mV. L-NAME + magnesium-rats and L-arginine + magnesium-rats exhibited worsened severe muscle weakness and lesions, brain lesions, hypermagnesemia and serum enzymes values, with emerging hyperkalaemia. However, L-NAME + L-arginine + magnesium-rats exhibited all control values and normokalaemia. BPC 157 abrogated hypermagnesemia and counteracted all of the magnesium-induced disturbances (including those aggravated by L-NAME or L-arginine). Thus, cell depolarization due to increasing magnesium concentration was inhibited in the presence of BPC 157 (1 µM) in vitro. BPC 157 likely counteracts the initial event leading to hypermagnesemia and the life-threatening actions after a magnesium overdose. In contrast, a worsened clinical course, higher hypermagnesemia, and emerging hyperkalaemia might cause both L-NAME and L-arginine to affect the same events adversely. These events were also opposed by BPC 157.

Analysis of three different equations for predicting quadriceps femoris muscle strength in patients with COPD *

PubMed Central

Nellessen, Aline Gonçalves; Donária, Leila; Hernandes, Nidia Aparecida; Pitta, Fabio

2015-01-01

Abstract Objective: To compare equations for predicting peak quadriceps femoris (QF) muscle force; to determine the agreement among the equations in identifying QF muscle weakness in COPD patients; and to assess the differences in characteristics among the groups of patients classified as having or not having QF muscle weakness by each equation. Methods: Fifty-six COPD patients underwent assessment of peak QF muscle force by dynamometry (maximal voluntary isometric contraction of knee extension). Predicted values were calculated with three equations: an age-height-weight-gender equation (Eq-AHWG); an age-weight-gender equation (Eq-AWG); and an age-fat-free mass-gender equation (Eq-AFFMG). Results: Comparison of the percentage of predicted values obtained with the three equations showed that the Eq-AHWG gave higher values than did the Eq-AWG and Eq-AFFMG, with no difference between the last two. The Eq-AHWG showed moderate agreement with the Eq-AWG and Eq-AFFMG, whereas the last two also showed moderate, albeit lower, agreement with each other. In the sample as a whole, QF muscle weakness (< 80% of predicted) was identified by the Eq-AHWG, Eq-AWG, and Eq-AFFMG in 59%, 68%, and 70% of the patients, respectively (p > 0.05). Age, fat-free mass, and body mass index are characteristics that differentiate between patients with and without QF muscle weakness. Conclusions: The three equations were statistically equivalent in classifying COPD patients as having or not having QF muscle weakness. However, the Eq-AHWG gave higher peak force values than did the Eq-AWG and the Eq-AFFMG, as well as showing greater agreement with the other equations. PMID:26398750

Mutation-Specific Effects on Thin Filament Length in Thin Filament Myopathy

PubMed Central

de Winter, Josine M.; Joureau, Barbara; Lee, Eun-Jeong; Kiss, Balázs; Yuen, Michaela; Gupta, Vandana A.; Pappas, Christopher T.; Gregorio, Carol C.; Stienen, Ger J. M.; Edvardson, Simon; Wallgren-Pettersson, Carina; Lehtokari, Vilma-Lotta; Pelin, Katarina; Malfatti, Edoardo; Romero, Norma B.; van Engelen, Baziel G.; Voermans, Nicol C.; Donkervoort, Sandra; Bönnemann, C. G.; Clarke, Nigel F.; Beggs, Alan H.; Granzier, Henk; Ottenheijm, Coen A. C.

2016-01-01

Objective Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation. Methods We investigated the sarcomere length-dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41. Results Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in NEB and ACTA1, the lower force was associated with downward shifted force–sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional Neb knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin–thick filament overlap. Interpretation These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths. PMID:27074222

Severe polymyositis due to Toxoplasma gondii in an adult immunocompetent patient: a case report and review of the literature.

PubMed

Cuomo, G; D'Abrosca, V; Rizzo, V; Nardiello, S; La Montagna, G; Gaeta, G B; Valentini, G

2013-08-01

Toxoplasmosis, a worldwide zoonosis caused by a coccidian parasite Toxoplasma gondii, is more often asymptomatic in immunocompetent patients. We report the case of a 38-year-old immunocompetent male with a polymyositis as the presenting manifestation of T. gondii infection. The patient was hospitalized for a 30-day history of fever (T max 39.5°C), muscle pain, and progressive weakness of the muscles. A diagnosis of polymyositis was made, and he was started on corticosteroid treatment, which caused no reduction of symptoms. After finding a positive polymerase chain reaction (PCR) assay for T. gondii, together with additional clinical findings, a diagnosis of acute toxoplasmosis was made. Specific treatment with pyrimethamine and sulfadiazine was started, with a progressive reduction of symptoms and normalization of laboratory tests.

Genetics Home Reference: nemaline myopathy

MedlinePlus

... nemaline myopathy interact within the sarcomere to facilitate muscle contraction. When the skeletal muscle cells of people with ... The disorganized proteins cannot interact normally, which disrupts muscle contraction. Inefficient muscle contraction leads to muscle weakness and ...

Global muscle dysfunction as a risk factor of readmission to hospital due to COPD exacerbations.

PubMed

Vilaró, Jordi; Ramirez-Sarmiento, Alba; Martínez-Llorens, Juana M A; Mendoza, Teresa; Alvarez, Miguel; Sánchez-Cayado, Natalia; Vega, Angeles; Gimeno, Elena; Coronell, Carlos; Gea, Joaquim; Roca, Josep; Orozco-Levi, Mauricio

2010-12-01

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with several modifiable (sedentary life-style, smoking, malnutrition, hypoxemia) and non-modifiable (age, co-morbidities, severity of pulmonary function, respiratory infections) risk factors. We hypothesise that most of these risk factors may have a converging and deleterious effects on both respiratory and peripheral muscle function in COPD patients. A multicentre study was carried out in 121 COPD patients (92% males, 63 ± 11 yr, FEV(1), 49 ± 17%pred). Assessments included anthropometrics, lung function, body composition using bioelectrical impedance analysis (BIA), and global muscle function (peripheral muscle (dominant and non-dominant hand grip strength, HGS), inspiratory (PI(max)), and expiratory (PE(max)) muscle strength). GOLD stage, clinical status (stable vs. non-stable) and both current and past hospital admissions due to COPD exacerbations were included as covariates in the analyses. Respiratory and peripheral muscle weakness were observed in all subsets of patients. Muscle weakness, was significantly associated with both current and past hospitalisations. Patients with history of multiple admissions showed increased global muscle weakness after adjusting by FEV(1) (PE(max), OR = 6.8, p < 0.01; PI(max), OR = 2.9, p < 0.05; HGSd, OR = 2.4, and HGSnd, OR = 2.6, p = 0.05). Moreover, a significant increase in both respiratory and peripheral muscle weakness, after adjusting by FEV(1), was associated with current acute exacerbations. Muscle dysfunction, adjusted by GOLD stage, is associated with an increased risk of hospital admissions due to acute episodes of exacerbation of the disease. Current exacerbations further deteriorate muscle dysfunction. Copyright © 2010 Elsevier Ltd. All rights reserved.

The expanding phenotype of mitochondrial myopathy.

PubMed

DiMauro, Salvatore; Gurgel-Giannetti, Juliana

2005-10-01

Our understanding of mitochondrial diseases (defined restrictively as defects in the mitochondrial respiratory chain) continues to progress apace. In this review we provide an update of information regarding disorders that predominantly or exclusively affect skeletal muscle. Most recently described mitochondrial myopathies are due to defects in nuclear DNA, including coenzyme Q10 deficiency, and mutations in genes that control mitochondrial DNA (mtDNA) abundance and structure such as POLG and TK2. Barth syndrome, an X-linked recessive mitochondrial myopathy/cardiopathy, is associated with altered lipid composition of the inner mitochondrial membrane, but a putative secondary impairment of the respiratory chain remains to be documented. Concerning the 'other genome', the role played by mutations in protein encoding genes of mtDNA in causing isolated myopathies has been confirmed. It has also been confirmed that mutations in tRNA genes of mtDNA can cause predominantly myopathic syndromes and - contrary to conventional wisdom - these mutations can be homoplasmic. Defects in the mitochondrial respiratory chain impair energy production and almost invariably involve skeletal muscle, causing exercise intolerance, myalgia, cramps, or fixed weakness, which often affects extraocular muscles and results in droopy eyelids (ptosis) and progressive external ophthalmoplegia.

Physical complications in acute lung injury survivors: a two-year longitudinal prospective study.

PubMed

Fan, Eddy; Dowdy, David W; Colantuoni, Elizabeth; Mendez-Tellez, Pedro A; Sevransky, Jonathan E; Shanholtz, Carl; Himmelfarb, Cheryl R Dennison; Desai, Sanjay V; Ciesla, Nancy; Herridge, Margaret S; Pronovost, Peter J; Needham, Dale M

2014-04-01

Survivors of severe critical illness frequently develop substantial and persistent physical complications, including muscle weakness, impaired physical function, and decreased health-related quality of life. Our objective was to determine the longitudinal epidemiology of muscle weakness, physical function, and health-related quality of life and their associations with critical illness and ICU exposures. A multisite prospective study with longitudinal follow-up at 3, 6, 12, and 24 months after acute lung injury. Thirteen ICUs from four academic teaching hospitals. Two hundred twenty-two survivors of acute lung injury. None. At each time point, patients underwent standardized clinical evaluations of extremity, hand grip, and respiratory muscle strength; anthropometrics (height, weight, mid-arm circumference, and triceps skin fold thickness); 6-minute walk distance, and the Medical Outcomes Short-Form 36 health-related quality of life survey. During their hospitalization, survivors also had detailed daily evaluation of critical illness and related treatment variables. Over one third of survivors had objective evidence of muscle weakness at hospital discharge, with most improving within 12 months. This weakness was associated with substantial impairments in physical function and health-related quality of life that persisted at 24 months. The duration of bed rest during critical illness was consistently associated with weakness throughout 24-month follow-up. The cumulative dose of systematic corticosteroids and use of neuromuscular blockers in the ICU were not associated with weakness. Muscle weakness is common after acute lung injury, usually recovering within 12 months. This weakness is associated with substantial impairments in physical function and health-related quality of life that continue beyond 24 months. These results provide valuable prognostic information regarding physical recovery after acute lung injury. Evidence-based methods to reduce the duration of bed rest during critical illness may be important for improving these long-term impairments.

Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms.

PubMed

Phillips, William D; Vincent, Angela

2016-01-01

Myasthenia gravis is an autoimmune disease of the neuromuscular junction (NMJ) caused by antibodies that attack components of the postsynaptic membrane, impair neuromuscular transmission, and lead to weakness and fatigue of skeletal muscle. This can be generalised or localised to certain muscle groups, and involvement of the bulbar and respiratory muscles can be life threatening. The pathogenesis of myasthenia gravis depends upon the target and isotype of the autoantibodies. Most cases are caused by immunoglobulin (Ig)G1 and IgG3 antibodies to the acetylcholine receptor (AChR). They produce complement-mediated damage and increase the rate of AChR turnover, both mechanisms causing loss of AChR from the postsynaptic membrane. The thymus gland is involved in many patients, and there are experimental and genetic approaches to understand the failure of immune tolerance to the AChR. In a proportion of those patients without AChR antibodies, antibodies to muscle-specific kinase (MuSK), or related proteins such as agrin and low-density lipoprotein receptor-related protein 4 (LRP4), are present. MuSK antibodies are predominantly IgG4 and cause disassembly of the neuromuscular junction by disrupting the physiological function of MuSK in synapse maintenance and adaptation. Here we discuss how knowledge of neuromuscular junction structure and function has fed into understanding the mechanisms of AChR and MuSK antibodies. Myasthenia gravis remains a paradigm for autoantibody-mediated conditions and these observations show how much there is still to learn about synaptic function and pathological mechanisms.

Inhibition of myostatin does not ameliorate disease features of severe spinal muscular atrophy mice.

PubMed

Sumner, Charlotte J; Wee, Claribel D; Warsing, Leigh C; Choe, Dong W; Ng, Andrew S; Lutz, Cathleen; Wagner, Kathryn R

2009-09-01

There is currently no treatment for the inherited motor neuron disease, spinal muscular atrophy (SMA). Severe SMA causes lower motor neuron loss, impaired myofiber development, profound muscle weakness and early mortality. Myostatin is a transforming growth factor-beta family member that inhibits muscle growth. Loss or blockade of myostatin signaling increases muscle mass and improves muscle strength in mouse models of primary muscle disease and in the motor neuron disease, amyotrophic lateral sclerosis. In this study, we evaluated the effects of blocking myostatin signaling in severe SMA mice (hSMN2/delta7SMN/mSmn(-/-)) by two independent strategies: (i) transgenic overexpression of the myostatin inhibitor follistatin and (ii) post-natal administration of a soluble activin receptor IIB (ActRIIB-Fc). SMA mice overexpressing follistatin showed little increase in muscle mass and no improvement in motor function or survival. SMA mice treated with ActRIIB-Fc showed minimal improvement in motor function, and no extension of survival compared with vehicle-treated mice. Together these results suggest that inhibition of myostatin may not be a promising therapeutic strategy in severe forms of SMA.

Glutaric aciduria type II presenting as myopathy and rhabdomyolysis in a teenager.

PubMed

Prasad, Manish; Hussain, Shanawaz

2015-01-01

Late-onset glutaric aciduria type II has been described recently as a rare but treatable cause of proximal myopathy in teenagers and adults. It is an autosomal recessive disease affecting fatty acid, amino acid, and choline metabolism. This is usually a result of 2 defective flavoproteins: either electron transfer flavoprotein (ETF) or electron transfer flavoprotein-ubiquinone oxidoreductase (ETF:QO). We present a 14-year-old boy with a background of autistic spectrum disorder who presented with severe muscle weakness and significant rhabdomyolysis. Before the onset of muscle weakness, he was very active but was completely bedridden at presentation. Diagnosis was established quickly by urine organic acid and plasma acylcarnitine analysis. He has shown significant improvement after starting oral riboflavin supplementation and is now fully mobile. This case highlights that late-onset glutaric aciduria type II is an important differential diagnosis to consider in teenagers presenting with proximal myopathy and rhabdomyolysis and it may not be associated with hypoglycemia. © The Author(s) 2014.

Guidelines for pre-clinical assessment of the acetylcholine receptor--specific passive transfer myasthenia gravis model-Recommendations for methods and experimental designs.

PubMed

Kusner, Linda L; Losen, Mario; Vincent, Angela; Lindstrom, Jon; Tzartos, Socrates; Lazaridis, Konstantinos; Martinez-Martinez, Pilar

2015-08-01

Antibodies against the muscle acetylcholine receptor (AChR) are the most common cause of myasthenia gravis (MG). Passive transfer of AChR antibodies from MG patients into animals reproduces key features of human disease, including antigenic modulation of the AChR, complement-mediated damage of the neuromuscular junction, and muscle weakness. Similarly, AChR antibodies generated by active immunization in experimental autoimmune MG models can subsequently be passively transferred to other animals and induce weakness. The passive transfer model is useful to test therapeutic strategies aimed at the effector mechanism of the autoantibodies. Here we summarize published and unpublished experience using the AChR passive transfer MG model in mice, rats and rhesus monkeys, and give recommendations for the design of preclinical studies in order to facilitate translation of positive and negative results to improve MG therapies. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Cannabinoid signalling inhibits sarcoplasmic Ca2+ release and regulates excitation–contraction coupling in mammalian skeletal muscle

PubMed Central

Oláh, Tamás; Bodnár, Dóra; Tóth, Adrienn; Vincze, János; Fodor, János; Reischl, Barbara; Kovács, Adrienn; Ruzsnavszky, Olga; Dienes, Beatrix; Szentesi, Péter; Friedrich, Oliver

2016-01-01

Key points Marijuana was found to cause muscle weakness, although the exact regulatory role of its receptors (CB1 cannabinoid receptor; CB1R) in the excitation–contraction coupling (ECC) of mammalian skeletal muscle remains unknown.We found that CB1R activation or its knockout did not affect muscle force directly, whereas its activation decreased the Ca2+‐sensitivity of the contractile apparatus and made the muscle fibres more prone to fatigue.We demonstrate that CB1Rs are not connected to the inositol 1,4,5‐trisphosphate pathway either in myotubes or in adult muscle fibres.By contrast, CB1Rs constitutively inhibit sarcoplasmic Ca2+ release and sarcoplasmic reticulum Ca2+ ATPase during ECC in a Gi/o protein‐mediated way in adult skeletal muscle fibres but not in myotubes.These results help with our understanding of the physiological effects and pathological consequences of CB1R activation in skeletal muscle and may be useful in the development of new cannabinoid drugs. Abstract Marijuana was found to cause muscle weakness, although it is unknown whether it affects the muscles directly or modulates only the motor control of the central nervous system. Although the presence of CB1 cannabinoid receptors (CB1R), which are responsible for the psychoactive effects of the drug in the brain, have recently been demonstrated in skeletal muscle, it is unclear how CB1R‐mediated signalling affects the contraction and Ca²⁺ homeostasis of mammalian skeletal muscle. In the present study, we demonstrate that in vitro CB1R activation increased muscle fatigability and decreased the Ca2+‐sensitivity of the contractile apparatus, whereas it did not alter the amplitude of single twitch contractions. In myotubes, CB1R agonists neither evoked, nor influenced inositol 1,4,5‐trisphosphate (IP3)‐mediated Ca2+ transients, nor did they alter excitation–contraction coupling. By contrast, in isolated muscle fibres of wild‐type mice, although CB1R agonists did not evoke IP3‐mediated Ca2+ transients too, they significantly reduced the amplitude of the depolarization‐evoked transients in a pertussis‐toxin sensitive manner, indicating a Gi/o protein‐dependent mechanism. Concurrently, on skeletal muscle fibres isolated from CB1R‐knockout animals, depolarization‐evoked Ca2+ transients, as well qas Ca2+ release flux via ryanodine receptors (RyRs), and the total amount of released Ca2+ was significantly greater than that from wild‐type mice. Our results show that CB1R‐mediated signalling exerts both a constitutive and an agonist‐mediated inhibition on the Ca2+ transients via RyR, regulates the activity of the sarcoplasmic reticulum Ca2+ ATPase and enhances muscle fatigability, which might decrease exercise performance, thus playing a role in myopathies, and therefore should be considered during the development of new cannabinoid drugs. PMID:27641745

Myasthenia Gravis and the Myasthenic Syndrome

PubMed Central

Herrmann, Christian

1970-01-01

Two disorders of neuromuscular transmission producing muscle weakness and easy fatigability which may confront the physician are myasthenia gravis and the myasthenic syndrome. The former has early symptoms and signs of oculobulbar and then extremity weakness with rapid decline of action potential and contractile strength with repetitive use and nerve-muscle stimulation. Anticholinesterases improve strength. The myasthenic syndrome has early symptoms and signs of pelvic girdle, pectoral girdle and proximal limb muscle weakness. This is worst when first starting to use or carry out nerve muscle stimulation in the rested muscles. It improves significantly for a time with use or on rapid stimulation, and then declines with continued activation. Deep tendon reflexes are sluggish or absent. Small cell carcinoma of the lung is often associated. Guanidine improves the strength. Other features and possible underlying mechanisms of the two disorders help to differentiate and treat them. PMID:5457513

Importance and challenges of measuring intrinsic foot muscle strength

PubMed Central

2012-01-01

Background Intrinsic foot muscle weakness has been implicated in a range of foot deformities and disorders. However, to establish a relationship between intrinsic muscle weakness and foot pathology, an objective measure of intrinsic muscle strength is needed. The aim of this review was to provide an overview of the anatomy and role of intrinsic foot muscles, implications of intrinsic weakness and evaluate the different methods used to measure intrinsic foot muscle strength. Method Literature was sourced from database searches of MEDLINE, PubMed, SCOPUS, Cochrane Library, PEDro and CINAHL up to June 2012. Results There is no widely accepted method of measuring intrinsic foot muscle strength. Methods to estimate toe flexor muscle strength include the paper grip test, plantar pressure, toe dynamometry, and the intrinsic positive test. Hand-held dynamometry has excellent interrater and intrarater reliability and limits toe curling, which is an action hypothesised to activate extrinsic toe flexor muscles. However, it is unclear whether any method can actually isolate intrinsic muscle strength. Also most methods measure only toe flexor strength and other actions such as toe extension and abduction have not been adequately assessed. Indirect methods to investigate intrinsic muscle structure and performance include CT, ultrasonography, MRI, EMG, and muscle biopsy. Indirect methods often discriminate between intrinsic and extrinsic muscles, but lack the ability to measure muscle force. Conclusions There are many challenges to accurately measure intrinsic muscle strength in isolation. Most studies have measured toe flexor strength as a surrogate measure of intrinsic muscle strength. Hand-held dynamometry appears to be a promising method of estimating intrinsic muscle strength. However, the contribution of extrinsic muscles cannot be excluded from toe flexor strength measurement. Future research should clarify the relative contribution of intrinsic and extrinsic muscles during intrinsic foot muscle strength testing. PMID:23181771

The ICM research agenda on intensive care unit-acquired weakness.

PubMed

Latronico, Nicola; Herridge, Margaret; Hopkins, Ramona O; Angus, Derek; Hart, Nicholas; Hermans, Greet; Iwashyna, Theodore; Arabi, Yaseen; Citerio, Giuseppe; Wesley Ely, E; Hall, Jesse; Mehta, Sangeeta; Puntillo, Kathleen; Van den Hoeven, Johannes; Wunsch, Hannah; Cook, Deborah; Dos Santos, Claudia; Rubenfeld, Gordon; Vincent, Jean-Louis; Van den Berghe, Greet; Azoulay, Elie; Needham, Dale M

2017-09-01

We present areas of uncertainty concerning intensive care unit-acquired weakness (ICUAW) and identify areas for future research. Age, pre-ICU functional and cognitive state, concurrent illness, frailty, and health trajectories impact outcomes and should be assessed to stratify patients. In the ICU, early assessment of limb and diaphragm muscle strength and function using nonvolitional tests may be useful, but comparison with established methods of global and specific muscle strength and physical function and determination of their reliability and normal values would be important to advance these techniques. Serial measurements of limb and respiratory muscle strength, and systematic screening for dysphagia, would be helpful to clarify if and how weakness of these muscle groups is independently associated with outcome. ICUAW, delirium, and sedatives and analgesics may interact with each other, amplifying the effects of each individual factor. Reduced mobility in patients with hypoactive delirium needs investigations into dysfunction of central and peripheral nervous system motor pathways. Interventional nutritional studies should include muscle mass, strength, and physical function as outcomes, and prioritize elucidation of mechanisms. At follow-up, ICU survivors may suffer from prolonged muscle weakness and wasting and other physical impairments, as well as fatigue without demonstrable weakness on examination. Further studies should evaluate the prevalence and severity of fatigue in ICU survivors and define its association with psychiatric disorders, pain, cognitive impairment, and axonal loss. Finally, methodological issues, including accounting for baseline status, handling of missing data, and inclusion of patient-centered outcome measures should be addressed in future studies.

Immune mechanisms in polymyositis and dermatomyositis and potential targets for therapy.

PubMed

Venalis, Paulius; Lundberg, Ingrid E

2014-03-01

PM and DM are characterized clinically by weakness and low endurance of skeletal muscle. Other organs are frequently involved, suggesting that idiopathic inflammatory myopathies (IIMs) are systemic inflammatory diseases. Involvement of immune mechanisms in IIMs is supported by the presence of T cells, macrophages and dendritic cells in muscle tissue, by the presence of autoantibodies and by HLA-DR being a strong genetic risk factor. T cells may have direct and indirect toxic effects on muscle fibres, causing muscle fibre necrosis and muscle weakness, but the target of the immune reaction is not known. A newly identified T cell subset, CD28(null) T cells, may have cytotoxic effects in the CD4(+) and CD8(+) T cell phenotype. These cells are apoptosis resistant and may contribute to treatment resistance. Several myositis-specific autoantibodies have been identified, but they are all directed against ubiquitously expressed autoantigens and the specificity of the T cell reactivity is not known. These autoantibodies are associated with distinct clinical phenotypes and some with distinct molecular pathways; e.g. sera from patients with anti-Jo-1 autoantibodies may activate the type I IFN system and these sera also contain high levels of B cell activating factor compared with other IIM subsets. The characterization of patients into subgroups based on autoantibody profiles seems to be a promising way to learn more about the specificities of the immune reactions. Careful phenotyping of infiltrating immune cells in muscle tissue before and after specific therapies and relating the molecular findings to clinical outcome measures may be another way to improve knowledge on specific immune mechanism in IIMs. Such information will be important for the development of new therapies.

Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy

PubMed Central

Ling, Karen K. Y.; Gibbs, Rebecca M.; Feng, Zhihua; Ko, Chien-Ping

2012-01-01

Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy. PMID:21968514

Muscle response to leg lengthening during distraction osteogenesis.

PubMed

Thorey, Fritz; Bruenger, Jens; Windhagen, Henning; Witte, Frank

2009-04-01

Continuous lengthening of intact muscles during distraction osteogenesis leads to an increase of sarcomeres and enhances the regeneration of tendons and blood vessels. A high distraction rate leads to an excessive leg and muscle lengthening and might cause damages of muscle fibers with fibrosis, necrosis, and muscle weakness. Complications like muscle contractures or atrophy after postoperative immobilization emphazize the importance of muscles and their function in the clinical outcome. In an animal model of distraction osteogenesis, 18 sheep were operated with an external fixator followed by 4 days latency, 21 days distraction (1.25 mm per day) and 51 days consolidation. The anatomical location (gastrocnemius, peroneus tertius, and first flexor digitorum longus muscle), dimension and occurrence of muscular defects were characterized histologically. The callus formation and leg axis was monitored by weekly X-rays. Additionally, serum creatine kinase was analyzed during a distraction and consolidation period. Significant signs of muscle lesions in all three observed muscles can be found postoperatively, whereas normal callus formation and regular leg axis was observed radiologically. The peroneus tertius and first flexor digitorum longus muscles were found to have significantly more signs of fibrosis, inflammatory, and necrosis. Creatine kinase showed two peaks: 4 and 39 days postoperative as an indication of muscle damage and regeneration. The study implicates that muscle damages should be considered when a long-distance distraction osteogenesis is planned. The surgeon should consider these muscle responses and individually discuss a two-stage treatment or additional muscle tendon releases to minimize the risk of muscle damages.

Osteogenesis Imperfecta: Muscle-Bone Interactions when Bi-directionally Compromised.

PubMed

Phillips, Charlotte L; Jeong, Youngjae

2018-06-16

Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder of skeletal fragility and more recently muscle weakness. This review highlights our current knowledge of the impact of compromised OI muscle function on muscle-bone interactions and skeletal strength in OI. The ramifications of inherent muscle weakness in OI muscle-bone interactions are just beginning to be elucidated. Studies in patients and in OI mouse models implicate altered mechanosensing, energy metabolism, mitochondrial dysfunction, and paracrine/endocrine crosstalk in the pathogenesis of OI. Compromised muscle-bone unit impacts mechanosensing and the ability of OI muscle and bone to respond to physiotherapeutic and pharmacologic treatment strategies. Muscle and bone are both compromised in OI, making it essential to understand the mechanisms responsible for both impaired muscle and bone functions and their interdependence, as this will expand and drive new physiotherapeutic and pharmacological approaches to treat OI and other musculoskeletal disorders.

Impact of Fat Infiltration in Cervical Extensor Muscles on Cervical Lordosis and Neck Pain: A Cross-Sectional Study.

PubMed

Kim, Choong-Young; Lee, Sang-Min; Lim, Seong-An; Choi, Yong-Soo

2018-06-01

Weakness of cervical extensor muscles causes loss of cervical lordosis, which could also cause neck pain. The aim of this study was to investigate the impact of fat infiltration in cervical extensor muscles on cervical lordosis and neck pain. Fifty-six patients who suffered from neck pain were included in this study. Fat infiltration in cervical extensor muscles was measured at each level of C2-3 and C6-7 using axial magnetic resonance imaging. The visual analogue scale (VAS), 12-Item Short Form Health Survey (SF-12), and Neck Disability Index (NDI) were used for clinical assessment. The mean fat infiltration was 206.3 mm 2 (20.3%) at C2-3 and 240.6 mm 2 (19.5%) at C6-7. Fat infiltration in cervical extensor muscles was associated with high VAS scores at both levels ( p = 0.047 at C2-3; p = 0.009 at C6-7). At C2-3, there was a negative correlation between fat infiltration of the cervical extensor muscles and cervical lordosis (r = -0.216; p = 0.020). At C6-7, fat infiltration in the cervical extensor muscles was closely related to NDI ( p = 0.003) and SF-12 ( p > 0.05). However, there was no significant correlation between cervical lordosis and clinical outcomes (VAS, p = 0.112; NDI, p = 0.087; and SF-12, p > 0.05). These results suggest that fat infiltration in the upper cervical extensor muscles has relevance to the loss of cervical lordosis, whereas fat infiltration in the lower cervical extensor muscles is associated with cervical functional disability.

Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F

PubMed Central

Putker, K.; Tanganyika-de Winter, C. L.; Boertje-van der Meulen, J. W.; van Vliet, L.; Overzier, M.; Plomp, J. J.; Aartsma-Rus, A.; van Putten, M.

2017-01-01

Limb-girdle muscular dystrophy types 2D and 2F (LGMD 2D and 2F) are autosomal recessive disorders caused by mutations in the alpha- and delta sarcoglycan genes, respectively, leading to severe muscle weakness and degeneration. The cause of the disease has been well characterized and a number of animal models are available for pre-clinical studies to test potential therapeutic interventions. To facilitate transition from drug discovery to clinical trials, standardized procedures and natural disease history data were collected for these mouse models. Implementing the TREAD-NMD standardized operating procedures, we here subjected LGMD2D (SGCA-null), LGMD2F (SGCD-null) and wild type (C57BL/6J) mice to five functional tests from the age of 4 to 32 weeks. To assess whether the functional test regime interfered with disease pathology, sedentary groups were taken along. Muscle physiology testing of tibialis anterior muscle was performed at the age of 34 weeks. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Mice successfully accomplished the functional tests, which did not interfere with disease pathology. Muscle function of SGCA- and SGCD-null mice was impaired and declined over time. Interestingly, female SGCD-null mice outperformed males in the two and four limb hanging tests, which proved the most suitable non-invasive tests to assess muscle function. Muscle physiology testing of tibialis anterior muscle revealed lower specific force and higher susceptibility to eccentric-induced damage in LGMD mice. Analyzing muscle histopathology and gene expression, we identified the diaphragm as the most affected muscle in LGMD strains. Cardiac fibrosis was found in SGCD-null mice, being more severe in males than in females. Our study offers a comprehensive natural history dataset which will be useful to design standardized tests and future pre-clinical studies in LGMD2D and 2F mice. PMID:28797108

Congenital Myasthenic Syndromes or Inherited Disorders of Neuromuscular Transmission: Recent Discoveries and Open Questions

PubMed Central

Nicole, Sophie; Azuma, Yoshiteru; Bauché, Stéphanie; Eymard, Bruno; Lochmüller, Hanns; Slater, Clarke

2017-01-01

Congenital myasthenic syndromes (CMS) form a heterogeneous group of rare diseases characterized by fatigable muscle weakness. They are genetically-inherited and caused by defective synaptic transmission at the cholinergic neuromuscular junction (NMJ). The number of genes known to cause CMS when mutated is currently 30, and the relationship between fatigable muscle weakness and defective functions is quite well-understood for many of them. However, some of the most recent discoveries in individuals with CMS challenge our knowledge of the NMJ, where the basis of the pathology has mostly been investigated in animal models. Frontier forms between CMS and congenital myopathy, which have been genetically and clinically identified, underline the poorly understood interplay between the synaptic and extrasynaptic molecules in the neuromuscular system. In addition, precise electrophysiological and histopathological investigations of individuals with CMS suggest an important role of NMJ plasticity in the response to CMS pathogenesis. While efficient drug-based treatments are already available to improve neuromuscular transmission for most forms of CMS, others, as well as neurological and muscular comorbidities, remain resistant. Taken together, the available pathological data point to physiological issues which remain to be understood in order to achieve precision medicine with efficient therapeutics for all individuals suffering from CMS. PMID:29125502

Respiratory muscle function in infants with spinal muscular atrophy type I.

PubMed

Finkel, Richard S; Weiner, Daniel J; Mayer, Oscar H; McDonough, Joseph M; Panitch, Howard B

2014-12-01

To determine the feasibility and safety of respiratory muscle function testing in weak infants with a progressive neuromuscular disorder. Respiratory insufficiency is the major cause of morbidity and mortality in infants with spinal muscular atrophy type I (SMA-I). Tests of respiratory muscle strength, endurance, and breathing patterns can be performed safely in SMA-I infants. Useful data can be collected which parallels the clinical course of pulmonary function in SMA-I. An exploratory study of respiratory muscle function testing and breathing patterns in seven infants with SMA-I seen in our neuromuscular clinic. Measurements were made at initial study visit and, where possible, longitudinally over time. We measured maximal inspiratory (MIP) and transdiaphragmatic pressures, mean transdiaphragmatic pressure, airway occlusion pressure at 100 msec of inspiration, inspiratory and total respiratory cycle time, and aspects of relative thoracoabdominal motion using respiratory inductive plethysmography (RIP). The tension time index of the diaphragm and of the respiratory muscles, phase angle (Φ), phase relation during the total breath, and labored breathing index were calculated. Age at baseline study was 54-237 (median 131) days. Reliable data were obtained safely for MIP, phase angle, labored breathing index, and the invasive and non-invasive tension time indices, even in very weak infants. Data obtained corresponded to the clinical estimate of severity and predicted the need for respiratory support. The testing employed was both safe and feasible. Measurements of MIP and RIP are easily performed tests that are well tolerated and provide clinically useful information for infants with SMA-I. © 2014 Wiley Periodicals, Inc.

Effects of muscle contraction on cervical vestibular evoked myogenic potentials in normal subjects.

PubMed

Rosengren, Sally M

2015-11-01

Cervical vestibular evoked myogenic potentials (cVEMPs) are vestibular-dependent muscle reflexes recorded from the sternocleidomastoid (SCM) muscles in humans. cVEMP amplitude is modulated by stimulus intensity and SCM muscle contraction strength, but the effect of muscle contraction is less well-documented. The effects of intensity and contraction were therefore compared in 25 normal subjects over a wide range of contractions. cVEMPs were recorded at different contraction levels while holding stimulus intensity constant and at different intensities while holding SCM contraction constant. The effect of muscle contraction on cVEMP amplitude was linear for most of the range of muscle contractions in the majority of subjects (mean R(2)=0.93), although there were some nonlinearities when the contraction was either very weak or very strong. Very weak contractions were associated with absent responses, incomplete morphology and prolonged p13 latencies. Normalization of amplitudes, by dividing the p13-n23 amplitude by the muscle contraction estimate, reduced the effect of muscle contraction, but tended to underestimate the amplitude with weak contractions. Minimum contraction levels are required for accurate interpretation of cVEMPs. These data highlight the importance of measuring SCM contraction strength when recording cVEMPs. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Bunion: Strengthening Foot Muscles to Reduce Pain and Improve Mobility.

PubMed

2016-07-01

Foot pain discourages physical activity, and less activity harms overall health. Bunion, extra bone and tissue at the base of the big toe, is a frequent cause of foot pain. More than 64 million Americans have bunions that can lead to painful walking. Bunions affect some 35% of women over the age of 65. Bunions can be removed by surgery, which can reduce pain and improve your ability to walk and exercise, but up to 15% of bunions return. Weak muscles may play a role in bunion-related pain and movement problems. In a review of prior research and commentary on this topic published in the July 2016 issue of JOSPT, the author identifies muscle-strengthening exercises that may help people with bunions. J Orthop Sports Phys Ther 2016;46(7):606. doi:10.2519/jospt.2016.0504.

Biomechanical consequences of running with deep core muscle weakness.

PubMed

Raabe, Margaret E; Chaudhari, Ajit M W

2018-01-23

The deep core muscles are often neglected or improperly trained in athletes. Improper function of this musculature may lead to abnormal spinal loading, muscle strain, or injury to spinal structures, all of which have been associated with increased low back pain (LBP) risk. The purpose of this study was to identify potential strategies used to compensate for weakness of the deep core musculature during running and to identify accompanying changes in compressive and shear spinal loads. Kinematically-driven simulations of overground running were created for eight healthy young adults in OpenSim at increasing levels of deep core muscle weakness. The deep core muscles (multifidus, quadratus lumborum, psoas, and deep fascicles of the erector spinae) were weakened individually and together. The superficial longissimus thoracis was a significant compensator for 4 out of 5 weakness conditions (p < 0.05). The deep erector spinae required the largest compensations when weakened individually (up to a 45 ± 10% increase in compensating muscle force production, p = 0.004), revealing it may contribute most to controlling running kinematics. With complete deep core muscle weakness, peak anterior shear loading increased on all lumbar vertebrae (up to 19%, p = 0.001). Additionally, compressive spinal loading increased on the upper lumbar vertebrae (up to 15%, p = 0.007) and decreased on the lower lumbar vertebrae (up to 8%, p = 0.008). Muscular compensations may increase risk of muscular fatigue or injury and increased spinal loading over numerous gait cycles may result in damage to spinal structures. Therefore, insufficient strength of the deep core musculature may increase a runner's risk of developing LBP. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sarcopenia and its individual criteria are associated, in part, with mortality among patients on hemodialysis.

PubMed

Kittiskulnam, Piyawan; Chertow, Glenn M; Carrero, Juan J; Delgado, Cynthia; Kaysen, George A; Johansen, Kirsten L

2017-07-01

The relative importance of sarcopenia and its individual components as independent predictors of mortality in the dialysis population has not been determined. We estimated whole-body muscle mass using pre-dialysis bioimpedance spectroscopy measurements in 645 ACTIVE/ADIPOSE-enrolled prevalent hemodialysis patients from San Francisco and Atlanta. Low muscle mass was defined as two standard deviations below sex-specific means for young adults from NHANES and indexed to height 2 , body weight, body surface area, or body mass index. We evaluated the association of sarcopenia (low muscle mass) by four indexing methods, weak hand grip strength, and slow gait speed with mortality. Seventy-eight deaths were observed during a mean follow-up of 1.9 years. Sarcopenia was not significantly associated with mortality after adjusting for covariates. No muscle mass criteria were associated with death, regardless of indexing metrics. In contrast, having weak grip strength or slow walking speed was associated with mortality in the adjusted model. Only gait slowness significantly improved the predictive accuracy for death with an increase in C-statistic from 0.63 to 0.68. However, both gait slowness and hand grip weakness significantly improved the net reclassification index compared to models without performance measures (50.5% for slowness and 33.7% for weakness), whereas models with muscle size did not. Neither sarcopenia nor low muscle mass by itself was a better predictor of mortality than functional limitation alone in patients receiving hemodialysis. Thus, physical performance measures, including slow gait speed and weak hand grip strength, were associated with mortality even after adjustment for muscle size and other confounders. Published by Elsevier Inc.

Cautious Use of Intrathecal Baclofen in Walking Spastic Patients: Results on Long-term Follow-up.

PubMed

Dones, Ivano; Nazzi, Vittoria; Tringali, Giovanni; Broggi, Giovanni

2006-04-01

Intrathecal baclofen is presently the most effective treatment for diffuse spasticity whatever the cause. The fact that both spasticity is always accompanied by a degree of muscle weakness and that any antispastic treatment causes a decrease in muscle strength indicate that major attention must be paid in treating spasticity in ambulant patients. Methods.  We present here a retrospective study, approved by the insitutional ethics committee, of 22 ambulant spastic patients, selected as homogeneous for disease and disease duration, who were treated with intrathecal baclofen at the Istituto Nazionale Neurologico "C.Besta" in Milan. These patients were followed-up for to 15 years of treatment and their clinical assessment was enriched by the evaluation of their functional independence measurement (FIM) before and during treatment. Results.  There was improvement in quality of life as measured by the FIM scale; however, an increase in the patient's motor performance could not be detected. Conclusion.  Although we did not show any improvement in muscle performance, intrathecal baclofen did improve daily quality of life, even in spastic patients who were able to walk.

Post-Polio Syndrome and the Late Effects of Poliomyelitis: Part 2. Treatment, Management and Prognosis.

PubMed

Lo, Julian K; Robinson, Lawrence R

2018-05-12

Post-Polio Syndrome (PPS) is characterized by new muscle weakness and/or muscle fatigability that occurs many years following the initial poliomyelitis illness. An individualized approach to rehabilitation management is critical. Interventions may include rehabilitation management strategies, adaptive equipment, orthotic equipment, gait/mobility aids and a variety of therapeutic exercises. The progression of muscle weakness in PPS is typically slow and gradual; however, there is also variability in both the natural history of weakness and functional prognosis. Further research is required to determine the effectiveness of selected medical treatment. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Clinical spectrum of rhabdomyolysis presented to pediatric emergency department

PubMed Central

2013-01-01

Background Rhabdomyolysis is a potentially life-threatening syndrome that can develop from a variety of causes. The aim of the work is to analyze the clinical spectrum and to evaluate the prevalence of various etiologies in children, who present to the emergency department (ED) with rhabdomyolysis. Methods During a 6-year study period, we retrospectively analyzed the medical charts of patients, aged 18 years or younger, with a definite diagnosis of rhabdomyolysis and serum creatinine phosphokinase (CK) levels greater than 1000IU/L. We analyzed the clinical spectrum and evaluated the potential risk factors of acute renal failure (ARF). Results Thirty-seven patients (mean age = 10.2 ± 5.5 years), including 26 males and 11 females, were enrolled in the study. Two of the most common presented symptoms in these 37 patients were muscle pain and muscle weakness (83.8% and 73%, respectively). Dark urine was reported in only 5.4% of the patients. The leading cause of rhabdomyolysis in the 0- to 9-year age group was presumed infection, and the leading cause in the 10- to 18-year age group was trauma and exercise. The incidence of ARF associated with rhabdomyolysis was 8.1 % and no child needed for renal replacement therapy (RRT). We did not identify any reliable predictors of ARF or need for RRT. Conclusions The classic triad of symptoms of rhabdomyolysis includes myalgia, weakness and dark urine are not always presented in children. The cause of rhabdomyolysis in younger age is different from that of teenager group. However, the prognosis of rhabdomyolysis was good with appropriate management. PMID:24004920

Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations.

PubMed

Guergueltcheva, Velina; Müller, Juliane S; Dusl, Marina; Senderek, Jan; Oldfors, Anders; Lindbergh, Christopher; Maxwell, Susan; Colomer, Jaume; Mallebrera, Cecilia Jimenez; Nascimento, Andres; Vilchez, Juan J; Muelas, Nuria; Kirschner, Janbernd; Nafissi, Shahriar; Kariminejad, Ariana; Nilipour, Yalda; Bozorgmehr, Bita; Najmabadi, Hossein; Rodolico, Carmelo; Sieb, Jörn P; Schlotter, Beate; Schoser, Benedikt; Herrmann, Ralf; Voit, Thomas; Steinlein, Ortrud K; Najafi, Abdolhamid; Urtizberea, Andoni; Soler, Doriette M; Muntoni, Francesco; Hanna, Michael G; Chaouch, Amina; Straub, Volker; Bushby, Kate; Palace, Jacqueline; Beeson, David; Abicht, Angela; Lochmüller, Hanns

2012-05-01

Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders of the neuromuscular junction. A difficult to diagnose subgroup of CMS is characterised by proximal muscle weakness and fatigue while ocular and facial involvement is only minimal. DOK7 mutations have been identified as causing the disorder in about half of the cases. More recently, using classical positional cloning, we have identified mutations in a previously unrecognised CMS gene, GFPT1, in a series of DOK7-negative cases. However, detailed description of clinical features of GFPT1 patients has not been reported yet. Here we describe the clinical picture of 24 limb-girdle CMS (LG-CMS) patients and pathological findings of 18 of them, all carrying GFPT1 mutations. Additional patients with CMS, but without tubular aggregates, and patients with non-fatigable weakness with tubular aggregates were also screened. In most patients with GFPT1 mutations, onset of the disease occurs in the first decade of life with characteristic limb-girdle weakness and fatigue. A common feature was beneficial and sustained response to acetylcholinesterase inhibitor treatment. Most of the patients who had a muscle biopsy showed tubular aggregates in myofibers. Analysis of endplate morphology in one of the patients revealed unspecific abnormalities. Our study delineates the phenotype of CMS associated with GFPT1 mutations and expands the understanding of neuromuscular junction disorders. As tubular aggregates in context of a neuromuscular transmission defect appear to be highly indicative, we suggest calling this condition congenital myasthenic syndrome with tubular aggregates (CMS-TA).

Changes in actin structural transitions associated with oxidative inhibition of muscle contraction.

PubMed

Prochniewicz, Ewa; Spakowicz, Daniel; Thomas, David D

2008-11-11

We have used transient phosphorescence anisotropy (TPA) to detect changes in actin structural dynamics associated with oxidative inhibition of muscle contraction. Contractility of skinned rabbit psoas muscle fibers was inhibited by treatment with 50 mM H 2O 2, which induced oxidative modifications in the myosin head and in actin, as previously reported. Using proteins purified from oxidized and unoxidized muscle, we used TPA to measure the effects of weakly (+ATP) and strongly (no ATP) bound myosin heads (S1) on the microsecond dynamics of actin labeled at Cys374 with erythrosine iodoacetamide. Oxidative modification of S1 had no effect on actin dynamics in the absence of ATP (strong binding complex), but restricted the dynamics in the presence of ATP (weakly bound complex). In contrast, oxidative modification of actin did not have a significant effect on the weak-to-strong transitions. Thus, we concluded that (1) the effects of oxidation on the dynamics of actin in the actomyosin complex are predominantly determined by oxidation-induced changes in S1, and (2) changes in weak-to-strong structural transitions in actin and myosin are coupled to each other and are associated with oxidative inhibition of muscle contractility.

Changes in actin structural transitions associated with oxidative inhibition of muscle contraction

PubMed Central

Prochniewicz, Ewa; Spakowicz, Daniel; Thomas, David D.

2011-01-01

We have used transient phosphorescence anisotropy (TPA) to detect changes in actin structural dynamics associated with oxidative inhibition of muscle contraction. Contractility of skinned rabbit psoas muscle fibers was inhibited by treatment with 50 mM H2O2, which induced oxidative modifications in the myosin head and in actin, as previously reported. Using proteins purified from oxidized and unoxidized muscle, we used TPA to measure the effects of weakly (+ATP) and strongly (no ATP) bound myosin heads (S1) on the microsecond dynamics of actin labeled at Cys374 with erythrosine iodoacetamide. Oxidative modification of S1 had no effect on actin dynamics in the absence of ATP (strong binding complex), but restricted the dynamics in the presence of ATP (weakly bound complex). In contrast, oxidative modification of actin did not have a significant effect on the weak-to-strong transitions. Thus, we concluded that (1) the effects of oxidation on the dynamics of actin in the actomyosin complex are predominantly determined by oxidation-induced changes in S1, and (2) changes in weak-to-strong structural transitions in actin and myosin are coupled to each other and are associated with oxidative inhibition of muscle contractility. PMID:18855423

Muscle Strength Imbalance in the Hip Joint Caused by Fast Movements

NASA Astrophysics Data System (ADS)

Pontaga, I.

2003-07-01

Eleven male sportsmen at the age of 24.3 ± 4.5 were examined. Their hip joint flexors and extensors were tested by an "REV-9000" Technogym dynamometer system during isokinetic movements at angular velocities of 100 (low) and 200 (high) °/s. The range of hip joint movements was from 30 (in flexion) to 130° (in extension). Torque values and their ratios for hip flexors and extensors at different angular positions were obtained and compared. It is shown that, at high speeds, the flexion movement significantly raises ( p < 0.001) the torque ratios of flexors and extensors in flexion positions of the hip (50 and 60°). These ratios approximately twofold exceed their values at moderate velocities. The weakness of hip joint extensors in extreme flexion positions of the hip may cause injury of this group of muscles at fast movements.

Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.

PubMed

Béhin, A; Jardel, C; Claeys, K G; Fagart, J; Louha, M; Romero, N B; Laforêt, P; Eymard, B; Lombès, A

2012-02-28

In this study we aim to demonstrate the occurrence of adult forms of TK2 mutations causing progressive mitochondrial myopathy with significant muscle mitochondrial DNA (mtDNA) depletion. Patients' investigations included serum creatine kinase, blood lactate, electromyographic, echocardiographic, and functional respiratory analyses as well as TK2 gene sequencing and TK2 activity measurement. Mitochondrial activities and mtDNA were analyzed in the patients' muscle biopsy. The 3 adult patients with TK2 mutations presented with slowly progressive myopathy compatible with a fairly normal life during decades. Apart from its much slower progression, these patients' phenotype closely resembled that of pediatric cases including early onset, absence of CNS symptoms, generalized muscle weakness predominating on axial and proximal muscles but affecting facial, ocular, and respiratory muscles, typical mitochondrial myopathy with a mosaic pattern of COX-negative and ragged-red fibers, combined mtDNA-dependent respiratory complexes deficiency and mtDNA depletion. In accordance with the disease's relatively slow progression, the residual mtDNA content was higher than that observed in pediatric cases. That difference was not explained by the type of the TK2 mutations or by the residual TK2 activity. TK2 mutations can cause mitochondrial myopathy with a slow progression. Comparison of patients with similar mutations but different disease progression might address potential mechanisms of mtDNA maintenance modulation.

Pharmacological inhibition of myostatin protects against skeletal muscle atrophy and weakness after anterior cruciate ligament tear.

PubMed

Wurtzel, Caroline Nw; Gumucio, Jonathan P; Grekin, Jeremy A; Khouri, Roger K; Russell, Alan J; Bedi, Asheesh; Mendias, Christopher L

2017-11-01

Anterior cruciate ligament (ACL) tears are among the most frequent knee injuries in sports medicine, with tear rates in the US up to 250,000 per year. Many patients who suffer from ACL tears have persistent atrophy and weakness even after considerable rehabilitation. Myostatin is a cytokine that directly induces muscle atrophy, and previous studies rodent models and patients have demonstrated an upregulation of myostatin after ACL tear. Using a preclinical rat model, our objective was to determine if the use of a bioneutralizing antibody against myostatin could prevent muscle atrophy and weakness after ACL tear. Rats underwent a surgically induced ACL tear and were treated with either a bioneutralizing antibody against myostatin (10B3, GlaxoSmithKline) or a sham antibody (E1-82.15, GlaxoSmithKline). Muscles were harvested at either 7 or 21 days after induction of a tear to measure changes in contractile function, fiber size, and genes involved in muscle atrophy and hypertrophy. These time points were selected to evaluate early and later changes in muscle structure and function. Compared to the sham antibody group, 7 days after ACL tear, myostatin inhibition reduced the expression of proteolytic genes and induced the expression of hypertrophy genes. These early changes in gene expression lead to a 22% increase in muscle fiber cross-sectional area and a 10% improvement in maximum isometric force production that were observed 21 days after ACL tear. Overall, myostatin inhibition lead to several favorable, although modest, changes in molecular biomarkers of muscle regeneration and reduced muscle atrophy and weakness following ACL tear. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2499-2505, 2017. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Effect of complement and its regulation on myasthenia gravis pathogenesis

PubMed Central

Kusner, Linda L; Kaminski, Henry J; Soltys, Jindrich

2015-01-01

Myasthenia gravis (MG) is primarily caused by antibodies directed towards the skeletal muscle acetylcholine receptor, leading to muscle weakness. Although these antibodies may induce compromise of neuromuscular transmission by blocking acetylcholine receptor function or antigenic modulation, the predominant mechanism of injury to the neuromuscular junction is complement-mediated lysis of the postsynaptic membrane. The vast majority of data to support the role of complement derives from experimentally acquired MG (EAMG). In this article, we review studies that demonstrate the central role of complement in EAMG and MG pathogenesis along with the emerging role of complement in T- and B-cell function, as well as the potential for complement inhibitor-based therapy to treat human MG. PMID:20477586

Mutation-specific effects on thin filament length in thin filament myopathy.

PubMed

Winter, Josine M de; Joureau, Barbara; Lee, Eun-Jeong; Kiss, Balázs; Yuen, Michaela; Gupta, Vandana A; Pappas, Christopher T; Gregorio, Carol C; Stienen, Ger J M; Edvardson, Simon; Wallgren-Pettersson, Carina; Lehtokari, Vilma-Lotta; Pelin, Katarina; Malfatti, Edoardo; Romero, Norma B; Engelen, Baziel G van; Voermans, Nicol C; Donkervoort, Sandra; Bönnemann, C G; Clarke, Nigel F; Beggs, Alan H; Granzier, Henk; Ottenheijm, Coen A C

2016-06-01

Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation. We investigated the sarcomere length-dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41. Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in NEB and ACTA1, the lower force was associated with downward shifted force-sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional Neb knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin-thick filament overlap. These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths. Ann Neurol 2016;79:959-969. © 2016 American Neurological Association.

Evaluation of muscle hyperactivity of the grimacing muscles by unilateral tight eyelid closure and stapedius muscle tone.

PubMed

Shiba, Masato; Matsuo, Kiyoshi; Ban, Ryokuya; Nagai, Fumio

2012-10-01

Muscle hyperactivity of grimacing muscles, including the orbicularis oculi and corrugator supercilii muscles that cause crow's feet and a glabellar frown line with ageing, cannot be accurately evaluated by surface observation. In 71 subjects, this study investigated the extent to which grimacing muscles are innervated by the bilateral motor cortices, whether the corticofacial projection to the grimacing muscles affects the facially innervated stapedius muscle tone by measuring static compliance of the tympanic membrane, and whether unilateral tight eyelid closure with contraction of the grimacing muscles changes static compliance. Unilateral tight eyelid closure and its subsequent change in the contralateral vertical medial eyebrow position revealed that motor neurons of the orbicularis oculi and corrugator supercilii muscles were innervated by the bilateral motor cortices with weak-to-strong contralateral dominance. The orbicularis oculi, corrugator supercilii, and stapedius muscles innervated by the bilateral motor cortices had increased muscle hyperactivity, which lowered the vertical medial eyebrow position and decreased the static compliance of the tympanic membrane more than those innervated by the unilateral motor cortex. Unilateral enhanced tight eyelid closure with contraction of the grimacing muscles in certain subjects ipsilaterally decreased the static compliance with increased contraction of the stapedius muscle, which probably occurs to immobilise the tympanic membrane and protect the inner ear from loud sound. Evaluation of unilateral tight eyelid closure and the subsequent change in the contralateral vertical medial eyebrow position as well as a measurement of the static compliance for the stapedius muscle tone has revealed muscle hyperactivity of grimacing muscles.

GNE Myopathy in Turkish Sisters with a Novel Homozygous Mutation

PubMed Central

Diniz, Gulden; Secil, Yaprak; Ceylaner, Serdar; Tokucoglu, Figen; Türe, Sabiha; Celebisoy, Mehmet; İncesu, Tülay Kurt; Akhan, Galip

2016-01-01

Background. Hereditary inclusion body myopathy is caused by biallelic defects in the GNE gene located on chromosome 9p13. It generally affects adults older than 20 years of age. Methods and Results. In this study, we present two Turkish sisters with progressive myopathy and describe a novel mutation in the GNE gene. Both sisters had slightly higher levels of creatine kinase (CK) and muscle weakness. The older sister presented at 38 years of age with an inability to climb steps, weakness, and a steppage gait. Her younger sister was 36 years old and had similar symptoms. The first symptoms of the disorder were seen when the sisters were 30 and 34 years old, respectively. The muscle biopsy showed primary myopathic features and presence of rimmed vacuoles. DNA analysis demonstrated the presence of previously unknown homozygous mutations [c.2152 G>A (p.A718T)] in the GNE genes. Conclusion. Based on our literature survey, we believe that ours is the first confirmed case of primary GNE myopathy with a novel missense mutation in Turkey. These patients illustrate that the muscle biopsy is still an important method for the differential diagnosis of vacuolar myopathies in that the detection of inclusions is required for the definitive diagnosis. PMID:27298745

A new case of limb girdle muscular dystrophy 2G in a Greek patient, founder effect and review of the literature.

PubMed

Brusa, Roberta; Magri, Francesca; Papadimitriou, Dimitra; Govoni, Alessandra; Del Bo, Roberto; Ciscato, Patrizia; Savarese, Marco; Cinnante, Claudia; Walter, Maggie C; Abicht, Angela; Bulst, Stefanie; Corti, Stefania; Moggio, Maurizio; Bresolin, Nereo; Nigro, Vincenzo; Comi, Giacomo Pietro

2018-04-13

Limb girdle muscular dystrophy (LGMD) type 2G is a rare form of muscle disease, described only in a few patients worldwide, caused by mutations in TCAP gene, encoding the protein telethonin. It is characterised by proximal limb muscle weakness associated with distal involvement of lower limbs, starting in the first or second decade of life. We describe the case of a 37-year-old woman of Greek origin, affected by disto-proximal lower limb weakness. No cardiac or respiratory involvement was detected. Muscle biopsy showed myopathic changes with type I fibre hypotrophy, cytoplasmic vacuoles, lipid overload, multiple central nuclei and fibre splittings; ultrastructural examination showed metabolic abnormalities. Next generation sequencing analysis detected a homozygous frameshift mutation in the TCAP gene (c.90_91del), previously described in one Turkish family. Immunostaining and Western blot analysis showed complete absence of telethonin. Interestingly, Single Nucleotide Polymorphism analysis of the 10 Mb genomic region containing the TCAP gene showed a shared homozygous haplotype of both the Greek and the Turkish patients, thus suggesting a possible founder effect of TCAP gene c.90_91del mutation in this part of the Mediterranean area. Copyright © 2018 Elsevier B.V. All rights reserved.

Cortical drive to breathe in amyotrophic lateral sclerosis: a dyspnoea-worsening defence?

PubMed

Georges, Marjolaine; Morawiec, Elise; Raux, Mathieu; Gonzalez-Bermejo, Jésus; Pradat, Pierre-François; Similowski, Thomas; Morélot-Panzini, Capucine

2016-06-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing diaphragm weakness that can be partially compensated by inspiratory neck muscle recruitment. This disappears during sleep, which is compatible with a cortical contribution to the drive to breathe. We hypothesised that ALS patients with respiratory failure exhibit respiratory-related cortical activity, relieved by noninvasive ventilation (NIV) and related to dyspnoea.We studied 14 ALS patients with respiratory failure. Electroencephalographic recordings (EEGs) and electromyographic recordings of inspiratory neck muscles were performed during spontaneous breathing and NIV. Dyspnoea was evaluated using the Multidimensional Dyspnea Profile.Eight patients exhibited slow EEG negativities preceding inspiration (pre-inspiratory potentials) during spontaneous breathing. Pre-inspiratory potentials were attenuated during NIV (p=0.04). Patients without pre-inspiratory potentials presented more advanced forms of ALS and more severe respiratory impairment, but less severe dyspnoea. Patients with pre-inspiratory potentials had stronger inspiratory neck muscle activation and more severe dyspnoea during spontaneous breathing.ALS-related diaphragm weakness can engage cortical resources to augment the neural drive to breathe. This might reflect a compensatory mechanism, with the intensity of dyspnoea a negative consequence. Disease progression and the corresponding neural loss could abolish this phenomenon. A putative cognitive cost should be investigated. Copyright ©ERS 2016.

Influenza A Virus Infection Damages Zebrafish Skeletal Muscle and Exacerbates Disease in Zebrafish Modeling Duchenne Muscular Dystrophy

PubMed Central

Goody, Michelle; Jurczyszak, Denise; Kim, Carol; Henry, Clarissa

2017-01-01

INTRODUCTION: Both genetic and infectious diseases can result in skeletal muscle degeneration, inflammation, pain, and/or weakness. Duchenne muscular dystrophy (DMD) is the most common congenital muscle disease. DMD causes progressive muscle wasting due to mutations in Dystrophin. Influenza A and B viruses are frequently associated with muscle complications, especially in children. Infections activate an immune response and immunosuppressant drugs reduce DMD symptoms. These data suggest that the immune system may contribute to muscle pathology. However, roles of the immune response in DMD and Influenza muscle complications are not well understood. Zebrafish with dmd mutations are a well-characterized model in which to study the molecular and cellular mechanisms of DMD pathology. We recently showed that zebrafish can be infected by human Influenza A virus (IAV). Thus, the zebrafish is a powerful system with which to ask questions about the etiology and mechanisms of muscle damage due to genetic and/or infectious diseases. METHODS: We infected zebrafish with IAV and assayed muscle tissue structure, sarcolemma integrity, cell-extracellular matrix (ECM) attachment, and molecular and cellular markers of inflammation in response to IAV infection alone or in the context of DMD. RESULTS: We find that IAV-infected zebrafish display mild muscle degeneration with sarcolemma damage and compromised ECM adhesion. An innate immune response is elicited in muscle in IAV-infected zebrafish: NFkB signaling is activated, pro-inflammatory cytokine expression is upregulated, and neutrophils localize to sites of muscle damage. IAV-infected dmd mutants display more severe muscle damage than would be expected from an additive effect of dmd mutation and IAV infection, suggesting that muscle damage caused by Dystrophin-deficiency and IAV infection is synergistic. DISCUSSION: These data demonstrate the importance of preventing IAV infections in individuals with genetic muscle diseases. Elucidating the mechanisms of immune-mediated muscle damage will not only apply to DMD and IAV, but also to other conditions where the immune system, inflammation, and muscle tissue are known to be affected, such as autoimmune diseases, cancer, and aging. PMID:29188128

Influenza A Virus Infection Damages Zebrafish Skeletal Muscle and Exacerbates Disease in Zebrafish Modeling Duchenne Muscular Dystrophy.

PubMed

Goody, Michelle; Jurczyszak, Denise; Kim, Carol; Henry, Clarissa

2017-10-25

Both genetic and infectious diseases can result in skeletal muscle degeneration, inflammation, pain, and/or weakness. Duchenne muscular dystrophy (DMD) is the most common congenital muscle disease. DMD causes progressive muscle wasting due to mutations in Dystrophin. Influenza A and B viruses are frequently associated with muscle complications, especially in children. Infections activate an immune response and immunosuppressant drugs reduce DMD symptoms. These data suggest that the immune system may contribute to muscle pathology. However, roles of the immune response in DMD and Influenza muscle complications are not well understood. Zebrafish with dmd mutations are a well-characterized model in which to study the molecular and cellular mechanisms of DMD pathology. We recently showed that zebrafish can be infected by human Influenza A virus (IAV). Thus, the zebrafish is a powerful system with which to ask questions about the etiology and mechanisms of muscle damage due to genetic and/or infectious diseases. We infected zebrafish with IAV and assayed muscle tissue structure, sarcolemma integrity, cell-extracellular matrix (ECM) attachment, and molecular and cellular markers of inflammation in response to IAV infection alone or in the context of DMD. We find that IAV-infected zebrafish display mild muscle degeneration with sarcolemma damage and compromised ECM adhesion. An innate immune response is elicited in muscle in IAV-infected zebrafish: NFkB signaling is activated, pro-inflammatory cytokine expression is upregulated, and neutrophils localize to sites of muscle damage. IAV-infected dmd mutants display more severe muscle damage than would be expected from an additive effect of dmd mutation and IAV infection, suggesting that muscle damage caused by Dystrophin-deficiency and IAV infection is synergistic. These data demonstrate the importance of preventing IAV infections in individuals with genetic muscle diseases. Elucidating the mechanisms of immune-mediated muscle damage will not only apply to DMD and IAV, but also to other conditions where the immune system, inflammation, and muscle tissue are known to be affected, such as autoimmune diseases, cancer, and aging.

Skeletal Muscle Fibrosis and Stiffness Increase after Rotator Cuff Tendon Injury and Neuromuscular Compromise in a Rat Model

PubMed Central

Sato, Eugene J.; Killian, Megan L.; Choi, Anthony J.; Lin, Evie; Esparza, Mary C.; Galatz, Leesa M.; Thomopoulos, Stavros; Ward, Samuel R.

2015-01-01

Rotator cuff tears can cause irreversible changes (e.g., fibrosis) to the structure and function of the injured muscle(s). Fibrosis leads to increased muscle stiffness resulting in increased tension at the rotator cuff repair site. This tension influences repairability and healing potential in the clinical setting. However, the micro- and meso-scale structural and molecular sources of these whole-muscle mechanical changes are poorly understood. Here, single muscle fiber and fiber bundle passive mechanical testing was performed on rat supraspinatus and infraspinatus muscles with experimentally induced massive rotator cuff tears (Tenotomy) as well as massive tears with chemical denervation (Tenotomy+BTX) at 8 and 16 weeks post-injury. Titin molecular weight, collagen content, and myosin heavy chain profiles were measured and correlated with mechanical variables. Single fiber stiffness was not different between controls and experimental groups. However, fiber bundle stiffness was significantly increased at 8 weeks in the Tenotomy+BTX group compared to Tenotomy or control groups. Many of the changes were resolved by 16 weeks. Only fiber bundle passive mechanics was weakly correlated with collagen content. These data suggest that tendon injury with concomitant neuromuscular compromise results in extracellular matrix production and increases in stiffness of the muscle, potentially complicating subsequent attempts for surgical repair. PMID:24838823

Young girl presenting with exercise-induced myoglobinuria.

PubMed

Krishnaiah, Balaji; Lee, Jennifer Jheesoo; Wicklund, Matthew Paul; Kaur, Divpreet

2016-06-01

The sarcoglycanopathies are a heterogeneous group of autosomal recessive limb-girdle muscular dystrophies that cause varying degrees of progressive proximal muscle weakness. We describe the case of a Caucasian girl who presented with exercise intolerance, myalgia, and dark urine. Onset of symptoms was at age 4, and she had myalgia with physical activity throughout childhood. Creatine kinase levels were as high as 18,000. Immunostaining of a muscle biopsy showed mildly diminished alpha sarcoglycan staining, and SGCA gene sequencing revealed n.C229T; p.Arg77Cys (R77C) and n.C850T; p.Arg284Cys (R284C), which is associated with alpha sarcoglycanopathy. This patient presented with exercise intolerance, myoglobinuria, and almost normal muscle strength into adolescence, which is uncommon in sarcoglycanopathies. This uncommon presentation should be kept in mind, so that early recognition and intervention may prevent future comorbidities and help preserve the quality of life. Muscle Nerve 54: 161-164, 2016. © 2016 Wiley Periodicals, Inc.

Narcolepsy with cataplexy in a child with Charcot-Marie-Tooth disease. Case Report.

PubMed

Zheng, Feixia; Wang, Shuang

2016-09-01

We report an 8-year-old boy diagnosed with both CMT1 and narcolepsy, which were not reported simultaneously presenting in one person. The boy presented with a history of increased suddenly falling frequency and excessive daytime sleepiness for 3 months. CMT1 was diagnosed by electrophysiology and genetic testing. Narcolepsy had not been diagnosed until the frequently falling caused by sudden and transient episodes of legs weakness triggered by emotion was found. Multiple sleep latency test showed multiple sleep onset REM periods with reduced sleep latency. When CMT1 and narcolepsy were coexist in an individual, the latter might be overlooked. Cataplexy caused by narcolepsy might be disregard as distal muscle weakness of CMT1. The daytime sleepiness might also be ignored. Therefore, we recommend that patients with sleep disorders should be queried about the symptoms of narcolepsy.

Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study.

PubMed

Duyff, R F; Van den Bosch, J; Laman, D M; van Loon, B J; Linssen, W H

2000-06-01

To evaluate neuromuscular signs and symptoms in patients with newly diagnosed hypothyroidism and hyperthyroidism. A prospective cohort study was performed in adult patients with newly diagnosed thyroid dysfunction. Patients were evaluated clinically with hand held dynamometry and with electrodiagnosis. The clinical features of weakness and sensory signs and the biochemical data were evaluated during treatment. In hypothyroid patients 79% had neuromuscular complaints, 38% had clinical weakness (manual muscle strength testing) in one or more muscle groups, 42% had signs of sensorimotor axonal neuropathy, and 29% had carpal tunnel syndrome. Serum creatine kinase did not correlate with weakness. After 1 year of treatment 13% of the patients still had weakness. In hyperthyroid patients 67% had neuromuscular symptoms, 62% had clinical weakness in at least one muscle group that correlated with FT4 concentrations, but not with serum CK. Nineteen per cent of the patients had sensory-motor axonal neuropathy and 0% had carpal tunnel syndrome. The neuromuscular signs developed rapidly, early in the course of the disorder and were severe, but resolved rapidly and completely during treatment (average time 3.6 months). Neuromuscular symptoms and signs were present in most patients. About 40% of the hypothyroid patients and 20% of the hyperthyroid patients had predominantly sensory signs of a sensorimotor axonal neuropathy early in the course of thyroid disease. Weakness in hyperthyroidism evolved rapidly at an early stage of the disorder and resolved completely during treatment, suggesting a functional muscle disorder. Hand held dynamometry is sensitive for the detection of weakness and for the clinical evaluation of treatment effects. Weakness in hypothyroidism is more difficult to treat, suggesting myopathy.

Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms

PubMed Central

Phillips, William D.; Vincent, Angela

2016-01-01

Myasthenia gravis is an autoimmune disease of the neuromuscular junction (NMJ) caused by antibodies that attack components of the postsynaptic membrane, impair neuromuscular transmission, and lead to weakness and fatigue of skeletal muscle. This can be generalised or localised to certain muscle groups, and involvement of the bulbar and respiratory muscles can be life threatening. The pathogenesis of myasthenia gravis depends upon the target and isotype of the autoantibodies. Most cases are caused by immunoglobulin (Ig)G1 and IgG3 antibodies to the acetylcholine receptor (AChR). They produce complement-mediated damage and increase the rate of AChR turnover, both mechanisms causing loss of AChR from the postsynaptic membrane. The thymus gland is involved in many patients, and there are experimental and genetic approaches to understand the failure of immune tolerance to the AChR. In a proportion of those patients without AChR antibodies, antibodies to muscle-specific kinase (MuSK), or related proteins such as agrin and low-density lipoprotein receptor-related protein 4 (LRP4), are present. MuSK antibodies are predominantly IgG4 and cause disassembly of the neuromuscular junction by disrupting the physiological function of MuSK in synapse maintenance and adaptation. Here we discuss how knowledge of neuromuscular junction structure and function has fed into understanding the mechanisms of AChR and MuSK antibodies. Myasthenia gravis remains a paradigm for autoantibody-mediated conditions and these observations show how much there is still to learn about synaptic function and pathological mechanisms. PMID:27408701

Molecular and biological pathways of skeletal muscle dysfunction in chronic obstructive pulmonary disease

PubMed Central

Gea, Joaquim

2016-01-01

Chronic obstructive pulmonary disease (COPD) will be a major leading cause of death worldwide in the near future. Weakness and atrophy of the quadriceps are associated with a significantly poorer prognosis and increased mortality in COPD. Despite that skeletal muscle dysfunction may affect both respiratory and limb muscle groups in COPD, the latter are frequently more severely affected. Therefore, muscle dysfunction in COPD is a common systemic manifestation that should be evaluated on routine basis in clinical settings. In the present review, several aspects of COPD muscle dysfunction are being reviewed, with special emphasis on the underlying biological mechanisms. Figures on the prevalence of COPD muscle dysfunction and the most relevant etiologic contributors are also provided. Despite that ongoing research will shed light into the contribution of additional mechanisms to COPD muscle dysfunction, current knowledge points toward the involvement of a wide spectrum of cellular and molecular events that are differentially expressed in respiratory and limb muscles. Such mechanisms are thoroughly described in the article. The contribution of epigenetic events on COPD muscle dysfunction is also reviewed. We conclude that in view of the latest discoveries, from now, on new avenues of research should be designed to specifically target cellular mechanisms and pathways that impair muscle mass and function in COPD using pharmacological strategies and/or exercise training modalities. PMID:27056059

Post-Polio Syndrome and the Late Effects of Poliomyelitis: Part 1. Pathogenesis, Biomechanical Considerations, Diagnosis, and Investigations.

PubMed

Lo, Julian K; Robinson, Lawrence R

2018-05-12

Post-Polio Syndrome (PPS) is characterized by new muscle weakness and/or muscle fatigability that occurs many years following the initial poliomyelitis illness. There are many theories that exist on the pathogenesis of PPS, which remains incompletely understood. In contrast, the Late Effects of Poliomyelitis are often a consequence of biomechanical alterations that occur as a result of polio-related surgeries, musculoskeletal deformities or weakness. Osteoporosis and fractures of the polio-involved limbs are common. A comprehensive clinical evaluation with appropriate investigations is essential to fulfilling the established PPS diagnostic criteria. PPS is a diagnosis of exclusion, in which a key clinical feature required for the diagnosis is new muscle weakness and/or muscle fatigability that is persistent for at least one year. Electromyographic and muscle biopsy findings including evidence of ongoing denervation cannot reliably distinguish between patients with or without PPS. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Objective evaluation of muscle strength in infants with hypotonia and muscle weakness.

PubMed

Reus, Linda; van Vlimmeren, Leo A; Staal, J Bart; Janssen, Anjo J W M; Otten, Barto J; Pelzer, Ben J; Nijhuis-van der Sanden, Maria W G

2013-04-01

The clinical evaluation of an infant with motor delay, muscle weakness, and/or hypotonia would improve considerably if muscle strength could be measured objectively and normal reference values were available. The authors developed a method to measure muscle strength in infants and tested 81 typically developing infants, 6-36 months of age, and 17 infants with Prader-Willi Syndrome (PWS) aged 24 months. The inter-rater reliability of the measurement method was good (ICC=.84) and the convergent validity was confirmed by high Pearson's correlations between muscle strength, age, height, and weight (r=.79-.85). A multiple linear regression model was developed to predict muscle strength based on age, height, and weight, explaining 73% of the variance in muscle strength. In infants with PWS, muscle strength was significantly decreased. Pearson's correlations showed that infants with PWS in which muscle strength was more severely affected also had a larger motor developmental delay (r=.75). Copyright © 2013 Elsevier Ltd. All rights reserved.

Identification of disease specific pathways using in vivo SILAC proteomics in dystrophin deficient mdx mouse.

PubMed

Rayavarapu, Sree; Coley, William; Cakir, Erdinc; Jahnke, Vanessa; Takeda, Shin'ichi; Aoki, Yoshitsugu; Grodish-Dressman, Heather; Jaiswal, Jyoti K; Hoffman, Eric P; Brown, Kristy J; Hathout, Yetrib; Nagaraju, Kanneboyina

2013-05-01

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder caused by a mutation in the dystrophin gene. DMD is characterized by progressive weakness of skeletal, cardiac, and respiratory muscles. The molecular mechanisms underlying dystrophy-associated muscle weakness and damage are not well understood. Quantitative proteomics techniques could help to identify disease-specific pathways. Recent advances in the in vivo labeling strategies such as stable isotope labeling in mouse (SILAC mouse) with (13)C6-lysine or stable isotope labeling in mammals (SILAM) with (15)N have enabled accurate quantitative analysis of the proteomes of whole organs and tissues as a function of disease. Here we describe the use of the SILAC mouse strategy to define the underlying pathological mechanisms in dystrophin-deficient skeletal muscle. Differential SILAC proteome profiling was performed on the gastrocnemius muscles of 3-week-old (early stage) dystrophin-deficient mdx mice and wild-type (normal) mice. The generated data were further confirmed in an independent set of mdx and normal mice using a SILAC spike-in strategy. A total of 789 proteins were quantified; of these, 73 were found to be significantly altered between mdx and normal mice (p < 0.05). Bioinformatics analyses using Ingenuity Pathway software established that the integrin-linked kinase pathway, actin cytoskeleton signaling, mitochondrial energy metabolism, and calcium homeostasis are the pathways initially affected in dystrophin-deficient muscle at early stages of pathogenesis. The key proteins involved in these pathways were validated by means of immunoblotting and immunohistochemistry in independent sets of mdx mice and in human DMD muscle biopsies. The specific involvement of these molecular networks early in dystrophic pathology makes them potential therapeutic targets. In sum, our findings indicate that SILAC mouse strategy has uncovered previously unidentified pathological pathways in mouse models of human skeletal muscle disease.

Identification of Disease Specific Pathways Using in Vivo SILAC Proteomics in Dystrophin Deficient mdx Mouse*

PubMed Central

Rayavarapu, Sree; Coley, William; Cakir, Erdinc; Jahnke, Vanessa; Takeda, Shin'ichi; Aoki, Yoshitsugu; Grodish-Dressman, Heather; Jaiswal, Jyoti K.; Hoffman, Eric P.; Brown, Kristy J.; Hathout, Yetrib; Nagaraju, Kanneboyina

2013-01-01

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder caused by a mutation in the dystrophin gene. DMD is characterized by progressive weakness of skeletal, cardiac, and respiratory muscles. The molecular mechanisms underlying dystrophy-associated muscle weakness and damage are not well understood. Quantitative proteomics techniques could help to identify disease-specific pathways. Recent advances in the in vivo labeling strategies such as stable isotope labeling in mouse (SILAC mouse) with 13C6-lysine or stable isotope labeling in mammals (SILAM) with 15N have enabled accurate quantitative analysis of the proteomes of whole organs and tissues as a function of disease. Here we describe the use of the SILAC mouse strategy to define the underlying pathological mechanisms in dystrophin-deficient skeletal muscle. Differential SILAC proteome profiling was performed on the gastrocnemius muscles of 3-week-old (early stage) dystrophin-deficient mdx mice and wild-type (normal) mice. The generated data were further confirmed in an independent set of mdx and normal mice using a SILAC spike-in strategy. A total of 789 proteins were quantified; of these, 73 were found to be significantly altered between mdx and normal mice (p < 0.05). Bioinformatics analyses using Ingenuity Pathway software established that the integrin-linked kinase pathway, actin cytoskeleton signaling, mitochondrial energy metabolism, and calcium homeostasis are the pathways initially affected in dystrophin-deficient muscle at early stages of pathogenesis. The key proteins involved in these pathways were validated by means of immunoblotting and immunohistochemistry in independent sets of mdx mice and in human DMD muscle biopsies. The specific involvement of these molecular networks early in dystrophic pathology makes them potential therapeutic targets. In sum, our findings indicate that SILAC mouse strategy has uncovered previously unidentified pathological pathways in mouse models of human skeletal muscle disease. PMID:23297347

Toxic myopathy and acute hepatic necrosis in cattle caused by ingestion of Senna obtusifolia (sicklepod; coffee senna) in Brazil.

PubMed

Furlan, Fernando Henrique; Zanata, Carina; Damasceno, Everson Dos Santos; de Oliveira, Leonardo Pintar; da Silva, Leilane Aparecida; Colodel, Edson Moleta; Riet-Correa, Franklin

2014-12-15

The epidemiological, clinical and pathological findings of field and experimental Senna obtusifolia (sicklepod; coffee senna) poisoning in cattle are described. The low availability of good quality forage and high rate of infestation of pastures by S. obtusifolia were the factors that led to poisonous plant ingestion. In this study, the morbidity ranged between 2% and 27.9%, and the lethality was 100%. For the experimental study, six cattle were fed with the aerial parts of S. obtusifolia collected in three different seasons at 9%-38% of the animal's body weight. The experimental and field diseases were similar. The main clinical signs were diarrhea, reluctance to move, muscular weakness and recumbency. The gross findings included pale discoloration of the skeletal muscle. Microscopically, the affected cattle showed degeneration and necrosis of the skeletal muscles and occasionally of the cardiac muscles. Additionally, two cattle showed centrilobular hepatic necrosis. In this study, S. obtusifolia collected from the same farm showed seasonal variation in toxicity. Poisoning by S. obtusifolia is an important cause of death of cattle in the Central Western region of Brazil. The toxicosis caused by this plant is similar to S. occidentalis poisoning; however, in S. obtusifolia poisoning, acute hepatic necrosis is sometimes present. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Hypoglycaemic periodic paralysis in hyperthyroidism patients].

PubMed

Kratochvíl, J; Masopust, J; Martínková, V; Charvát, J

2008-11-01

Hypokalemic periodic paralysis (HPP) is a rare disorder characterised by acute, potentially fatal atacks of muscle weakness or paralysis. Massive shift of potassium into cells is caused by elevated levels of insulin and catecholamines in the blood. Hypophosphatemia and hypomagnesemia may be also present. Acidobasic status usually is not impaired. HPP occurs as familiar (caused by ion channels inherited defects) or acquired (in patients with hyperthyroidism). On the basis of two clinical cases we present a review of hypokalemic periodic paralysis in hyperthyroid patients. We discuss patogenesis, clinical and laboratory findings as well as the principles of prevention and treatment of this rare disorder.

Targeting DMPK with Antisense Oligonucleotide Improves Muscle Strength in Myotonic Dystrophy Type 1 Mice.

PubMed

Jauvin, Dominic; Chrétien, Jessina; Pandey, Sanjay K; Martineau, Laurie; Revillod, Lucille; Bassez, Guillaume; Lachon, Aline; MacLeod, A Robert; Gourdon, Geneviève; Wheeler, Thurman M; Thornton, Charles A; Bennett, C Frank; Puymirat, Jack

2017-06-16

Myotonic dystrophy type 1 (DM1), a dominant hereditary muscular dystrophy, is caused by an abnormal expansion of a (CTG) n trinucleotide repeat in the 3' UTR of the human dystrophia myotonica protein kinase (DMPK) gene. As a consequence, mutant transcripts containing expanded CUG repeats are retained in nuclear foci and alter the function of splicing regulatory factors members of the MBNL and CELF families, resulting in alternative splicing misregulation of specific transcripts in affected DM1 tissues. In the present study, we treated DMSXL mice systemically with a 2'-4'-constrained, ethyl-modified (ISIS 486178) antisense oligonucleotide (ASO) targeted to the 3' UTR of the DMPK gene, which led to a 70% reduction in CUG exp RNA abundance and foci in different skeletal muscles and a 30% reduction in the heart. Furthermore, treatment with ISIS 486178 ASO improved body weight, muscle strength, and muscle histology, whereas no overt toxicity was detected. This is evidence that the reduction of CUG exp RNA improves muscle strength in DM1, suggesting that muscle weakness in DM1 patients may be improved following elimination of toxic RNAs. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Inhibition of myostatin does not ameliorate disease features of severe spinal muscular atrophy mice

PubMed Central

Sumner, Charlotte J.; Wee, Claribel D.; Warsing, Leigh C.; Choe, Dong W.; Ng, Andrew S.; Lutz, Cathleen; Wagner, Kathryn R.

2009-01-01

There is currently no treatment for the inherited motor neuron disease, spinal muscular atrophy (SMA). Severe SMA causes lower motor neuron loss, impaired myofiber development, profound muscle weakness and early mortality. Myostatin is a transforming growth factor-β family member that inhibits muscle growth. Loss or blockade of myostatin signaling increases muscle mass and improves muscle strength in mouse models of primary muscle disease and in the motor neuron disease, amyotrophic lateral sclerosis. In this study, we evaluated the effects of blocking myostatin signaling in severe SMA mice (hSMN2/delta7SMN/mSmn−/−) by two independent strategies: (i) transgenic overexpression of the myostatin inhibitor follistatin and (ii) post-natal administration of a soluble activin receptor IIB (ActRIIB-Fc). SMA mice overexpressing follistatin showed little increase in muscle mass and no improvement in motor function or survival. SMA mice treated with ActRIIB-Fc showed minimal improvement in motor function, and no extension of survival compared with vehicle-treated mice. Together these results suggest that inhibition of myostatin may not be a promising therapeutic strategy in severe forms of SMA. PMID:19477958

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

Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis.

PubMed

Saroja, Aralikatte Onkarappa; Naik, Karkal Ravishankar; Nalini, Atcharayam; Gayathri, Narayanappa

2013-10-01

Bethlem myopathy and Ullrich congenital muscular dystrophy form a spectrum of collagenopathies caused by genetic mutations encoding for any of the three subunits of collagen VI. Bethlem phenotype is relatively benign and is characterized by proximal dominant myopathy, keloids, contractures, distal hyperextensibility, and follicular hyperkeratosis. Three patients from a single family were diagnosed to have Bethlem myopathy based on European Neuromuscular Centre Bethlem Consortium criteria. Affected father and his both sons had slowly progressive proximal dominant weakness and recurrent falls from the first decade. Both children aged 18 and 20 years were ambulant at presentation. All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy. Creatinine kinase was mildly elevated and electromyography revealed myopathic features. Muscle imaging revealed severe involvement of glutei and vasti with "central shadow" in rectus femoris. Muscle biopsy in the father showed dystrophic changes with normal immmunostaining for collagen VI, sarcoglycans, and dysferlin.

[Clinical case of acute renal failure revealing an autoimmune hypothyroidism].

PubMed

Montasser, Dina Ibrahim; Hassani, Mohamed; Zajjari, Yassir; Bahadi, Abdelali; Alayoud, Ahmed; Hamzi, Amine; Hassani, Kawtar; Moujoud, Omar; Asseraji, Mohamed; Kadiri, Moncif; Aatif, Taoufik; El Kabbaj, Driss; Benyahia, Mohamed; Allam, Mustapha; Akhmouch, Ismail; Oualim, Zouhir

2010-04-01

Although the clinic picture is often indicative of muscle manifestations in patients with hypothyroidism, signs and symptoms of this condition are variable from simple elevation of serum muscle enzymes with myalgia, muscle weakness, cramps to rhabdomyolysis with acute renal failure which remains a rare event. Thyroid hormones affect the function of almost every body organ, and thyroid dysfunction produces a wide range of metabolic disturbances. Hypothyroidism is associated with significant effects on the kidney which the pathophysiology seems to be multifactorial, but the exact mechanisms remain poorly understood. Hypothyroidism as a cause of renal impairment is usually overlooked, leading to unnecessary diagnostic procedures. The main objective of our observation is to report a case of acute renal failure revealing an autoimmune hypothyroidism in which thyroid hormone substitution led to a significant improvement in muscular, thyroid and renal disorders. Copyright 2010 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.

A Novel Mutation in DMD (c.10797+5G>A) Causes Becker Muscular Dystrophy Associated with Intellectual Disability.

PubMed

Banihani, Rudaina; Baskin, Berivan; Halliday, William; Kobayashi, Jeff; Kawamura, Anne; McAdam, Laura; Ray, Peter N; Yoon, Grace

2016-04-01

Severe intellectual disability has been reported in a subgroup of patients with Duchenne muscular dystrophy but is not typically associated with Becker muscular dystrophy. The authors report a 13-year-old boy, with severe intellectual disability (Wechsler Intelligence Scales for Children-IV, Full Scale IQ < 0.1 percentile), attention-deficit hyperactivity disorder, and mild muscle weakness. He had elevated serum creatine kinase and dystrophic changes on muscle biopsy. Dystrophin immunohistochemistry revealed decreased staining with the C-terminal and mid-rod antibodies and essentially absent staining of the N-terminal immunostain. Sequencing of muscle mRNA revealed aberrant splicing due to a c.10797+5G > A mutation in DMD. Dystrophinopathy may be associated with predominantly cognitive impairment and neurobehavioral disorder, and should be considered in the differential diagnosis of unexplained cognitive or psychiatric disturbance in males.

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy.

PubMed

Whitehead, Nicholas P; Kim, Min Jeong; Bible, Kenneth L; Adams, Marvin E; Froehner, Stanley C

2015-10-13

Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases.

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy

PubMed Central

Whitehead, Nicholas P.; Kim, Min Jeong; Bible, Kenneth L.; Adams, Marvin E.; Froehner, Stanley C.

2015-01-01

Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases. PMID:26417069

Transcranial direct current stimulation (tDCS) Paired with massed practice training to promote adaptive plasticity and motor recovery in chronic incomplete tetraplegia: a pilot study.

PubMed

Potter-Baker, Kelsey A; Janini, Daniel P; Lin, Yin-Liang; Sankarasubramanian, Vishwanath; Cunningham, David A; Varnerin, Nicole M; Chabra, Patrick; Kilgore, Kevin L; Richmond, Mary Ann; Frost, Frederick S; Plow, Ela B

2017-08-07

Objective Our goal was to determine if pairing transcranial direct current stimulation (tDCS) with rehabilitation for two weeks could augment adaptive plasticity offered by these residual pathways to elicit longer-lasting improvements in motor function in incomplete spinal cord injury (iSCI). Design Longitudinal, randomized, controlled, double-blinded cohort study. Setting Cleveland Clinic Foundation, Cleveland, Ohio, USA. Participants Eight male subjects with chronic incomplete motor tetraplegia. Interventions Massed practice (MP) training with or without tDCS for 2 hrs, 5 times a week. Outcome Measures We assessed neurophysiologic and functional outcomes before, after and three months following intervention. Neurophysiologic measures were collected with transcranial magnetic stimulation (TMS). TMS measures included excitability, representational volume, area and distribution of a weaker and stronger muscle motor map. Functional assessments included a manual muscle test (MMT), upper extremity motor score (UEMS), action research arm test (ARAT) and nine hole peg test (NHPT). Results We observed that subjects receiving training paired with tDCS had more increased strength of weak proximal (15% vs 10%), wrist (22% vs 10%) and hand (39% vs. 16%) muscles immediately and three months after intervention compared to the sham group. Our observed changes in muscle strength were related to decreases in strong muscle map volume (r=0.851), reduced weak muscle excitability (r=0.808), a more focused weak muscle motor map (r=0.675) and movement of weak muscle motor map (r=0.935). Conclusion Overall, our results encourage the establishment of larger clinical trials to confirm the potential benefit of pairing tDCS with training to improve the effectiveness of rehabilitation interventions for individuals with SCI. Trial Registration NCT01539109.

Can therapeutic Thai massage improve upper limb muscle strength in Parkinson's disease? An objective randomized-controlled trial.

PubMed

Miyahara, Yuka; Jitkritsadakul, Onanong; Sringean, Jirada; Aungkab, Nicharee; Khongprasert, Surasa; Bhidayasiri, Roongroj

2018-04-01

Muscle weakness is a frequent complaint amongst Parkinson's disease (PD) patients. However, evidence-based therapeutic options for this symptom are limited. We objectively measure the efficacy of therapeutic Thai massage (TTM) on upper limb muscle strength, using an isokinetic dynamometer. A total of 60 PD patients with muscle weakness that is not related to their 'off' periods or other neurological causes were equally randomized to TTM intervention (n = 30), consisting of six TTM sessions over a 3-week period, or standard medical care (no intervention, n = 30). Primary outcomes included peak extension and flexion torques. Scale-based outcomes, including Unified Parkinson's Disease Rating Scale (UPDRS) and visual analogue scale for pain (VAS) were also performed. From baseline to end of treatment, patients in the intervention group showed significant improvement on primary objective outcomes, including peak flexion torque (F = 30.613, p  < .001) and peak extension torque (F = 35.569, p  < .001) and time to maximal flexion speed (F = 14.216, p  = .001). Scale-based assessments mirrored improvements in the objective outcomes with a significant improvement from baseline to end of treatment of the UPDRS-bradykinesia of a more affected upper limb (F = 9.239, p  = .005), and VAS (F = 69.864, p  < .001) following the TTM intervention, compared to the control group. No patients reported adverse events in association with TTM. Our findings provide objective evidence that TTM used in combination with standard medical therapies is effective in improving upper limb muscle strength in patients with PD. Further studies are needed to determine the efficacy of TTM on other motor and non-motor symptoms in PD.

Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study

PubMed Central

Duyff, R.; Van den Bosch, J.; Laman, D; van Loon, B.-J. P.; Linssen, W.

2000-01-01

OBJECTIVES—To evaluate neuromuscular signs and symptoms in patients with newly diagnosed hypothyroidism and hyperthyroidism.
METHODS—A prospective cohort study was performed in adult patients with newly diagnosed thyroid dysfunction. Patients were evaluated clinically with hand held dynamometry and with electrodiagnosis. The clinical features of weakness and sensory signs and the biochemical data were evaluated during treatment.
RESULTS—In hypothyroid patients 79% had neuromuscular complaints, 38% had clinical weakness (manual muscle strength testing) in one or more muscle groups, 42% had signs of sensorimotor axonal neuropathy, and 29% had carpal tunnel syndrome. Serum creatine kinase did not correlate with weakness. After 1 year of treatment 13% of the patients still had weakness. In hyperthyroid patients 67% had neuromuscular symptoms, 62% had clinical weakness in at least one muscle group that correlated with FT4 concentrations, but not with serum CK. Nineteen per cent of the patients had sensory-motor axonal neuropathy and 0% had carpal tunnel syndrome. The neuromuscular signs developed rapidly, early in the course of the disorder and were severe, but resolved rapidly and completely during treatment (average time 3.6months).
CONCLUSIONS—Neuromuscular symptoms and signs were present in most patients. About 40% of the hypothyroid patients and 20% of the hyperthyroid patients had predominantly sensory signs of a sensorimotor axonal neuropathy early in the course of thyroid disease. Weakness in hyperthyroidism evolved rapidly at an early stage of the disorder and resolved completely during treatment, suggesting a functional muscle disorder. Hand held dynamometry is sensitive for the detection of weakness and for the clinical evaluation of treatment effects. Weakness in hypothyroidism is more difficult to treat, suggesting myopathy.

 PMID:10811699

Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy.

PubMed

Morales, Maria Gabriela; Gutierrez, Jaime; Cabello-Verrugio, Claudio; Cabrera, Daniel; Lipson, Kenneth E; Goldschmeding, Roel; Brandan, Enrique

2013-12-15

In Duchenne muscular dystrophy (DMD) and the mdx mouse model, the absence of the cytoskeletal protein dystrophin causes defective anchoring of myofibres to the basal lamina. The resultant myofibre degeneration and necrosis lead to a progressive loss of muscle mass, increased fibrosis and ultimately fatal weakness. Connective tissue growth factor (CTGF/CCN-2) is critically involved in several chronic fibro-degenerative diseases. In DMD, the role of CTGF might extend well beyond replacement fibrosis secondary to loss of muscle fibres, since its overexpression in skeletal muscle could by itself induce a dystrophic phenotype. Using two independent approaches, we here show that mdx mice with reduced CTGF availability do indeed have less severe muscular dystrophy. Mdx mice with hemizygous CTGF deletion (mdx-Ctgf+/-), and mdx mice treated with a neutralizing anti-CTGF monoclonal antibody (FG-3019), performed better in an exercise endurance test, had better muscle strength in isolated muscles and reduced skeletal muscle impairment, apoptotic damage and fibrosis. Transforming growth factor type-β (TGF-β), pERK1/2 and p38 signalling remained unaffected during CTGF suppression. Moreover, both mdx-Ctgf+/- and FG-3019 treated mdx mice had improved grafting upon intramuscular injection of dystrophin-positive satellite cells. These findings reveal the potential of targeting CTGF to reduce disease progression and to improve cell therapy in DMD.

Late-onset Becker muscular dystrophy: Refining the clinical features and electrophysiological findings.

PubMed

Beltran Papsdorf, Tania; Howard, James F; Chahin, Nizar

2015-11-01

The aim of this study was to characterize a unique distribution of muscle involvement in sporadic Becker muscle dystrophy (BMD). Retrospective chart review, clinical examination, electrophysiological studies, cardiac testing, and genetic testing were performed in 5 patients. Predominant weakness and atrophy of biceps brachii, hip adduction, and quadriceps muscles was noted along with calf and extensor forearm hypertrophy. Finger flexor muscles were severely weak in 3 of 5 patients, a feature that could lead to a misdiagnosis of inclusion body myositis. Creatinine kinase was only mildly elevated in most patients. Electromyography was abnormal in all patients. Muscle biopsy in 1 patient demonstrated normal immunostaining for dystrophin. We found a unique and uniform distribution of muscle involvement in 5 sporadic cases of BMD. Recognizing these features is important for differentiating it from other myopathies that may have similar features and avoids unnecessary invasive procedures such as muscle biopsy. © 2015 Wiley Periodicals, Inc.

Voluntary physical activity protects from susceptibility to skeletal muscle contraction-induced injury but worsens heart function in mdx mice.

PubMed

Hourdé, Christophe; Joanne, Pierre; Medja, Fadia; Mougenot, Nathalie; Jacquet, Adeline; Mouisel, Etienne; Pannerec, Alice; Hatem, Stéphane; Butler-Browne, Gillian; Agbulut, Onnik; Ferry, Arnaud

2013-05-01

It is well known that inactivity/activity influences skeletal muscle physiological characteristics. However, the effects of inactivity/activity on muscle weakness and increased susceptibility to muscle contraction-induced injury have not been extensively studied in mdx mice, a murine model of Duchenne muscular dystrophy with dystrophin deficiency. In the present study, we demonstrate that inactivity (ie, leg immobilization) worsened the muscle weakness and the susceptibility to contraction-induced injury in mdx mice. Inactivity also mimicked these two dystrophic features in wild-type mice. In contrast, we demonstrate that these parameters can be improved by activity (ie, voluntary wheel running) in mdx mice. Biochemical analyses indicate that the changes induced by inactivity/activity were not related to fiber-type transition but were associated with altered expression of different genes involved in fiber growth (GDF8), structure (Actg1), and calcium homeostasis (Stim1 and Jph1). However, activity reduced left ventricular function (ie, ejection and shortening fractions) in mdx, but not C57, mice. Altogether, our study suggests that muscle weakness and susceptibility to contraction-induced injury in dystrophic muscle could be attributable, at least in part, to inactivity. It also suggests that activity exerts a beneficial effect on dystrophic skeletal muscle but not on the heart. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Expression of the inclusion body myopathy 3 mutation in Drosophila depresses myosin function and stability and recapitulates muscle inclusions and weakness.

PubMed

Wang, Yang; Melkani, Girish C; Suggs, Jennifer A; Melkani, Anju; Kronert, William A; Cammarato, Anthony; Bernstein, Sanford I

2012-06-01

Hereditary myosin myopathies are characterized by variable clinical features. Inclusion body myopathy 3 (IBM-3) is an autosomal dominant disease associated with a missense mutation (E706K) in the myosin heavy chain IIa gene. Adult patients experience progressive muscle weakness. Biopsies reveal dystrophic changes, rimmed vacuoles with cytoplasmic inclusions, and focal disorganization of myofilaments. We constructed a transgene encoding E706K myosin and expressed it in Drosophila (E701K) indirect flight and jump muscles to establish a novel homozygous organism with homogeneous populations of fast IBM-3 myosin and muscle fibers. Flight and jump abilities were severely reduced in homozygotes. ATPase and actin sliding velocity of the mutant myosin were depressed >80% compared with wild-type myosin. Light scattering experiments and electron microscopy revealed that mutant myosin heads bear a dramatic propensity to collapse and aggregate. Thus E706K (E701K) myosin appears far more labile than wild-type myosin. Furthermore, mutant fly fibers exhibit ultrastructural hallmarks seen in patients, including cytoplasmic inclusions containing aberrant proteinaceous structures and disorganized muscle filaments. Our Drosophila model reveals the unambiguous consequences of the IBM-3 lesion on fast muscle myosin and fibers. The abnormalities observed in myosin function and muscle ultrastructure likely contribute to muscle weakness observed in our flies and patients.

Muscle weakness in a girl with autoimmune hepatitis and Graves' disease.

PubMed

Sarkhy, Ahmed; Persad, Rabindranath; Tarnopolsky, Mark

2009-02-01

Autoimmune hepatitis (AIH) is a chronic hepatic autoimmune disease of unknown etiology associated with inflammatory changes and autoantibodies. The combination of AIH, Grave's disease, and myasthenia gravis (MG) is rare, with only one other case reported. We report a pediatric patient with AIH type 2 and Grave's disease who developed MG whilst on a treatment with corticosteroids. A 13-year-old girl, diagnosed with thyrotoxicosis, was identified as having AIH type 2. During the course of her therapy, she developed muscle weakness. Investigations revealed increased anti-acetylcholine receptor (AChR) antibodies and her electromyography (EMG) was characteristic for MG. Her course is described here. This case highlights the importance of investigating muscle weakness in severely ill hospitalized patients.

Myotilinopathy in a family with late onset myopathy.

PubMed

Pénisson-Besnier, Isabelle; Talvinen, Kati; Dumez, Catherine; Vihola, Anna; Dubas, Frédéric; Fardeau, Michel; Hackman, Peter; Carpen, Olli; Udd, Bjarne

2006-07-01

Mutations in titin are well known cause of late onset autosomal dominant distal myopathy. Mutations in another sarcomeric protein, myotilin, were first identified in two families with dominant limb girdle muscular phenotype. Recently, however, myotilin mutations have been associated with more distal phenotypes in patients with late onset myofibrillar myopathy. We report here a multigenerational French family in which gene sequencing identified a S60F myotilin mutation in all patients with full penetrance despite very late onset. The family was originally reported as a distal myopathy but intrafamilial variability was remarkable with proximal or distal muscle weakness or both. Extended morphological characteristics of muscle biopsy findings in myotilinopathy indicate that immunohistochemistry may be important for selection of molecular genetic approach in myofibrillar myopathy.

Guide to Understanding Facial Palsy

MedlinePlus

... to many different facial muscles. These muscles control facial expression. The coordinated activity of this nerve and these ... involves a weakness of the muscles responsible for facial expression and side-to-side eye movement. Moebius syndrome ...

Daily Supplementation of D-ribose Shows No Therapeutic Benefits in the MHC-I Transgenic Mouse Model of Inflammatory Myositis

PubMed Central

Coley, William; Rayavarapu, Sree; van der Meulen, Jack H.; Duba, Ayyappa S.; Nagaraju, Kanneboyina

2013-01-01

Background Current treatments for idiopathic inflammatory myopathies (collectively called myositis) focus on the suppression of an autoimmune inflammatory response within the skeletal muscle. However, it has been observed that there is a poor correlation between the successful suppression of muscle inflammation and an improvement in muscle function. Some evidence in the literature suggests that metabolic abnormalities in the skeletal muscle underlie the weakness that continues despite successful immunosuppression. We have previously shown that decreased expression of a purine nucleotide cycle enzyme, adenosine monophosphate deaminase (AMPD1), leads to muscle weakness in a mouse model of myositis and may provide a mechanistic basis for muscle weakness. One of the downstream metabolites of this pathway, D-ribose, has been reported to alleviate symptoms of myalgia in patients with a congenital loss of AMPD1. Therefore, we hypothesized that supplementing exogenous D-ribose would improve muscle function in the mouse model of myositis. We treated normal and myositis mice with daily doses of D-ribose (4 mg/kg) over a 6-week time period and assessed its effects using a battery of behavioral, functional, histological and molecular measures. Results Treatment with D-ribose was found to have no statistically significant effects on body weight, grip strength, open field behavioral activity, maximal and specific forces of EDL, soleus muscles, or histological features. Histological and gene expression analysis indicated that muscle tissues remained inflamed despite treatment. Gene expression analysis also suggested that low levels of the ribokinase enzyme in the skeletal muscle might prevent skeletal muscle tissue from effectively utilizing D-ribose. Conclusions Treatment with daily oral doses of D-ribose showed no significant effect on either disease progression or muscle function in the mouse model of myositis. PMID:23785461

Daily supplementation of D-ribose shows no therapeutic benefits in the MHC-I transgenic mouse model of inflammatory myositis.

PubMed

Coley, William; Rayavarapu, Sree; van der Meulen, Jack H; Duba, Ayyappa S; Nagaraju, Kanneboyina

2013-01-01

Current treatments for idiopathic inflammatory myopathies (collectively called myositis) focus on the suppression of an autoimmune inflammatory response within the skeletal muscle. However, it has been observed that there is a poor correlation between the successful suppression of muscle inflammation and an improvement in muscle function. Some evidence in the literature suggests that metabolic abnormalities in the skeletal muscle underlie the weakness that continues despite successful immunosuppression. We have previously shown that decreased expression of a purine nucleotide cycle enzyme, adenosine monophosphate deaminase (AMPD1), leads to muscle weakness in a mouse model of myositis and may provide a mechanistic basis for muscle weakness. One of the downstream metabolites of this pathway, D-ribose, has been reported to alleviate symptoms of myalgia in patients with a congenital loss of AMPD1. Therefore, we hypothesized that supplementing exogenous D-ribose would improve muscle function in the mouse model of myositis. We treated normal and myositis mice with daily doses of D-ribose (4 mg/kg) over a 6-week time period and assessed its effects using a battery of behavioral, functional, histological and molecular measures. Treatment with D-ribose was found to have no statistically significant effects on body weight, grip strength, open field behavioral activity, maximal and specific forces of EDL, soleus muscles, or histological features. Histological and gene expression analysis indicated that muscle tissues remained inflamed despite treatment. Gene expression analysis also suggested that low levels of the ribokinase enzyme in the skeletal muscle might prevent skeletal muscle tissue from effectively utilizing D-ribose. Treatment with daily oral doses of D-ribose showed no significant effect on either disease progression or muscle function in the mouse model of myositis.

Myopathy in Childhood Muscle-Specific Kinase Myasthenia Gravis.

PubMed

Kirzinger, Lukas; Khomenko, Andrei; Schulte-Mattler, Wilhelm; Backhaus, Roland; Platen, Sabine; Schalke, Berthold

2016-12-01

Adult and pediatric patients suffering from MuSK (muscle-specific kinase) -antibody positive myasthenia gravis exhibit similar features to individuals with acetylcholine receptor (AChR) antibodies, but they differ in several characteristics such as a predominant bulbar, respiratory and neck weakness, a generally worse disease severity and a tendency to develop muscle atrophy. Muscle atrophy is a rare phenomenon that is usually restricted to the facial muscles. We describe a girl with MuSK-antibody positive myasthenia gravis who developed a myopathy with severe generalized muscular weakness, muscle atrophy, and myopathic changes on electromyography. This is the first published example of a generalized myopathic syndrome in myasthenia gravis. We review the relevant literature and discuss the hypothesis of a mitochondrial myopathy as a pathogenic mechanism in MuSK-antibody positive myasthenia gravis. Copyright © 2016 Elsevier Inc. All rights reserved.

High levels of sarcospan are well tolerated and act as a sarcolemmal stabilizer to address skeletal muscle and pulmonary dysfunction in DMD

PubMed Central

Gibbs, Elizabeth M.; Marshall, Jamie L.; Ma, Eva; Nguyen, Thien M.; Hong, Grace; Lam, Jessica S.; Spencer, Melissa J.

2016-01-01

Abstract Duchenne muscular dystrophy (DMD) is a genetic disorder that causes progressive muscle weakness, ultimately leading to early mortality in affected teenagers and young adults. Previous work from our lab has shown that a small transmembrane protein called sarcospan (SSPN) can enhance the recruitment of adhesion complex proteins to the cell surface. When human SSPN is expressed at three-fold levels in mdx mice, this increase in adhesion complex abundance improves muscle membrane stability, preventing many of the histopathological changes associated with DMD. However, expressing higher levels of human SSPN (ten-fold transgenic expression) causes a severe degenerative muscle phenotype in wild-type mice. Since SSPN-mediated stabilization of the sarcolemma represents a promising therapeutic strategy in DMD, it is important to determine whether SSPN can be introduced at high levels without toxicity. Here, we show that mouse SSPN (mSSPN) can be overexpressed at 30-fold levels in wild-type mice with no deleterious effects. In mdx mice, mSSPN overexpression improves dystrophic pathology and sarcolemmal stability. We show that these mice exhibit increased resistance to eccentric contraction-induced damage and reduced fatigue following exercise. mSSPN overexpression improved pulmonary function and reduced dystrophic histopathology in the diaphragm. Together, these results demonstrate that SSPN overexpression is well tolerated in mdx mice and improves sarcolemma defects that underlie skeletal muscle and pulmonary dysfunction in DMD. PMID:27798107

Metabolites of arachidonic acid formed by human gastrointestinal tissues and their actions on the muscle layers.

PubMed Central

Bennett, A.; Hensby, C. N.; Sanger, G. J.; Stamford, I. F.

1981-01-01

1. Gas chromatography-mass spectrometry demonstrated the presence of arachidonic acid (AA), 6-keto-prostaglandin F1 alpha and thromboxane B2 (TxB2) in all extracts of homogenized muscle or mucosa from human stomach, terminal ileum or sigmoid colon. Prostaglandin D2 (PGD2), PGE2 or PGF2 alpha were usually found more often in the mucosal extracts. The 12-hydroxy-derivative of AA (12-HETE) was detected in all extracts of the colon but in only some of the other tissues. 2. Most prostanoids tested contracted the longitudinal muscle, the order of potency being U-46619 (an epoxymethano analogue of PGH2) greater than PGE2 greater than PGF2 alpha greater than PGD2; PGI2 usually caused relaxation, whereas its breakdown products or TxB2 had weak and variable effects. 3. U-46619 or, less potently, PGF2 alpha contracted the circular muscle, whereas PGI2 and usually PGE2 caused relaxation. PGD2, 6-keto-PGF1 alpha, 6,15-diketo-PGF1 alpha or TxB2 usually had little or no effect. 4. PGI2 antagonized contractions to some excitatory prostanoids, without greatly affecting contractions to acetylcholine. 5. For both muscle layers there was a gradient in sensitivity to prostanoids along the gastrointestinal tract. The sensitivities were stomach greater than distal ileum greater than sigmoid colon. 6. The results are discussed in relation to gastrointestinal physiology and pathophysiology. PMID:7317691

Methylmercury exposure causes a persistent inhibition of myogenin expression and C2C12 myoblast differentiation.

PubMed

Prince, Lisa M; Rand, Matthew D

2018-01-15

Methylmercury (MeHg) is a ubiquitous environmental toxicant, best known for its selective targeting of the developing nervous system. MeHg exposure has been shown to cause motor deficits such as impaired gait and coordination, muscle weakness, and muscle atrophy, which have been associated with disruption of motor neurons. However, recent studies have suggested that muscle may also be a target of MeHg toxicity, both in the context of developmental myogenic events and of low-level chronic exposures affecting muscle wasting in aging. We therefore investigated the effects of MeHg on myotube formation, using the C2C12 mouse myoblast model. We found that MeHg inhibits both differentiation and fusion, in a concentration-dependent manner. Furthermore, MeHg specifically and persistently inhibits myogenin (MyoG), a transcription factor involved in myocyte differentiation, within the first six hours of exposure. MeHg-induced reduction in MyoG expression is contemporaneous with a reduction of a number of factors involved in mitochondrial biogenesis and mtDNA transcription and translation, which may implicate a role for mitochondria in mediating MeHg-induced change in the differentiation program. Unexpectedly, inhibition of myoblast differentiation with MeHg parallels inhibition of Notch receptor signaling. Our research establishes muscle cell differentiation as a target for MeHg toxicity, which may contribute to the underlying etiology of motor deficits with MeHg toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Experiment K-6-09. Morphological and biochemical investigation of microgravity-induced nerve and muscle breakdown. Part 1: Investigation of nerve and muscle breakdown during spaceflight; Part 2: Biochemical analysis of EDL and PLT muscles

NASA Technical Reports Server (NTRS)

Riley, D. A.; Ellis, S.; Bain, J.; Sedlak, F.; Slocum, G.; Oganov, V.

1990-01-01

The present findings on rat hindlimb muscles suggest that skeletal muscle weakness induced by prolonged spaceflight can result from a combination of muscle fiber atrophy, muscle fiber segmental necrosis, degeneration of motor nerve terminals and destruction of microcirculatory vessels. Damage was confined to the red adductor longus (AL) and soleus muscles. The midbelly region of the AL muscle had more segmental necrosis and edema than the ends. Macrophages and neutrophils were the major mononucleated cells infiltrating and phagocytosing the cellular debris. Toluidine blue-positive mast cells were significantly decreased in Flight AL muscles compared to controls; this indicated that degranulation of mast cells contributed to tissue edema. Increased ubiquitination of disrupted myofibrils may have promoted myofilament degradation. Overall, mitochondria content and SDH activity were normal, except for a decrease in the subsarcolemmal region. The myofibrillar ATPase activity shifted toward the fast type in the Flight AL muscles. Some of the pathological changes may have occurred or been exacerbated during the 2 day postflight period of readaptation to terrestrial gravity. While simple atrophy should be reversible by exercise, restoration of pathological changes depends upon complex processes of regeneration by stem cells. Initial signs of muscle and nerve fiber regeneration were detected. Even though regeneration proceeds on Earth, the space environment may inhibit repair and cause progressive irreversible deterioration during long term missions. Muscles obtained from Flight rats sacrificed immediately (within a few hours) after landing are needed to distinguish inflight changes from postflight readaptation.

Regulatory circuitry of TWEAK-Fn14 system and PGC-1α in skeletal muscle atrophy program.

PubMed

Hindi, Sajedah M; Mishra, Vivek; Bhatnagar, Shephali; Tajrishi, Marjan M; Ogura, Yuji; Yan, Zhen; Burkly, Linda C; Zheng, Timothy S; Kumar, Ashok

2014-03-01

Skeletal muscle wasting attributed to inactivity has significant adverse functional consequences. Accumulating evidence suggests that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and TNF-like weak inducer of apoptosis (TWEAK)-Fn14 system are key regulators of skeletal muscle mass in various catabolic states. While the activation of TWEAK-Fn14 signaling causes muscle wasting, PGC-1α preserves muscle mass in several conditions, including functional denervation and aging. However, it remains unknown whether there is any regulatory interaction between PGC-1α and TWEAK-Fn14 system during muscle atrophy. Here we demonstrate that TWEAK significantly reduces the levels of PGC-1α and mitochondrial content (∼50%) in skeletal muscle. Levels of PGC-1α are significantly increased in skeletal muscle of TWEAK-knockout (KO) and Fn14-KO mice compared to wild-type mice on denervation. Transgenic (Tg) overexpression of PGC-1α inhibited progressive muscle wasting in TWEAK-Tg mice. PGC-1α inhibited the TWEAK-induced activation of NF-κB (∼50%) and dramatically reduced (∼90%) the expression of atrogenes such as MAFbx and MuRF1. Intriguingly, muscle-specific overexpression of PGC-1α also prevented the inducible expression of Fn14 in denervated skeletal muscle. Collectively, our study demonstrates that TWEAK induces muscle atrophy through repressing the levels of PGC-1α. Overexpression of PGC-1α not only blocks the TWEAK-induced atrophy program but also diminishes the expression of Fn14 in denervated skeletal muscle.

Drug-induced abnormalities of potassium metabolism.

PubMed

Kokot, Franciszek; Hyla-Klekot, Lidia

2008-01-01

Pharmacotherapy has progressed rapidly over the last 20 years with the result that general practioners more and more often use drugs which may influence potassium metabolism at the kidney or gastrointestinal level, or the transmembrane transport of potassium at the cellular level. Potassium abnormalities may result in life-theatening clinical conditions. Hypokalemia is most frequently caused by renal loss of this electrolyte (thiazide, thiazide-like and loop diuretics, glucocorticoids) and the gastrointestinal tract (laxatives, diarrhea, vomiting, external fistula), and may be the result of an increased intracellular potassium influx induced by sympathicomimetics used mostly by patients with asthma, or by insulin overdosage in diabetic subjects. The leading symptoms of hypokalemia are skeletal and smooth muscle weakness and cardiac arrhythmias. Hyperkalemia may be caused by acute or end-stage renal failure, impaired tubular excretion of potassium (blockers of the renin-angiotensin-aldosterone system, nonsteroidal anti-inflammatory drugs, cyclosporine, antifungal drugs, potassium sparing diuretics), acidemia, and severe cellular injury (tumor lysis syndrome). Hyperkalemia may be the cause of severe injury of both skeletal and smooth muscle cells. The specific treatment counteracting hyperkalemia is a bolus injection of calcium salts and, when necessary, hemodialysis.

Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy.

PubMed

Nicole, Sophie; Chaouch, Amina; Torbergsen, Torberg; Bauché, Stéphanie; de Bruyckere, Elodie; Fontenille, Marie-Joséphine; Horn, Morten A; van Ghelue, Marijke; Løseth, Sissel; Issop, Yasmin; Cox, Daniel; Müller, Juliane S; Evangelista, Teresinha; Stålberg, Erik; Ioos, Christine; Barois, Annie; Brochier, Guy; Sternberg, Damien; Fournier, Emmanuel; Hantaï, Daniel; Abicht, Angela; Dusl, Marina; Laval, Steven H; Griffin, Helen; Eymard, Bruno; Lochmüller, Hanns

2014-09-01

Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of rare diseases resulting from impaired neuromuscular transmission. Their clinical hallmark is fatigable muscle weakness associated with a decremental muscle response to repetitive nerve stimulation and frequently related to postsynaptic defects. Distal myopathies form another clinically and genetically heterogeneous group of primary muscle disorders where weakness and atrophy are restricted to distal muscles, at least initially. In both congenital myasthenic syndromes and distal myopathies, a significant number of patients remain genetically undiagnosed. Here, we report five patients from three unrelated families with a strikingly homogenous clinical entity combining congenital myasthenia with distal muscle weakness and atrophy reminiscent of a distal myopathy. MRI and neurophysiological studies were compatible with mild myopathy restricted to distal limb muscles, but decrement (up to 72%) in response to 3 Hz repetitive nerve stimulation pointed towards a neuromuscular transmission defect. Post-exercise increment (up to 285%) was observed in the distal limb muscles in all cases suggesting presynaptic congenital myasthenic syndrome. Immunofluorescence and ultrastructural analyses of muscle end-plate regions showed synaptic remodelling with denervation-reinnervation events. We performed whole-exome sequencing in two kinships and Sanger sequencing in one isolated case and identified five new recessive mutations in the gene encoding agrin. This synaptic proteoglycan with critical function at the neuromuscular junction was previously found mutated in more typical forms of congenital myasthenic syndrome. In our patients, we found two missense mutations residing in the N-terminal agrin domain, which reduced acetylcholine receptors clustering activity of agrin in vitro. Our findings expand the spectrum of congenital myasthenic syndromes due to agrin mutations and show an unexpected correlation between the mutated gene and the associated phenotype. This provides a good rationale for examining patients with apparent distal myopathy for a neuromuscular transmission disorder and agrin mutations. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Severe rhabdomyolysis and acute renal failure in an adolescent with hypothyroidism.

PubMed

Comak, Elif; Koyun, Mustafa; Kiliçarslan-Akkaya, Bahar; Bircan, Iffet; Akman, Sema

2011-01-01

Hypothyroidism has been reported rarely as the cause of rhabdomyolysis in adults and children. We present here a non-compliant adolescent with a diagnosis of hypothyroidism who developed rhabdomyolysis and acute renal failure with no additional predisposing factor. A 13-year-old girl with a previous history of hypothyroidism due to thyroid hypoplasia presented with generalized myalgia, malaise, vomiting, and oliguria lasting for three days. Neurological examination revealed bilateral marked weakness and tenderness of muscles of both lower and upper extremities. Urine had bloody appearance and urine analysis showed blood reaction with dipstick test, but there were no erythrocytes on microscopic examination. Serum creatine phosphokinase and myoglobin levels were elevated. Thyroid stimulating hormone (TSH) levels were high, and free thyroxine (T4) and triiodothyronine (T3) levels were low, compatible with uncontrolled hypothyroidism. Renal function tests showed acute renal failure. Other causes of rhabdomyolysis such as muscular trauma, drugs, toxins, infections, vigorous exercise, and electrolyte abnormalities were excluded. Hemodialysis was administered for 24 sessions. After L-thyroxine therapy, thyroid function tests normalized, muscle strength improved, serum muscle enzyme levels returned to normal levels, and renal function tests recovered. One must be aware that rhabdomyolysis may develop in a non-compliant patient with hypothyroidism.

Vitamin D and muscle function

USDA-ARS?s Scientific Manuscript database

Muscle weakness is a hallmark of severe vitamin D deficiency, but the effect of milder vitamin D deficiency or insufficiency on muscle mass and performance and risk of falling is uncertain. In this presentation, I review the evidence that vitamin D influences muscle mass and performance, balance, an...

Diaphragm Plasticity in Aging and Disease: Therapies for Muscle Weakness go from Strength to Strength.

PubMed

Greising, Sarah M; Ottenheijm, Coen A C; O'Halloran, Ken D; Barreiro, Esther

2018-04-19

The diaphragm is the main inspiratory muscle and is required to be highly active throughout the lifespan. The diaphragm muscle must be able to produce and sustain various behaviors that range from ventilatory to non-ventilatory such as those required for airway maintenance and clearance. Throughout the lifespan various circumstances and conditions may affect the ability of the diaphragm muscle to generate requisite forces and in turn the diaphragm muscle may undergo significant weakness and dysfunction. For example, hypoxic stress, critical illness, cancer cachexia, chronic obstructive pulmonary disorder (COPD), and age-related sarcopenia all represent conditions in which significant diaphragm muscle dysfunction exits. This perspective review article presents several interesting topics involving diaphragm plasticity in aging and disease that were presented at the International Union of Physiological Sciences (IUPS) Conference in 2017.This review seeks to maximize the broad and collective research impact on diaphragm muscle dysfunction in the search for transformative treatment approaches to improve the diaphragm muscle health during aging and disease.

[Combined spinal-epidural anesthesia for cesarean section in a parturient with myotonic dystrophy].

PubMed

Mori, Kosuke; Mizuno, Ju; Nagaoka, Takehiko; Harashima, Toshiya; Morita, Sigeho

2010-08-01

Myotonic dystrophy (MD) is a muscle disorder characterized by progressive muscle wasting and weakness, and is the most common form of muscular dystrophy that begins in adulthood, often after pregnancy. MD might be related to occurrence of malignant hyperthermia. Therefore, the cesarean section is often performed for the parturient with MD. We had an experience of combined spinal-epidural anesthesia for cesarean section in a parturient complicated with MD. A 40-year-old woman had rhabdomyolysis caused by ritodrine at 15-week gestation and was diagnosed as MD by electromyography. Her first baby died due to respiratory failure fourth day after birth. She had hatchet face, slight weakness of her lower extremities, and easy fatigability. Her manual muscle test was 5/5 at upper extremities and 4/5 at lower extremities. She underwent emergency cesarean section for premature rupture of the membrane, weak pain during labor, and obstructed labor at 33-week gestation. We placed an epidural catheter from T12/L1 and punctured arachnoid with 25 G spinal needle. We performed spinal anesthesia using 0.5% hyperbaric bupivacaine 1.5 ml and epidural anesthesia using 2% lidocaine 6 ml. Her anesthetic level reached bilaterally to T7 and operation started 18 minutes after combined spinal-epidural anesthesia. Her baby was born 23 minutes after the anesthesia. As her baby was 1/5 at Apgar score, the baby was tracheally intubated and artificially ventilated. The cesarean section was finished in 33 minutes uneventfully. She had no adverse events and was discharged on the 8th postoperative day. Later her baby was diagnosed as congenital MD by gene analysis. Combined spinal-epidural anesthesia with the amide-typed local anesthetic agents could be useful and safe for cesarean section in the parturient with MD.

Hindlimb unloading increases oxidative stress and disrupts antioxidant capacity in skeletal muscle

NASA Technical Reports Server (NTRS)

Lawler, John M.; Song, Wook; Demaree, Scott R.; Bloomfield, S. A. (Principal Investigator)

2003-01-01

Skeletal muscle disuse with space-flight and ground-based models (e.g., hindlimb unloading) results in dramatic skeletal muscle atrophy and weakness. Pathological conditions that cause muscle wasting (i.e., heart failure, muscular dystrophy, sepsis, COPD, cancer) are characterized by elevated "oxidative stress," where antioxidant defenses are overwhelmed by oxidant production. However, the existence, cellular mechanisms, and ramifications of oxidative stress in skeletal muscle subjected to hindlimb unloading are poorly understood. Thus we examined the effects of hindlimb unloading on hindlimb muscle antioxidant enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase), nonenzymatic antioxidant scavenging capacity (ASC), total hydroperoxides, and dichlorohydrofluorescein diacetate (DCFH-DA) oxidation, a direct indicator of oxidative stress. Twelve 6 month old Sprague Dawley rats were divided into two groups: 28 d of hindlimb unloading (n = 6) and controls (n = 6). Hindlimb unloading resulted in a small decrease in Mn-superoxide dismutase activity (10.1%) in the soleus muscle, while Cu,Zn-superoxide dismutase increased 71.2%. In contrast, catalase and glutathione peroxidase, antioxidant enzymes that remove hydroperoxides, were significantly reduced in the soleus with hindlimb unloading by 54.5 and 16.1%, respectively. Hindlimb unloading also significantly reduced ASC. Hindlimb unloading increased soleus lipid hydroperoxide levels by 21.6% and hindlimb muscle DCFH-DA oxidation by 162.1%. These results indicate that hindlimb unloading results in a disruption of antioxidant status, elevation of hydroperoxides, and an increase in oxidative stress.

Acute antibody-directed myostatin inhibition attenuates disuse muscle atrophy and weakness in mice.

PubMed

Murphy, Kate T; Cobani, Vera; Ryall, James G; Ibebunjo, Chikwendu; Lynch, Gordon S

2011-04-01

Counteracting the atrophy of skeletal muscle associated with disuse has significant implications for minimizing the wasting and weakness in plaster casting, joint immobilization, and other forms of limb unloading, with relevance to orthopedics, sports medicine, and plastic and reconstructive surgery. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the loss of muscle mass and functional capacity in mice during 14 or 21 days of unilateral hindlimb casting. Twelve-week-old C57BL/10 mice were subjected to unilateral hindlimb plaster casting or served as controls. Mice received subcutaneous injections of saline or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg/kg; n = 6-9) on days 0 and 7 and were tested for muscle function on day 14, or were treated on days 0, 7, and 14 and tested for muscle function on day 21. Hindlimb casting reduced muscle mass, fiber size, and function of isolated soleus and extensor digitorum longus (EDL) muscles (P < 0.05). PF-354 attenuated the loss of muscle mass, fiber size, and function with greater effects after 14 days than after 21 days of casting, when wasting and weakness had plateaued (P < 0.05). Antibody-directed myostatin inhibition therefore attenuated the atrophy and loss of functional capacity in muscles from mice subjected to unilateral hindlimb casting with reductions in muscle size and strength being most apparent during the first 14 days of disuse. These findings highlight the therapeutic potential of antibody-directed myostatin inhibition for disuse atrophy especially within the first 2 wk of disuse.

Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness.

PubMed

Hu, Hao; Matter, Michelle L; Issa-Jahns, Lina; Jijiwa, Mayumi; Kraemer, Nadine; Musante, Luciana; de la Vega, Michelle; Ninnemann, Olaf; Schindler, Detlev; Damatova, Natalia; Eirich, Katharina; Sifringer, Marco; Schrötter, Sandra; Eickholt, Britta J; van den Heuvel, Lambert; Casamina, Chanel; Stoltenburg-Didinger, Gisela; Ropers, Hans-Hilger; Wienker, Thomas F; Hübner, Christoph; Kaindl, Angela M

2014-12-01

To identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). We characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild-type and mutant mice and in patient and control fibroblasts. In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts. We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease.

Isolated Medial Rectus Nuclear Palsy as a Rare Presentation of Midbrain Infarction.

PubMed

Al-Sofiani, Mohammed; Lee Kwen, Peterkin

2015-10-08

Diplopia is a common subjective complaint that can be the first manifestation of a serious pathology. Here, we report a rare case of midbrain infarction involving the lateral subnucleus of the oculomotor nuclear complex presenting as diplopia, with no other stroke manifestations. An 83-year-old right-handed white man with past medical history of diabetes mellitus, hypertension, dyslipidemia, and coronary artery disease presented to the emergency department (ED) with diplopia and unsteadiness. Two days prior to admission, the patient woke up with constant horizontal diplopia and unsteadiness, which limited his daily activities and led to a fall at home. He denied any weakness, clumsiness, nausea, vomiting, photophobia, fever, or chills. Ocular exam showed a disconjugate gaze at rest, weakness of the left medial rectus muscle, impaired convergence test, and bilateral 3-mm reactive pupils. The diplopia resolved by closing either eye. The remaining extraocular muscles and other cranial nerves were normal. There was no nystagmus, ptosis, or visual field deficit. Sensation, muscle tone, and strength were normal in all extremities. Magnetic resonance imaging (MRI) of the brain revealed a tiny focus of restricted diffusion in the left posterior lateral midbrain. A thorough history and physical examination is essential to diagnose and manage diplopia. Isolated extraocular palsy is usually thought to be caused by orbital lesions or muscular diseases. Here, we report a case of midbrain infarction manifested as isolated medial rectus palsy.

Dysfunctional Muscle and Liver Glycogen Metabolism in mdx Dystrophic Mice

PubMed Central

Stapleton, David I.; Lau, Xianzhong; Flores, Marcelo; Trieu, Jennifer; Gehrig, Stefan M.; Chee, Annabel; Naim, Timur; Lynch, Gordon S.; Koopman, René

2014-01-01

Background Duchenne muscular dystrophy (DMD) is a severe, genetic muscle wasting disorder characterised by progressive muscle weakness. DMD is caused by mutations in the dystrophin (dmd) gene resulting in very low levels or a complete absence of the dystrophin protein, a key structural element of muscle fibres which is responsible for the proper transmission of force. In the absence of dystrophin, muscle fibres become damaged easily during contraction resulting in their degeneration. DMD patients and mdx mice (an animal model of DMD) exhibit altered metabolic disturbances that cannot be attributed to the loss of dystrophin directly. We tested the hypothesis that glycogen metabolism is defective in mdx dystrophic mice. Results Dystrophic mdx mice had increased skeletal muscle glycogen (79%, (P<0.01)). Skeletal muscle glycogen synthesis is initiated by glycogenin, the expression of which was increased by 50% in mdx mice (P<0.0001). Glycogen synthase activity was 12% higher (P<0.05) but glycogen branching enzyme activity was 70% lower (P<0.01) in mdx compared with wild-type mice. The rate-limiting enzyme for glycogen breakdown, glycogen phosphorylase, had 62% lower activity (P<0.01) in mdx mice resulting from a 24% reduction in PKA activity (P<0.01). In mdx mice glycogen debranching enzyme expression was 50% higher (P<0.001) together with starch-binding domain protein 1 (219% higher; P<0.01). In addition, mdx mice were glucose intolerant (P<0.01) and had 30% less liver glycogen (P<0.05) compared with control mice. Subsequent analysis of the enzymes dysregulated in skeletal muscle glycogen metabolism in mdx mice identified reduced glycogenin protein expression (46% less; P<0.05) as a possible cause of this phenotype. Conclusion We identified that mdx mice were glucose intolerant, and had increased skeletal muscle glycogen but reduced amounts of liver glycogen. PMID:24626262

Influence of rotator cuff tears on glenohumeral stability during abduction tasks.

PubMed

Hölscher, Thomas; Weber, Tim; Lazarev, Igor; Englert, Carsten; Dendorfer, Sebastian

2016-09-01

One of the main goals in reconstructing rotator cuff tears is the restoration of glenohumeral joint stability, which is subsequently of utmost importance in order to prevent degenerative damage such as superior labral anterior posterior (SLAP) lesion, arthrosis, and malfunction. The goal of the current study was to facilitate musculoskeletal models in order to estimate glenohumeral instability introduced by muscle weakness due to cuff lesions. Inverse dynamics simulations were used to compute joint reaction forces for several static abduction tasks with different muscle weakness. Results were compared with the existing literature in order to ensure the model validity. Further arm positions taken from activities of daily living, requiring the rotator cuff muscles were modeled and their contribution to joint kinetics computed. Weakness of the superior rotator cuff muscles (supraspinatus; infraspinatus) leads to a deviation of the joint reaction force to the cranial dorsal rim of the glenoid. Massive rotator cuff defects showed higher potential for glenohumeral instability in contrast to single muscle ruptures. The teres minor muscle seems to substitute lost joint torque during several simulated muscle tears to maintain joint stability. Joint instability increases with cuff tear size. Weakness of the upper part of the rotator cuff leads to a joint reaction force closer to the upper glenoid rim. This indicates the comorbidity of cuff tears with SLAP lesions. The teres minor is crucial for maintaining joint stability in case of massive cuff defects and should be uprated in clinical decision-making. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1628-1635, 2016. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Muscle atrophy, voluntary activation disturbances, and low serum concentrations of IGF-1 and IGFBP-3 are associated with weakness in people with chronic stroke.

PubMed

Silva-Couto, Marcela de Abreu; Prado-Medeiros, Christiane Lanatovitz; Oliveira, Ana Beatriz; Alcântara, Carolina Carmona; Guimarães, Araci Teixeira; Salvini, Tania de Fatima; Mattioli, Rosana; de Russo, Thiago Luiz

2014-07-01

The muscle weakness that is exhibited poststroke is due to a multifactorial etiology involving the central nervous system and skeletal muscle changes. Insulinlike growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) have been described as biomarkers of neuromuscular performance in many conditions. However, no information about these biomarkers is available for people with chronic hemiparesis. The purpose of this study was to investigate possible factors involved in muscle weakness, such as IGF-1 and IGFBP-3 serum concentrations, muscle volume, and neuromuscular performance of the knee flexors and extensors, in people with chronic hemiparesis poststroke. This was a cross-sectional study. A cross-sectional study was performed on 14 individuals poststroke who were paired with healthy controls. Mobility, function, balance, and quality of life were recorded as outcome measures. Knee flexor and extensor muscle volumes and neuromuscular performance were measured using nuclear magnetic resonance imaging, dynamometry, and electromyography. The serum concentrations of IGF-1 and IGFBP-3 were quantified by enzyme-linked immunosorbent assay (ELISA). The hemiparetic group had low serum concentrations of IGF-1 (25%) and IGFBP-3 (40%); reduced muscle volume in the vastus medialis (32%), vastus intermedius (29%), biceps femoris (16%), and semitendinosus and semimembranosus (12%) muscles; reduced peak torque, power, and work of the knee flexors and extensors; and altered agonist and antagonist muscle activation compared with controls. Low serum concentrations of IGF-1 and IGFBP-3, deficits in neuromuscular performance, selective muscle atrophy, and decreased agonist muscle activation were found in the group with chronic hemiparesis poststroke. Both hemorrhagic and ischemic stroke were considered, and the data reflect a chronic poststroke population with good function. © 2014 American Physical Therapy Association.

Impaired control of weight bearing ankle inversion in subjects with chronic ankle instability.

PubMed

Terrier, R; Rose-Dulcina, K; Toschi, B; Forestier, N

2014-04-01

Previous studies have proposed that evertor muscle weakness represents an important factor affecting chronic ankle instability. For research purposes, ankle evertor strength is assessed by means of isokinetic evaluations. However, this methodology is constraining for daily clinical use. The present study proposes to assess ankle evertor muscle weakness using a new procedure, one that is easily accessible for rehabilitation specialists. To do so, we compared weight bearing ankle inversion control between patients suffering from chronic ankle instability and healthy subjects. 12 healthy subjects and 11 patients suffering from chronic ankle instability conducted repetitions of one leg weight bearing ankle inversion on a specific ankle destabilization device equipped with a gyroscope. Ankle inversion control was performed by means of an eccentric recruitment of evertor muscles. Instructions were to perform, as slow as possible, the ankle inversion while resisting against full body weight applied on the tested ankle. Data clearly showed higher angular inversion velocity peaks in patients suffering from chronic ankle instability. This illustrates an impaired control of weight bearing ankle inversion and, by extension, an eccentric weakness of evertor muscles. The present study supports the hypothesis of a link between the decrease of ankle joint stability and evertor muscle weakness. Moreover, it appears that the new parameter is of use in a clinical setting. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Group B streptococcus meningitis and infection surrounding the spinal canal caused by bacterial transmission from rectal ulcer via Batson's plexus].

PubMed

Tsutsumi, Ryosuke; Saito, Masaaki; Yoshizawa, Toshihiro

2011-07-01

A 62-year-old man was admitted to our hospital because of fever and disturbed consciousness. He suffered from persistent constipation due to diabetic autonomic neuropathy. On admission, neck stiffness and weakness of the lower extremities were observed. Cerebrospinal fluid (CSF) pleocytosis and decreased CSF glucose concentration showed the presence of meningitis. Bacterial culture of CSF was negative. One week after admission, he suddenly suffered from massive bleeding from the rectum, where a hemorrhagic ulcer caused by severe persistent constipation was observed. Contrast-enhanced CT scans and gadolinium-enhanced MR scans demonstrated a lumbar spinal epidural abscess, paraspinal muscle abscess, and cervical osteomyelitis. Streptococcus agalactiae, a bacterial species belonging to the group B streptococci, was isolated from pus obtained by needle puncture of the paraspinal muscle abscess. His entire condition was treated successfully with ampicillin and cefotaxime. Group B streptococci normally colonize the mucous membrane of the genital or lower gastrointestinal regions and rarely cause a spinal epidural abscess. However, in this case, the existence of a rectal ulcer probably made it possible for S. agalactiae to cause an infection of the epidural space or paraspinal muscles via the spinal valveless venous system named Batson's plexus communicating with the sacral, pelvic, and prostatic venous plexus. Our case indicated the importance of Batson's plexus in group B streptococcus infections surrounding the spinal canal and the necessity to explore for intrapelvic lesions including a rectal ulcer.

Diabetes and Stem Cell Function

PubMed Central

Fujimaki, Shin; Wakabayashi, Tamami; Takemasa, Tohru; Asashima, Makoto; Kuwabara, Tomoko

2015-01-01

Diabetes mellitus is one of the most common serious metabolic diseases that results in hyperglycemia due to defects of insulin secretion or insulin action or both. The present review focuses on the alterations to the diabetic neuronal tissues and skeletal muscle, including stem cells in both tissues, and the preventive effects of physical activity on diabetes. Diabetes is associated with various nervous disorders, such as cognitive deficits, depression, and Alzheimer's disease, and that may be caused by neural stem cell dysfunction. Additionally, diabetes induces skeletal muscle atrophy, the impairment of energy metabolism, and muscle weakness. Similar to neural stem cells, the proliferation and differentiation are attenuated in skeletal muscle stem cells, termed satellite cells. However, physical activity is very useful for preventing the diabetic alteration to the neuronal tissues and skeletal muscle. Physical activity improves neurogenic capacity of neural stem cells and the proliferative and differentiative abilities of satellite cells. The present review proposes physical activity as a useful measure for the patients in diabetes to improve the physiological functions and to maintain their quality of life. It further discusses the use of stem cell-based approaches in the context of diabetes treatment. PMID:26075247

A chemical chaperone improves muscle function in mice with a RyR1 mutation.

PubMed

Lee, Chang Seok; Hanna, Amy D; Wang, Hui; Dagnino-Acosta, Adan; Joshi, Aditya D; Knoblauch, Mark; Xia, Yan; Georgiou, Dimitra K; Xu, Jianjun; Long, Cheng; Amano, Hisayuki; Reynolds, Corey; Dong, Keke; Martin, John C; Lagor, William R; Rodney, George G; Sahin, Ergun; Sewry, Caroline; Hamilton, Susan L

2017-03-24

Mutations in the RYR1 gene cause severe myopathies. Mice with an I4895T mutation in the type 1 ryanodine receptor/Ca 2+ release channel (RyR1) display muscle weakness and atrophy, but the underlying mechanisms are unclear. Here we show that the I4895T mutation in RyR1 decreases the amplitude of the sarcoplasmic reticulum (SR) Ca 2+ transient, resting cytosolic Ca 2+ levels, muscle triadin content and calsequestrin (CSQ) localization to the junctional SR, and increases endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and mitochondrial ROS production. Treatment of mice carrying the I4895T mutation with a chemical chaperone, sodium 4-phenylbutyrate (4PBA), reduces ER stress/UPR and improves muscle function, but does not restore SR Ca 2+ transients in I4895T fibres to wild type levels, suggesting that decreased SR Ca 2+ release is not the major driver of the myopathy. These findings suggest that 4PBA, an FDA-approved drug, has potential as a therapeutic intervention for RyR1 myopathies that are associated with ER stress.

A chemical chaperone improves muscle function in mice with a RyR1 mutation

PubMed Central

Lee, Chang Seok; Hanna, Amy D.; Wang, Hui; Dagnino-Acosta, Adan; Joshi, Aditya D.; Knoblauch, Mark; Xia, Yan; Georgiou, Dimitra K.; Xu, Jianjun; Long, Cheng; Amano, Hisayuki; Reynolds, Corey; Dong, Keke; Martin, John C.; Lagor, William R.; Rodney, George G.; Sahin, Ergun; Sewry, Caroline; Hamilton, Susan L.

2017-01-01

Mutations in the RYR1 gene cause severe myopathies. Mice with an I4895T mutation in the type 1 ryanodine receptor/Ca2+ release channel (RyR1) display muscle weakness and atrophy, but the underlying mechanisms are unclear. Here we show that the I4895T mutation in RyR1 decreases the amplitude of the sarcoplasmic reticulum (SR) Ca2+ transient, resting cytosolic Ca2+ levels, muscle triadin content and calsequestrin (CSQ) localization to the junctional SR, and increases endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and mitochondrial ROS production. Treatment of mice carrying the I4895T mutation with a chemical chaperone, sodium 4-phenylbutyrate (4PBA), reduces ER stress/UPR and improves muscle function, but does not restore SR Ca2+ transients in I4895T fibres to wild type levels, suggesting that decreased SR Ca2+ release is not the major driver of the myopathy. These findings suggest that 4PBA, an FDA-approved drug, has potential as a therapeutic intervention for RyR1 myopathies that are associated with ER stress. PMID:28337975

Patient autoantibodies deplete postsynaptic muscle-specific kinase leading to disassembly of the ACh receptor scaffold and myasthenia gravis in mice

PubMed Central

Cole, R N; Ghazanfari, N; Ngo, S T; Gervásio, O L; Reddel, S W; Phillips, W D

2010-01-01

The postsynaptic muscle-specific kinase (MuSK) coordinates formation of the neuromuscular junction (NMJ) during embryonic development. Here we have studied the effects of MuSK autoantibodies upon the NMJ in adult mice. Daily injections of IgG from four MuSK autoantibody-positive myasthenia gravis patients (MuSK IgG; 45 mg day−1i.p. for 14 days) caused reductions in postsynaptic ACh receptor (AChR) packing as assessed by fluorescence resonance energy transfer (FRET). IgG from the patients with the highest titres of MuSK autoantibodies caused large (51–73%) reductions in postsynaptic MuSK staining (cf. control mice; P < 0.01) and muscle weakness. Among mice injected for 14 days with control and MuSK patient IgGs, the residual level of MuSK correlated with the degree of impairment of postsynaptic AChR packing. However, the loss of postsynaptic MuSK preceded this impairment of postsynaptic AChR. When added to cultured C2 muscle cells the MuSK autoantibodies caused tyrosine phosphorylation of MuSK and the AChR β-subunit, and internalization of MuSK from the plasma membrane. The results suggest a pathogenic mechanism in which MuSK autoantibodies rapidly deplete MuSK from the postsynaptic membrane leading to progressive dispersal of postsynaptic AChRs. Moreover, maintenance of postsynaptic AChR packing at the adult NMJ would appear to depend upon physical engagement of MuSK with the AChR scaffold, notwithstanding activation of the MuSK-rapsyn system of AChR clustering. PMID:20603331

Development of rhabdomyolysis in a child after norovirus gastroenteritis.

PubMed

Nishio, Tomohiro; Yonetani, Ryoko; Ito, Eisuke; Yoneta, Makiko; Maruo, Yoshihiro; Yoshida, Tokiko; Sugimoto, Tohru

2016-11-04

In children, the most significant cause of rhabdomyolysis or muscle breakdown is viral infection. However, there are no reports that norovirus, a gastroenteric virus that commonly infects children, specifically causes rhabdomyolysis. Here, we report the first pediatric case of norovirus-associated rhabdomyolysis. The patient, a 2-year-old boy with fever, diarrhea, and vomiting, was referred to our hospital with dysstasia and transaminitis. He was diagnosed with rhabdomyolysis. Additionally, norovirus genogroup GII was detected from stool samples by real-time quantitative reverse transcription Polymerase Chain Reaction, and thereafter, the norovirus GII.4 variant was identified. However, the association between rhabdomyolysis and the isolated norovirus variant was not clarified. After treatment the patient recovered without renal failure or disseminated intravascular coagulation. Rhabdomyolysis is a disease for which there is a need for early detection and treatment. If abnormal posture or muscle weakness is observed during the course of gastroenteritis, blood and urinary tests should be performed to rule out rhabdomyolysis.

Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds

PubMed Central

Cherry, Jonathan J; Osman, Erkan Y; Evans, Matthew C; Choi, Sungwoon; Xing, Xuechao; Cuny, Gregory D; Glicksman, Marcie A; Lorson, Christian L; Androphy, Elliot J

2013-01-01

Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the SMN1 gene. SMN2 is a nearly identical copy of SMN1, which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full-length SMN protein from the endogenous SMN2 gene should lessen disease severity. We have developed and implemented a new high-throughput screening assay to identify small molecules that increase the expression of full-length SMN from a SMN2 reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA. PMID:23740718

Novel SNP array analysis and exome sequencing detect a homozygous exon 7 deletion of MEGF10 causing early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD)

PubMed Central

Pierson, Tyler Mark; Markello, Thomas; Accardi, John; Wolfe, Lynne; Adams, David; Sincan, Murat; Tarazi, Noor M.; Fajardo, Karin Fuentes; Cherukuri, Praveen F.; Bajraktari, Ilda; Meilleur, Katy G.; Donkervoort, Sandra; Jain, Mina; Hu, Ying; Lehky, Tanya J.; Cruz, Pedro; Mullikin, James C.; Bonnemann, Carsten; Gahl, William A.; Boerkoel, Cornelius F.; Tifft, Cynthia J.

2013-01-01

Early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) is a myopathic disorder associated with mutations in MEGF10. By novel analysis of SNP array hybridization and exome sequence coverage, we diagnosed a 10-year old girl with EMARDD following identification of a novel homozygous deletion of exon 7 in MEGF10. In contrast to previously reported EMARDD patients, her weakness was more prominent proximally than distally, and involved her legs more than her arms. MRI of her pelvis and thighs showed muscle atrophy and fatty replacement. Ultrasound of several muscle groups revealed dense homogenous increases in echogenicity. Cloning and sequencing of the deletion breakpoint identified features suggesting the mutation arose by fork stalling and template switching. These findings constitute the first genomic deletion causing EMARDD, expand the clinical phenotype, and provide new insight into the pattern and histology of its muscular pathology. PMID:23453856

An Unusual Presentation of Addison's Disease-A Case Report.

PubMed

Choudhary, Sandeep; Alam, Anwer; Dewan, Vivek; Yadav, Dinesh; Dubey, N K

2011-07-01

Addison's disease is most commonly due to autoimmune adrenalitis and tuberculosis and refers to primary hypoadrenalism caused by a total or near total destruction or dysfunction of both adrenal cortices. Usual manifestations involve chronic fatigue, muscle weakness, loss of appetite, nausea, vomiting, diarrhea, hypotension and hyperpigmentation of skin. We herein report a case of primary adrenal insufficiency presenting with fever and seizures in an 11-yr-old boy. His symptoms resolved after starting specific therapy. This kind of presentation of Addison's disease is rather unusual.

Generalized tetanus could be complicated with Guillain-Barré syndrome.

PubMed

Lee, Jae Hoon; Hwang, Yun Su; Cho, Ji Hyun

2016-07-01

A retrospective analysis of patients diagnosed with tetanus was conducted to evaluate the occurrence of Guillain-Barré syndrome (GBS). Two of 13 tetanus cases were complicated with GBS. Their symptoms and signs related to GBS improved markedly after a 5-day infusion of intravenous immunoglobulin. Physicians should keep in mind that GBS can be an important cause of muscle weakness in patients with tetanus. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Long thoracic neuropathy from athletic activity.

PubMed

Schultz, J S; Leonard, J A

1992-01-01

Four cases of long thoracic mononeuropathy associated with sports participation are presented. Each patient developed shoulder pain or dysfunction after an acute event or vigorous activity, and demonstrated scapular winging consistent with serratus anterior weakness. The diagnosis was confirmed with electromyography in each case. It is suggested that the athletic activity caused a stretch injury to the long thoracic nerve. Conservative management, consisting of range of motion exercises for the shoulder and strengthening of the serratus anterior muscle, resulted in a favorable outcome in all patients.

Combination Antisense Treatment for Destructive Exon Skipping of Myostatin and Open Reading Frame Rescue of Dystrophin in Neonatal mdx Mice.

PubMed

Lu-Nguyen, Ngoc B; Jarmin, Susan A; Saleh, Amer F; Popplewell, Linda; Gait, Michael J; Dickson, George

2015-08-01

The fatal X-linked Duchenne muscular dystrophy (DMD), characterized by progressive muscle wasting and muscle weakness, is caused by mutations within the DMD gene. The use of antisense oligonucleotides (AOs) modulating pre-mRNA splicing to restore the disrupted dystrophin reading frame, subsequently generating a shortened but functional protein has emerged as a potential strategy in DMD treatment. AO therapy has recently been applied to induce out-of-frame exon skipping of myostatin pre-mRNA, knocking-down expression of myostatin protein, and such an approach is suggested to enhance muscle hypertrophy/hyperplasia and to reduce muscle necrosis. Within this study, we investigated dual exon skipping of dystrophin and myostatin pre-mRNAs using phosphorodiamidate morpholino oligomers conjugated with an arginine-rich peptide (B-PMOs). Intraperitoneal administration of B-PMOs was performed in neonatal mdx males on the day of birth, and at weeks 3 and 6. At week 9, we observed in treated mice (as compared to age-matched, saline-injected controls) normalization of muscle mass, a recovery in dystrophin expression, and a decrease in muscle necrosis, particularly in the diaphragm. Our data provide a proof of concept for antisense therapy combining dystrophin restoration and myostatin inhibition for the treatment of DMD.

Muscle strength, gait, and balance in 20 patients with hip osteoarthritis followed for 2 years after THA

PubMed Central

Dalén, Nils; Berg, Hans E

2010-01-01

Background Patients with hip osteoarthritis (OA) have muscular weakness, impaired balance, and limp. Deficits in the different limb muscles and their recovery courses are largely unknown, however. We hypothesized that there is persisting muscular weakness in lower limb muscles and an impaired balance and gait 2 years after THA. Patients and methods 20 elderly patients with unilateral OA were assessed before, and 6 and 24 months after surgery for maximal voluntary isometric strength of hip and knee muscles and by gait analysis, postural stability, and clinical scores (HHS, SF-36, EuroQoL). Results Hip muscles showed a remaining 6% weakness compared to the contralateral healthy limb 2 years after THA. Preoperatively and 6 months postoperatively, that deficit was 18% and 12%, respectively. Knee extensors fully recovered a preoperative 27% deficit after 2 years. Gait analysis demonstrated a shorter single stance phase for the OA limb compared to healthy limb preoperatively, that had already recovered at the 6-month follow-up. Balance of two-foot standing showed improvement in both sagittal and lateral sway after operation. All clinical scores improved. Interpretation Muscle strength data demonstrated a slow but full recovery of muscles acting about the knee, but there was still a deficit in hip muscle strength 2 years after THA. Gait and balance recovered after the operation. To accelerate improvement in muscular strength after THA, postoperative training should probably be more intense and target hip abductors. PMID:20367414

Weaker lower extremity muscle strength predicts traumatic knee injury in youth female but not male athletes.

PubMed

Ryman Augustsson, Sofia; Ageberg, Eva

2017-01-01

The role of lower extremity (LE) muscle strength for predicting traumatic knee injury in youth athletes is largely unknown. The aim was to investigate the influence of LE muscle strength on traumatic knee injury in youth female and male athletes. 225 athletes (40% females) from sport senior high schools in Sweden were included in this case-control study. The athletes recorded any traumatic knee injury that had occurred during their high-school period in a web-based injury form. A one repetition maximum (1RM) barbell squat test was used to measure LE muscle strength. The 1RM was dichotomised to analyse 'weak' versus 'strong' athletes according to the median (weak median vs strong median ). 63 traumatic knee injuries, including 18 ACL injuries, were registered. The majority of injured female athletes were in the weak group compared with the strong group (p=0.0001). The odds of sustaining a traumatic knee injury and an ACL injury was 9.5 times higher and 7 times higher, respectively, in the weak median group compared with the strong median group in females (p ≤0.011). A relative 1RM squat ≤1.05 kg (105% of bodyweight) was established as the best cut-off value to distinguish high versus low risk of injury in female athletes. No strength-injury relationships were observed for the male athletes (p ≥0.348). Weaker LE muscle strength predicted traumatic knee injury in youth female athletes, but not in males. This suggests that LE muscle strength should be included in injury screening in youth female athletes.

The spectrum of muscle histopathologic findings in 42 weak scleroderma patients

PubMed Central

Paik, Julie J.; Wigley, Fredrick M.; Lloyd, Thomas E.; Corse, Andrea M.; Casciola-Rosen, Livia; Shah, Ami A.; Boin, Francesco; Hummers, Laura K.; Mammen, Andrew L.

2015-01-01

Objective To determine if distinct muscle pathological features exist in scleroderma subjects with weakness. Methods This retrospective study included weak scleroderma subjects with muscle biopsies available for review. Biopsies were systematically assessed for individual pathologic features including inflammation, necrosis, fibrosis, and acute neurogenic atrophy. Based on the aggregate individual features, biopsies were assigned a histopathologic category of polymyositis, dermatomyositis, necrotizing myopathy, non-specific myositis, “acute denervation”, “fibrosis only”, or “other”. Clinical data analyzed included autoantibody profiles, scleroderma subtype and disease duration, Medsger muscle severity scores, creatine kinase (CK), electromyography (EMG), and muscle magnetic resonance imaging (MRI). Results 42 subjects (79% female and 64% diffuse scleroderma) were included in this study. Necrosis (67%), inflammation (48%), acute neurogenic atrophy (48%), and fibrosis (33%) were the most prevalent pathologic features. The presence of fibrosis was strongly associated with anti-PM-Scl antibodies. Histopathologic categories included non-specific myositis (36%), necrotizing myopathy (21%), dermatomyositis (7%), “acute denervation” (7%), “fibrosis only” (7%), and polymyositis (5%). Disease duration of scleroderma at the time of muscle biopsy was shorter in polymyositis than other histopathologic categories. Patients with anti-PM-Scl and Scl-70 antibodies also had a shorter disease duration than those with other auto-antibody profiles. Conclusion Non-specific myositis and necrotizing myopathy were the most common histopathologic categories in weak scleroderma subjects. Surprisingly, nearly half of the subjects studied had histological evidence of acute motor denervation (acute neurogenic atrophy); this has not been previously reported. Taken together, these observations suggest that a variety of pathologic mechanisms may underlie the development of myopathy in scleroderma. PMID:25989455

Regulatory circuitry of TWEAK-Fn14 system and PGC-1α in skeletal muscle atrophy program

PubMed Central

Hindi, Sajedah M.; Mishra, Vivek; Bhatnagar, Shephali; Tajrishi, Marjan M.; Ogura, Yuji; Yan, Zhen; Burkly, Linda C.; Zheng, Timothy S.; Kumar, Ashok

2014-01-01

Skeletal muscle wasting attributed to inactivity has significant adverse functional consequences. Accumulating evidence suggests that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and TNF-like weak inducer of apoptosis (TWEAK)-Fn14 system are key regulators of skeletal muscle mass in various catabolic states. While the activation of TWEAK-Fn14 signaling causes muscle wasting, PGC-1α preserves muscle mass in several conditions, including functional denervation and aging. However, it remains unknown whether there is any regulatory interaction between PGC-1α and TWEAK-Fn14 system during muscle atrophy. Here we demonstrate that TWEAK significantly reduces the levels of PGC-1α and mitochondrial content (∼50%) in skeletal muscle. Levels of PGC-1α are significantly increased in skeletal muscle of TWEAK-knockout (KO) and Fn14-KO mice compared to wild-type mice on denervation. Transgenic (Tg) overexpression of PGC-1α inhibited progressive muscle wasting in TWEAK-Tg mice. PGC-1α inhibited the TWEAK-induced activation of NF-κB (∼50%) and dramatically reduced (∼90%) the expression of atrogenes such as MAFbx and MuRF1. Intriguingly, muscle-specific overexpression of PGC-1α also prevented the inducible expression of Fn14 in denervated skeletal muscle. Collectively, our study demonstrates that TWEAK induces muscle atrophy through repressing the levels of PGC-1α. Overexpression of PGC-1α not only blocks the TWEAK-induced atrophy program but also diminishes the expression of Fn14 in denervated skeletal muscle.—Hindi, S. M., Mishra, V., Bhatnagar, S., Tajrishi, M. M., Ogura, Y., Yan, Z., Burkly, L. C., Zheng, T. S., Kumar, A. Regulatory circuitry of TWEAK-Fn14 system and PGC-1α in skeletal muscle atrophy program. PMID:24327607

Hypokalemia causing rhabdomyolysis in a patient with short bowel syndrome.

PubMed

Balhara, Kamna S; Highet, Bridget; Omron, Rodney

2015-04-01

Rhabdomyolysis, usually in the setting of trauma or drug use, is frequently seen in the emergency setting, and often leads to hyperkalemia at presentation. Hypokalemia, however, is a potentially underrecognized cause of rhabdomyolysis. We present a case of rhabdomyolysis likely due to hypokalemia in the setting of short bowel syndrome. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although less common, hypokalemia can be a significant cause of rhabdomyolysis via its effects on muscle. This scenario should be considered in the differential diagnosis of patients at risk for hypokalemia who present with weakness. Rapid recognition of this relationship and rapid correction of hypokalemia may prove very important in preventing the deleterious effects of rhabdomyolysis. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of microgravity on rat muscle

NASA Technical Reports Server (NTRS)

Riley, D. A.

1990-01-01

It is well known that humans exposed to long term spaceflight experience undesirable progressive muscle weakness and increased fatigability. This problem has prompted the implementation of inflight exercise programs because most investigators believe that the major cause of diminished muscle performance is a combination of disuse and decreased workload. Inflight exercise has improved muscle health, but deficits have persisted, indicating that either the regimens utilized were suboptimal or there existed additional debilitating factors which were not remedied by exercise. Clarification of this question requires an improved understanding of the cellular and molecular basis of spaceflight-induced muscle deterioration. To this end, multiple investigations have been performed on the muscles from rats orbited 5 to 22 days in Cosmos biosatellites and Spacelab-3 (2,4,5,8,10 to 14,16,18,19,21 to 23,25,27,28). The eight Cosmos 1887 investigations examined the structural and biochemical changes in skeletal and cardiac muscles of rats exposed to microgravity for 12.5 days and returned to terrestrial gravity 2.3 days before tissues were collected. Even though interpretation of these results was complicated by the combination of inflight and postflight induced alterations, the consensus is that there is marked heterogeneity in both degree and type of responses from the whole muscle level down to the molecular level. Collectively, the muscle investigations of Cosmos 1887 clearly illustrate the wide diversity of muscle tissue responses to spaceflight. Judging from the summary report of this mission, heterogeneity of responses is not unique to muscle tissue. Elucidating the mechanism underlying this heterogeneity holds the key to explaining adaptation of the organism to prolonged spaceflight.

Are pain location and physical examinations useful in locating a tear site of the rotator cuff?

PubMed

Itoi, Eiji; Minagawa, Hiroshi; Yamamoto, Nobuyuki; Seki, Nobutoshi; Abe, Hidekazu

2006-02-01

Pain is the most common symptom of patients with rotator cuff tendinopathy, but little is known about the relationship between the site of pain and the site of cuff pathologic lesions. Also, accuracies of physical examinations used to locate a tear by assessing the muscle strength seem to be affected by the threshold for muscle weakness, but no studies have been reported regarding the efficacies of physical examinations in reference to their threshold. Pain location is useful in locating a tear site. Efficacies of physical examinations to evaluate the function of the cuff muscles depend on the threshold for muscle weakness. Case series; Level of evidence, 4. The authors retrospectively reviewed the clinical charts of 160 shoulders of 149 patients (mean age, 53 years) with either rotator cuff tears (140 shoulders) or cuff tendinitis (20 shoulders). The location of pain was recorded on a standardized form with 6 different areas. The diagnostic accuracies of the following tests were assessed with various thresholds for muscle weakness: supraspinatus test, the external rotation strength test, and the lift-off test. Lateral and anterior portions of the shoulder were the most common sites of pain regardless of existence of tear or tear location. The supraspinatus test was most accurate when it was assessed to have positive results with the muscle strength less than manual muscle testing grade 5, whereas the lift-off test was most accurate with a threshold less than grade 3. The external rotation strength test was most accurate with a threshold of less than grade 4+. The authors conclude that pain location is not useful in locating the site of a tear, whereas the physical examinations aiming to locate the tear site are clinically useful when assessed to have positive results with appropriate threshold for muscle weakness.

Hsp72 preserves muscle function and slows progression of severe muscular dystrophy.

PubMed

Gehrig, Stefan M; van der Poel, Chris; Sayer, Timothy A; Schertzer, Jonathan D; Henstridge, Darren C; Church, Jarrod E; Lamon, Severine; Russell, Aaron P; Davies, Kay E; Febbraio, Mark A; Lynch, Gordon S

2012-04-04

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilizing protein dystrophin. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca(2+), which activates inflammatory and muscle degenerative pathways. At present there is no cure for DMD, and existing therapies are ineffective. Here we show that increasing the expression of intramuscular heat shock protein 72 (Hsp72) preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy. Treatment with BGP-15 (a pharmacological inducer of Hsp72 currently in clinical trials for diabetes) improved muscle architecture, strength and contractile function in severely affected diaphragm muscles in mdx dystrophic mice. In dko mice, a phenocopy of DMD that results in severe spinal curvature (kyphosis), muscle weakness and premature death, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles and extended lifespan. We found that the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca(2+)) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with SERCA to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation. Treatment with BGP-15 similarly increased SERCA activity in dystrophic skeletal muscles. Our results provide evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell and pharmacological therapies.

Rhabdomyolysis in adolescent athletes: review of cases.

PubMed

Hummel, Kevin; Gregory, Andrew; Desai, Neerav; Diamond, Alex

2016-01-01

Rhabdomyolysis is a syndrome characterized by muscle pain, weakness and myoglobinuria and ranges in severity from asymptomatic to life threatening with acute kidney failure. While a common condition in adult populations, it is understudied in pediatrics and the majority of adolescent cases are likely exercise-induced, caused by strenuous exercise in athletes. Recently, in our pediatric sports medicine practice, we have seen numerous cases of late adolescent high school athletes who present with severe muscle pain and were found to have elevated creatine kinase levels. The cases review potential contributing factors including characteristics of the workout, use of supplements, caffeine, medication, and metabolic or genetic predisposition. Treatment for exercised-induced rhabdomyolysis rarely requires more than rehydration. Return to play should be progressive, individualized, and include acclimatization and monitoring of hydration status, though guidelines require further review.

Detection of myasthenia gravis using electrooculography signals.

PubMed

Liang, T; Boulos, M I; Murray, B J; Krishnan, S; Katzberg, H; Umapathy, K

2016-08-01

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder resulting from skeletal muscle weakness and fatigue. An early common symptom is fatigable weakness of the extrinsic ocular muscles; if symptoms remain confined to the ocular muscles after a few years, this is classified as ocular myasthenia gravis (OMG). Diagnosis of MG when there are mild, isolated ocular symptoms can be difficult, and currently available diagnostic techniques are insensitive, non-specific or technically cumbersome. In addition, there are no accurate biomarkers to follow severity of ocular dysfunction in MG over time. Single-fiber electromyography (SFEMG) and repetitive nerve stimulation (RNS) offers a way of detecting and measuring ocular muscle dysfunction in MG, however, challenges of these methods include a poor signal to noise ratio in quantifying eye muscle weakness especially in mild cases. This paper presents one of the attempts to use the electric potentials from the eyes or electrooculography (EOG) signals but obtained from three different forms of sleep testing to differentiate MG patients from age- and gender-matched controls. We analyzed 8 MG patients and 8 control patients and demonstrated a difference in the average eye movements detected between the groups. A classification accuracy as high as 68.8% was achieved using a linear discriminant analysis based classifier.

Hypothyroidism simulating as polymyositis.

PubMed

Aslam, Hina; Sayeed, Mohammad Ahsan; Qadeer, Rashid; Afsar, Salahuddin

2015-05-01

Polymyositis-like syndrome in hypothyroidism is a rare condition characterised by proximal muscle weakness and elevated muscle enzymes. Patients with this condition can initially be misdiagnosed as having polymyositis due to similar characteristics of both diseases; however a response to thyroxine is the main differentiating feature. This report highlights the case of a 30-year-old male who had severe myalgia and proximal muscle weakness. In addition to raised creatinine phosphokinase (CPK) levels, his biochemical profile showed hypothyroidism. Initially thought to be suffering from polymyositis, improvement in both clinical and biochemical profile with thyroxine led to the diagnosis of polymyositis-like syndrome associated with hypothyroidism.

Multi-slice MRI reveals heterogeneity in disease distribution along the length of muscle in Duchenne muscular dystrophy.

PubMed

Chrzanowski, Stephen M; Baligand, Celine; Willcocks, Rebecca J; Deol, Jasjit; Schmalfuss, Ilona; Lott, Donovan J; Daniels, Michael J; Senesac, Claudia; Walter, Glenn A; Vandenborne, Krista

2017-09-01

Duchenne muscular dystrophy (DMD) causes progressive pathologic changes to muscle secondary to a cascade of inflammation, lipid deposition, and fibrosis. Clinically, this manifests as progressive weakness, functional loss, and premature mortality. Though insult to whole muscle groups is well established, less is known about the relationship between intramuscular pathology and function. Differences of intramuscular heterogeneity across muscle length were assessed using an ordinal MRI grading scale in lower leg muscles of boys with DMD and correlated to patient's functional status. Cross sectional T 1 weighted MRI images with fat suppression were obtained from ambulatory boys with DMD. Six muscles (tibialis anterior, extensor digitorum longus, peroneus, soleus, medial and lateral gastrocnemii) were graded using an ordinal grading scale over 5 slice sections along the lower leg length. The scores from each slice were combined and results were compared to global motor function and age. Statistically greater differences of involvement were observed at the proximal ends of muscle compared to the midbellies. Multi-slice assessment correlated significantly to age and the Vignos functional scale, whereas single-slice assessment correlated to the Vignos functional scale only. Lastly, differential disease involvement of whole muscle groups and intramuscular heterogeneity were observed amongst similar age subjects. A multi-slice ordinal MRI grading scale revealed that muscles are not uniformly affected, with more advanced disease visible near the tendons in a primarily ambulatory population with DMD. A geographically comprehensive evaluation of the heterogeneously affected muscle in boys with DMD may more accurately assess disease involvement.

Recurrent exercise-induced rhabdomyolysis due to low intensity fitness exercise in a healthy young patient

PubMed Central

Karre, Premnath Reddy; Gujral, Jeetinder

2011-01-01

Rhabdomyolysis is an uncommon but life threatening condition that develops due to breakdown of muscle and release of intracellular components into the circulation. A 24-year-old man otherwise healthy was admitted to our hospital because of muscle aches and weakness as well as cola coloured urine developed 3 days after carrying out the low intensity exercise. Diagnosis of rhabdomyolysis was made with creatine kinase (CK) levels of 214 356 U/l. He was treated for a similar condition at age 21. A muscle biopsy was done and the findings were normal. Rhabdomyolysis can develop with low intensity exercise; thus, it be considered in healthy young people. Young people with recurrent rhabdomyolysis due to low intensity exercise, in the absence of obvious medical and physical causes, should be evaluated further to rule out uncommon metabolic diseases. Our case demonstrates that complications especially renal failure in patients with rhabdomyolysis do not correspond to CK levels. PMID:22700603

Recurrent exercise-induced rhabdomyolysis due to low intensity fitness exercise in a healthy young patient.

PubMed

Karre, Premnath Reddy; Gujral, Jeetinder

2011-04-01

Rhabdomyolysis is an uncommon but life threatening condition that develops due to breakdown of muscle and release of intracellular components into the circulation. A 24-year-old man otherwise healthy was admitted to our hospital because of muscle aches and weakness as well as cola coloured urine developed 3 days after carrying out the low intensity exercise. Diagnosis of rhabdomyolysis was made with creatine kinase (CK) levels of 214 356 U/l. He was treated for a similar condition at age 21. A muscle biopsy was done and the findings were normal. Rhabdomyolysis can develop with low intensity exercise; thus, it be considered in healthy young people. Young people with recurrent rhabdomyolysis due to low intensity exercise, in the absence of obvious medical and physical causes, should be evaluated further to rule out uncommon metabolic diseases. Our case demonstrates that complications especially renal failure in patients with rhabdomyolysis do not correspond to CK levels.

Myasthenia gravis - autoantibody characteristics and their implications for therapy.

PubMed

Gilhus, Nils Erik; Skeie, Geir Olve; Romi, Fredrik; Lazaridis, Konstantinos; Zisimopoulou, Paraskevi; Tzartos, Socrates

2016-05-01

Myasthenia gravis (MG) is an autoimmune disorder caused by autoantibodies that target the neuromuscular junction, leading to muscle weakness and fatigability. Currently available treatments for the disease include symptomatic pharmacological treatment, immunomodulatory drugs, plasma exchange, thymectomy and supportive therapies. Different autoantibody patterns and clinical manifestations characterize different subgroups of the disease: early-onset MG, late-onset MG, thymoma MG, muscle-specific kinase MG, low-density lipoprotein receptor-related protein 4 MG, seronegative MG, and ocular MG. These subtypes differ in terms of clinical characteristics, disease pathogenesis, prognosis and response to therapies. Patients would, therefore, benefit from treatment that is tailored to their disease subgroup, as well as other possible disease biomarkers, such as antibodies against cytoplasmic muscle proteins. Here, we discuss the different MG subtypes, the sensitivity and specificity of the various antibodies involved in MG for distinguishing between these subtypes, and the value of antibody assays in guiding optimal therapy. An understanding of these elements should be useful in determining how to adapt existing therapies to the requirements of each patient.

Late-onset dysferlinopathy presented as "liver enzyme" abnormalities: a technical note.

PubMed

Li, Fang; Yin, Geng; Xie, Qibing; Shi, Guixiu

2014-08-01

Limb-girdle muscular dystrophy type 2B,a type of dysferlinopathy, is caused by mutations in the dysferlin gene (DYSE). It is characterized by predominant weakness and atrophy of muscles of the pelvic and shoulder girdles, massive elevation of serum CK concentration, slow progression, and onset usually within the second or third decade of life. We present a Chinese patient whose disease onset was at the age of 50 years with persistent elevation of transaminases for 3 years before weakness appeared. She had been considered as having liver disease for a long time and then polymyositis. Finally, biceps brachii biopsy revealed dystrophic morphology and depletion of dysferlin in immunohistochemistry. This case should remind readers that late-age onset of dysferlinopathy can be misdiagnosed as liver disease or polymyositis.

Spontaneous brain activity in the sensorimotor cortex in amyotrophic lateral sclerosis can be negatively regulated by corticospinal fiber integrity.

PubMed

Sako, Wataru; Abe, Takashi; Izumi, Yuishin; Yamazaki, Hiroki; Matsui, Naoko; Harada, Masafumi; Kaji, Ryuji

2017-05-01

Previous studies failed to detect reduced value of the amplitude of low frequency fluctuation (ALFF) derived from resting state functional magnetic resonance imaging in the primary motor cortex in amyotrophic lateral sclerosis (ALS) though primary motor cortex was mainly affected with ALS. We aimed to investigate the cause of masking the abnormality in the primary motor cortex in ALS and usefulness of ALFF for differential diagnosis among diseases showing muscle weakness. We enrolled ten patients with ALS and eleven disease controls showing muscle weakness. Voxel-wise analysis revealed that significant reduction of ALFF value was present in the right sensorimotor cortex in ALS. There was a significant negative correlation between ALFF value in the right sensorimotor cortex and fractional anisotropy (FA) value in the posterior limbs of the internal capsule (PLIC). For a diagnostic tool, the area under receiver operating characteristic curve improved if the ALS patients with disease duration >1 year were excluded. The present findings raised the possibility of usefulness of ALFF value in the sensorimotor cortex for differential diagnosis of ALS, and supported the notion that adjustment for FA value in the PLIC could improve accuracy.

Biceps-Related Physical Findings Are Useful to Prevent Misdiagnosis of Cervical Spondylotic Amyotrophy as a Rotator Cuff Tear.

PubMed

Iwata, Eiichiro; Shigematsu, Hideki; Inoue, Kazuya; Egawa, Takuya; Tanaka, Masato; Okuda, Akinori; Morimoto, Yasuhiko; Masuda, Keisuke; Yamamoto, Yusuke; Sakamoto, Yoshihiro; Koizumi, Munehisa; Tanaka, Yasuhito

2018-02-01

Case-control study. The aim of the present study was to identify physical findings useful for differentiating between cervical spondylotic amyotrophy (CSA) and rotator cuff tears to prevent the misdiagnosis of CSA as a rotator cuff tear. CSA and rotator cuff tears are often confused among patients presenting with difficulty in shoulder elevation. Twenty-five patients with CSA and 27 with rotator cuff tears were enrolled. We included five physical findings specific to CSA that were observed in both CSA and rotator cuff tear patients. The findings were as follows: (1) weakness of the deltoid muscle, (2) weakness of the biceps muscle, (3) atrophy of the deltoid muscle, (4) atrophy of the biceps muscle, and (5) swallow-tail sign (assessment of the posterior fibers of the deltoid). Among 25 CSA patients, 10 (40.0%) were misdiagnosed with a rotator cuff tear on initial diagnosis. The sensitivity and specificity of each physical finding were as follows: (1) deltoid weakness (sensitivity, 92.0%; specificity, 55.6%), (2) biceps weakness (sensitivity, 80.0%; specificity, 100%), (3) deltoid atrophy (sensitivity, 96.0%; specificity, 77.8%), (4) biceps atrophy (sensitivity, 88.8%; specificity, 92.6%), and (5) swallow-tail sign (sensitivity, 56.0%; specificity, 74.1%). There were statistically significant differences in each physical finding. CSA is likely to be misdiagnosed as a rotator cuff tear; however, weakness and atrophy of the biceps are useful findings for differentiating between CSA and rotator cuff tears to prevent misdiagnosis.

[Fenofibrate--induced myopathy in a patient with undiagnosed hypothyroidism--case report and a review of the literature].

PubMed

Lukjanowicz, Małgorzata; Trzcińska-Butkiewicz, Beata; Brzosko, Marek

2006-01-01

Hypothyroidism is one of the common causes of the secondary hypercholesterolemia. The prevalence of hypothyroidism in the general population is estimated to be as high as about 1.5%. Frequency of the hypothyroidism in patients with hyperlipidemia is high, and can be observed in 4.2-10% in different populations. Most commonly, there is no need to treat the hypothyroid patients with the hypolipidemic drugs. Substitution treatment with the thyroid hormones usually results in either normalization or significant decreasing of the lipid levels. Hypothyroidism with symptoms of involvement of skeletal muscles is referred as to hypothyroid myopathy in English literature, and can be present in 30-80% patients with deficiency of the thyroid hormones. Hypothyroidism is a risk factor of developing of toxic injury of muscles, what is thought to be related to hypolipidemic drug intake. We report a case of a patient with undiagnosed hypothyroidism with muscle involvement manifestation, who was treated with fenofibrate due to accidentally diagnosed hypercholesterolemia. Hypolipidemic management resulted in rapid exacerbation of previously moderate myopathy. High concentrations of muscle enzymes and moderate increasing of creatinine concentration were detected. Improvement was observed after discontinuation of fenofibrate administration, but muscle symptoms and elevation of muscle enzymes and creatinine persisted. After administration of levothyroxin, muscle weakness and laboratory abnormalities were observed no longer. After several months of follow-up we believe that treatment with fenofibrate in our patient was complicated with muscle tissue damage and exacerbated symptoms of myopathy originally related to decompensated hypothyroidism.

A novel mouse model carrying a human cytoplasmic dynein mutation shows motor behavior deficits consistent with Charcot-Marie-Tooth type 2O disease.

PubMed

Sabblah, Thywill T; Nandini, Swaran; Ledray, Aaron P; Pasos, Julio; Calderon, Jami L Conley; Love, Rachal; King, Linda E; King, Stephen J

2018-01-29

Charcot-Marie-Tooth disease (CMT) is a peripheral neuromuscular disorder in which axonal degeneration causes progressive loss of motor and sensory nerve function. The loss of motor nerve function leads to distal muscle weakness and atrophy, resulting in gait problems and difficulties with walking, running, and balance. A mutation in the cytoplasmic dynein heavy chain (DHC) gene was discovered to cause an autosomal dominant form of the disease designated Charcot-Marie-Tooth type 2 O disease (CMT2O) in 2011. The mutation is a single amino acid change of histidine into arginine at amino acid 306 (H306R) in DHC. In order to understand the onset and progression of CMT2, we generated a knock-in mouse carrying the corresponding CMT2O mutation (H304R/+). We examined H304R/+ mouse cohorts in a 12-month longitudinal study of grip strength, tail suspension, and rotarod assays. H304R/+ mice displayed distal muscle weakness and loss of motor coordination phenotypes consistent with those of individuals with CMT2. Analysis of the gastrocnemius of H304R/+ male mice showed prominent defects in neuromuscular junction (NMJ) morphology including reduced size, branching, and complexity. Based on these results, the H304R/+ mouse will be an important model for uncovering functions of dynein in complex organisms, especially related to CMT onset and progression.

Laminin-111 protein therapy reduces muscle pathology and improves viability of a mouse model of merosin-deficient congenital muscular dystrophy.

PubMed

Rooney, Jachinta E; Knapp, Jolie R; Hodges, Bradley L; Wuebbles, Ryan D; Burkin, Dean J

2012-04-01

Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a lethal muscle-wasting disease that is caused by mutations in the LAMA2 gene, resulting in the loss of laminin-α2 protein. MDC1A patients exhibit severe muscle weakness from birth, are confined to a wheelchair, require ventilator assistance, and have reduced life expectancy. There are currently no effective treatments or cures for MDC1A. Laminin-α2 is required for the formation of heterotrimeric laminin-211 (ie, α2, β1, and γ1) and laminin-221 (ie, α2, β2, and γ1), which are major constituents of skeletal muscle basal lamina. Laminin-111 (ie, α1, β1, and γ1) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development in laminin-α2-deficient muscle but is absent from adult skeletal muscle. In this study, we determined whether treatment with Engelbreth-Holm-Swarm-derived mouse laminin-111 protein could rescue MDC1A in the dy(W-/-) mouse model. We demonstrate that laminin-111 protein systemically delivered to the muscles of laminin-α2-deficient mice prevents muscle pathology, improves muscle strength, and dramatically increases life expectancy. Laminin-111 also prevented apoptosis in laminin-α2-deficient mouse muscle and primary human MDC1A myogenic cells, which indicates a conserved mechanism of action and cross-reactivity between species. Our results demonstrate that laminin-111 can serve as an effective protein substitution therapy for the treatment of muscular dystrophy in the dy(W-/-) mouse model and establish the potential for its use in the treatment of MDC1A. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Persistence of long term isokinetic strength deficits in subjects with lateral ankle sprain as measured with a protocol including maximal preloading.

PubMed

Perron, Marc; Moffet, Hélène; Nadeau, Sylvie; Hébert, Luc J; Belzile, Sylvain

2014-12-01

The assessment of muscle function is a cornerstone in the management of subjects who have sustained a lateral ankle sprain. The ankle range of motion being relatively small, the use of preloading allows to measure maximal strength throughout the whole amplitude and therefore to better characterize ankle muscles weaknesses. This study aimed to assess muscle strength of the injured and uninjured ankles in subjects with a lateral ankle sprain, to document the timeline of strength recovery, and to determine the influence of sprain grade on strength loss. Maximal torque of the periarticular muscles of the ankle in a concentric mode using a protocol with maximal preloading was tested in 32 male soldiers at 8 weeks and 6 months post-injury. The evertor muscles of the injured ankles were weaker than the uninjured ones at 8 weeks and 6 months post-injury (P<0.0001, effect size=0.31-0.42). Muscle weaknesses also persisted in the plantarflexors of the injured ankles at 8 weeks (P=0.0014, effect size=0.52-0.58) while at 6 months, only the subjects with a grade II sprain displayed such weaknesses (P<0.0001, effect size 0.27-0.31). The strength of the invertor and dorsiflexor muscles did not differ between sides. The use of an isokinetic protocol with preloading demonstrates significant but small strength deficits in the evertor and plantarflexor muscles. These impairments may contribute to the high incidence of recurrence of lateral ankle sprain in very active individuals. Copyright © 2014 Elsevier Ltd. All rights reserved.

A REVIEW OF ELECTRICAL STIMULATION AND ITS EFFECT ON LINGUAL, LABIAL AND BUCCAL MUSCLE STRENGTH.

PubMed

Safi, Mohammed F; Wright-Harp, Wilhelmina; Lucker, Jay R; Payne, Joan C; Harris, Ovetta

2014-11-01

Lingual, labial and buccal weakness (LLBW) is a widespread consequence of several neurological insults. LLBW impact on oral motor functions such as speech production and swallowing is well documented in the literature. Therefore, it is important for the speech-language pathologists to have access to evidence-based approaches for treatment. Thus, it is imperative that the speech-language pathology field search for effective treatment approaches and explore new treatment modalities that can improve therapy outcomes. One relatively new modality in this field is neuromuscular electrical stimulation (NMES). The purpose of this paper is fivefold: (a) to provide an overview of the general effects of NMES on skeletal muscles; (b) to review the effect of NMES on orofacial musculature evaluating the potential appropriateness of NMES for use in strengthening lingual, labial and buccal muscles; (c) to identify future directions for research with consideration of its potential role in improving speech intelligibility and the oral preparatory phase of swallowing in patients with oral motor weakness; (d) to provide a brief anatomic and physiologic bases of LLBW; (e) to provide background information for orofacial myologists who may encounter individuals with LLBW. NMES is a modality that is commonly used in physical therapy and occupational therapy fields that assists in treating several motor and sensory muscular disorders including muscular weakness. The literature reviewed demonstrate that very limited data related to the use of NMES on orofacial muscles exist despite the fact that these muscles can be easily accessed by electrical stimulation from the surface. This review of the research using electrical stimulation of muscles highlights the need for experimental treatment studies that investigate the effect of NMES on orofacial weakness.

Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness

PubMed Central

Hu, Hao; Matter, Michelle L; Issa-Jahns, Lina; Jijiwa, Mayumi; Kraemer, Nadine; Musante, Luciana; de la Vega, Michelle; Ninnemann, Olaf; Schindler, Detlev; Damatova, Natalia; Eirich, Katharina; Sifringer, Marco; Schrötter, Sandra; Eickholt, Britta J; van den Heuvel, Lambert; Casamina, Chanel; Stoltenburg-Didinger, Gisela; Ropers, Hans-Hilger; Wienker, Thomas F; Hübner, Christoph; Kaindl, Angela M

2014-01-01

Objective To identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). Methods We characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild-type and mutant mice and in patient and control fibroblasts. Results In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts. Interpretation We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease. PMID:25574476

Control of the Ability of Profilin to Bind and Facilitate Nucleotide Exchange from G-actin*

PubMed Central

Wen, Kuo-Kuang; McKane, Melissa; Houtman, Jon C. D.; Rubenstein, Peter A.

2008-01-01

A major factor in profilin regulation of actin cytoskeletal dynamics is its facilitation of G-actin nucleotide exchange. However, the mechanism of this facilitation is unknown. We studied the interaction of yeast (YPF) and human profilin 1 (HPF1) with yeast and mammalian skeletal muscle actins. Homologous pairs (YPF and yeast actin, HPF1 and muscle actin) bound more tightly to one another than heterologous pairs. However, with saturating profilin, HPF1 caused a faster etheno-ATP exchange with both yeast and muscle actins than did YPF. Based on the -fold change in ATP exchange rate/Kd, however, the homologous pairs are more efficient than the heterologous pairs. Thus, strength of binding of profilin to actin and nucleotide exchange rate are not tightly coupled. Actin/HPF interactions were entropically driven, whereas YPF interactions were enthalpically driven. Hybrid yeast actins containing subdomain 1 (sub1) or subdomain 1 and 2 (sub12) muscle actin residues bound more weakly to YPF than did yeast actin (Kd = 2 μm versus 0.6 μm). These hybrids bound even more weakly to HPF than did yeast actin (Kd = 5 μm versus 3.2 μm). sub1/YPF interactions were entropically driven, whereas the sub12/YPF binding was enthalpically driven. Compared with WT yeast actin, YPF binding to sub1 occurred with a 5 times faster koff and a 2 times faster kon. sub12 bound with a 3 times faster koff and a 1.5 times slower kon. Profilin controls the energetics of its interaction with nonhybrid actin, but interactions between actin subdomains 1 and 2 affect the topography of the profilin binding site. PMID:18223293

New concepts of the reinnervated motor unit revealed by vaccine-associated poliomyelitis.

PubMed

Wiechers, D O

1988-04-01

A late onset of slowly progressive muscle weakness 30-40 years after acute polio is well known. Previous studies by the author and others have demonstrated transmission abnormalities within the reinnervated motor unit. These transmission abnormalities shown by motor unit action potential (MUAP) instability in size and shape with repetitive discharges occurs in postpolio patients who are and who are not complaining of progressive muscle weakness. Although some reinnervated MUAPs do seem to stabilize their neuromuscular transmission with time in mildly affected muscles, the question arises as to whether or not some MUAPs ever stabilize after polio. Two cases of acute polio personally followed by the author, one over a 9 1/2 year period, are presented. In both cases, in muscles where there are more deinnervated muscle fibers than could possibly be reinnervated, the MUAPs have remained unstable. New concepts of function in the reinnervated motor unit following polio are presented.

[Progressive cerebral infraction initially presenting with pseudo-ulnar nerve palsy in a patient with severe internal carotid artery stenosis].

PubMed

Kakinuma, Kanako; Nakajima, Masashi; Hieda, Soutarou; Ichikawa, Hiroo; Kawamura, Mitsuru

2010-09-01

A 63-year-old man with hypercholesterolemia developed sensory and motor disturbances in the ulnar side of the right hand, and over three days the weakness evolved to entire right arm. Examination on the 6th day after onset showed mild lower facial palsy in addition to the upper limb weakness on the right. The weakness involved entire right arm sparing shoulder girdle muscles, which was worse in the 4th and 5th digits with claw hand deformity of the hand. Magnetic resonance imaging showed multiple small infracts in the centrum semiovale as well as in the medial side of the precentral knob on the left. Magnetic resonance angiography, ultrasonography, and 3D-CT angiography of the neck showed severe stenosis associated with unstable plaque of the left internal carotid artery. Hemodynamic mechanisms including microemboli and hypoperfusion associated with severe internal carotid artery stenosis are likely to cause stroke in evolution after initial presentation of pseudo-ulnar palsy in the present case.

A human in vitro model of Duchenne muscular dystrophy muscle formation and contractility.

PubMed

Nesmith, Alexander P; Wagner, Matthew A; Pasqualini, Francesco S; O'Connor, Blakely B; Pincus, Mark J; August, Paul R; Parker, Kevin Kit

2016-10-10

Tongue weakness, like all weakness in Duchenne muscular dystrophy (DMD), occurs as a result of contraction-induced muscle damage and deficient muscular repair. Although membrane fragility is known to potentiate injury in DMD, whether muscle stem cells are implicated in deficient muscular repair remains unclear. We hypothesized that DMD myoblasts are less sensitive to cues in the extracellular matrix designed to potentiate structure-function relationships of healthy muscle. To test this hypothesis, we drew inspiration from the tongue and engineered contractile human muscle tissues on thin films. On this platform, DMD myoblasts formed fewer and smaller myotubes and exhibited impaired polarization of the cell nucleus and contractile cytoskeleton when compared with healthy cells. These structural aberrations were reflected in their functional behavior, as engineered tongues from DMD myoblasts failed to achieve the same contractile strength as healthy tongue structures. These data suggest that dystrophic muscle may fail to organize with respect to extracellular cues necessary to potentiate adaptive growth and remodeling. © 2016 Nesmith et al.

Atypical Initial Presentation of Painful Muscle Cramps in a Patient with Amyotrophic Lateral Sclerosis: A Case Report and Brief Review of the Literature.

PubMed

Kuzel, Aaron R; Lodhi, Muhammad Uzair; Syed, Intekhab Askari; Rahim, Mustafa

2017-11-10

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized clinically by progressive muscle weakness that can occur proximally or distally in either the upper or lower extremities. It includes both upper motor neuron signs (spasticity, hyperreflexia, clonus, and Babinski sign) and lower motor neuron signs (atrophy, weakness, and muscle fasciculation). Initial presentation of progressively painful muscle cramps should lead the physician to screen for other signs of amyotrophic lateral sclerosis. We report the case of a 51-year-old male, who presented with dull muscle cramps in the right upper shoulder and arm. After a careful history and physical exam, it was found that patient had both upper and lower motor neuron signs; therefore, a diagnosis of amyotrophic lateral sclerosis was made. Amyotrophic lateral sclerosis should strongly be considered in the differential diagnosis of patients presenting with an atypical initial presentation of progressively painful muscle cramps.

Paroxetine

MedlinePlus

... sleepiness or feeling ''drugged'' nausea vomiting diarrhea constipation gas stomach pain heartburn changes in ability to taste ... symptoms yellowing of the skin and eyes aggressive behavior muscle pain, stiffness, or weakness sudden muscle twitching ...

Cerium oxide nanozyme modulate the ‘exercise’ redox biology of skeletal muscle

NASA Astrophysics Data System (ADS)

Arya, Aditya; Sethy, Niroj Kumar; Gangwar, Anamika; Bhargava, Neelima; Dubey, Amarish; Roy, Manas; Srivastava, Gaurav; Singh, Sushil Kumar; Das, Mainak; Bhargava, Kalpana

2017-05-01

‘Exercise’ is a double-edged sword for the skeletal muscle. Small amount of ROS generated during mild exercise, is essential for normal force generation; whereas large quantity of ROS generated during intense exercise, may cause contractile dysfunction, resulting in muscle weakness and fatigue. One of the key question in skeletal muscle physiology is ‘could antioxidant therapy improve the skeletal muscle endurance? A question, which has resulted in contradictory experimental findings till this date. This work has addressed this ‘very question’ using a synthetic, inorganic, antioxidant nano-material viz., ‘cerium oxide nanozyme’ (CON). It has been introduced in the rat by intramuscular injection, and the skeletal muscle endurance has been evaluated. Intramuscular injections of CON, concurrent with exercise, enhanced muscle mass, glycogen and ATP content, type I fiber ratio, thus resulting in significantly higher muscle endurance. Electron microscope studies confirmed the presence of CON in the vicinity of muscle mitochondria. There was an increase in the number and size of the muscle mitochondria in the CON treated muscle, following exercise, as compared to the untreated group with only exercised muscle. Quantitative proteomics data and subsequent biological network analysis studies, identified higher levels of oxidative phosphorylation, TCA cycle output and glycolysis in CON supplemented exercised muscle over only exercised muscle. This was further associated with significant increase in the mitochondrial respiratory capacity and muscle contraction, primarily due to higher levels of electron transport chain proteins like NDUFA9, SDHA, ATP5B and ATP5D, which were validated by real-time PCR and western blotting. Along with this, persistence of CON in muscle was evaluated with ICP-MS analysis, which revealed clearance of the particles after 90 d, without exhibiting any inflammation or adverse affects on the health of the experimental animals. Thus a higher physiological endurance of the CON supplemented exercised muscle’ opens new avenues in skeletal muscle therapeutic, space and sports medicine.

Retrospective natural history of thymidine kinase 2 deficiency.

PubMed

Garone, Caterina; Taylor, Robert W; Nascimento, Andrés; Poulton, Joanna; Fratter, Carl; Domínguez-González, Cristina; Evans, Julie C; Loos, Mariana; Isohanni, Pirjo; Suomalainen, Anu; Ram, Dipak; Hughes, M Imelda; McFarland, Robert; Barca, Emanuele; Lopez Gomez, Carlos; Jayawant, Sandeep; Thomas, Neil D; Manzur, Adnan Y; Kleinsteuber, Karin; Martin, Miguel A; Kerr, Timothy; Gorman, Grainne S; Sommerville, Ewen W; Chinnery, Patrick F; Hofer, Monika; Karch, Christoph; Ralph, Jeffrey; Cámara, Yolanda; Madruga-Garrido, Marcos; Domínguez-Carral, Jana; Ortez, Carlos; Emperador, Sonia; Montoya, Julio; Chakrapani, Anupam; Kriger, Joshua F; Schoenaker, Robert; Levin, Bruce; Thompson, John L P; Long, Yuelin; Rahman, Shamima; Donati, Maria Alice; DiMauro, Salvatore; Hirano, Michio

2018-03-30

Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. The study was conducted by 42 investigators across 31 academic medical centres. We identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion. In TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Inhibition of forkhead boxO-specific transcription prevents mechanical ventilation-induced diaphragm dysfunction.

PubMed

Smuder, Ashley J; Sollanek, Kurt J; Min, Kisuk; Nelson, W Bradley; Powers, Scott K

2015-05-01

Mechanical ventilation is a lifesaving measure for patients with respiratory failure. However, prolonged mechanical ventilation results in diaphragm weakness, which contributes to problems in weaning from the ventilator. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragm weakness is essential to developing effective countermeasures to combat this important problem. In this regard, the forkhead boxO family of transcription factors is activated in the diaphragm during mechanical ventilation, and forkhead boxO-specific transcription can lead to enhanced proteolysis and muscle protein breakdown. Currently, the role that forkhead boxO activation plays in the development of mechanical ventilation-induced diaphragm weakness remains unknown. This study tested the hypothesis that mechanical ventilation-induced increases in forkhead boxO signaling contribute to ventilator-induced diaphragm weakness. University research laboratory. Young adult female Sprague-Dawley rats. Cause and effect was determined by inhibiting the activation of forkhead boxO in the rat diaphragm through the use of a dominant-negative forkhead boxO adeno-associated virus vector delivered directly to the diaphragm. Our results demonstrate that prolonged (12 hr) mechanical ventilation results in a significant decrease in both diaphragm muscle fiber size and diaphragm-specific force production. However, mechanically ventilated animals treated with dominant-negative forkhead boxO showed a significant attenuation of both diaphragm atrophy and contractile dysfunction. In addition, inhibiting forkhead boxO transcription attenuated the mechanical ventilation-induced activation of the ubiquitin-proteasome system, the autophagy/lysosomal system, and caspase-3. Forkhead boxO is necessary for the activation of key proteolytic systems essential for mechanical ventilation-induced diaphragm atrophy and contractile dysfunction. Collectively, these results suggest that targeting forkhead boxO transcription could be a key therapeutic target to combat ventilator-induced diaphragm dysfunction.

Intercostal and forearm muscle deoxygenation during respiratory fatigue in patients with heart failure: potential role of a respiratory muscle metaboreflex.

PubMed

Moreno, A M; Castro, R R T; Silva, B M; Villacorta, H; Sant'Anna Junior, M; Nóbrega, A C L

2014-11-01

The purpose of this study was to determine the effect of respiratory muscle fatigue on intercostal and forearm muscle perfusion and oxygenation in patients with heart failure. Five clinically stable heart failure patients with respiratory muscle weakness (age, 66 ± 12 years; left ventricle ejection fraction, 34 ± 3%) and nine matched healthy controls underwent a respiratory muscle fatigue protocol, breathing against a fixed resistance at 60% of their maximal inspiratory pressure for as long as they could sustain the predetermined inspiratory pressure. Intercostal and forearm muscle blood volume and oxygenation were continuously monitored by near-infrared spectroscopy with transducers placed on the seventh left intercostal space and the left forearm. Data were compared by two-way ANOVA and Bonferroni correction. Respiratory fatigue occurred at 5.1 ± 1.3 min in heart failure patients and at 9.3 ± 1.4 min in controls (P<0.05), but perceived effort, changes in heart rate, and in systolic blood pressure were similar between groups (P>0.05). Respiratory fatigue in heart failure reduced intercostal and forearm muscle blood volume (P<0.05) along with decreased tissue oxygenation both in intercostal (heart failure, -2.6 ± 1.6%; controls, +1.6 ± 0.5%; P<0.05) and in forearm muscles (heart failure, -4.5 ± 0.5%; controls, +0.5 ± 0.8%; P<0.05). These results suggest that respiratory fatigue in patients with heart failure causes an oxygen demand/delivery mismatch in respiratory muscles, probably leading to a reflex reduction in peripheral limb muscle perfusion, featuring a respiratory metaboreflex.

The value of electrical stimulation as an exercise training modality

NASA Technical Reports Server (NTRS)

Currier, Dean P.; Ray, J. Michael; Nyland, John; Noteboom, Tim

1994-01-01

Voluntary exercise is the traditional way of improving performance of the human body in both the healthy and unhealthy states. Physiological responses to voluntary exercise are well documented. It benefits the functions of bone, joints, connective tissue, and muscle. In recent years, research has shown that neuromuscular electrical stimulation (NMES) simulates voluntary exercise in many ways. Generically, NMES can perform three major functions: suppression of pain, improve healing of soft tissues, and produce muscle contractions. Low frequency NMES may gate or disrupt the sensory input to the central nervous system which results in masking or control of pain. At the same time NMES may contribute to the activation of endorphins, serotonin, vasoactive intestinal polypeptides, and ACTH which control pain and may even cause improved athletic performances. Soft tissue conditions such as wounds and inflammations have responded very favorably to NMES. NMES of various amplitudes can induce muscle contractions ranging from weak to intense levels. NMES seems to have made its greatest gains in rehabilitation where directed muscle contractions may improve joint ranges of motion correct joint contractures that result from shortening muscles; control abnormal movements through facilitating recruitment or excitation into the alpha motoneuron in orthopedically, neurologically, or healthy subjects with intense sensory, kinesthetic, and proprioceptive information; provide a conservative approach to management of spasticity in neurological patients; by stimulation of the antagonist muscle to a spastic muscle stimulation of the agonist muscle, and sensory habituation; serve as an orthotic substitute to conventional bracing used with stroke patients in lieu of dorsiflexor muscles in preventing step page gait and for shoulder muscles to maintain glenohumeral alignment to prevent subluxation; and of course NMES is used in maintaining or improving the performance or torque producing capability of muscle. NMES in exercise training is our major concern.

Cancer Cachexia: Cause, Diagnosis, and Treatment.

PubMed

Mattox, Todd W

2017-10-01

Patients with cancer frequently experience unintended weight loss due to gastrointestinal (GI) dysfunction caused by the malignancy or treatment of the malignancy. However, others may present with weight loss related to other symptoms not clearly associated with identifiable GI dysfunction such as anorexia and early satiety. Cancer cachexia (CC) is a multifactorial syndrome that is generally characterized by ongoing loss of skeletal muscle mass with or without fat loss, often accompanied by anorexia, weakness, and fatigue. CC is associated with poor tolerance of antitumor treatments, reduced quality of life (QOL), and negative impact on survival. Symptoms associated with CC are thought to be caused in part by tumor-induced changes in host metabolism that result in systemic inflammation and abnormal neurohormonal responses. Unfortunately, there is no single standard treatment for CC. Nutrition consequences of oncologic treatments should be identified early with nutrition screening and assessment. Pharmacologic agents directed at improving appetite and countering metabolic abnormalities that cause inefficient nutrient utilization are currently the foundation for treating CC. Multiple agents have been investigated for their effects on weight, muscle wasting, and QOL. However, few are commercially available for use. Considerations for choosing the most appropriate treatment include effect on appetite, weight, QOL, risk of adverse effects, and cost and availability of the agent.

BAG3-related myopathy, polyneuropathy and cardiomyopathy with long QT syndrome.

PubMed

Kostera-Pruszczyk, Anna; Suszek, Małgorzata; Płoski, Rafał; Franaszczyk, Maria; Potulska-Chromik, Anna; Pruszczyk, Piotr; Sadurska, Elżbieta; Karolczak, Justyna; Kamińska, Anna M; Rędowicz, Maria Jolanta

2015-12-01

BAG3 belongs to BAG family of molecular chaperone regulators interacting with HSP70 and anti-apoptotic protein Bcl-2. It is ubiquitously expressed with strong expression in skeletal and cardiac muscle, and is involved in a panoply of cellular processes. Mutations in BAG3 and aberrations in its expression cause fulminant myopathies, presenting with progressive limb and axial muscle weakness, and respiratory insufficiency and neuropathy. Herein, we report a sporadic case of a 15-years old girl with symptoms of myopathy, demyelinating polyneuropathy and asymptomatic long QT syndrome. Genetic testing demonstrated heterozygous mutation Pro209Leu (c.626C > T) in exon 3 of BAG3 gene causing severe myopathy and neuropathy, often associated with restrictive cardiomyopathy. We did not find a mutation in any known LQT syndrome genes. Analysis of muscle biopsy revealed profound disintegration of Z-discs with extensive accumulation of granular debris and large inclusions within fibers. We demonstrated profound alterations in BAG3 distribution as the protein localized to long filamentous structures present across the fibers that were positively stained not only for α-actinin but also for desmin and filamin indicating that those disintegrated Z-disc regions contained also other sarcomeric proteins. The mutation caused a decrease in the content of BAG3 and HSP70, and also of α-actinin desmin, filamin and fast myosin heavy chain, confirming its severe effect on the muscle fiber morphology and thus function. We provide further evidence that BAG3 is associated with Z-disc maintenance, and the Pro209Leu mutation may occur worldwide. We also provide a summary of cases associated with this mutation reported so far.

Distinct Clinical Features and Outcomes in Motor Neuron Disease Associated with Behavioural Variant Frontotemporal Dementia.

PubMed

Cortés-Vicente, Elena; Turon-Sans, Janina; Gelpi, Ellen; Clarimón, Jordi; Borrego-Écija, Sergi; Dols-Icardo, Oriol; Illán-Gala, Ignacio; Lleó, Alberto; Illa, Isabel; Blesa, Rafael; Al-Chalabi, Ammar; Rojas-García, Ricard

2018-06-08

To determine the motor phenotype and outcome in a clinically ascertained group of patients with motor neuron disease (MND) and frontotemporal dementia (FTD). This is an observational retrospective clinical study of patients fulfilling the clinical criteria for MND-FTD. A contemporary series of patients with amyotrophic lateral sclerosis (ALS) without dementia were included for comparison. Demographic, clinical, genetic, and neuropathological data were collected. A descriptive and comparative data analysis was performed. We identified 22 patients with MND-FTD. Selective distal upper limb muscle weakness and atrophy with non-significant lower limb weakness during follow-up was the most frequent motor pattern, present in 18 patients - in 15 of them associated with severe dysphagia. Aspiration pneumonia was the most common cause of death (12/19; 63%) despite gastrostomy. One-third of the patients did not develop upper motor neuron dysfunction. When compared to classic ALS without dementia (n = 162), these features were significantly different. A neuro-pathological examination was performed on 7 patients, and it confirmed the presence of MND with TDP43 protein aggregates in all patients. The MND-FTD patients frequently displayed a distinctive motor pattern characterized by weakness and atrophy in distal upper limb muscles and dysphagia, with no or little spreading to other regions. These features may help to define specific subgroups of patients, which is important with regard to clinical management, outcome, and research. © 2018 S. Karger AG, Basel.

Neuromuscular activity during bench press exercise performed with and without the preexhaustion method.

PubMed

Brennecke, Allan; Guimarães, Thiago M; Leone, Ricardo; Cadarci, Mauro; Mochizuki, Luiz; Simão, Roberto; Amadio, Alberto Carlos; Serrão, Júlio C

2009-10-01

The purpose of the present study was to investigate the effects of exercise order on the tonic and phasic characteristics of upper-body muscle activity during bench press exercise in trained subjects. The preexhaustion method involves working a muscle or a muscle group combining a single-joint exercise immediately followed by a multi-joint exercise (e.g., flying exercise followed by bench press exercise). Twelve subjects performed 1 set of bench press exercises with and without the preexhaustion method following 2 protocols (P1-flying before bench press; P2-bench press). Both exercises were performed at a load of 10 repetition maximum (10RM). Electromyography (EMG) sampled at 1 kHz was recorded from the pectoralis major (PM), anterior deltoid (DA), and triceps brachii (TB). Kinematic data (60 Hz) were synchronized to define upward and downward phases of exercise. No significant (p > 0.05) changes were seen in tonic control of PM and DA muscles between P1 and P2. However, TB tonic aspect of neurophysiologic behavior of motor units was significantly higher (p < 0.05) during P1. Moreover, phasic control of PM, DA, and TB muscles were not affected (p > 0.05). The kinematic pattern of movement changed as a result of muscular weakness in P1. Angular velocity of the right shoulder performed during the upward phase of the bench press exercise was significantly slower (p < 0.05) during P1. Our results suggest that the strategies set by the central nervous system to provide the performance required by the exercise are held constant throughout the exercise, but the tonic aspects of the central drive are increased so as to adapt to the progressive occurrence of the neuromuscular fatigue. Changes in tonic control as a result of the muscular weakness and fatigue can cause changes in movement techniques. These changes may be related to limited ability to control mechanical loads and mechanical energy transmission to joints and passive structures.

A rare cause of acute flaccid paralysis: Human coronaviruses

PubMed Central

Turgay, Cokyaman; Emine, Tekin; Ozlem, Koken; Muhammet, S. Paksu; Haydar, A. Tasdemir

2015-01-01

Acute flaccid paralysis (AFP) is a life-threatening clinical entity characterized by weakness in the whole body muscles often accompanied by respiratory and bulbar paralysis. The most common cause is Gullian–Barre syndrome, but infections, spinal cord diseases, neuromuscular diseases such as myasthenia gravis, drugs and toxins, periodic hypokalemic paralysis, electrolyte disturbances, and botulism should be considered as in the differential diagnosis. Human coronaviruses (HCoVs) cause common cold, upper and lower respiratory tract disease, but in the literature presentation with the lower respiratory tract infection and AFP has not been reported previously. In this study, pediatric case admitted with lower respiratory tract infection and AFP, who detected for HCoV 229E and OC43 co-infection by the real-time polymerase chain reaction, has been reported for the first time. PMID:26557177

A rare cause of acute flaccid paralysis: Human coronaviruses.

PubMed

Turgay, Cokyaman; Emine, Tekin; Ozlem, Koken; Muhammet, S Paksu; Haydar, A Tasdemir

2015-01-01

Acute flaccid paralysis (AFP) is a life-threatening clinical entity characterized by weakness in the whole body muscles often accompanied by respiratory and bulbar paralysis. The most common cause is Gullian-Barre syndrome, but infections, spinal cord diseases, neuromuscular diseases such as myasthenia gravis, drugs and toxins, periodic hypokalemic paralysis, electrolyte disturbances, and botulism should be considered as in the differential diagnosis. Human coronaviruses (HCoVs) cause common cold, upper and lower respiratory tract disease, but in the literature presentation with the lower respiratory tract infection and AFP has not been reported previously. In this study, pediatric case admitted with lower respiratory tract infection and AFP, who detected for HCoV 229E and OC43 co-infection by the real-time polymerase chain reaction, has been reported for the first time.

Novel autosomal dominant TNNT1 mutation causing nemaline myopathy.

PubMed

Konersman, Chamindra G; Freyermuth, Fernande; Winder, Thomas L; Lawlor, Michael W; Lagier-Tourenne, Clotilde; Patel, Shailendra B

2017-11-01

Nemaline myopathy (NEM) is one of the three major forms of congenital myopathy and is characterized by diffuse muscle weakness, hypotonia, respiratory insufficiency, and the presence of nemaline rod structures on muscle biopsy. Mutations in troponin T1 (TNNT1) is 1 of 10 genes known to cause NEM. To date, only homozygous nonsense mutations or compound heterozygous truncating or internal deletion mutations in TNNT1 gene have been identified in NEM. This extended family is of historical importance as some members were reported in the 1960s as initial evidence that NEM is a hereditary disorder. Proband and extended family underwent Sanger sequencing for TNNT1. We performed RT-PCR and immunoblot on muscle to assess TNNT1 RNA expression and protein levels in proband and father. We report a novel heterozygous missense mutation of TNNT1 c.311A>T (p.E104V) that segregated in an autosomal dominant fashion in a large family residing in the United States. Extensive sequencing of the other known genes for NEM failed to identify any other mutant alleles. Muscle biopsies revealed a characteristic pattern of nemaline rods and severe myofiber hypotrophy that was almost entirely restricted to the type 1 fiber population. This novel mutation alters a residue that is highly conserved among vertebrates. This report highlights not only a family with autosomal dominant inheritance of NEM, but that this novel mutation likely acts via a dominant negative mechanism. © 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene.

PubMed

Chanprasert, Sirisak; Wang, Jing; Weng, Shao-Wen; Enns, Gregory M; Boué, Daniel R; Wong, Brenda L; Mendell, Jerry R; Perry, Deborah A; Sahenk, Zarife; Craigen, William J; Alcala, Francisco J Climent; Pascual, Juan M; Melancon, Serge; Zhang, Victor Wei; Scaglia, Fernando; Wong, Lee-Jun C

2013-01-01

Mitochondrial DNA (mtDNA) depletion syndromes (MDSs) are a clinically and molecularly heterogeneous group of mitochondrial cytopathies characterized by severe mtDNA copy number reduction in affected tissues. Clinically, MDSs are mainly categorized as myopathic, encephalomyopathic, hepatocerebral, or multi-systemic forms. To date, the myopathic form of MDS is mainly caused by mutations in the TK2 gene, which encodes thymidine kinase 2, the first and rate limiting step enzyme in the phosphorylation of pyrimidine nucleosides. We analyzed 9 unrelated families with 11 affected subjects exhibiting the myopathic form of MDS, by sequencing the TK2 gene. Twelve mutations including 4 novel mutations were detected in 9 families. Skeletal muscle specimens were available from 7 out of 11 subjects. Respiratory chain enzymatic activities in skeletal muscle were measured in 6 subjects, and enzymatic activities were reduced in 3 subjects. Quantitative analysis of mtDNA content in skeletal muscle was performed in 5 subjects, and marked mtDNA content reduction was observed in each. In addition, we outline the molecular and clinical characteristics of this syndrome in a total of 52 patients including those previously reported, and a total of 36 TK2 mutations are summarized. Clinically, hypotonia and proximal muscle weakness are the major phenotypes present in all subjects. In summary, our study expands the molecular and clinical spectrum associated with TK2 deficiency. © 2013.

Suppression of CHRN endocytosis by carbonic anhydrase CAR3 in the pathogenesis of myasthenia gravis

PubMed Central

Du, Ailian; Huang, Shiqian; Zhao, Xiaonan; Feng, Kuan; Zhang, Shuangyan; Huang, Jiefang; Miao, Xiang; Baggi, Fulvio; Ostrom, Rennolds S.; Zhang, Yanyun; Chen, Xiangjun; Xu, Congfeng

2017-01-01

ABSTRACT Myasthenia gravis is an autoimmune disorder of the neuromuscular junction manifested as fatigable muscle weakness, which is typically caused by pathogenic autoantibodies against postsynaptic CHRN/AChR (cholinergic receptor nicotinic) in the endplate of skeletal muscle. Our previous studies have identified CA3 (carbonic anhydrase 3) as a specific protein insufficient in skeletal muscle from myasthenia gravis patients. In this study, we investigated the underlying mechanism of how CA3 insufficiency might contribute to myasthenia gravis. Using an experimental autoimmune myasthenia gravis animal model and the skeletal muscle cell C2C12, we find that inhibition of CAR3 (the mouse homolog of CA3) promotes CHRN internalization via a lipid raft-mediated pathway, leading to accelerated degradation of postsynaptic CHRN. Activation of CAR3 reduces CHRN degradation by suppressing receptor endocytosis. CAR3 exerts this effect by suppressing chaperone-assisted selective autophagy via interaction with BAG3 (BCL2-associated athanogene 3) and by dampening endoplasmic reticulum stress. Collectively, our study illustrates that skeletal muscle cell CAR3 is critical for CHRN homeostasis in the neuromuscular junction, and its deficiency leads to accelerated degradation of CHRN and development of myasthenia gravis, potentially revealing a novel therapeutic approach for this disorder. PMID:28933591

Suppression of CHRN endocytosis by carbonic anhydrase CAR3 in the pathogenesis of myasthenia gravis.

PubMed

Du, Ailian; Huang, Shiqian; Zhao, Xiaonan; Feng, Kuan; Zhang, Shuangyan; Huang, Jiefang; Miao, Xiang; Baggi, Fulvio; Ostrom, Rennolds S; Zhang, Yanyun; Chen, Xiangjun; Xu, Congfeng

2017-01-01

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction manifested as fatigable muscle weakness, which is typically caused by pathogenic autoantibodies against postsynaptic CHRN/AChR (cholinergic receptor nicotinic) in the endplate of skeletal muscle. Our previous studies have identified CA3 (carbonic anhydrase 3) as a specific protein insufficient in skeletal muscle from myasthenia gravis patients. In this study, we investigated the underlying mechanism of how CA3 insufficiency might contribute to myasthenia gravis. Using an experimental autoimmune myasthenia gravis animal model and the skeletal muscle cell C2C12, we find that inhibition of CAR3 (the mouse homolog of CA3) promotes CHRN internalization via a lipid raft-mediated pathway, leading to accelerated degradation of postsynaptic CHRN. Activation of CAR3 reduces CHRN degradation by suppressing receptor endocytosis. CAR3 exerts this effect by suppressing chaperone-assisted selective autophagy via interaction with BAG3 (BCL2-associated athanogene 3) and by dampening endoplasmic reticulum stress. Collectively, our study illustrates that skeletal muscle cell CAR3 is critical for CHRN homeostasis in the neuromuscular junction, and its deficiency leads to accelerated degradation of CHRN and development of myasthenia gravis, potentially revealing a novel therapeutic approach for this disorder.

Reliability of muscle strength assessment in chronic post-stroke hemiparesis: a systematic review and meta-analysis.

PubMed

Rabelo, Michelle; Nunes, Guilherme S; da Costa Amante, Natália Menezes; de Noronha, Marcos; Fachin-Martins, Emerson

2016-02-01

Muscle weakness is the main cause of motor impairment among stroke survivors and is associated with reduced peak muscle torque. To systematically investigate and organize the evidence of the reliability of muscle strength evaluation measures in post-stroke survivors with chronic hemiparesis. Two assessors independently searched four electronic databases in January 2014 (Medline, Scielo, CINAHL, Embase). Inclusion criteria comprised studies on reliability on muscle strength assessment in adult post-stroke patients with chronic hemiparesis. We extracted outcomes from included studies about reliability data, measured by intraclass correlation coefficient (ICC) and/or similar. The meta-analyses were conducted only with isokinetic data. Of 450 articles, eight articles were included for this review. After quality analysis, two studies were considered of high quality. Five different joints were analyzed within the included studies (knee, hip, ankle, shoulder, and elbow). Their reliability results varying from low to very high reliability (ICCs from 0.48 to 0.99). Results of meta-analysis for knee extension varying from high to very high reliability (pooled ICCs from 0.89 to 0.97), for knee flexion varying from high to very high reliability (pooled ICCs from 0.84 to 0.91) and for ankle plantar flexion showed high reliability (pooled ICC = 0.85). Objective muscle strength assessment can be reliably used in lower and upper extremities in post-stroke patients with chronic hemiparesis.

Organophosphate-induced intermediate syndrome: aetiology and relationships with myopathy.

PubMed

Karalliedde, Lakshman; Baker, David; Marrs, Timothy C

2006-01-01

The intermediate syndrome (IMS) following organophosphorus (OP) insecticide poisoning was first described in the mid-1980s. The syndrome described comprised characteristic symptoms and signs occurring after apparent recovery from the acute cholinergic syndrome. As the syndrome occurred after the acute cholinergic syndrome but before organophosphate-induced delayed polyneuropathy, the syndrome was called 'intermediate syndrome'. The IMS occurs in approximately 20% of patients following oral exposure to OP pesticides, with no clear association between the particular OP pesticide involved and the development of the syndrome. It usually becomes established 2-4 days after exposure when the symptoms and signs of the acute cholinergic syndrome (e.g. muscle fasciculations, muscarinic signs) are no longer obvious. The characteristic features of the IMS are weakness of the muscles of respiration (diaphragm, intercostal muscles and accessory muscles including neck muscles) and of proximal limb muscles. Accompanying features often include weakness of muscles innervated by some cranial nerves. It is now emerging that the degree and extent of muscle weakness may vary following the onset of the IMS. Thus, some patients may only have weakness of neck muscles whilst others may have weakness of neck muscles and proximal limb muscles. These patients may not require ventilatory care but close observation and monitoring of respiratory function is mandatory. Management is essentially that of rapidly developing respiratory distress and respiratory failure. Delays in instituting ventilatory care will result in death. Initiation of ventilatory care and maintenance of ventilatory care often requires minimal doses of non-depolarising muscle relaxants. The use of depolarising muscle relaxants such as suxamethonium is contraindicated in OP poisoning. The duration of ventilatory care required by patients may differ considerably and it is usual for patients to need ventilatory support for 7-15 days and even up to 21 days. Weaning from ventilatory care is best carried out in stages, with provision of continuous positive airway pressure prior to complete weaning. Continuous and close monitoring of respiratory function (arterial oxygen saturation, partial pressure of oxygen in arterial blood, partial pressure of carbon dioxide in arterial blood) and acid-base status are an absolute necessity. Prophylactic antibiotics are usually not required unless there has been evidence of aspiration of material into the lungs. Close monitoring of fluid and electrolyte balance is mandatory in view of the profuse offensive diarrhoea that most patients develop. Maintenance of nutrition, physiotherapy, prevention of bed sores and other routine measures to minimise discomfort during ventilatory care are necessary. Recovery from the intermediate syndrome is normally complete and without any sequelae. The usefulness of oximes during the IMS remains uncertain. In animal experiments, very early administration of oximes has prevented the occurrence of myopathy. There are reports from developed countries where administration of oximes at recommended doses and within 2 hours of ingestion of OP insecticide did not prevent the onset of the IMS. Controlled randomised clinical studies are necessary to evaluate the efficacy of oximes in combating the IMS. Electrophysiological studies following OP poisoning have revealed three characteristic phenomena: (i) repetitive firing following a single stimulus; (ii) gradual reduction in twitch height or compound muscle action potential followed by an increase with repetitive stimulation (the 'decrement-increment response'); and (iii) continued reduction in twitch height or compound muscle action potential with repetitive simulation ('decrementing response'). Of these, the decrementing response is the most frequent finding during the IMS, whilst repetitive firing is observed during the acute cholinergic syndrome. The distribution of the weakness in human cases of the IMS, in general, parallels the distribution of the myopathy observed in a number of studies in experimental animals. This has led to speculation that myopathy is involved in the causation of the IMS. However, while myopathy and the IMS have a common origin in acetylcholine accumulation, they are not causally related to one another.

Weakness

MedlinePlus

... ALS) Weakness of the muscles of the face ( Bell palsy ) Group of disorders involving brain and nervous system ... them ( myasthenia gravis ) Polio Home Care Follow the treatment your health care provider recommends to treat the ...

Riboflavin transporter deficiency mimicking mitochondrial myopathy caused by complex II deficiency.

PubMed

Nimmo, Graeme A M; Ejaz, Resham; Cordeiro, Dawn; Kannu, Peter; Mercimek-Andrews, Saadet

2018-02-01

Biallelic likely pathogenic variants in SLC52A2 and SLC52A3 cause riboflavin transporter deficiency. It is characterized by muscle weakness, ataxia, progressive ponto-bulbar palsy, amyotrophy, and sensorineural hearing loss. Oral riboflavin halts disease progression and may reverse symptoms. We report two new patients whose clinical and biochemical features were mimicking mitochondrial myopathy. Patient 1 is an 8-year-old male with global developmental delay, axial and appendicular hypotonia, ataxia, and sensorineural hearing loss. His muscle biopsy showed complex II deficiency and ragged red fibers consistent with mitochondrial myopathy. Whole exome sequencing revealed a homozygous likely pathogenic variant in SLC52A2 (c.917G>A; p.Gly306Glu). Patient 2 is a 14-month-old boy with global developmental delay, respiratory insufficiency requiring ventilator support within the first year of life. His muscle biopsy revealed combined complex II + III deficiency and ragged red fibers consistent with mitochondrial myopathy. Whole exome sequencing identified a homozygous likely pathogenic variant in SCL52A3 (c.1223G>A; p.Gly408Asp). We report two new patients with riboflavin transporter deficiency, caused by mutations in two different riboflavin transporter genes. Both patients presented with complex II deficiency. This treatable neurometabolic disorder can mimic mitochondrial myopathy. In patients with complex II deficiency, riboflavin transporter deficiency should be included in the differential diagnosis to allow early treatment and improve neurodevelopmental outcome. © 2017 Wiley Periodicals, Inc.

[A case of Leigh syndrome associated with respiratory chain complex I deficiency due to mitochondrial gene 13513G>A mutation].

PubMed

Wei, Xiao-Qiong; Kong, Qing-Peng; Zhang, Yao; Yang, Yan-Ling; Chang, Xing-Zhi; Qi, Yu; Qi, Zhao-Yue; Xiao, Jiang-Xi; Qin, Jiong; Wu, Xi-Ru

2009-05-01

Leigh syndrome is a genetically heterogeneous disease caused by defects in enzymes involved in aerobic energy metabolism and the Krebs', cycle. Mitonchondrial complex I deficiency is a main cause of Leigh syndrome. In this study, a Chinese child with Leigh syndrome caused by 13513G>A mutation was reported. The proband was the first child of his parents. The previously healthy boy presented with generalized epilepsy at 12 years of age. When he visited Peking University First Hospital at 13 years of age, he had subacute loss of vision in two eyes and temporal defect of visual field in the left eye. He walked with a spastic gait. His blood lactate and pyruvate levels were elevated. Muscle biopsy showed mild lipid accumulation in muscle fiber. An electrocardiogram showed incomplete right bundle branch block. Brain magnetic resonance imaging showed bilateral, symmetrical lesions in the basal ganglia, supporting the diagnosis of Leigh syndrome. 13513G>A mutation was identified by gene analysis in the patient, which led to mitochondrial respiratory chain complex I deficiency. Multivitamins and L-carnitine were administered. At present, the patient is 16 years old and has progressive deterioration with significant muscle weakness and body weight loss. He is absent from school. He has no obvious retardation in intelligence. 13513G>A mutation was first identified by gene analysis in Chinese population with Leigh syndrome. This may be helpful in genetic counseling.

The floppy infant: evaluation of hypotonia.

PubMed

Peredo, Dawn E; Hannibal, Mark C

2009-09-01

Hypotonia is characterized by reduced resistance to passive range of motion in joints versus weakness, which is a reduction in the maximum muscle power that can be generated. (Dubowitz, 1985; Crawford, 1992; Martin, 2005) Based on strong research evidence, central hypotonia accounts for 60% to 80% of cases of hypotonia, whereas peripheral hypotonia is the cause in about 15% to 30% of cases. Disorders causing hypotonia often are associated with a depressed level of consciousness, predominantly axial weakness, normal strength accompanying the hypotonia, and hyperactive or normal reflexes. (Martin, 2005; Igarashi, 2004; Richer, 2001; Miller, 1992; Crawford, 1992; Bergen, 1985; Dubowitz, 1985) Based on some research evidence, 50% of patients who have hypotonia are diagnosed by history and physical examination alone. (Paro-Panjan, 2004) Based on some research evidence, an appropriate medical and genetic evaluation of hypotonia in infants includes a karyotype, DNA-based diagnostic tests, and cranial imaging. (Battaglia, 2008; Laugel, 2008; Birdi, 2005; Paro-Panjan, 2004; Prasad, 2003; Richer, 2001; Dimario, 1989) Based on strong research evidence, infant botulism should be suspected in an acute or subacute presentation of hypotonia in an infant younger than 6 months of age who has signs and symptoms such as constipation, listlessness, poor feeding, weak cry, and a decreased gag reflex. (Francisco, 2007; Muensterer, 2000)

Oncogenic osteomalacia associated with phosphaturic mesenchymal tumour, mixed connective tissue type of the knee.

PubMed

Szumera-Ciećkiewicz, Anna; Ptaszyński, Konrad; Pawełas, Andrzej; Rutkowski, Piotr

2009-01-01

One of the most unusual and uncommon types of osteomalacia is the oncogenic osteomalacia that is predominantly caused by a soft tissue or bone tumour, mostly by a phosphaturic mesenchymal tumour, mixed connective tissue type (PMTMCT). We report a case of a 27-year-old male presented with complaints of progressive and generalized muscle weakness, bone pains and multiple fractures. Intra-articular PMTMCT of the knee was diagnosed and surgically removed. We describe histopathological features of PMTMCT and review the most recent studies concerning this diagnostic problem.

Reduced force of diaphragm muscle fibers in patients with chronic thromboembolic pulmonary hypertension

PubMed Central

Manders, Emmy; Bonta, Peter I.; Kloek, Jaap J.; Symersky, Petr; Bogaard, Harm-Jan; Hooijman, Pleuni E.; Jasper, Jeff R.; Malik, Fady I.; Stienen, Ger J. M.; Vonk-Noordegraaf, Anton; de Man, Frances S.

2016-01-01

Patients with pulmonary hypertension (PH) suffer from inspiratory muscle weakness. However, the pathophysiology of inspiratory muscle dysfunction in PH is unknown. We hypothesized that weakness of the diaphragm, the main inspiratory muscle, is an important contributor to inspiratory muscle dysfunction in PH patients. Our objective was to combine ex vivo diaphragm muscle fiber contractility measurements with measures of in vivo inspiratory muscle function in chronic thromboembolic pulmonary hypertension (CTEPH) patients. To assess diaphragm muscle contractility, function was studied in vivo by maximum inspiratory pressure (MIP) and ex vivo in diaphragm biopsies of the same CTEPH patients (N = 13) obtained during pulmonary endarterectomy. Patients undergoing elective lung surgery served as controls (N = 15). Muscle fiber cross-sectional area (CSA) was determined in cryosections and contractility in permeabilized muscle fibers. Diaphragm muscle fiber CSA was not significantly different between control and CTEPH patients in both slow-twitch and fast-twitch fibers. Maximal force-generating capacity was significantly lower in slow-twitch muscle fibers of CTEPH patients, whereas no difference was observed in fast-twitch muscle fibers. The maximal force of diaphragm muscle fibers correlated significantly with MIP. The calcium sensitivity of force generation was significantly reduced in fast-twitch muscle fibers of CTEPH patients, resulting in a ∼40% reduction of submaximal force generation. The fast skeletal troponin activator CK-2066260 (5 μM) restored submaximal force generation to levels exceeding those observed in control subjects. In conclusion, diaphragm muscle fiber contractility is hampered in CTEPH patients and contributes to the reduced function of the inspiratory muscles in CTEPH patients. PMID:27190061

Lifting the nebula: novel insights into skeletal muscle contractility.

PubMed

Ottenheijm, Coen A C; Granzier, Henk

2010-10-01

Nebulin is a giant protein and a constituent of the skeletal muscle sarcomere. The name of this protein refers to its unknown (i.e., nebulous) function. However, recent rapid advances reveal that nebulin plays important roles in the regulation of muscle contraction. When these functions of nebulin are compromised, muscle weakness ensues, as is the case in patients with nemaline myopathy.

Nutrient-rich meat proteins in offsetting age-related muscle loss.

PubMed

Phillips, Stuart M

2012-11-01

From a health perspective, an underappreciated consequence of the normal aging process is the impacts that the gradual loss of skeletal muscle mass, termed sarcopenia, has on health beyond an effect on locomotion. Sarcopenia, refers to the loss of muscle mass, and associated muscle weakness, which occurs in aging and is thought to proceed at a rate of approximately 1% loss per year. However, periods of inactivity due to illness or recovery from orthopedic procedures such as hip or knee replacement are times of accelerated sarcopenic muscle loss from which it may be more difficult for older persons to recover. Some of the consequences of age-related sarcopenia are easy to appreciate such as weakness and, eventually, reduced mobility; however, other lesser recognized consequences include, due to the metabolic role the skeletal muscle plays, an increased risk for poor glucose control and a predisposition toward weight gain. What we currently know is that two stimuli can counter this age related muscle loss and these are physical activity, specifically resistance exercise (weightlifting), and nutrition. The focus of this paper is on the types of dietary protein that people might reasonably consume to offset sarcopenic muscle loss. Copyright © 2012 Elsevier Ltd. All rights reserved.

Functional Consequences of Sarcopenia and Dynapenia in the Elderly

PubMed Central

Clark, Brian C.; Manini, Todd M.

2010-01-01

Purpose of review The economic burden due to the sequela of sarcopenia (muscle wasting in the elderly) are staggering and rank similarly to the costs associated with osteoporotic fractures. In this article we discuss the societal burden and determinants of the loss of physical function with advancing age, the physiologic mechanisms underlying dynapenia (muscle weakness in the elderly), and provide perspectives on related critical issues to be addressed. Recent findings Recent epidemiological findings from longitudinal aging studies suggest that dynapenia is highly associated with both mortality and physical disability even when adjusting for sarcopenia, indicating that sarcopenia may be secondary to the effects of dynapenia. These findings are consistent with the physiologic underpinnings of muscle strength, as recent evidence demonstrates that alterations in muscle quantity, contractile quality and neural activation all collectively contribute to dynapenia. Summary While muscle mass is essential for regulation of whole body metabolic balance, overall neuromuscular function seems to be a critical factor for maintaining muscle strength and physical independence in the elderly. The relative contribution of physiologic factors contributing to muscle weakness are not fully understood, and further research is needed to better elucidate these mechanisms between muscle groups and across populations. PMID:20154609

Functional consequences of sarcopenia and dynapenia in the elderly.

PubMed

Clark, Brian C; Manini, Todd M

2010-05-01

The economic burden due to the sequela of sarcopenia (muscle wasting in the elderly) are staggering and rank similarly to the costs associated with osteoporotic fractures. In this article, we discuss the societal burden and determinants of the loss of physical function with advancing age, the physiologic mechanisms underlying dynapenia (muscle weakness in the elderly), and provide perspectives on related critical issues to be addressed. Recent epidemiological findings from longitudinal aging studies suggest that dynapenia is highly associated with both mortality and physical disability even when adjusting for sarcopenia indicating that sarcopenia may be secondary to the effects of dynapenia. These findings are consistent with the physiologic underpinnings of muscle strength, as recent evidence demonstrates that alterations in muscle quantity, contractile quality and neural activation all collectively contribute to dynapenia. Although muscle mass is essential for regulation of whole body metabolic balance, overall neuromuscular function seems to be a critical factor for maintaining muscle strength and physical independence in the elderly. The relative contribution of physiologic factors contributing to muscle weakness are not fully understood and further research is needed to better elucidate these mechanisms between muscle groups and across populations.

Review of the Diagnosis and Treatment of Periodic Paralysis

PubMed Central

Fontaine, Bertrand; Hanna, Michael G.; Johnson, Nicholas E.; Kissel, John T.; Sansone, Valeria A.; Shieh, Perry B.; Tawil, Rabi N.; Trivedi, Jaya; Cannon, Stephen C.; Griggs, Robert C.

2017-01-01

ABSTRACT Periodic paralyses (PPs) are rare neuromuscular disorders caused by mutations in skeletal muscle sodium, calcium, and potassium channel genes. PPs include hypokalemic paralysis, hyperkalemic paralysis, and Andersen‐Tawil syndrome. Common features of PP include autosomal dominant inheritance, onset typically in the first or second decades, episodic attacks of flaccid weakness, which are often triggered by diet or rest after exercise. Diagnosis is based on the characteristic clinic presentation then confirmed by genetic testing. In the absence of an identified genetic mutation, documented low or high potassium levels during attacks or a decrement on long exercise testing support diagnosis. The treatment approach should include both management of acute attacks and prevention of attacks. Treatments include behavioral interventions directed at avoidance of triggers, modification of potassium levels, diuretics, and carbonic anhydrase inhibitors. Muscle Nerve 57: 522–530, 2018 PMID:29125635

Limb-girdle muscular dystrophies

MedlinePlus

... diseases in which there is muscle weakness and wasting (muscular dystrophy). In most cases, both parents must ... which are not actually strong Loss of muscle mass, thinning of certain body parts Low back pain ...

[Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia].

PubMed

Hayashi, Yukiko

2013-01-01

Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disease caused by mutations in the VCP gene. VCP encodes a well-conserved multifunctional protein, valosin containing protein (VCP), which has important roles in protein quality control via proteasome and autophagy, protein aggregation, quality control of mitochondria, cell proliferation, and so on. Clinically, muscle weakness is the most common symptom of which disease onset is around 40 years. Affected muscles are variable, and the patients are sometimes diagnosed as limb girdle muscular dystrophy or GNE myopathy. Muscle pathology shows characteristic features including cytoplasmic/nuclear inclusions, rimmed vacuoles, and disorganized myofibrills, together with neurogenic changes. Paget's disease of bone is reported to be observed in a half of the patients around the age of 40 years, but less common in Japanese patients. Frontotemporal dementia is seen around one third of the patients which appears nearly 10 years later than muscle or bone disease. In addition to cognitive dysfunctions, motor neuron involvement and cerebellar signs were also seen in our series. IBMPFD is not so rare disease as previously thought, but complicate clinical findings may make its diagnosis difficult.

Duane retraction syndrome in a patient with Duchenne muscular dystrophy.

PubMed

Bosley, Thomas M; Salih, Mustafa A; Alkhalidi, Hisham; Oystreck, Darren T; El Khashab, Heba Y; Kondkar, Altaf A; Abu-Amero, Khaled K

2016-09-01

We describe the clinical features of a boy with bilateral Duane retraction syndrome (DRS), Duchenne muscular dystrophy (DMD), and other medical problems. The child was followed-up for five years; his chart was reviewed, including the results of a muscle biopsy and genetic testing. Multiplex ligation-dependent probe amplification (MLPA) was used to interrogate deletions/duplications in the dystrophin gene. The proband had bilateral DRS with otherwise normal ocular motility; he also had developmental delay, mild mental retardation, and seizures. Clinical diagnosis of DMD included progressive proximal weakness, highly elevated creatine kinase levels, and a muscle biopsy showing significant dystrophic changes including contracted, degenerative, and regenerative fibers, and negative dystrophin immunostaining. MLPA documented duplication of exons 3 and 4 of the dystrophin gene. This boy is the third patient to be reported with DRS and DMD, the second with bilateral DRS and the only one with other neurologic features. Mutated dystrophin is present in extraocular muscles and in the central nervous system (CNS) in DMD, leaving open the question of whether this co-occurrence is the result of the genetic muscle abnormality, CNS effects caused by dystrophin mutations, or chance.

Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich’s ataxia

PubMed Central

Rocca, Celine J.; Goodman, Spencer M.; Dulin, Jennifer N.; Haquang, Joseph H.; Gertsman, Ilya; Blondelle, Jordan; Smith, Janell L. M.; Heyser, Charles J.; Cherqui, Stephanie

2017-01-01

Friedreich’s ataxia (FRDA) is an incurable autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin due to an intronic GAA-repeat expansion in the FXN gene. We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA. In the HSPC-transplanted YG8R mice, development of muscle weakness and locomotor deficits was abrogated as was degeneration of large sensory neurons in the dorsal root ganglia (DRGs) and mitochondrial capacity was improved in brain, skeletal muscle, and heart. Transplanted HSPCs engrafted and then differentiated into microglia in the brain and spinal cord and into macrophages in the DRGs, heart, and muscle of YG8R FRDA mice. We observed the transfer of wild-type frataxin and Cox8 mitochondrial proteins from HSPC-derived microglia/macrophages to FRDA mouse neurons and muscle myocytes in vivo. Our results show the HSPC-mediated phenotypic rescue of FRDA in YG8R mice and suggest that this approach should be investigated further as a strategy for treating FRDA. PMID:29070698

Acute quadriplegic myopathy in a 17-month-old boy.

PubMed

Salviati, L; Laverda, A M; Zancan, L; Fanin, M; Angelini, C; Meznaric-Petrusa, M

2000-01-01

Acute quadriplegic myopathy is a rare condition associated with the use of nondepolarizing muscle-blocking agents and corticosteroids in the course of severe systemic illness. A 17-month-old boy underwent liver transplantation for fulminant hepatitis. He was intubated for 24 days and treated with vecuronium bromide and high-dose methylprednisolone. The child was weaned from the ventilator and presented extreme weakness in the upper limbs and total paralysis of the lower limbs. Serum creatine kinase level was normal and electromyography showed myopathic abnormalities. Muscle biopsy showed severe type-1 fiber atrophy and selective loss of myosin thick filaments was seen on electron microscopy. Scattered regenerating fetal myosin-positive fibers were present, mu calpain was absent, while m calpain was diffusely expressed. Physical therapy was immediately started and the child recovered even though corticosteroids were not discontinued. The pathogenesis of acute quadriplegic myopathy is still unknown. We suggest that it could be due to abnormal protein turnover in the muscle. Several independent factors, such as corticosteroid treatment, immobilization, or cytokines, could take part in a cascade of events that leads to an excessive yet selective degradation of proteins involving myosin thick filaments and possibly components of sarcolemma, causing muscle inexcitability.

38 CFR 4.56 - Evaluation of muscle disabilities.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., the cardinal signs and symptoms of muscle disability are loss of power, weakness, lowered threshold of... signs or symptoms of muscle disability as defined in paragraph (c) of this section. (iii) Objective... injury. Through and through or deep penetrating wound of short track from a single bullet, small shell or...

38 CFR 4.56 - Evaluation of muscle disabilities.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., the cardinal signs and symptoms of muscle disability are loss of power, weakness, lowered threshold of... signs or symptoms of muscle disability as defined in paragraph (c) of this section. (iii) Objective... injury. Through and through or deep penetrating wound of short track from a single bullet, small shell or...

NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation

PubMed Central

Ryu, Dongryeol; Zhang, Hongbo; Ropelle, Eduardo R.; Sorrentino, Vincenzo; Mázala, Davi A. G.; Mouchiroud, Laurent; Marshall, Philip L.; Campbell, Matthew D.; Ali, Amir Safi; Knowels, Gary M.; Bellemin, Stéphanie; Iyer, Shama R.; Wang, Xu; Gariani, Karim; Sauve, Anthony A.; Cantó, Carles; Conley, Kevin E.; Walter, Ludivine; Lovering, Richard M.; Chin, Eva R.; Jasmin, Bernard J.; Marcinek, David J.; Menzies, Keir J.; Auwerx, Johan

2017-01-01

Neuromuscular diseases are often caused by inherited mutations that lead to progressive skeletal muscle weakness and degeneration. In diverse populations of normal healthy mice, we observed correlations between the abundance of mRNA transcripts related to mitochondrial biogenesis, the dystrophin-sarcoglycan complex, and nicotinamide adenine dinucleotide (NAD+) synthesis, consistent with a potential role for the essential cofactor NAD+ in protecting muscle from metabolic and structural degeneration. Furthermore, the skeletal muscle transcriptomes of patients with Duchene’s muscular dystrophy (DMD) and other muscle diseases were enriched for various poly[adenosine 5’-diphosphate (ADP)–ribose] polymerases (PARPs) and for nicotinamide N-methyltransferase (NNMT), enzymes that are major consumers of NAD+ and are involved in pleiotropic events, including inflammation. In the mdx mouse model of DMD, we observed significant reductions in muscle NAD+ levels, concurrent increases in PARP activity, and reduced expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ biosynthesis. Replenishing NAD+ stores with dietary nicotinamide riboside supplementation improved muscle function and heart pathology in mdx and mdx/Utr−/− mice and reversed pathology in Caenorhabditis elegans models of DMD. The effects of NAD+ repletion in mdx mice relied on the improvement in mitochondrial function and structural protein expression (α-dystrobrevin and δ-sarcoglycan) and on the reductions in general poly(ADP)-ribosylation, inflammation, and fibrosis. In combination, these studies suggest that the replenishment of NAD+ may benefit patients with muscular dystrophies or other neuromuscular degenerative conditions characterized by the PARP/NNMT gene expression signatures. PMID:27798264

Determining the role of skewed X-chromosome inactivation in developing muscle symptoms in carriers of Duchenne muscular dystrophy.

PubMed

Viggiano, Emanuela; Ergoli, Manuela; Picillo, Esther; Politano, Luisa

2016-07-01

Duchenne and Becker dystrophinopathies (DMD and BMD) are X-linked recessive disorders caused by mutations in the dystrophin gene that lead to absent or reduced expression of dystrophin in both skeletal and heart muscles. DMD/BMD female carriers are usually asymptomatic, although about 8 % may exhibit muscle or cardiac symptoms. Several mechanisms leading to a reduced dystrophin have been hypothesized to explain the clinical manifestations and, in particular, the role of the skewed XCI is questioned. In this review, the mechanism of XCI and its involvement in the phenotype of BMD/DMD carriers with both a normal karyotype or with X;autosome translocations with breakpoints at Xp21 (locus of the DMD gene) will be analyzed. We have previously observed that DMD carriers with moderate/severe muscle involvement, exhibit a moderate or extremely skewed XCI, in particular if presenting with an early onset of symptoms, while DMD carriers with mild muscle involvement present a random XCI. Moreover, we found that among 87.1 % of the carriers with X;autosome translocations involving the locus Xp21 who developed signs and symptoms of dystrophinopathy such as proximal muscle weakness, difficulty to run, jump and climb stairs, 95.2 % had a skewed XCI pattern in lymphocytes. These data support the hypothesis that skewed XCI is involved in the onset of phenotype in DMD carriers, the X chromosome carrying the normal DMD gene being preferentially inactivated and leading to a moderate-severe muscle involvement.

Dominant-negative inhibition of Ca2+ influx via TRPV2 ameliorates muscular dystrophy in animal models.

PubMed

Iwata, Yuko; Katanosaka, Yuki; Arai, Yuji; Shigekawa, Munekazu; Wakabayashi, Shigeo

2009-03-01

Muscular dystrophy is a severe degenerative disorder of skeletal muscle characterized by progressive muscle weakness. One subgroup of this disease is caused by a defect in the gene encoding one of the components of the dystrophin-glycoprotein complex, resulting in a significant disruption of membrane integrity and/or stability and, consequently, a sustained increase in the cytosolic Ca(2+) concentration ([Ca(2+)](i)). In the present study, we demonstrate that muscular dystrophy is ameliorated in two animal models, dystrophin-deficient mdx mice and delta-sarcoglycan-deficient BIO14.6 hamsters by dominant-negative inhibition of the transient receptor potential cation channel, TRPV2, a principal candidate for Ca(2+)-entry pathways. When transgenic (Tg) mice expressing a TRPV2 mutant in muscle were crossed with mdx mice, the [Ca(2+)](i) increase in muscle fibers was reduced by dominant-negative inhibition of endogenous TRPV2. Furthermore, histological, biochemical and physiological indices characterizing dystrophic pathology, such as an increased number of central nuclei and fiber size variability/fibrosis/apoptosis, elevated serum creatine kinase levels, and reduced muscle performance, were all ameliorated in the mdx/Tg mice. Similar beneficial effects were also observed in the muscles of BIO14.6 hamsters infected with adenovirus carrying mutant TRPV2. We propose that TRPV2 is a principal Ca(2+)-entry route leading to a sustained [Ca(2+)](i) increase and muscle degeneration, and that it is a promising therapeutic target for the treatment of muscular dystrophy.

Joint proprioception, muscle strength, and functional ability in patients with osteoarthritis of the knee.

PubMed

van der Esch, M; Steultjens, M; Harlaar, J; Knol, D; Lems, W; Dekker, J

2007-06-15

To test the hypotheses that poor knee joint proprioception is related to limitations in functional ability, and poor proprioception aggravates the impact of muscle weakness on limitations in functional ability in osteoarthritis (OA) of the knee. Sixty-three patients with symptomatic OA of the knee were tested. Proprioceptive acuity was assessed by establishing the joint motion detection threshold (JMDT) in the anteroposterior direction. Muscle strength was measured using a computer-driven isokinetic dynamometer. Functional ability was assessed by the 100-meter walking test, the Get Up and Go (GUG) test, and the Western Ontario and McMaster Universities Osteoarthritis Index physical function (WOMAC-PF) questionnaire. Correlation analyses were performed to assess the relationship between proprioception, muscle strength, and functional ability. Regression analyses were performed to assess the impact of proprioception on the relationship between muscle strength and functional ability. Poor proprioception (high JMDT) was related to more limitation in functional ability (walking time r = 0.30, P < 0.05; GUG time r = 0.30, P < 0.05; WOMAC-PF r = 0.26, P <0.05). In regression analyses, the interaction between proprioception and muscle strength was significantly related to functional ability (walking time, P < 0.001 and GUG time, P < 0.001) but not to WOMAC-PF score (P = 0.625). In patients with poor proprioception, reduction of muscle strength was associated with more severe deterioration of functional ability than in patients with accurate proprioception. Patients with poor proprioception show more limitation in functional ability, but this relationship is rather weak. In patients with poor proprioception, muscle weakness has a stronger impact on limitations in functional ability than in patients with accurate proprioception.

Active shortening protects against stretch-induced force deficits in human skeletal muscle.

PubMed

Saripalli, Anjali L; Sugg, Kristoffer B; Mendias, Christopher L; Brooks, Susan V; Claflin, Dennis R

2017-05-01

Skeletal muscle contraction results from molecular interactions of myosin "crossbridges" with adjacent actin filament binding sites. The binding of myosin to actin can be "weak" or "strong," and only strong binding states contribute to force production. During active shortening, the number of strongly bound crossbridges declines with increasing shortening velocity. Forcibly stretching a muscle that is actively shortening at high velocity results in no apparent negative consequences, whereas stretch of an isometrically (fixed-length) contracting muscle causes ultrastructural damage and a decline in force-generating capability. Our working hypothesis is that stretch-induced damage is uniquely attributable to the population of crossbridges that are strongly bound. We tested the hypothesis that stretch-induced force deficits decline as the prevailing shortening velocity is increased. Experiments were performed on permeabilized segments of individual skeletal muscle fibers obtained from human subjects. Fibers were maximally activated and allowed either to generate maximum isometric force (F o ), or to shorten at velocities that resulted in force maintenance of ≈50% F o or ≈2% F o For each test condition, a rapid stretch equivalent to 0.1 × optimal fiber length was applied. Relative to prestretch F o , force deficits resulting from stretches applied during force maintenance of 100, ≈50, and ≈2% F o were 23.2 ± 8.6, 7.8 ± 4.2, and 0.3 ± 3.3%, respectively (means ± SD, n = 20). We conclude that stretch-induced damage declines with increasing shortening velocity, consistent with the working hypothesis that the fraction of strongly bound crossbridges is a causative factor in the susceptibility of skeletal muscle to stretch-induced damage. NEW & NOTEWORTHY Force deficits caused by stretch of contracting muscle are most severe when the stretch is applied during an isometric contraction, but prevented if the muscle is shortening at high velocity when the stretch occurs. This study indicates that velocity-controlled modulation of the number of strongly bound crossbridges is the basis for the observed relationship between stretch-induced muscle damage and prevailing shortening velocity. Copyright © 2017 the American Physiological Society.

Respiratory weakness in patients with chronic neck pain.

PubMed

Dimitriadis, Zacharias; Kapreli, Eleni; Strimpakos, Nikolaos; Oldham, Jacqueline

2013-06-01

Respiratory muscle strength is one parameter that is currently proposed to be affected in patients with chronic neck pain. This study was aimed at examining whether patients with chronic neck pain have reduced respiratory strength and with which neck pain problems their respiratory strength is associated. In this controlled cross-sectional study, 45 patients with chronic neck pain and 45 healthy well-matched controls were recruited. Respiratory muscle strength was assessed through maximal mouth pressures. The subjects were additionally assessed for their pain intensity and disability, neck muscle strength, endurance of deep neck flexors, neck range of movement, forward head posture and psychological states. Paired t-tests showed that patients with chronic neck pain have reduced Maximal Inspiratory (MIP) (r = 0.35) and Maximal Expiratory Pressures (MEP) (r = 0.39) (P < 0.05). Neck muscle strength (r > 0.5), kinesiophobia (r < -0.3) and catastrophizing (r < -0.3) were significantly associated with maximal mouth pressures (P < 0.05), whereas MEP was additionally negatively correlated with neck pain and disability (r < -0.3, P < 0.05). Neck muscle strength was the only predictor that remained as significant into the prediction models of MIP and MEP. It can be concluded that patients with chronic neck pain present weakness of their respiratory muscles. This weakness seems to be a result of the impaired global and local muscle system of neck pain patients, and psychological states also appear to have an additional contribution. Clinicians are advised to consider the respiratory system of patients with chronic neck pain during their usual assessment and appropriately address their treatment. Copyright © 2012 Elsevier Ltd. All rights reserved.

Muscle atrophy in chronic inflammatory demyelinating polyneuropathy: a computed tomography assessment.

PubMed

Ohyama, K; Koike, H; Katsuno, M; Takahashi, M; Hashimoto, R; Kawagashira, Y; Iijima, M; Adachi, H; Watanabe, H; Sobue, G

2014-07-01

Muscle atrophy is generally mild in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) compared with the severity and duration of the muscle weakness. Muscle atrophy was evaluated using computed tomography (CT) in patients with CIDP. Thirty-one patients with typical CIDP who satisfied the diagnostic criteria for the definite CIDP classification proposed by the European Federation of Neurological Societies and the Peripheral Nerve Society were assessed. The clinicopathological findings in patients with muscle atrophy were also compared with those in patients without atrophy. Computed tomography evidence was found of marked muscle atrophy with findings suggestive of fatty degeneration in 11 of the 31 patients with CIDP. CT-assessed muscle atrophy was in the lower extremities, particularly in the ankle plantarflexor muscles. Muscle weakness, which reflects the presence of muscle atrophy, tended to be more pronounced in the lower extremities than in the upper extremities in patients with muscle atrophy, whereas the upper and lower limbs tended to be equally affected in patients without muscle atrophy. Nerve conduction examinations revealed significantly greater reductions in compound muscle action potential amplitudes in the tibial nerves of patients with muscle atrophy. Sural nerve biopsy findings were similar in both groups. The functional prognoses after immunomodulatory therapies were significantly poorer amongst patients with muscle atrophy. Muscle atrophy was present in a subgroup of patients with CIDP, including patients with a typical form of the disease. These patients tended to demonstrate predominant motor impairments of the lower extremities and poorer functional prognoses. © 2014 The Author(s) European Journal of Neurology © 2014 EFNS.

Aspiration pneumonia induces muscle atrophy in the respiratory, skeletal, and swallowing systems.

PubMed

Komatsu, Riyo; Okazaki, Tatsuma; Ebihara, Satoru; Kobayashi, Makoto; Tsukita, Yoko; Nihei, Mayumi; Sugiura, Hisatoshi; Niu, Kaijun; Ebihara, Takae; Ichinose, Masakazu

2018-05-22

Repetition of the onset of aspiration pneumonia in aged patients is common and causes chronic inflammation. The inflammation induces proinflammatory cytokine production and atrophy in the muscles. The proinflammatory cytokines induce muscle proteolysis by activating calpains and caspase-3, followed by further degradation by the ubiquitin-proteasome system. Autophagy is another pathway of muscle atrophy. However, little is known about the relationship between aspiration pneumonia and muscle. For swallowing muscles, it is not clear whether they produce cytokines. The main objective of this study was to determine whether aspiration pneumonia induces muscle atrophy in the respiratory (the diaphragm), skeletal (the tibialis anterior, TA), and swallowing (the tongue) systems, and their possible mechanisms. We employed a mouse aspiration pneumonia model and computed tomography (CT) scans of aged pneumonia patients. To induce aspiration pneumonia, mice were inoculated with low dose pepsin and lipopolysaccharide solution intra-nasally 5 days a week. The diaphragm, TA, and tongue were isolated, and total RNA, proteins, and frozen sections were stored. Quantitative real-time polymerase chain reaction determined the expression levels of proinflammatory cytokines, muscle E3 ubiquitin ligases, and autophagy related genes. Western blot analysis determined the activation of the muscle proteolysis pathway. Frozen sections determined the presence of muscle atrophy. CT scans were used to evaluate the muscle atrophy in aged aspiration pneumonia patients. The aspiration challenge enhanced the expression levels of proinflammatory cytokines in the diaphragm, TA, and tongue. Among muscle proteolysis pathways, the aspiration challenge activated caspase-3 in all the three muscles examined, whereas calpains were activated in the diaphragm and the TA but not in the tongue. Activation of the ubiquitin-proteasome system was detected in all the three muscles examined. The aspiration challenge activated autophagy in the TA and the tongue, whereas weak or little activation was detected in the diaphragm. The aspiration challenge resulted in a greater proportion of smaller myofibers than in controls in the diaphragm, TA, and tongue, suggesting muscle atrophy. CT scans clearly showed that aspiration pneumonia was followed by muscle atrophy in aged patients. Aspiration pneumonia induced muscle atrophy in the respiratory, skeletal, and swallowing systems in a preclinical animal model and in human patients. Diaphragmatic atrophy may weaken the force of cough to expectorate sputum or mis-swallowed contents. Skeletal muscle atrophy may cause secondary sarcopenia. The atrophy of swallowing muscles may weaken the swallowing function. Thus, muscle atrophy could become a new therapeutic target of aspiration pneumonia. © 2018 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.

A case of adult-onset reducing body myopathy presenting a novel clinical feature, asymmetrical involvement of the sternocleidomastoid and trapezius muscles.

PubMed

Fujii, Takayuki; Hayashi, Shintaro; Kawamura, Nobutoshi; Higuchi, Masa-Aki; Tsugawa, Jun; Ohyagi, Yasumasa; Hayashi, Yukiko K; Nishino, Ichizo; Kira, Jun-Ichi

2014-08-15

We herein report a 32-year-old woman with adult-onset reducing body myopathy (RBM) who had a mutation in the four-and-a-half LIM domain 1 gene (FHL1) and showed a marked asymmetrical involvement of sternocleidomastoid and trapezius muscles. At 30 years of age she noticed bilateral foot drop, and over the next two years developed difficulty raising her right arm. At 32 years of age she was admitted to our hospital for a diagnostic evaluation. Neurological examination showed moderate weakness and atrophy of her right sternocleidomastoid muscle, right trapezius muscle, and bilateral upper proximal muscles. There were severe weakness and atrophy of her bilateral tibialis anterior muscles. Her deep tendon reflexes were hypoactive in her upper extremities. Her serum creatine kinase level was mildly increased. Muscle biopsy specimens from the left tibialis anterior muscle revealed marked variation in fiber size, some necrotic or regenerating fibers, and reducing bodies. Gene analysis of FHL1 demonstrated a mutation: a heterozygous missense mutation of c.377G>A (p. C126T) in FHL1. Compared with previous adult-onset RBM cases harboring mutations in FHL1, our case was characterized by asymmetrical atrophy of the sternocleidomastoid and trapezius muscles. Copyright © 2014 Elsevier B.V. All rights reserved.

Patellofemoral pain in athletes

PubMed Central

Petersen, Wolf; Rembitzki, Ingo; Liebau, Christian

2017-01-01

Patellofemoral pain (PFP) is a frequent cause of anterior knee pain in athletes, which affects patients with and without structural patellofemoral joint (PFJ) damage. Most younger patients do not have any structural changes to the PFJ, such as an increased Q angle and a cartilage damage. This clinical entity is known as patellofemoral pain syndrome (PFPS). Older patients usually present with signs of patellofemoral osteoarthritis (PFOA). A key factor in PFPS development is dynamic valgus of the lower extremity, which leads to lateral patellar maltracking. Causes of dynamic valgus include weak hip muscles and rearfoot eversion with pes pronatus valgus. These factors can also be observed in patients with PFOA. The available evidence suggests that patients with PFP are best managed with a tailored, multimodal, nonoperative treatment program that includes short-term pain relief with nonsteroidal anti-inflammatory drugs (NSAIDs), passive correction of patellar maltracking with medially directed tape or braces, correction of the dynamic valgus with exercise programs that target the muscles of the lower extremity, hip, and trunk, and the use of foot orthoses in patients with additional foot abnormalities. PMID:28652829

Post-natal myogenic and adipogenic developmental

PubMed Central

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

2011-01-01

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

Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies

PubMed Central

Belaya, Katsiaryna; Rodríguez Cruz, Pedro M.; Liu, Wei Wei; Maxwell, Susan; McGowan, Simon; Farrugia, Maria E.; Petty, Richard; Walls, Timothy J.; Sedghi, Maryam; Basiri, Keivan; Yue, Wyatt W.; Sarkozy, Anna; Bertoli, Marta; Pitt, Matthew; Kennett, Robin; Schaefer, Andrew; Bushby, Kate; Parton, Matt; Lochmüller, Hanns; Palace, Jacqueline; Muntoni, Francesco

2015-01-01

Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments. PMID:26133662

Muscular Dystrophy

MedlinePlus

... be affected. Limb-girdle muscular dystrophy (LGMD) affects boys and girls equally, weakening muscles in the shoulders and upper ... weakness and poor muscle tone. Occurring in both girls and boys, it can have different symptoms. It varies in ...

Cariprazine

MedlinePlus

... severe muscle stiffness muscle weakness or aching blank facial expression difficulty swallowing or breathing tightness in the throat tongue that sticks out of the mouth rash itching hives swelling of the face, throat, tongue, lips, or eyes dark or cola- ...

Pediatric Myasthenia Gravis.

PubMed

Peragallo, Jason H

2017-05-01

Myasthenia gravis is a disorder of neuromuscular transmission that leads to fatigue of skeletal muscles and fluctuating weakness. Myasthenia that affects children can be classified into the following 3 forms: transient neonatal myasthenia, congenital myasthenic syndromes, and juvenile myasthenia gravis (JMG). JMG is an autoimmune disorder that has a tendency to affect the extraocular muscles, but can also affect all skeletal muscles leading to generalized weakness and fatigability. Respiratory muscles may be involved leading to respiratory failure requiring ventilator support. Diagnosis should be suspected clinically, and confirmatory diagnostic testing be performed, including serum acetylcholine receptor antibodies, repetitive nerve stimulation, and electromyography. Treatment for JMG includes acetylcholinesterase inhibitors, immunosuppressive medications, plasma exchange, intravenous immunoglobulins, and thymectomy. Children with myasthenia gravis require monitoring by a pediatric ophthalmologist for the development of amblyopia from ptosis or strabismus. Copyright © 2017 Elsevier Inc. All rights reserved.

Cyclic AMP-dependent signaling system is a primary metabolic target for non-thermal effect of microwaves on heart muscle hydration.

PubMed

Narinyan, Lilia; Ayrapetyan, Sinerik

2017-01-01

Previously, we have suggested that cell hydration is a universal and extra-sensitive sensor for the structural changes of cell aqua medium caused by the impact of weak chemical and physical factors. The aim of present work is to elucidate the nature of the metabolic messenger through which physiological solution (PS) treated by non-thermal (NT) microwaves (MW) could modulate heart muscle hydration of rats. For this purpose, the effects of NT MW-treated PS on heart muscle hydration, [ 3 H]-ouabain binding with cell membrane, 45 Ca 2+ uptake and intracellular cyclic nucleotides contents in vivo and in vitro experiments were studied. It is shown that intraperitoneal injections of both Sham-treated PS and NT MW-treated PS elevate heart muscle hydration. However, the effect of NT MW-treated PS on muscle hydration is more pronounced than the effect of Sham-treated PS. In vitro experiments NT MW-treated PS has dehydration effect on muscle, which is not changed by decreasing Na + gradients on membrane. Intraperitoneal injection of Sham- and NT MW-treated PS containing 45 Ca 2+ have similar dehydration effect on muscle, while NT MW-treated PS has activation effect on Na + /Ca 2+ exchange in reverse mode. The intraperitoneal injection of NT MW-treated PS depresses [ 3 H]-ouabain binding with its high-affinity membrane receptors, elevates intracellular cAMP and decreases cGMP contents. Based on the obtained data, it is suggested that cAMP-dependent signaling system serves as a primary metabolic target for NT MW effect on heart muscle hydration.

The outbreak of West Nile virus infection in the New York City area in 1999.

PubMed

Nash, D; Mostashari, F; Fine, A; Miller, J; O'Leary, D; Murray, K; Huang, A; Rosenberg, A; Greenberg, A; Sherman, M; Wong, S; Layton, M

2001-06-14

In late August 1999, an unusual cluster of cases of meningoencephalitis associated with muscle weakness was reported to the New York City Department of Health. The initial epidemiologic and environmental investigations suggested an arboviral cause. Active surveillance was implemented to identify patients hospitalized with viral encephalitis and meningitis. Cerebrospinal fluid, serum, and tissue specimens from patients with suspected cases underwent serologic and viral testing for evidence of arboviral infection. Outbreak surveillance identified 59 patients who were hospitalized with West Nile virus infection in the New York City area during August and September of 1999. The median age of these patients was 71 years (range, 5 to 95). The overall attack rate of clinical West Nile virus infection was at least 6.5 cases per million population, and it increased sharply with age. Most of the patients (63 percent) had clinical signs of encephalitis; seven patients died (12 percent). Muscle weakness was documented in 27 percent of the patients and flaccid paralysis in 10 percent; in all of the latter, nerve conduction studies indicated an axonal polyneuropathy in 14 percent. An age of 75 years or older was an independent risk factor for death (relative risk adjusted for the presence or absence of diabetes mellitus, 8.5; 95 percent confidence interval, 1.2 to 59.1), as was the presence of diabetes mellitus (age-adjusted relative risk, 5.1; 95 percent confidence interval, 1.5 to 17.3). This outbreak of West Nile meningoencephalitis in the New York City metropolitan area represents the first time this virus has been detected in the Western Hemisphere. Given the subsequent rapid spread of the virus, physicians along the eastern seaboard of the United States should consider West Nile virus infection in the differential diagnosis of encephalitis and viral meningitis during the summer months, especially in older patients and in those with muscle weakness.

Gait deviations in Duchenne muscular dystrophy-Part 2. Statistical non-parametric mapping to analyze gait deviations in children with Duchenne muscular dystrophy.

PubMed

Goudriaan, Marije; Van den Hauwe, Marleen; Simon-Martinez, Cristina; Huenaerts, Catherine; Molenaers, Guy; Goemans, Nathalie; Desloovere, Kaat

2018-04-30

Prolonged ambulation is considered important in children with Duchenne muscular dystrophy (DMD). However, previous studies analyzing DMD gait were sensitive to false positive outcomes, caused by uncorrected multiple comparisons, regional focus bias, and inter-component covariance bias. Also, while muscle weakness is often suggested to be the main cause for the altered gait pattern in DMD, this was never verified. Our research question was twofold: 1) are we able to confirm the sagittal kinematic and kinetic gait alterations described in a previous review with statistical non-parametric mapping (SnPM)? And 2) are these gait deviations related to lower limb weakness? We compared gait kinematics and kinetics of 15 children with DMD and 15 typical developing (TD) children (5-17 years), with a two sample Hotelling's T 2 test and post-hoc two-tailed, two-sample t-test. We used canonical correlation analyses to study the relationship between weakness and altered gait parameters. For all analyses, α-level was corrected for multiple comparisons, resulting in α = 0.005. We only found one of the previously reported kinematic deviations: the children with DMD had an increased knee flexion angle during swing (p = 0.0006). Observed gait deviations that were not reported in the review were an increased hip flexion angle during stance (p = 0.0009) and swing (p = 0.0001), altered combined knee and ankle torques (p = 0.0002), and decreased power absorption during stance (p = 0.0001). No relationships between weakness and these gait deviations were found. We were not able to replicate the gait deviations in DMD previously reported in literature, thus DMD gait remains undefined. Further, weakness does not seem to be linearly related to altered gait features. The progressive nature of the disease requires larger study populations and longitudinal analyses to gain more insight into DMD gait and its underlying causes. Copyright © 2018 Elsevier B.V. All rights reserved.

Recessive variants of MuSK are associated with late onset CMS and predominant limb girdle weakness.

PubMed

Owen, David; Töpf, Ana; Preethish-Kumar, Veeramani; Lorenzoni, Paulo José; Vroling, Bas; Scola, Rosana Herminia; Dias-Tosta, Elza; Geraldo, Argemiro; Polavarapu, Kiran; Nashi, Saraswati; Cox, Daniel; Evangelista, Teresinha; Dawson, John; Thompson, Rachel; Senderek, Jan; Laurie, Steven; Beltran, Sergi; Gut, Marta; Gut, Ivo; Nalini, Atchayaram; Lochmüller, Hanns

2018-04-28

Congenital myasthenic syndrome (CMS) is a heterogeneous disorder that causes fatigable muscle weakness. CMS has been associated with variants in the MuSK gene and, to date, 16 patients have been reported. MuSK-CMS patients present a different phenotypic pattern of limb girdle weakness. Here, we describe four additional patients and discuss the phenotypic and clinical relationship with those previously reported. Two novel damaging missense variants are described: c.1742T > A; p.I581N found in homozygosis, and c.1634T > C; p.L545P found in compound heterozygosis with p.R166*. The reported patients had predominant limb girdle weakness with symptom onset at 12, 17, 18, and 30 years of age, and the majority exhibited a good clinical response to Salbutamol therapy, but not to esterase inhibitors. Meta-analysis including previously reported variants revealed an increased likelihood of a severe, respiratory phenotype with null alleles. Missense variants exclusively affecting the kinase domain, but not the catalytic site, are associated with late onset. These data refine the phenotype associated with MuSK-related CMS. © 2018 Wiley Periodicals, Inc.

Rare acute kidney injury secondary to hypothyroidism-induced rhabdomyolysis.

PubMed

Cai, Ying; Tang, Lin

2013-01-01

Acute kidney injury (AKI) caused by hypothyroidism-induced rhabdomyolysis is a rare and potentially life-threatening syndrome. The aim of this study was to investigate the clinical characteristics of such patients. We retrospectively analyzed five patients treated at the Second Affiliated Hospital of Chongqing Medical University with AKI secondary to hypothyroidism- induced rhabdomyolysis from January 2006 to December 2010. Of the five cases reviewed (4 males, age range of 37 to 62 years), adult primary hypothyroidism was caused by amiodarone (1 case), chronic autoimmune thyroiditis (1 case), and by uncertain etiologies (3 cases). All patients presented with facial and lower extremity edema. Three patients presented with weakness, while two presented with blunted facies and oliguria. Only one patient reported experiencing myalgia and proximal muscle weakness, in addition to fatigue and chills. Creatine kinase, lactate dehydrogenase, and renal function normalized after thyroid hormone replacement, except in two patients who improved through blood purification. Hypothyroidism should be considered in patients presenting with renal impairment associated with rhabdomyolysis. Moreover, further investigation into the etiology of the hypothyroidism is warranted.

Electromyography of the quadriceps in patellofemoral pain with patellar subluxation.

PubMed

Mohr, Karen J; Kvitne, Ronald S; Pink, Marilyn M; Fideler, Bradley; Perry, Jacquelin

2003-10-01

This study compared muscle activity and timing of gait phases during functional activities in 13 subjects with patellofemoral pain associated with lateral subluxation and in 11 subjects with healthy knees. Fine wire electromyography recorded activity in the vastus lateralis and vastus medialis oblique during walking and ascending and descending stairs. Subjects were filmed to divide the activities into phases and determine timing. The vastus medialis oblique and vastus lateralis had similar patterns during all activities. Subjects with patellofemoral pain had significantly increased activity in the vastus medialis oblique and vastus lateralis compared with the healthy subjects during the most demanding phases of the gait cycle, suggesting a generalized quadriceps weakness in the patients with patellofemoral pain. Timing differences were seen in walking and stair ascending with the subjects with patellofemoral pain spending significantly more time in stance compared with the healthy subjects. This may be an attempt to reduce the load on weak quadriceps. These data reflect a generalized quadriceps muscle weakness, rather than the prevailing theory of quadriceps muscle imbalance as an etiology of patellofemoral pain. Therefore, we support the practice of strengthening the entire quadriceps muscle group, rather than attempting to specifically target the vastus medialis oblique.

Neuromuscular signs associated with acute hypophosphatemia in a dog.

PubMed

Claus, Kimberly N; Day, Thomas K; Wolf, Christina

2015-01-01

The purpose of this report was to describe the successful recognition and management of neuromuscular dysfunction secondary to severe, acute hypophosphatemia in an adult dog with a 2 day history of vomiting, anorexia, and abdominal pain. Radiographs were suggestive of a foreign body obstruction, and surgery was recommended. Resection and anastomosis of the distal duodenum and proximal jejunum was performed. The dog recovered uneventfully, but approximately 36 hr postoperatively, he was found to have significant weakness and muscle tremors that were accompanied by hyperthermia. The only significant abnormality on a serum biochemical profile was a phosphorous level of 0.26 mmol/L. Within 6 hr of initiating phosphorous supplementation, the patient fully recovered and had no residual signs of neuromuscular dysfunction. Signs of neurologic dysfunction secondary to hypophosphatemia are commonly recognized in human patients. Reports of patients with severe muscle weakness, some of which necessitate ventilation due to weakening of muscles of respiration, are common throughout the literature. Less commonly, tremors are noted. This is the first known report of neuromuscular signs recognized and rapidly corrected in a dog. Although it is likely to be uncommon, hypophosphatemia should be recognized as a differential diagnosis in patients with tremors and/or muscle weakness.

Physical activity in youth with osteogenesis imperfecta type I

PubMed Central

Pouliot-Laforte, A.; Veilleux, L-N.; Rauch, F.; Lemay, M.

2015-01-01

Introduction: Individuals with Osteogenesis Imperfecta (OI) type I often show muscular weakness. However, it is unclear whether muscular weakness is a consequence of physical inactivity or a result of the disease itself. The aim was to assess muscle function in youth with OI type I and evaluate physical activity (PA). Methods: Fourteen children with OI type I (mean age [SD]: 12.75 [4.62] years) were compared to 14 age- and gender-matched controls (mean age [SD]: 12.75 [4.59] years). Muscle force and power were determined through mechanography. PA and daily energy expenditure were measured with an accelerometer and a questionnaire. Results: Compared to controls, children with OI type I had lower muscle force and power. OI type I children were as active as their healthy counterparts. Conclusions: Children and adolescents with OI type I and their healthy counterparts did not reached daily recommendations of PA. Given their muscle function deficit, youth with OI type I would benefit to reach these recommendations to prevent precocious effect of aging on muscles. PMID:26032209

Common input to motor units of intrinsic and extrinsic hand muscles during two-digit object hold.

PubMed

Winges, Sara A; Kornatz, Kurt W; Santello, Marco

2008-03-01

Anatomical and physiological evidence suggests that common input to motor neurons of hand muscles is an important neural mechanism for hand control. To gain insight into the synaptic input underlying the coordination of hand muscles, significant effort has been devoted to describing the distribution of common input across motor units of extrinsic muscles. Much less is known, however, about the distribution of common input to motor units belonging to different intrinsic muscles and to intrinsic-extrinsic muscle pairs. To address this void in the literature, we quantified the incidence and strength of near-simultaneous discharges of motor units residing in either the same or different intrinsic hand muscles (m. first dorsal, FDI, and m. first palmar interosseus, FPI) during two-digit object hold. To extend the characterization of common input to pairs of extrinsic muscles (previous work) and pairs of intrinsic muscles (present work), we also recorded electromyographic (EMG) activity from an extrinsic thumb muscle (m. flexor pollicis longus, FPL). Motor-unit synchrony across FDI and FPI was weak (common input strength, CIS, mean +/- SE: 0.17 +/- 0.02). Similarly, motor units from extrinsic-intrinsic muscle pairs were characterized by weak synchrony (FPL-FDI: 0.25 +/- 0.02; FPL-FPI: 0.29 +/- 0.03) although stronger than FDI-FPI. Last, CIS from within FDI and FPI was more than three times stronger (0.70 +/- 0.06 and 0.66 +/- 0.06, respectively) than across these muscles. We discuss present and previous findings within the framework of muscle-pair specific distribution of common input to hand muscles based on their functional role in grasping.

Electromyographic and kinetic analysis of two abdominal muscle performance tests.

PubMed

Haladay, Douglas E; Denegar, Craig R; Miller, Sayers J; Challis, John

2015-01-01

In order to accurately assess the abdominal muscles, clinicians need valid clinical measures. The double leg lowering test (DLLT) and lower abdominal muscle progression (LAMP) are two common tests of abdominal muscle performance. The purposes of this study were to determine the relation between surface electromyographic (EMG) activity during the DLLT and LAMP levels; hip joint resultant moments and DLLT and LAMP levels; and the two measures of DLLT and LAMP. Ten healthy participants were tested under both conditions. Surface EMG activity of the abdominal muscles was obtained, while pelvic movement was detected simultaneously. A moderate to strong association was found between rectus abdominus muscle activity and a moderate association with the external obliques with both test levels. For the internal oblique/transversus abdominus, a moderate and weak association was found with the DLLT and LAMP, respectively. A very strong association existed between the hip resultant joint moments (RJM) and the DLLT, while there was a weak correlation between hip RJM and the LAMP. No significant correlation was found between the DLLT and LAMP grades. This finding suggests that these tests may measure different qualities of muscle performance and provides preliminary support for their use. Further evaluation of these assessments with clinical populations is necessary.

Novel excitation-contraction coupling related genes reveal aspects of muscle weakness beyond atrophy—new hopes for treatment of musculoskeletal diseases

PubMed Central

Manring, Heather; Abreu, Eduardo; Brotto, Leticia; Weisleder, Noah; Brotto, Marco

2013-01-01

Research over the last decade strengthened the understanding that skeletal muscles are not only the major tissue in the body from a volume point of view but also function as a master regulator contributing to optimal organismal health. These new contributions to the available body of knowledge triggered great interest in the roles of skeletal muscle beyond contraction. The World Health Organization, through its Global Burden of Disease (GBD) report, recently raised further awareness about the key importance of skeletal muscles as the GDB reported musculoskeletal (MSK) diseases have become the second greatest cause of disability, with more than 1.7 billion people in the globe affected by a diversity of MSK conditions. Besides their role in MSK disorders, skeletal muscles are also seen as principal metabolic organs with essential contributions to metabolic disorders, especially those linked to physical inactivity. In this review, we have focused on the unique function of new genes/proteins (i.e., MTMR14, MG29, sarcalumenin, KLF15) that during the last few years have helped provide novel insights about muscle function in health and disease, muscle fatigue, muscle metabolism, and muscle aging. Next, we provide an in depth discussion of how these genes/proteins converge into a common function of acting as regulators of intracellular calcium homeostasis. A clear link between dysfunctional calcium homeostasis is established and the special role of store-operated calcium entry is analyzed. The new knowledge that has been generated by the understanding of the roles of previously unknown modulatory genes of the skeletal muscle excitation-contraction coupling (ECC) process brings exciting new possibilities for treatment of MSK diseases, muscle regeneration, and skeletal muscle tissue engineering. The next decade of skeletal muscle and MSK research is bound to bring to fruition applied knowledge that will hopefully offset the current heavy and sad burden of MSK diseases on the planet. PMID:24600395

Novel excitation-contraction coupling related genes reveal aspects of muscle weakness beyond atrophy-new hopes for treatment of musculoskeletal diseases.

PubMed

Manring, Heather; Abreu, Eduardo; Brotto, Leticia; Weisleder, Noah; Brotto, Marco

2014-01-01

Research over the last decade strengthened the understanding that skeletal muscles are not only the major tissue in the body from a volume point of view but also function as a master regulator contributing to optimal organismal health. These new contributions to the available body of knowledge triggered great interest in the roles of skeletal muscle beyond contraction. The World Health Organization, through its Global Burden of Disease (GBD) report, recently raised further awareness about the key importance of skeletal muscles as the GDB reported musculoskeletal (MSK) diseases have become the second greatest cause of disability, with more than 1.7 billion people in the globe affected by a diversity of MSK conditions. Besides their role in MSK disorders, skeletal muscles are also seen as principal metabolic organs with essential contributions to metabolic disorders, especially those linked to physical inactivity. In this review, we have focused on the unique function of new genes/proteins (i.e., MTMR14, MG29, sarcalumenin, KLF15) that during the last few years have helped provide novel insights about muscle function in health and disease, muscle fatigue, muscle metabolism, and muscle aging. Next, we provide an in depth discussion of how these genes/proteins converge into a common function of acting as regulators of intracellular calcium homeostasis. A clear link between dysfunctional calcium homeostasis is established and the special role of store-operated calcium entry is analyzed. The new knowledge that has been generated by the understanding of the roles of previously unknown modulatory genes of the skeletal muscle excitation-contraction coupling (ECC) process brings exciting new possibilities for treatment of MSK diseases, muscle regeneration, and skeletal muscle tissue engineering. The next decade of skeletal muscle and MSK research is bound to bring to fruition applied knowledge that will hopefully offset the current heavy and sad burden of MSK diseases on the planet.

Differential Muscle Hypertrophy Is Associated with Satellite Cell Numbers and Akt Pathway Activation Following Activin Type IIB Receptor Inhibition in Mtm1 p.R69C Mice

PubMed Central

Lawlor, Michael W.; Viola, Marissa G.; Meng, Hui; Edelstein, Rachel V.; Liu, Fujun; Yan, Ke; Luna, Elizabeth J.; Lerch-Gaggl, Alexandra; Hoffmann, Raymond G.; Pierson, Christopher R.; Buj-Bello, Anna; Lachey, Jennifer L.; Pearsall, Scott; Yang, Lin; Hillard, Cecilia J.; Beggs, Alan H.

2015-01-01

X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1δ4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials. PMID:24726641

Differential muscle hypertrophy is associated with satellite cell numbers and Akt pathway activation following activin type IIB receptor inhibition in Mtm1 p.R69C mice.

PubMed

Lawlor, Michael W; Viola, Marissa G; Meng, Hui; Edelstein, Rachel V; Liu, Fujun; Yan, Ke; Luna, Elizabeth J; Lerch-Gaggl, Alexandra; Hoffmann, Raymond G; Pierson, Christopher R; Buj-Bello, Anna; Lachey, Jennifer L; Pearsall, Scott; Yang, Lin; Hillard, Cecilia J; Beggs, Alan H

2014-06-01

X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1δ4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Pathogenic immune mechanisms at the neuromuscular synapse: the role of specific antibody-binding epitopes in myasthenia gravis.

PubMed

Huijbers, M G; Lipka, A F; Plomp, J J; Niks, E H; van der Maarel, S M; Verschuuren, J J

2014-01-01

Autoantibodies against three different postsynaptic antigens and one presynaptic antigen at the neuromuscular junction are known to cause myasthenic syndromes. The mechanisms by which these antibodies cause muscle weakness vary from antigenic modulation and complement-mediated membrane damage to inhibition of endogenous ligand binding and blocking of essential protein-protein interactions. These mechanisms are related to the autoantibody titre, specific epitopes on the target proteins and IgG autoantibody subclass. We here review the role of specific autoantibody-binding epitopes in myasthenia gravis, their possible relevance to the pathophysiology of the disease and potential implications of epitope mapping knowledge for new therapeutic strategies. © 2013 The Association for the Publication of the Journal of Internal Medicine.

Guillain-Barre syndrome caused by hepatitis E infection: case report and literature review.

PubMed

Zheng, Xiaoqin; Yu, Liang; Xu, Qiaomai; Gu, Silan; Tang, Lingling

2018-01-23

Hepatitis E infection is a global disorder that causes substantial morbidity. Numerous neurologic illnesses, including Guillain-Barre syndrome (GBS), have occurred in patients with hepatitis E virus (HEV) infection. We report a 58 year-old non-immunocompromised man who presented with progressive muscle weakness in all extremities during an episode of acute HEV infection, which was confirmed by measuring the anti-HEV IgM antibodies in the serum. Both cerebrospinal fluid examination and electrophysiological study were in agreement with the diagnosis of HEV-associated GBS. Following the treatment with intravenous immunoglobulin, the patient's neurological condition improved rapidly. HEV infection should be strongly considered in patients with neurological symptoms, especially those with elevated levels of liver enzymes.

Strength deficits identified with concentric action of the hip extensors and eccentric action of the hamstrings predispose to hamstring injury in elite sprinters.

PubMed

Sugiura, Yusaku; Saito, Tomoyuki; Sakuraba, Keishoku; Sakuma, Kazuhiko; Suzuki, Eiichi

2008-08-01

Prospective cohort study. In this prospective cohort study of elite sprinters, muscle strength of the hip extensors, as well as of the knee extensors and flexors, was measured to determine a possible relationship between strength deficits and subsequent hamstring injury within 12 months of testing. The method used for testing muscle strength simulated the specific muscle action during late swing and early contact phases when sprinting. There have been no prospective studies in elite sprinters that examine the concentric and eccentric isokinetic strength of the hip extensors and the quadriceps and hamstring muscles in a manner that reflects their actions in late swing or early contact phases of sprinting. Consequently, the causal relationship between hip and thigh muscle strength and hamstring injury in elite sprinters may not be fully understood. Isokinetic testing was performed on 30 male elite sprinters to assess hip extensors, quadriceps, and hamstring muscle strength. The occurrence of hamstring injury among the subjects was determined during the year following the muscle strength measurements. The strength of the hip extensors, quadriceps, and hamstring muscles, as well as the hamstrings-quadriceps and hip extensors- quadriceps ratios were compared. Hamstring injury occurred in 6 subjects during the 1-year period. Isokinetic testing at a speed of 60 degrees /s revealed weakness of the injured limb with eccentric action of the hamstring muscles and during concentric action of the hip extensors. When performing a side-to-side comparison for the injured sprinters, the hamstring injury always occurred on the weaker side. Differences in the hamstrings-quadriceps and hip extensors-quadriceps strength ratios were also evident between uninjured and injured limbs, and this was attributable to deficits in hamstring strength. Hamstring injury in elite sprinters was associated with weakness during eccentric action of the hamstrings and weakness during concentric action of the hip extensors, but only when tested at the slower speed of 60 degrees /s.

Handgrip Strength Cutoff Points to Identify Mobility Limitation in Community-dwelling Older People and Associated Factors.

PubMed

Vasconcelos, K S de Souza; Dias, J M Domingues; Bastone, A de Carvalho; Vieira, R Alvarenga; Andrade, A C de Souza; Perracini, M Rodrigues; Guerra, R Oliveira; Dias, R Corrêa

2016-03-01

Sarcopenia is defined as a progressive and generalized loss of skeletal muscle mass and strength. The specific threshold of muscle weakness that leads to mobility limitations has not been identified. To determine the best cutoff point of handgrip strength for identifying mobility limitation and to investigate the factors associated with muscle weakness and mobility limitation in community-dwelling older people. Transversal study. Cities of Belo Horizonte, Barueri and Santa Cruz in Brazil. 1374 community-dwelling older people from the Frailty study in Brazilian older people (FIBRA Study). Outcomes included muscle weakness determined according to gender-specific handgrip strength cutoff points generated by Receiver Operating Characteristic curves, mobility limitation defined as a gait speed ≤ 0.8 m/s; and a combination of both muscle weakness and mobility limitation. Associated factors included socio-demographic variables, lifestyle, anthropometrics, health conditions, use of health services and disability. The cutoff points of handgrip strength with the best balancing between sensitivity and specificity for mobility limitation were 25.8 kgf for men (sensitivity 69%, specificity 73%) and 17.4 kgf (sensitivity 60%, specificity 66%) for women. Age and disability in instrumental activities of daily living were associated with all outcomes. Women had greater odds of mobility limitation than men. Physical inactivity, body fat, diabetes, depression, sleeping disturbances, number of medications and occurrence of falls remained as significant associated factors in the final model. Handgrip strength can be a useful tool to identify mobility limitation in clinical practice. Interventions to prevent or minimize impacts of sarcopenia should stimulate physical activity and improvement of body composition in addition to the management of chronic diseases and disabilities.

Renal Effects of Long Term Administration of Triamcinolone Acetonide in Normal Dogs

PubMed Central

Osbaldiston, G. W.

1971-01-01

Triamcinolone acetonide was administered in excessive dosage to dogs to study the renal mechanism responsible for polyuria which is a clinically undesirable side effect of long term glucocorticoid therapy. Polyuria occurred coincident with a significant increase in urinary solute output. Although continuous administration of triamcinolone acetonide at 0.1 or 0.2 mg/lb/day caused a small but significant increase in creatinine output, the primary mechanism for the polyuria was increased solute excretion. Associated with the polyuria was pronounced hyperphagia and polydipsia. The cause of the hyperphagia was not established. The increase in electrolyte excretion caused by this synthetic steroid was probably compensated for by the hyperphagia. Because all the dogs showed muscle weakness and loss of body condition, it is likely that alteration in protein and amino acid metabolism was responsible for the hyperphagia. PMID:4251411

Dropped head congenital muscular dystrophy caused by de novo mutations in LMNA.

PubMed

Karaoglu, Pakize; Quizon, Nicolas; Pergande, Matthias; Wang, Haicui; Polat, Ayşe Ipek; Ersen, Ayca; Özer, Erdener; Willkomm, Lena; Hiz Kurul, Semra; Heredia, Raúl; Yis, Uluç; Selcen, Duygu; Çirak, Sebahattin

2017-04-01

Dropped head syndrome is an easily recognizable clinical presentation of Lamin A/C-related congenital muscular dystrophy. Patients usually present in the first year of life with profound neck muscle weakness, dropped head, and elevated serum creatine kinase. Two patients exhibited head drop during infancy although they were able to sit independently. Later they developed progressive axial and limb-girdle weakness. Creatine kinase levels were elevated and muscle biopsies of both patients showed severe dystrophic changes. The distinctive clinical hallmark of the dropped head led us to the diagnosis of Lamin A/C-related congenital muscular dystrophy, with a pathogenic de novo mutation p.Glu31del in the head domain of the Lamin A/C gene in both patients. Remarkably, one patient also had a central involvement with white matter changes on brain magnetic resonance imaging. Lamin A/C-related dropped-head syndrome is a rapidly progressive congenital muscular dystrophy and may lead to loss of ambulation, respiratory insufficiency, and cardiac complications. Thus, the genetic diagnosis of dropped-head syndrome as L-CMD and the implicated clinical care protocols are of vital importance for these patients. This disease may be underdiagnosed, as only a few genetically confirmed cases have been reported. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Assessing pathogenicity for novel mutation/sequence variants: the value of healthy older individuals.

PubMed

Zatz, Mayana; Pavanello, Rita de Cassia M; Lourenço, Naila Cristina V; Cerqueira, Antonia; Lazar, Monize; Vainzof, Mariz

2012-12-01

Improvement in DNA technology is increasingly revealing unexpected/unknown mutations in healthy persons and generating anxiety due to their still unknown health consequences. We report a 44-year-old healthy father of a 10-year-old daughter with bilateral coloboma and hearing loss, but without muscle weakness, in whom a whole-genome CGH revealed a deletion of exons 38-44 in the dystrophin gene. This mutation was inherited from her asymptomatic father, who was further clinically and molecularly evaluated for prognosis and genetic counseling (GC). This deletion was never identified by us in 982 Duchenne/Becker patients. To assess whether the present case represents a rare case of non-penetrance, and aiming to obtain more information for prognosis and GC, we suggested that healthy older relatives submit their DNA for analysis, to which several complied. Mutation analysis revealed that his mother, brother, and 56-year-old maternal uncle also carry the 38-44 deletion, suggesting it an unlikely cause of muscle weakness. Genome sequencing will disclose mutations and variants whose health impact are still unknown, raising important problems in interpreting results, defining prognosis, and discussing GC. We suggest that, in addition to family history, keeping the DNA of older relatives could be very informative, in particular for those interested in having their genome sequenced.

[Cervical cord infarction associated with unilateral vertebral artery dissection due to golf swing].

PubMed

Tokumoto, Kazuki; Ueda, Nobuhiko

2014-01-01

A-68-year-old man experienced nuchal pain and bilateral shoulder weakness that occurred suddenly after he performed a golf swing. He was conscious. His cranial nerves were normal, but bilateral deltoid and biceps muscle strengths weakened. Magnetic resonance image (MRI) showed no brain stem infarctions or cervical epidural hematoma. We tentatively diagnosed him with concussion of the spinal cord because of mild recovery of his bilateral upper limb weakness after several hours; he was later discharged. The next day, he suddenly developed serious tetraplegia and was admitted to the emergency department. His breathing was controlled by a respirator as he had expectoration difficulty and respiratory muscle paralysis. A lesion in the cervical cord became apparent on MRI; the right vertebral artery was not detected on magnetic resonance angiography. Cervical MRI showed the intimal flap and a lack of flow void in the right vertebral artery. These findings revealed a right vertebral artery dissection. Cervical cord infarction due to unilateral vertebral artery dissection is rarer than posterior cerebral infarction due to the same pathogenesis; however, some such cases have been reported. We consider the present case to be caused by cervical cord infarction associated with unilateral vertebral artery dissection resulting from golf swing.

Definition and classification of negative motor signs in childhood.

PubMed

Sanger, Terence D; Chen, Daofen; Delgado, Mauricio R; Gaebler-Spira, Deborah; Hallett, Mark; Mink, Jonathan W

2006-11-01

In this report we describe the outcome of a consensus meeting that occurred at the National Institutes of Health in Bethesda, Maryland, March 12 through 14, 2005. The meeting brought together 39 specialists from multiple clinical and research disciplines including developmental pediatrics, neurology, neurosurgery, orthopedic surgery, physical therapy, occupational therapy, physical medicine and rehabilitation, neurophysiology, muscle physiology, motor control, and biomechanics. The purpose of the meeting was to establish terminology and definitions for 4 aspects of motor disorders that occur in children: weakness, reduced selective motor control, ataxia, and deficits of praxis. The purpose of the definitions is to assist communication between clinicians, select homogeneous groups of children for clinical research trials, facilitate the development of rating scales to assess improvement or deterioration with time, and eventually to better match individual children with specific therapies. "Weakness" is defined as the inability to generate normal voluntary force in a muscle or normal voluntary torque about a joint. "Reduced selective motor control" is defined as the impaired ability to isolate the activation of muscles in a selected pattern in response to demands of a voluntary posture or movement. "Ataxia" is defined as an inability to generate a normal or expected voluntary movement trajectory that cannot be attributed to weakness or involuntary muscle activity about the affected joints. "Apraxia" is defined as an impairment in the ability to accomplish previously learned and performed complex motor actions that is not explained by ataxia, reduced selective motor control, weakness, or involuntary motor activity. "Developmental dyspraxia" is defined as a failure to have ever acquired the ability to perform age-appropriate complex motor actions that is not explained by the presence of inadequate demonstration or practice, ataxia, reduced selective motor control, weakness, or involuntary motor activity.

Lubrication Theory Model to Evaluate Surgical Alterations in Flow Mechanics of the Lower Esophageal Sphincter

NASA Astrophysics Data System (ADS)

Ghosh, Sudip K.; Brasseur, James G.; Zaki, Tamer; Kahrilas, Peter J.

2003-11-01

Surgery is commonly used to rebuild a weak lower esophageal sphincter (LES) and reduce reflux. Because the driving pressure (DP) is proportional to muscle tension generated in the esophagus, we developed models using lubrication theory to evaluate the consequences of surgery on muscle force required to open the LES and drive the flow. The models relate time changes in DP to lumen geometry and trans-LES flow with a manometric catheter. Inertial effects were included and found negligible. Two models, direct (opening specified) and indirect (opening predicted), were combined with manometric pressure and imaging data from normal and post-surgery LES. A very high sensitivity was predicted between the details of the DP and LES opening. The indirect model accurately captured LES opening and predicted a 3-phase emptying process, with phases I and III requiring rapid generation of muscle tone to open the LES and empty the esophagus. Data showed that phases I and III are adversely altered by surgery causing incomplete emptying. Parametric model studies indicated that changes to the surgical procedure can positively alter LES flow mechanics and improve clinical outcomes.

Respiratory failure in a patient with antecedent poliomyelitis: amyotrophic lateral sclerosis or post-polio syndrome?

PubMed

Terao, Shin-ichi; Miura, Naofumi; Noda, Aiji; Yoshida, Mari; Hashizume, Yoshio; Ikeda, Hiroshi; Sobue, Gen

2006-10-01

We report a 69-year-old man who developed paralytic poliomyelitis in childhood and then decades later suffered from fatal respiratory failure. Six months before this event, he had progressive weight loss and shortness of breath. He had severe muscular atrophy of the entire right leg as a sequela of the paralytic poliomyelitis. He showed mild weakness of the facial muscle and tongue, dysarthria, and severe muscle atrophy from the neck to proximal upper extremities and trunk, but no obvious pyramidal signs. Electromyogram revealed neurogenic changes in the right leg, and in the paraspinal, sternocleidomastoid, and lingual muscles. There was a slight increase in central motor conduction time from the motor cortex to the lumbar anterior horn. Pulmonary function showed restrictive ventilation dysfunction, which was the eventual cause of death. Some neuropathological features were suggestive of amyotrophic lateral sclerosis (ALS), namely Bunina bodies. In patients with a history of paralytic poliomyelitis who present after a long stable period with advanced fatal respiratory failure, one may consider not only respiratory impairment from post-polio syndrome but also the onset of ALS.

Effective Classification and Gene Expression Profiling for the Facioscapulohumeral Muscular Dystrophy

PubMed Central

González-Navarro, Félix F.; Belanche-Muñoz, Lluís A.; Silva-Colón, Karen A.

2013-01-01

The Facioscapulohumeral Muscular Dystrophy (FSHD) is an autosomal dominant neuromuscular disorder whose incidence is estimated in about one in 400,000 to one in 20,000. No effective therapeutic strategies are known to halt progression or reverse muscle weakness and atrophy. It is known that the FSHD is caused by modifications located within a D4ZA repeat array in the chromosome 4q, while recent advances have linked these modifications to the DUX4 gene. Unfortunately, the complete mechanisms responsible for the molecular pathogenesis and progressive muscle weakness still remain unknown. Although there are many studies addressing cancer databases from a machine learning perspective, there is no such precedent in the analysis of the FSHD. This study aims to fill this gap by analyzing two specific FSHD databases. A feature selection algorithm is used as the main engine to select genes promoting the highest possible classification capacity. The combination of feature selection and classification aims at obtaining simple models (in terms of very low numbers of genes) capable of good generalization, that may be associated with the disease. We show that the reported method is highly efficient in finding genes to discern between healthy cases (not affected by the FSHD) and FSHD cases, allowing the discovery of very parsimonious models that yield negligible repeated cross-validation error. These models in turn give rise to very simple decision procedures in the form of a decision tree. Current biological evidence regarding these genes shows that they are linked to skeletal muscle processes concerning specific human conditions. PMID:24349187

Single-fiber electromyography analysis of botulinum toxin diffusion in patients with fatigue and pseudobotulism.

PubMed

Ruet, Alexis; Durand, Marie Christine; Denys, Pierre; Lofaso, Frederic; Genet, François; Schnitzler, Alexis

2015-06-01

To characterize electromyographic abnormalities according to symptoms (asymptomatic, fatigue, pseudobotulism) reported 1 month after botulinum toxin injection. Retrospective, single-center study comparing single-fiber electromyography (SFEMG) in the extensor digitorum communis (EDC) or orbicularis oculi (OO) muscles. Hospital. Four groups of adults treated for spasticity or neurologic bladder hyperactivity (N=55): control group (asymptomatic patients: n=17), fatigue group (unusual fatigue with no weakness: n=15), pseudobotulism group (muscle weakness and/or visual disturbance: n=20), and botulism group (from intensive care unit of the same hospital: n=3). Not applicable. Mean jitter, percentage of pathologic fibers, and percentage of blocked fibers were compared between groups. SFEMG was abnormal for 17.6% of control patients and 75% of patients in the pseudobotulism group. There were no differences between the control and fatigue groups. Mean jitter, percentage of pathologic fibers, and percentage of blocked fibers of the EDC muscle were significantly higher in the pseudobotulism group than in the fatigue and control groups. There were no differences between groups for the OO muscle. The SFEMG results in the botulism group were qualitatively similar to those of the pseudobotulism group. SFEMG of the EDC muscle confirmed diffusion of the toxin into muscles distant from the injection site in the pseudobotulism group. SFEMG in the OO muscle is not useful for the diagnosis of diffusion. No major signs of diffusion of botulinum toxin type A were found away from the injection site in patients with fatigue but no motor weakness. Such fatigue may be related to other mechanisms. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

[Correlation factors of 127 times pre-crisis state in patients with myasthenia gravis].

PubMed

Ou, C Y; Ran, H; Qiu, L; Huang, Z D; Lin, Z Z; Deng, J; Liu, W B

2017-10-10

Objective: To investigate the clinical features of the Pre-Crisis State and analyze the correlated risk factors of Pre-Crisis State of myasthenia crisis. Methods: We included 93 patients with myasthenia gravis (MG) who experienced 127 times Pre-Crisis State between October 2007 and July 2016. Those patients were hospitalized in the MG specialize center, Department of Neurological Science, first Affiliated Hospital of Sun Yat-sen University. The information of the general situation, the clinical manifestations and the blood gas analysis in those patients were collected using our innovated clinical research form. Statistic methods were applied including descriptive analysis, univariate logistic analysis, multivariate correlation logistic analysis, etc. Results: (1)The typical features of MG Pre-Crisis State included: dyspnea (127 times, 100% not requiring intubation or non-invasive ventilation), bulbar-muscle weakness (121 times, 95.28%), the increased blood partial pressure of carbon dioxide (PCO(2)) (94 times, 85.45%), expectoration weakness (99 times, 77.95%), sleep disorders (107 times, 84.25%) and the infection (99 times, 77.95%). The occurrence of dyspnea in combination with bulbar-muscle weakness ( P =0.002) or the increased blood PCO(2) ( P =0.042) often indicated the tendency of crisis. (2) The MG symptoms which were proportion to the occurrence of crisis includes: bulbar-muscle weakness ( P =0.028), fever ( P =0.028), malnutrition ( P =0.066), complications ( P =0.071), excess oropharyngeal secretions ( P =0.005) and the increased blood PCO(2) ( P =0.007). The perioperative period of thymectomy would not increase the risk of crisis. Conclusions: Dyspnea indicates the occurrence of the Pre-Crisis State of MG. In order to significantly reduce the morbidity of myasthenia crisis, the bulbar-muscle weakness, the increased blood PCO(2), expectoration weakness, sleep disorders, infection & fever and excess oropharyngeal secretions should be treated timely.

Relationship between lower extremity isometric muscle strength and standing balance in patients with multiple sclerosis.

PubMed

Citaker, Seyit; Guclu-Gunduz, Arzu; Yazici, Gokhan; Bayraktar, Deniz; Nazliel, Bijen; Irkec, Ceyla

2013-01-01

Muscle strength and standing balance decrease in patients with Multiple Sclerosis (MS). The aim of the present study was to investigate the relationship between the lower extremity isometric muscle strength and standing balance in patients with MS. Forty-seven patients with MS and 10 healthy volunteers were included. Neurological disability level was assessed using Expanded Disability Status Scale (EDSS). Isometric strength of seven lower extremity muscles (hip flexor-extensor-abductor-adductor, knee flexor-extensor, and ankle dorsal flexor) was assessed using hand-held dynamometer. Duration of static one-leg standing balance was measured using digital chronometer. Hip flexor-extensor-abductor-adductor, knee flexor-extensor, and ankle dorsal flexor isometric muscle strength, and duration of one-leg standing balance were decreased in patients with MS when compared with controls (p < 0.05). All assessed lower extremity isometric muscle strength and EDSS level was related duration of one-leg standing balance in patients with MS. All assessed lower extremity isometric muscle strength (except ankle dorsal flexor) was related with EDSS. Hip flexor-extensor-abductor-adductor, knee flexor-extensor, and ankle dorsal flexor isometric muscle strength decreases in ambulatory MS patients. Lower extremity muscle weakness and neurological disability level are related with imbalance in MS population. Hip and knee region muscles weakness increases the neurological disability level. For the better balance and decrease neurological disability level whole lower extremity muscle strengthening should be included in rehabilitation programs.

Paraneoplastic Lambert-Eaton syndrome in a patient with disseminated metastatic cancer.

PubMed

Arellano-Aguilar, Gregorio; Núñez-Mojica, Erik Santiago; Gutiérrez-Velazco, José Luis; Domínguez-Carrillo, Luis Gerardo

2018-01-01

Neurological paraneoplastic syndromes are rare, occur in 0.01% of all cancer patients; like part of them, the Lambert-Eaton syndrome is an autoimmune presynaptic disorder of neuromuscular transmission characterized by muscle weakness and neurovegetative dysfunction, and often associated with small cell lung cancer. A 72 years old female with a family history of lung cancer and leukemia, with 7 months of dry cough and 3 months with waist and pelvic muscle weakness, oropharyngeal dysphagia, dry mouth, chronic constipation and weight loss of 10 kg. Physical examination: patient prostrated; clinical muscle examination: pelvic muscles waist -3/5 and -4/5 the rest; diminished reflexes. Laboratory normal parathormone and hypercalcemia. With electrophysiological study and positive anti-voltage-gated calcium channel antibodies, confirming Lambert-Eaton syndrome and imaging studies with neoplastic condition in brain, liver and kidney, with unspecified primary origin. Copyright: © 2018 Permanyer.

A Rare Manifestation of Hypothyroid Myopathy: Hoffmann's Syndrome

PubMed Central

Lee, Kang Won; Kim, Kyoung Jin; Kim, Sang Hyun; Kim, Hee Young; Kim, Byung-Jo; Kim, Sin Gon; Choi, Dong Seop

2015-01-01

Hypothyroid myopathy is observed frequently and the resolution of the clinical manifestations of myopathy following thyroid hormone replacement is well known. However, a specific subtype of hypothyroid myopathy, Hoffmann's syndrome, characterized by increased muscular mass (pseudohypertrophy), proximal muscle weakness, muscle stiffness and cramps, is rarely reported. Herein, we describe a 34-year-old male who presented with proximal muscle weakness and non-pitting edema of the lower extremities. He initially visited the neurology department where he was suspected of having polymyositis. Additional laboratory evaluation revealed profound autoimmune hypothyroidism and elevated muscle enzymes including creatine kinase. The patient was started on levothyroxine treatment and, subsequently, clinical symptoms and biochemical parameters resolved with the treatment. The present case highlights that hypothyroidism should be considered in the differential diagnosis of musculoskeletal symptoms even in the absence of overt manifestations of hypothyroidism. To our knowledge, this is the first case reported in Korea. PMID:26394732

Two families with MYH7 distal myopathy associated with cardiomyopathy and core formations.

PubMed

Naddaf, Elie; Waclawik, Andrew J

2015-03-01

Laing distal myopathy is caused by MYH7 gene mutations. Multiple families have been reported with varying patterns of skeletal and cardiac involvement as well as histopathological findings. We report 2 families with p.Glu1508del mutation with detailed electrophysiological and muscle pathology findings. All patients displayed the classic phenotype with weakness starting in the anterior compartment of the legs with a "hanging great toe." It was followed by finger extensors involvement, relatively sparing the extensor indicis proprius, giving the appearance of a "pointing index" finger. All the affected individuals had a dilated cardiomyopathy and core formations on muscle biopsy. Unexpectedly, neurogenic changes were also observed in some individuals. Both families were initially misdiagnosed with either central core disease or hereditary neuropathy. Recognizing the classic phenotype, screening for cardiac involvement that may be clinically silent, and determining the mode of inheritance help with selecting the appropriate genetic test.

Kennedy's disease and partial androgen insensitivity syndrome. Report of 4 cases and literature review.

PubMed

Valera Yepes, Rocío; Virgili Casas, Maria; Povedano Panades, Monica; Guerrero Gual, Mireia; Villabona Artero, Carles

2015-05-01

Kennedy's disease, also known as bulbospinal muscular atrophy, is a rare, X-linked recessive neurodegenerative disorder affecting adult males. It is caused by expansion of an unstable cytosine-adenine-guanine tandem-repeat in exon 1 of the androgen-receptor gene on chromosome Xq11-12, and is characterized by spinal motor neuron progressive degeneration. Endocrinologically, these patients often have the features of hypogonadism associated to the androgen insensitivity syndrome, particularly its partial forms. We report 4 cases with the typical neurological presentation, consisting of slowly progressing generalized muscle weakness with atrophy and bulbar muscle involvement; these patients also had several endocrine manifestations; the most common non-neurological manifestation was gynecomastia. In all cases reported, molecular analysis showed an abnormal cytosine-adenine-guanine triplet repeat expansion in the androgen receptor gene. Copyright © 2014 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

Acute nutritional axonal neuropathy.

PubMed

Hamel, Johanna; Logigian, Eric L

2018-01-01

This study describes clinical, laboratory, and electrodiagnostic features of a severe acute axonal polyneuropathy common to patients with acute nutritional deficiency in the setting of alcoholism, bariatric surgery (BS), or anorexia. Retrospective analysis of clinical, electrodiagnostic, and laboratory data of patients with acute axonal neuropathy. Thirteen patients were identified with a severe, painful, sensory or sensorimotor axonal polyneuropathy that developed over 2-12 weeks with sensory ataxia, areflexia, variable muscle weakness, poor nutritional status, and weight loss, often with prolonged vomiting and normal cerebrospinal fluid protein. Vitamin B6 was low in half and thiamine was low in all patients when obtained before supplementation. Patients improved with weight gain and vitamin supplementation, with motor greater than sensory recovery. We suggest that acute or subacute axonal neuropathy in patients with weight loss or vomiting associated with alcohol abuse, BS, or dietary deficiency is one syndrome, caused by micronutrient deficiencies. Muscle Nerve 57: 33-39, 2018. © 2017 Wiley Periodicals, Inc.

Clinical features and ryanodine receptor type 1 gene mutation analysis in a Chinese family with central core disease.

PubMed

Chang, Xingzhi; Jin, Yiwen; Zhao, Haijuan; Huang, Qionghui; Wang, Jingmin; Yuan, Yun; Han, Ying; Qin, Jiong

2013-03-01

Central core disease is a rare inherited neuromuscular disorder caused by mutations in ryanodine receptor type 1 gene. The clinical phenotype of the disease is highly variable. We report a Chinese pedigree with central core disease confirmed by the gene sequencing. All 3 patients in the family presented with mild proximal limb weakness. The serum level of creatine kinase was normal, and electromyography suggested myogenic changes. The histologic analysis of muscle biopsy showed identical central core lesions in almost all of the muscle fibers in the index case. Exon 90-106 in the C-terminal domain of the ryanodine receptor type 1 gene was amplified using polymerase chain reaction. One heterozygous missense mutation G14678A (Arg4893Gln) in exon 102 was identified in all 3 patients. This is the first report of a familial case of central core disease confirmed by molecular study in mainland China.

Global muscular dystrophy research: A 25-year bibliometric perspective.

PubMed

Ram, Shri

2017-01-01

Muscular dystrophy is a genetic disorder leading to progressive weakness of muscles caused due to dysfunction in or lack of protein in muscle cells. The prevalence of muscular dystrophy has been observed globally and is becoming a critical area of study for better health services. The purpose of the study is to analyze the research strength of muscular dystrophy using bibliographic literature. A quantitative literature analysis was carried out on muscular dystrophy from 1991 to 2015 for assessing the global research trends. This literature-based study was conducted using the documents retrieved from the Science Citation Index using the keywords: Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), Congenital Muscular Dystrophy (CMD), Myotonic Dystrophy, Emery-Dreifuss Muscular Dystrophy, Facioscapulohumeral Muscular Dystrophy, Oculopharyngeal Muscular Dystrophy, and Limb-Girdle Muscular Dystrophy. Analysis was done for annual productivity of publication, authorship, collaboration, country performance, citation frequency, characteristics of most cited document, journal productivity, etc.

Rhabdomyolysis Due to Severe Hypophosphatemia in Diabetic Ketoacidosis.

PubMed

Shah, S K; Shah, L; Bhattarai, S; Giri, M

2015-01-01

Rhabdomyolysis is a syndrome characterized by injury to skeletal muscle fibers with disruption and release of toxic metabolites into circulation. It is characterized by triad of muscle weakness, myalgia and dark urine and is associated with increased creatine kinase and lactate dehydrogenase. A severely malnourished 10 year old girl with severe diabetic ketoacidosis as hemr initial presentation of type 1 diabetes mellitus developed rhabdomyolysis (CK- 12,000 U/L) with non-oliguric renal failure during her initial course of hospital stay. The possible cause of her RM was attributed to severe hypophosphatemia (minimum serum phosphate, 0.8 mg/dL). Management of diabetic ketoacidosis phosphate supplementation and urinary alkalinization with diuresis improved her clinical course. She was discharged on Day 9 with Insulin. We recommend frequent monitoring of serum phosphate during early period of DKA, particularly in malnourished children, and its normalization in case of severe hypophosphatemia.

A novel PNPLA2 mutation causes neutral lipid storage disease with myopathy (NLSDM) presenting muscular dystrophic features with lipid storage and rimmed vacuoles.

PubMed

Chen, J; Hong, D; Wang, Z; Yuan, Y

2010-01-01

Neutral lipid storage disease with myopathy (NLSDM) is a type of lipid storage myopathy arising due to a mutation in the PNPLA2 gene encoding an adipose triglyceride lipase responsible for the degradation of intracellular triglycerides. Herein, we report the cases of two siblings manifesting slowly progressive proximal and distal limb weakness in adulthood. One of the patients had dilated cardiomyopathy, hearing loss and short stature. Muscle specimens of the 2 patients revealed muscular dystrophic features with massive lipid droplets and numerous rimmed vacuoles in the fibers. A novel homozygous mutation IVS2+1G > A in the PNPLA2 gene was identified in the 2 cases, but not in the healthy familial individuals. The presence of massive lipid droplets with muscular dystrophic changes and rimmed vacuoles in muscle fibers might be one of the characteristic pathological changes of NLSDM.

A case report: Becker muscular dystrophy presenting with epilepsy and dysgnosia induced by duplication mutation of Dystrophin gene.

PubMed

Miao, Jing; Feng, Jia-Chun; Zhu, Dan; Yu, Xue-Fan

2016-12-12

Becker muscular dystrophy (BMD), a genetic disorder of X-linked recessive inheritance, typically presents with gradually progressive muscle weakness. The condition is caused by mutations of Dystrophin gene located at Xp21.2. Epilepsy is an infrequent manifestation of BMD, while cases of BMD with dysgnosia are extremely rare. We describe a 9-year-old boy with BMD, who presented with epilepsy and dysgnosia. Serum creatine kinase level was markedly elevated (3665 U/L). Wechsler intelligence tests showed a low intelligence quotient (IQ = 65). Electromyogram showed slight myogenic changes and skeletal muscle biopsy revealed muscular dystrophy. Immunohistochemical staining showed partial positivity of sarcolemma for dystrophin-N. Multiplex ligation-dependent probe amplification revealed a duplication mutation in exons 37-44 in the Dystrophin gene. The present case report helps to better understand the clinical and genetic features of BMD.

Drop finger caused by 8th cervical nerve root impairment: a clinical case series.

PubMed

Koda, Masao; Furuya, Takeo; Rokkaku, Tomoyuki; Murakami, Masazumi; Ijima, Yasushi; Saito, Junya; Kitamura, Mitsuhiro; Ohtori, Seiji; Orita, Sumihisa; Inage, Kazuhide; Yamazaki, Masashi; Mannoji, Chikato

2017-04-01

Recently, it has been reported that impairment by an 8th cervical nerve root lesion can cause drop finger, namely C8 drop finger. Here, we report a clinical case series of C8 drop finger to reveal the clinical outcome of surgical treatments to allow for a better choice of treatment. The present study included 17 consecutive patients who were diagnosed as having C8 drop finger, in which muscle strength of the extensor digitorum communis (EDC) showed a manual muscle testing (MMT) grade of 3 or less. We retrospectively investigated the clinical characteristics of C8 drop finger and recovery of muscle power was measured by subtraction of preoperative MMT of the EDC from the final follow-up values. Nine cases showed recovery of muscle power of EDC, whereas the remaining eight cases did not show any recovery including two cases of deterioration. None of the conservatively treated patients showed any recovery. Surgically treated cases included two cases of deterioration. In the cases showing recovery, recovery began 9.9 months after surgery on average and recovery took 13.8 months after surgery on average. There was a significant difference in the recovery of MMT grade between the groups treated conservatively and surgically (p = 0.049). Preoperative MMT grade of EDC showed a moderate correlation with postoperative recovery (r 2  = 0.45, p = 0.003). In other words, the severity of preoperative muscular weakness correlated negatively with postoperative recovery. C8 drop finger is better treated by surgery than conservative therapy.

Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.

PubMed

Martinez, Tara L; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A; Crowder, Melissa E; Van Meerbeke, James P; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J; Lutz, Cathleen M; Rich, Mark M; Sumner, Charlotte J

2012-06-20

The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

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

Abnormalities in Skeletal Muscle Myogenesis, Growth, and Regeneration in Myotonic Dystrophy.

PubMed

André, Laurène M; Ausems, C Rosanne M; Wansink, Derick G; Wieringa, Bé

2018-01-01

Myotonic dystrophy type 1 (DM1) and 2 (DM2) are autosomal dominant degenerative neuromuscular disorders characterized by progressive skeletal muscle weakness, atrophy, and myotonia with progeroid features. Although both DM1 and DM2 are characterized by skeletal muscle dysfunction and also share other clinical features, the diseases differ in the muscle groups that are affected. In DM1, distal muscles are mainly affected, whereas in DM2 problems are mostly found in proximal muscles. In addition, manifestation in DM1 is generally more severe, with possible congenital or childhood-onset of disease and prominent CNS involvement. DM1 and DM2 are caused by expansion of (CTG•CAG)n and (CCTG•CAGG)n repeats in the 3' non-coding region of DMPK and in intron 1 of CNBP , respectively, and in overlapping antisense genes. This critical review will focus on the pleiotropic problems that occur during development, growth, regeneration, and aging of skeletal muscle in patients who inherited these expansions. The current best-accepted idea is that most muscle symptoms can be explained by pathomechanistic effects of repeat expansion on RNA-mediated pathways. However, aberrations in DNA replication and transcription of the DM loci or in protein translation and proteome homeostasis could also affect the control of proliferation and differentiation of muscle progenitor cells or the maintenance and physiological integrity of muscle fibers during a patient's lifetime. Here, we will discuss these molecular and cellular processes and summarize current knowledge about the role of embryonic and adult muscle-resident stem cells in growth, homeostasis, regeneration, and premature aging of healthy and diseased muscle tissue. Of particular interest is that also progenitor cells from extramuscular sources, such as pericytes and mesoangioblasts, can participate in myogenic differentiation. We will examine the potential of all these types of cells in the application of regenerative medicine for muscular dystrophies and evaluate new possibilities for their use in future therapy of DM.

Genetic Variations in the Androgen Receptor Are Associated with Steroid Concentrations and Anthropometrics but Not with Muscle Mass in Healthy Young Men

PubMed Central

De Naeyer, Hélène; Bogaert, Veerle; De Spaey, Annelies; Roef, Greet; Vandewalle, Sara; Derave, Wim; Taes, Youri; Kaufman, Jean-Marc

2014-01-01

Objective The relationship between serum testosterone (T) levels, muscle mass and muscle force in eugonadal men is incompletely understood. As polymorphisms in the androgen receptor (AR) gene cause differences in androgen sensitivity, no straightforward correlation can be observed between the interindividual variation in T levels and different phenotypes. Therefore, we aim to investigate the relationship between genetic variations in the AR, circulating androgens and muscle mass and function in young healthy male siblings. Design 677 men (25–45 years) were recruited in a cross-sectional, population-based sibling pair study. Methods Relations between genetic variation in the AR gene (CAGn, GGNn, SNPs), sex steroid levels (by LC-MS/MS), body composition (by DXA), muscle cross-sectional area (CSA) (by pQCT), muscle force (isokinetic peak torque, grip strength) and anthropometrics were studied using linear mixed-effect modelling. Results Muscle mass and force were highly heritable and related to age, physical activity, body composition and anthropometrics. Total T (TT) and free T (FT) levels were positively related to muscle CSA, whereas estradiol (E2) and free E2 (FE2) concentrations were negatively associated with muscle force. Subjects with longer CAG repeat length had higher circulating TT, FT, and higher E2 and FE2 concentrations. Weak associations with TT and FT were found for the rs5965433 and rs5919392 SNP in the AR, whereas no association between GGN repeat polymorphism and T concentrations were found. Arm span and 2D:4D finger length ratio were inversely associated, whereas muscle mass and force were not associated with the number of CAG repeats. Conclusions Age, physical activity, body composition, sex steroid levels and anthropometrics are determinants of muscle mass and function in young men. Although the number of CAG repeats of the AR are related to sex steroid levels and anthropometrics, we have no evidence that these variations in the AR gene also affect muscle mass or function. PMID:24465978

Genetic variations in the androgen receptor are associated with steroid concentrations and anthropometrics but not with muscle mass in healthy young men.

PubMed

De Naeyer, Hélène; Bogaert, Veerle; De Spaey, Annelies; Roef, Greet; Vandewalle, Sara; Derave, Wim; Taes, Youri; Kaufman, Jean-Marc

2014-01-01

The relationship between serum testosterone (T) levels, muscle mass and muscle force in eugonadal men is incompletely understood. As polymorphisms in the androgen receptor (AR) gene cause differences in androgen sensitivity, no straightforward correlation can be observed between the interindividual variation in T levels and different phenotypes. Therefore, we aim to investigate the relationship between genetic variations in the AR, circulating androgens and muscle mass and function in young healthy male siblings. 677 men (25-45 years) were recruited in a cross-sectional, population-based sibling pair study. Relations between genetic variation in the AR gene (CAGn, GGNn, SNPs), sex steroid levels (by LC-MS/MS), body composition (by DXA), muscle cross-sectional area (CSA) (by pQCT), muscle force (isokinetic peak torque, grip strength) and anthropometrics were studied using linear mixed-effect modelling. Muscle mass and force were highly heritable and related to age, physical activity, body composition and anthropometrics. Total T (TT) and free T (FT) levels were positively related to muscle CSA, whereas estradiol (E2) and free E2 (FE2) concentrations were negatively associated with muscle force. Subjects with longer CAG repeat length had higher circulating TT, FT, and higher E2 and FE2 concentrations. Weak associations with TT and FT were found for the rs5965433 and rs5919392 SNP in the AR, whereas no association between GGN repeat polymorphism and T concentrations were found. Arm span and 2D:4D finger length ratio were inversely associated, whereas muscle mass and force were not associated with the number of CAG repeats. Age, physical activity, body composition, sex steroid levels and anthropometrics are determinants of muscle mass and function in young men. Although the number of CAG repeats of the AR are related to sex steroid levels and anthropometrics, we have no evidence that these variations in the AR gene also affect muscle mass or function.

Abnormalities in Skeletal Muscle Myogenesis, Growth, and Regeneration in Myotonic Dystrophy

PubMed Central

André, Laurène M.; Ausems, C. Rosanne M.; Wansink, Derick G.; Wieringa, Bé

2018-01-01

Myotonic dystrophy type 1 (DM1) and 2 (DM2) are autosomal dominant degenerative neuromuscular disorders characterized by progressive skeletal muscle weakness, atrophy, and myotonia with progeroid features. Although both DM1 and DM2 are characterized by skeletal muscle dysfunction and also share other clinical features, the diseases differ in the muscle groups that are affected. In DM1, distal muscles are mainly affected, whereas in DM2 problems are mostly found in proximal muscles. In addition, manifestation in DM1 is generally more severe, with possible congenital or childhood-onset of disease and prominent CNS involvement. DM1 and DM2 are caused by expansion of (CTG•CAG)n and (CCTG•CAGG)n repeats in the 3′ non-coding region of DMPK and in intron 1 of CNBP, respectively, and in overlapping antisense genes. This critical review will focus on the pleiotropic problems that occur during development, growth, regeneration, and aging of skeletal muscle in patients who inherited these expansions. The current best-accepted idea is that most muscle symptoms can be explained by pathomechanistic effects of repeat expansion on RNA-mediated pathways. However, aberrations in DNA replication and transcription of the DM loci or in protein translation and proteome homeostasis could also affect the control of proliferation and differentiation of muscle progenitor cells or the maintenance and physiological integrity of muscle fibers during a patient’s lifetime. Here, we will discuss these molecular and cellular processes and summarize current knowledge about the role of embryonic and adult muscle-resident stem cells in growth, homeostasis, regeneration, and premature aging of healthy and diseased muscle tissue. Of particular interest is that also progenitor cells from extramuscular sources, such as pericytes and mesoangioblasts, can participate in myogenic differentiation. We will examine the potential of all these types of cells in the application of regenerative medicine for muscular dystrophies and evaluate new possibilities for their use in future therapy of DM. PMID:29892259

Late-Onset Glycogen Storage Disease Type II (Pompe's Disease) with a Novel Mutation: A Malaysian Experience.

PubMed

Fu Liong, Hiew; Abdul Wahab, Siti Aishah; Yakob, Yusnita; Lock Hock, Ngu; Thong, Wong Kum; Viswanathan, Shanthi

2014-01-01

Pompe's disease (acid maltase deficiency, glycogen storage disease type II) is an autosomal recessive disorder caused by a deficiency of lysosomal acid α-1,4-glucosidase, resulting in excessive accumulation of glycogen in the lysosomes and cytoplasm of all tissues, most notably in skeletal muscles. We present a case of adult-onset Pompe's disease with progressive proximal muscles weakness over 5 years and respiratory failure on admission, requiring prolonged mechanical ventilation. Electromyography showed evidence of myopathic process with small amplitudes, polyphasic motor unit action potentials, and presence of pseudomyotonic discharges. Muscle biopsy showed glycogen-containing vacuoles in the muscle fibers consistent with glycogen storage disease. Genetic analysis revealed two compound heterozygous mutations at c.444C>G (p.Tyr148∗) in exon 2 and c.2238G>C (p.Trp746Cys) in exon 16, with the former being a novel mutation. This mutation has not been reported before, to our knowledge. The patient was treated with high protein diet during the admission and subsequently showed good clinical response to enzyme replacement therapy with survival now to the eighth year. Conclusion. In patients with late-onset adult Pompe's disease, careful evaluation and early identification of the disease and its treatment with high protein diet and enzyme replacement therapy improve muscle function and have beneficial impact on long term survival.

A shape prior-based MRF model for 3D masseter muscle segmentation

NASA Astrophysics Data System (ADS)

Majeed, Tahir; Fundana, Ketut; Lüthi, Marcel; Beinemann, Jörg; Cattin, Philippe

2012-02-01

Medical image segmentation is generally an ill-posed problem that can only be solved by incorporating prior knowledge. The ambiguities arise due to the presence of noise, weak edges, imaging artifacts, inhomogeneous interior and adjacent anatomical structures having similar intensity profile as the target structure. In this paper we propose a novel approach to segment the masseter muscle using the graph-cut incorporating additional 3D shape priors in CT datasets, which is robust to noise; artifacts; and shape deformations. The main contribution of this paper is in translating the 3D shape knowledge into both unary and pairwise potentials of the Markov Random Field (MRF). The segmentation task is casted as a Maximum-A-Posteriori (MAP) estimation of the MRF. Graph-cut is then used to obtain the global minimum which results in the segmentation of the masseter muscle. The method is tested on 21 CT datasets of the masseter muscle, which are noisy with almost all possessing mild to severe imaging artifacts such as high-density artifacts caused by e.g. the very common dental fillings and dental implants. We show that the proposed technique produces clinically acceptable results to the challenging problem of muscle segmentation, and further provide a quantitative and qualitative comparison with other methods. We statistically show that adding additional shape prior into both unary and pairwise potentials can increase the robustness of the proposed method in noisy datasets.

Overlapping features of polymyositis and inclusion body myositis in HIV-infected patients

PubMed Central

Lloyd, Thomas E.; Pinal-Fernandez, Iago; Michelle, E. Harlan; Christopher-Stine, Lisa; Pak, Katherine; Sacktor, Ned

2017-01-01

Objective: To characterize patients with myositis with HIV infection. Methods: All HIV-positive patients with myositis seen at the Johns Hopkins Myositis Center from 2003 to 2013 were included in this case series. Muscle biopsy features, weakness pattern, serum creatine kinase (CK) level, and anti–nucleotidase 1A (NT5C1A) status of HIV-positive patients with myositis were assessed. Results: Eleven of 1,562 (0.7%) patients with myositis were HIV-positive. Myositis was the presenting feature of HIV infection in 3 patients. Eight of 11 patients had weakness onset at age 45 years or less. The mean time from the onset of weakness to the diagnosis of myositis was 3.6 years (SD 3.2 years). The mean of the highest measured CK levels was 2,796 IU/L (SD 1,592 IU/L). On muscle biopsy, 9 of 10 (90%) had endomysial inflammation, 7 of 10 (70%) had rimmed vacuoles, and none had perifascicular atrophy. Seven of 11 (64%) patients were anti-NT5C1A-positive. Upon presentation, all had proximal and distal weakness. Five of 6 (83%) patients followed 1 year or longer on immunosuppressive therapy had improved proximal muscle strength. However, each eventually developed weakness primarily affecting wrist flexors, finger flexors, knee extensors, or ankle dorsiflexors. Conclusions: HIV-positive patients with myositis may present with some characteristic polymyositis features including young age at onset, very high CK levels, or proximal weakness that improves with treatment. However, all HIV-positive patients with myositis eventually develop features most consistent with inclusion body myositis, including finger and wrist flexor weakness, rimmed vacuoles on biopsy, or anti-NT5C1A autoantibodies. PMID:28283597

Functional correction of dystrophin actin binding domain mutations by genome editing

PubMed Central

Kyrychenko, Viktoriia; Kyrychenko, Sergii; Tiburcy, Malte; Shelton, John M.; Long, Chengzu; Schneider, Jay W.; Zimmermann, Wolfram-Hubertus; Bassel-Duby, Rhonda

2017-01-01

Dystrophin maintains the integrity of striated muscles by linking the actin cytoskeleton with the cell membrane. Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD) that result in progressive, debilitating muscle weakness, cardiomyopathy, and a shortened lifespan. Mutations of dystrophin that disrupt the amino-terminal actin-binding domain 1 (ABD-1), encoded by exons 2–8, represent the second-most common cause of DMD. In the present study, we compared three different strategies for CRISPR/Cas9 genome editing to correct mutations in the ABD-1 region of the DMD gene by deleting exons 3–9, 6–9, or 7–11 in human induced pluripotent stem cells (iPSCs) and by assessing the function of iPSC-derived cardiomyocytes. All three exon deletion strategies enabled the expression of truncated dystrophin protein and restoration of cardiomyocyte contractility and calcium transients to varying degrees. We show that deletion of exons 3–9 by genomic editing provides an especially effective means of correcting disease-causing ABD-1 mutations. These findings represent an important step toward eventual correction of common DMD mutations and provide a means of rapidly assessing the expression and function of internally truncated forms of dystrophin-lacking portions of ABD-1. PMID:28931764

Late onset of neutral lipid storage disease due to novel PNPLA2 mutations causing total loss of lipase activity in a patient with myopathy and slight cardiac involvement.

PubMed

Missaglia, Sara; Maggi, Lorenzo; Mora, Marina; Gibertini, Sara; Blasevich, Flavia; Agostoni, Piergiuseppe; Moro, Laura; Cassandrini, Denise; Santorelli, Filippo Maria; Gerevini, Simonetta; Tavian, Daniela

2017-05-01

Neutral lipid storage disease with myopathy (NLSDM) presents with skeletal muscle myopathy and severe dilated cardiomyopathy in nearly 40% of cases. NLSDM is caused by mutations in the PNPLA2 gene, which encodes the adipose triglyceride lipase (ATGL). Here we report clinical and genetic findings of a patient carrying two novel PNPLA2 mutations (c.696+4A>G and c.553_565delGTCCCCCTTCTCG). She presented at age 39 with right upper limb abduction weakness slowly progressing over the years with asymmetric involvement of proximal upper and lower limb muscles. Cardiological evaluation through ECG and heart echo scan was normal until the age 53, when mild left ventricular diastolic dysfunction was detected. Molecular analysis revealed that only one type of PNPLA2 transcript, with exon 5 skipping, was expressed in patient cells. Such aberrant mRNA causes the production of a shorter ATGL protein, lacking part of the catalytic domain. This is an intriguing case, displaying severe PNPLA2 mutations with clinical presentation characterized by slight cardiac impairment and full expression of severe asymmetric myopathy. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation.

PubMed

Ryu, Dongryeol; Zhang, Hongbo; Ropelle, Eduardo R; Sorrentino, Vincenzo; Mázala, Davi A G; Mouchiroud, Laurent; Marshall, Philip L; Campbell, Matthew D; Ali, Amir Safi; Knowels, Gary M; Bellemin, Stéphanie; Iyer, Shama R; Wang, Xu; Gariani, Karim; Sauve, Anthony A; Cantó, Carles; Conley, Kevin E; Walter, Ludivine; Lovering, Richard M; Chin, Eva R; Jasmin, Bernard J; Marcinek, David J; Menzies, Keir J; Auwerx, Johan

2016-10-19

Neuromuscular diseases are often caused by inherited mutations that lead to progressive skeletal muscle weakness and degeneration. In diverse populations of normal healthy mice, we observed correlations between the abundance of mRNA transcripts related to mitochondrial biogenesis, the dystrophin-sarcoglycan complex, and nicotinamide adenine dinucleotide (NAD + ) synthesis, consistent with a potential role for the essential cofactor NAD + in protecting muscle from metabolic and structural degeneration. Furthermore, the skeletal muscle transcriptomes of patients with Duchene's muscular dystrophy (DMD) and other muscle diseases were enriched for various poly[adenosine 5'-diphosphate (ADP)-ribose] polymerases (PARPs) and for nicotinamide N-methyltransferase (NNMT), enzymes that are major consumers of NAD + and are involved in pleiotropic events, including inflammation. In the mdx mouse model of DMD, we observed significant reductions in muscle NAD + levels, concurrent increases in PARP activity, and reduced expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD + biosynthesis. Replenishing NAD + stores with dietary nicotinamide riboside supplementation improved muscle function and heart pathology in mdx and mdx/Utr -/- mice and reversed pathology in Caenorhabditis elegans models of DMD. The effects of NAD + repletion in mdx mice relied on the improvement in mitochondrial function and structural protein expression (α-dystrobrevin and δ-sarcoglycan) and on the reductions in general poly(ADP)-ribosylation, inflammation, and fibrosis. In combination, these studies suggest that the replenishment of NAD + may benefit patients with muscular dystrophies or other neuromuscular degenerative conditions characterized by the PARP/NNMT gene expression signatures. Copyright © 2016, American Association for the Advancement of Science.

Gitelman's Syndrome Presenting with Hypocalcaemia - A Case Report.

PubMed

Cader, F A; Kabir, A; Mayedah, R; Masud, M S; Quadir, F; Hossen, M N

2015-04-01

Gitelman's syndrome is an autosomal recessive renal tubular disorder characterized by severe hypomagnesaemia, hypokalaemia, metabolic alkalosis and hypocalcaemia. It is caused by defective NaCl transport in the Distal Convoluted Tubule and presents in adolescence or adulthood, with a distinctly more benign course than Bartter's Syndrome. The dominant clinical features are muscle weakness, fatigue, carpopedal spasm, cramps and tetany. We report the case of a 26 year old male who presented with flaccid quadriparesis and carpopedal spasms, hypokalaemia, hypomagnesaemia, hypocalcaemia and severe urinary magnesium wasting. He was treated with potassium and magnesium supplementation and regained full function of all limbs.

Razi's description and treatment of facial paralysis.

PubMed

Tabatabaei, Seyed Mahmood; Kalantar Hormozi, Abdoljalil; Asadi, Mohsen

2011-01-01

In the modern medical era, facial paralysis is linked with the name of Charles Bell. This disease, which is usually unilateral and is a peripheral facial palsy, causes facial muscle weakness in the affected side. Bell gave a complete description of the disease; but historically other physicians had described it several hundred years prior although it had been ignored for different reasons, such as the difficulty of the original text language. The first and the most famous of these physicians who described this disease was Mohammad Ibn Zakaryya Razi (Rhazes). In this article, we discuss his opinion.

Primary Lateral Sclerosis.

PubMed

Statland, Jeffrey M; Barohn, Richard J; Dimachkie, Mazen M; Floeter, Mary Kay; Mitsumoto, Hiroshi

2015-11-01

Primary lateral sclerosis is characterized by insidious onset of progressive upper motor neuron dysfunction in the absence of clinical signs of lower motor neuron involvement. Patients experience stiffness; decreased balance and coordination; mild weakness; and, if the bulbar region is affected, difficulty speaking and swallowing, and emotional lability. The diagnosis is made based on clinical history, typical examination findings, and diagnostic testing negative for other causes of upper motor neuron dysfunction. Electromyogram is normal, or only shows mild neurogenic findings in a few muscles, not meeting El Escorial criteria. Treatment is largely supportive. Copyright © 2015 Elsevier Inc. All rights reserved.

Contractile properties and sarcoplasmic reticulum calcium content in type I and type II skeletal muscle fibres in active aged humans

PubMed Central

Lamboley, C R; Wyckelsma, V L; Dutka, T L; McKenna, M J; Murphy, R M; Lamb, G D

2015-01-01

This study examined the contractile properties and sarcoplasmic reticulum (SR) Ca2+ content in mechanically skinned vastus lateralis muscle fibres of Old (70 ± 4 years) and Young (22 ± 3 years) humans to investigate whether changes in muscle fibre properties contribute to muscle weakness in old age. In type II fibres of Old subjects, specific force was reduced by ∼17% and Ca2+ sensitivity was also reduced (pCa50 decreased ∼0.05 pCa units) relative to that in Young. S-Glutathionylation of fast troponin I (TnIf) markedly increased Ca2+ sensitivity in type II fibres, but the increase was significantly smaller in Old versus Young (+0.136 and +0.164 pCa unit increases, respectively). Endogenous and maximal SR Ca2+ content were significantly smaller in both type I and type II fibres in Old subjects. In fibres of Young, the SR could be nearly fully depleted of Ca2+ by a combined caffeine and low Mg2+ stimulus, whereas in fibres of Old the amount of non-releasable Ca2+ was significantly increased (by > 12% of endogenous Ca2+ content). Western blotting showed an increased proportion of type I fibres in Old subjects, and increased amounts of calsequestrin-2 and calsequestrin-like protein. The findings suggest that muscle weakness in old age is probably attributable in part to (i) an increased proportion of type I fibres, (ii) a reduction in both maximum specific force and Ca2+ sensitivity in type II fibres, and also a decreased ability of S-glutathionylation of TnIf to counter the fatiguing effects of metabolites on Ca2+ sensitivity, and (iii) a reduction in the amount of releasable SR Ca2+ in both fibre types. Key points Muscle weakness in old age is due in large part to an overall loss of skeletal muscle tissue, but it remains uncertain how much also stems from alterations in the properties of the individual muscle fibres. This study examined the contractile properties and amount of stored intracellular calcium in single muscle fibres of Old (70 ± 4 years) and Young (22 ± 3 years) adults. The maximum level of force production (per unit cross-sectional area) in fast twitch fibres in Old subjects was lower than in Young subjects, and the fibres were also less sensitive to activation by calcium. The amount of calcium stored inside muscle fibres and available to trigger contraction was also lower in both fast- and slow-twitch muscle fibres in the Old subjects. These findings indicate that muscle weakness in old age stems in part from an impaired capacity for force production in the individual muscle fibres. PMID:25809942

Contractile properties and sarcoplasmic reticulum calcium content in type I and type II skeletal muscle fibres in active aged humans.

PubMed

Lamboley, C R; Wyckelsma, V L; Dutka, T L; McKenna, M J; Murphy, R M; Lamb, G D

2015-06-01

Muscle weakness in old age is due in large part to an overall loss of skeletal muscle tissue, but it remains uncertain how much also stems from alterations in the properties of the individual muscle fibres. This study examined the contractile properties and amount of stored intracellular calcium in single muscle fibres of Old (70 ± 4 years) and Young (22 ± 3 years) adults. The maximum level of force production (per unit cross-sectional area) in fast twitch fibres in Old subjects was lower than in Young subjects, and the fibres were also less sensitive to activation by calcium. The amount of calcium stored inside muscle fibres and available to trigger contraction was also lower in both fast- and slow-twitch muscle fibres in the Old subjects. These findings indicate that muscle weakness in old age stems in part from an impaired capacity for force production in the individual muscle fibres. This study examined the contractile properties and sarcoplasmic reticulum (SR) Ca(2+) content in mechanically skinned vastus lateralis muscle fibres of Old (70 ± 4 years) and Young (22 ± 3 years) humans to investigate whether changes in muscle fibre properties contribute to muscle weakness in old age. In type II fibres of Old subjects, specific force was reduced by ∼17% and Ca(2+) sensitivity was also reduced (pCa50 decreased ∼0.05 pCa units) relative to that in Young. S-Glutathionylation of fast troponin I (TnIf ) markedly increased Ca(2+) sensitivity in type II fibres, but the increase was significantly smaller in Old versus Young (+0.136 and +0.164 pCa unit increases, respectively). Endogenous and maximal SR Ca(2+) content were significantly smaller in both type I and type II fibres in Old subjects. In fibres of Young, the SR could be nearly fully depleted of Ca(2+) by a combined caffeine and low Mg(2+) stimulus, whereas in fibres of Old the amount of non-releasable Ca(2+) was significantly increased (by > 12% of endogenous Ca(2+) content). Western blotting showed an increased proportion of type I fibres in Old subjects, and increased amounts of calsequestrin-2 and calsequestrin-like protein. The findings suggest that muscle weakness in old age is probably attributable in part to (i) an increased proportion of type I fibres, (ii) a reduction in both maximum specific force and Ca(2+) sensitivity in type II fibres, and also a decreased ability of S-glutathionylation of TnIf to counter the fatiguing effects of metabolites on Ca(2+) sensitivity, and (iii) a reduction in the amount of releasable SR Ca(2+) in both fibre types. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Amino Acid Sensing in Skeletal Muscle

PubMed Central

Moro, Tatiana; Ebert, Scott M.; Adams, Christopher M.; Rasmussen, Blake B.

2016-01-01

Aging impairs skeletal muscle protein synthesis, leading to muscle weakness and atrophy. However, the underlying molecular mechanisms remain poorly understood. Here, we review evidence that mTORC1- and ATF4-mediated amino acid sensing pathways, triggered by impaired amino acid delivery to aged skeletal muscle, may play important roles in skeletal muscle aging. Interventions that alleviate age-related impairments in muscle protein synthesis, strength and/or muscle mass appear to do so by reversing age-related changes in skeletal muscle amino acid delivery, mTORC1 activity and/or ATF4 activity. An improved understanding of the mechanisms and roles of amino acid sensing pathways in skeletal muscle may lead to evidence-based strategies to attenuate sarcopenia. PMID:27444066

Gait or Walking Problems

MedlinePlus

... be frank and upfront with your PT about cost, payment plans, and the benefits you can expect from therapy. Weakness Muscle weakness ... medical equipment) may be available through private or public insurance, community ... benefits if you have done military service. Reimbursement programs ...

Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study

PubMed Central

2012-01-01

Background Due partly to physicians’ unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults, and mapped out the distribution and severity of muscle weakness, and the sequence of involvement of the individual muscle groups. Furthermore, we defined the natural disease course and identified prognostic factors for disease progression. Methods We conducted a single-center, prospective, observational study. Muscle strength (manual muscle testing, and hand-held dynamometry), muscle function (quick motor function test), and pulmonary function (forced vital capacity in sitting and supine positions) were assessed every 3–6 months and analyzed using repeated-measures ANOVA. Results Between October 2004 and August 2009, 94 patients aged between 25 and 75 years were included in the study. Although skeletal muscle weakness was typically distributed in a limb-girdle pattern, many patients had unfamiliar features such as ptosis (23%), bulbar weakness (28%), and scapular winging (33%). During follow-up (average 1.6 years, range 0.5-4.2 years), skeletal muscle strength deteriorated significantly (mean declines of −1.3% point/year for manual muscle testing and of −2.6% points/year for hand-held dynamometry; both p<0.001). Longer disease duration (>15 years) and pulmonary involvement (forced vital capacity in sitting position <80%) at study entry predicted faster decline. On average, forced vital capacity in supine position deteriorated by 1.3% points per year (p=0.02). Decline in pulmonary function was consistent across subgroups. Ten percent of patients declined unexpectedly fast. Conclusions Recognizing patterns of common and less familiar characteristics in adults with Pompe disease facilitates timely diagnosis. Longer disease duration and reduced pulmonary function stand out as predictors of rapid disease progression, and aid in deciding whether to initiate enzyme replacement therapy, or when. PMID:23147228

Bit-1 is an essential regulator of myogenic differentiation

PubMed Central

Griffiths, Genevieve S.; Doe, Jinger; Jijiwa, Mayumi; Van Ry, Pam; Cruz, Vivian; de la Vega, Michelle; Ramos, Joe W.; Burkin, Dean J.; Matter, Michelle L.

2015-01-01

Muscle differentiation requires a complex signaling cascade that leads to the production of multinucleated myofibers. Genes regulating the intrinsic mitochondrial apoptotic pathway also function in controlling cell differentiation. How such signaling pathways are regulated during differentiation is not fully understood. Bit-1 (also known as PTRH2) mutations in humans cause infantile-onset multisystem disease with muscle weakness. We demonstrate here that Bit-1 controls skeletal myogenesis through a caspase-mediated signaling pathway. Bit-1-null mice exhibit a myopathy with hypotrophic myofibers. Bit-1-null myoblasts prematurely express muscle-specific proteins. Similarly, knockdown of Bit-1 expression in C2C12 myoblasts promotes early differentiation, whereas overexpression delays differentiation. In wild-type mice, Bit-1 levels increase during differentiation. Bit-1-null myoblasts exhibited increased levels of caspase 9 and caspase 3 without increased apoptosis. Bit-1 re-expression partially rescued differentiation. In Bit-1-null muscle, Bcl-2 levels are reduced, suggesting that Bcl-2-mediated inhibition of caspase 9 and caspase 3 is decreased. Bcl-2 re-expression rescued Bit-1-mediated early differentiation in Bit-1-null myoblasts and C2C12 cells with knockdown of Bit-1 expression. These results support an unanticipated yet essential role for Bit-1 in controlling myogenesis through regulation of Bcl-2. PMID:25770104

2pBAb5. Validation of three-dimensional strain tracking by volumetric ultrasound image correlation in a pubovisceral muscle model

PubMed Central

Nagle, Anna S.; Nageswaren, Ashok R.; Haridas, Balakrishna; Mast, T. D.

2014-01-01

Little is understood about the biomechanical changes leading to pelvic floor disorders such as stress urinary incontinence. In order to measure regional biomechanical properties of the pelvic floor muscles in vivo, a three dimensional (3D) strain tracking technique employing correlation of volumetric ultrasound images has been implemented. In this technique, local 3D displacements are determined as a function of applied stress and then converted to strain maps. To validate this approach, an in vitro model of the pubovisceral muscle, with a hemispherical indenter emulating the downward stress caused by intra-abdominal pressure, was constructed. Volumetric B-scan images were recorded as a function of indenter displacement while muscle strain was measured independently by a sonomicrometry system (Sonometrics). Local strains were computed by ultrasound image correlation and compared with sonomicrometry-measured strains to assess strain tracking accuracy. Image correlation by maximizing an exponential likelihood function was found more reliable than the Pearson correlation coefficient. Strain accuracy was dependent on sizes of the subvolumes used for image correlation, relative to characteristic speckle length scales of the images. Decorrelation of echo signals was mapped as a function of indenter displacement and local tissue orientation. Strain measurement accuracy was weakly related to local echo decorrelation. PMID:24900165

Anti-Heat Shock Protein 70 antibody levels are increased in myasthenia gravis and Guillain-Barré syndrome.

PubMed

Helgeland, Geir; Petzold, Axel; Hoff, Jana Midelfart; Gilhus, Nils Erik; Plant, Gordon T; Romi, Fredrik Robert

2010-08-25

Myasthenia gravis (MG) is an autoimmune disorder where patients develop autoantibodies towards skeletal muscle proteins (e.g. acetylcholine receptor and muscle specific kinase), causing weakness in striated muscles. Ocular MG (OMG) represents a subtype of (MG) affecting only the periocular muscles. The pathogenesis of this phenotype remains unclear. Heat Shock Protein 70 (Hsp70) plays a role in immune regulation. Antibodies against this protein are associated with several autoimmune diseases, and its biological significance has been shown in vivo. We have therefore examined the concentration of anti-Hsp70 antibodies in sera from 35 OMG patients and 94 patients with generalized MG (GMG) using ELISA assays. The antibody concentrations were compared to those in patients with multiple sclerosis (MS), Guillain-Barré syndrome (GBS) and to healthy controls. MG patients had significantly higher anti-Hsp70 antibody concentrations than both MS patients and healthy controls. GBS patients had higher antibody levels than all other groups. No difference in antibody levels was found when comparing OMG and GMG. Our results suggest that patients with MG and GBS have a previous or current increased exposure to Hsp70 antigens. The similarity between GMG and OMG strengthens the hypothesis that OMG represents a systemic disease, similar to GMG. Copyright 2010 Elsevier B.V. All rights reserved.

Molecular Mechanisms of Treadmill Therapy on Neuromuscular Atrophy Induced via Botulinum Toxin A

PubMed Central

Tsai, Sen-Wei; Chen, Hsiao-Ling

2013-01-01

Botulinum toxin A (BoNT-A) is a bacterial zinc-dependent endopeptidase that acts specifically on neuromuscular junctions. BoNT-A blocks the release of acetylcholine, thereby decreasing the ability of a spastic muscle to generate forceful contraction, which results in a temporal local weakness and the atrophy of targeted muscles. BoNT-A-induced temporal muscle weakness has been used to manage skeletal muscle spasticity, such as poststroke spasticity, cerebral palsy, and cervical dystonia. However, the combined effect of treadmill exercise and BoNT-A treatment is not well understood. We previously demonstrated that for rats, following BoNT-A injection in the gastrocnemius muscle, treadmill running improved the recovery of the sciatic functional index (SFI), muscle contraction strength, and compound muscle action potential (CMAP) amplitude and area. Treadmill training had no influence on gastrocnemius mass that received BoNT-A injection, but it improved the maximal contraction force of the gastrocnemius, and upregulation of GAP-43, IGF-1, Myo-D, Myf-5, myogenin, and acetylcholine receptor (AChR) subunits α and β was found following treadmill training. Taken together, these results suggest that the upregulation of genes associated with neurite and AChR regeneration following treadmill training may contribute to enhanced gastrocnemius strength recovery following BoNT-A injection. PMID:24327926

A study of muscle involvement in scrub typhus.

PubMed

Kalita, Jayantee; Misra, Usha K; Mani, Vinita E; Mahadevan, Anita; Shankar, Susrala K

2015-01-15

Patients with scrub typhus often complain of myalgia, but a comprehensive study on muscle dysfunction is lacking. We therefore report the clinical, electromyographic and muscle biopsy findings in patients with scrub typhus. Consecutive patients with scrub typhus were included, and their clinical and laboratory findings were noted. The patients with myalgia or weakness and elevated serum creatine kinase (CK) were considered to have muscle involvement. Electromyography (EMG) and muscle biopsy were done in some patients. Patients were treated with doxycycline 200mg daily for 7 days, and their clinical and biochemical outcome on discharge and one month were evaluated. 13 out of 33 (39.4%) patients had muscle involvement and their CK levels ranged between 287 and 3166 (859 ± 829) U/L. EMG revealed short duration polyphasic potentials, and muscle histopathology revealed evidence of vasculitis. There were significant correlations between severity of weakness and CK levels (r = -0.6; p < 0.001), platelet counts (r = 0.4; p = 0.04), duration of illness (r = -0.4; p = 0.01) and disability on discharge (r = -0.4; p = 0.04). Patients with muscle involvement had more severe illness evidenced by a lower Glasgow Coma Scale score (p < 0.001), thrombocytopenia (p = 0.05) and greater disability on discharge (p = 0.007), when compared to those without muscle involvement. All the patients had complete recovery following doxycycline therapy, and CK levels also normalized. Muscle dysfunction was present in 39% patients with scrub typhus. Although muscle histopathology showed evidence of vasculitis, patients responded to doxycycline. Copyright © 2014 Elsevier B.V. All rights reserved.

Peroneus quartus and functional ankle instability.

PubMed

Lotito, G; Pruvost, J; Collado, H; Coudreuse, J-M; Bensoussan, L; Curvale, G; Viton, J-M; Delarque, A

2011-07-01

Physical and rehabilitation medicine physicians commonly see patients with chronic functional ankle instability. The main anatomical structures involved in ankle stability are the peroneus (fibularis) brevis and peroneus longus muscles. Several anatomical muscle-tendon variations have been described in the literature as being sometimes responsible for this instability, the peroneus quartus muscle being the most frequent. The objective of this clinical study is to discuss the implication of the bilateral peroneus quartus muscle in functional ankle instability. This 26-year-old patient was seen in PM&R consultation for recurrent episodes of lateral ankle sprains. The clinical examination found a moderate hyperlaxity on the right side in bilateral ankle varus. We also noted a bilateral weakness of the peroneus muscles. Additional imaging examinations showed a supernumerary bilateral peroneus quartus. The electroneuromyogram of the peroneus muscles was normal. In the literature the incidence of a supernumerary peroneus quartus muscle varies from 0 to 21.7%. Most times this muscle is asymptomatic and is only fortuitously discovered. However some cases of chronic ankle pain or instability have been reported in the literature. It seems relevant to discuss, around the clinical case of this patient, the impact of this muscle on ankle instability especially when faced with lingering weakness of the peroneus brevis and longus muscles in spite of eccentric strength training and in the absence of any neurological impairment. One of the hypotheses, previously described in the literature, would be the overcrowding effect resulting in a true conflict by reducing the available space for the peroneal muscles in the peroneal sheath. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Non-weight bearing-induced muscle weakness: the role of myosin quantity and quality in MHC type II fibers.

PubMed

Kim, Jong-Hee; Thompson, LaDora V

2014-07-15

We tested the hypothesis that non-weight bearing-induced muscle weakness (i.e., specific force) results from decreases in myosin protein quantity (i.e., myosin content per half-sarcomere and the ratio of myosin to actin) and quality (i.e., force per half-sarcomere and population of myosin heads in the strong-binding state during muscle contraction) in single myosin heavy chain (MHC) type II fibers. Fisher-344 rats were assigned to weight-bearing control (Con) or non-weight bearing (NWB). The NWB rats were hindlimb unloaded for 2 wk. Diameter, force, and MHC content were determined in permeabilized single fibers from the semimembranosus muscle. MHC isoform and the ratio of MHC to actin in each fiber were determined by gel electrophoresis and silver staining techniques. The structural distribution of myosin from spin-labeled fiber bundles during maximal isometric contraction was evaluated using electron paramagnetic resonance spectroscopy. Specific force (peak force per cross-sectional area) in MHC type IIB and IIXB fibers from NWB was significantly reduced by 38% and 18%, respectively. MHC content per half-sarcomere was significantly reduced by 21%. Two weeks of hindlimb unloading resulted in a reduced force per half-sarcomere of 52% and fraction of myosin strong-binding during contraction of 34%. The results suggest that reduced myosin and actin content (quantity) and myosin quality concomitantly contribute to non-weight bearing-related muscle weakness. Copyright © 2014 the American Physiological Society.

Current and emerging treatment strategies for Duchenne muscular dystrophy

PubMed Central

Mah, Jean K

2016-01-01

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. It is caused by mutations of the DMD gene, leading to progressive muscle weakness, loss of independent ambulation by early teens, and premature death due to cardiorespiratory complications. The diagnosis can usually be made after careful review of the history and examination of affected boys presenting with developmental delay, proximal weakness, and elevated serum creatine kinase, plus confirmation by muscle biopsy or genetic testing. Precise characterization of the DMD mutation is important for genetic counseling and individualized treatment. Current standard of care includes the use of corticosteroids to prolong ambulation and to delay the onset of secondary complications. Early use of cardioprotective agents, noninvasive positive pressure ventilation, and other supportive strategies has improved the life expectancy and health-related quality of life for many young adults with DMD. New emerging treatment includes viral-mediated microdystrophin gene replacement, exon skipping to restore the reading frame, and nonsense suppression therapy to allow translation and production of a modified dystrophin protein. Other potential therapeutic targets involve upregulation of compensatory proteins, reduction of the inflammatory cascade, and enhancement of muscle regeneration. So far, data from DMD clinical trials have shown limited success in delaying disease progression; unforeseen obstacles included immune response against the generated mini-dystrophin, inconsistent evidence of dystrophin production in muscle biopsies, and failure to demonstrate a significant improvement in the primary outcome measure, as defined by the 6-minute walk test in some studies. The long-term safety and efficacy of emerging treatments will depend on the selection of appropriate clinical end points and sensitive biomarkers to detect meaningful changes in disease progression. Correction of the underlying mutations using new gene-editing technologies and corticosteroid analogs with better safety profiles offers renewed hope for many individuals with DMD and their families. PMID:27524897

Surgical fasciectomy of the trapezius muscle combined with neurolysis of the Spinal accessory nerve; results and long-term follow-up in 30 consecutive cases of refractory chronic whiplash syndrome

PubMed Central

2010-01-01

Background Chronic problems from whiplash trauma generally include headache, pain and neck stiffness that may prove refractory to conservative treatment modalities. As has previously been reported, such afflicted patients may experience significant temporary relief with injections of local anesthetic to painful trigger points in muscles of the shoulder and neck, or lasting symptomatic improvement through surgical excision of myofascial trigger points. In a subset of patients who present with chronic whiplash syndrome, the clinical findings suggest an affliction of the spinal accessory nerve (CN XI, SAN) by entrapment under the fascia of the trapezius muscle. The present study was undertaken to assess the effectiveness of SAN neurolysis in chronic whiplash syndrome. Methods A standardized questionnaire and a linear visual-analogue scale graded 0-10 was used to assess disability related to five symptoms (pain, headache, insomnia, weakness, and stiffness) before, and one year after surgery in a series of thirty consecutive patients. Results The preoperative duration of symptoms ranged from seven months to 13 years. The following changes in disability scores were documented one year after surgery: Overall pain decreased from 9.5 +/- 0.9 to 3.2 +/- 2.6 (p < 0.001); headaches from 8.2 +/- 2.9 to 2.3 +/- 2.8 (p < 0.001); insomnia from 7.5 +/- 2.4 to 3.8 +/- 2.8 (p < 0.001); weakness from 7.6 +/- 2.6 to 3.6 +/- 2.8 (p < 0.001); and stiffness from 7.0 +/- 3.2 to 2.6 +/- 2.7 (p < 0.001). Conclusions Entrapment of the spinal accessory nerve and/or chronic compartment syndrome of the trapezius muscle may cause chronic debilitating pain after whiplash trauma, without radiological or electrodiagnostic evidence of injury. In such cases, surgical treatment may provide lasting relief. PMID:20374624

Rapamycin and Chloroquine: The In Vitro and In Vivo Effects of Autophagy-Modifying Drugs Show Promising Results in Valosin Containing Protein Multisystem Proteinopathy

PubMed Central

Nalbandian, Angèle; Llewellyn, Katrina J.; Nguyen, Christopher; Yazdi, Puya G.; Kimonis, Virginia E.

2015-01-01

Mutations in the valosin containing protein (VCP) gene cause hereditary Inclusion body myopathy (hIBM) associated with Paget disease of bone (PDB), frontotemporal dementia (FTD), more recently termed multisystem proteinopathy (MSP). Affected individuals exhibit scapular winging and die from progressive muscle weakness, and cardiac and respiratory failure, typically in their 40s to 50s. Histologically, patients show the presence of rimmed vacuoles and TAR DNA-binding protein 43 (TDP-43)-positive large ubiquitinated inclusion bodies in the muscles. We have generated a VCPR155H/+ mouse model which recapitulates the disease phenotype and impaired autophagy typically observed in patients with VCP disease. Autophagy-modifying agents, such as rapamycin and chloroquine, at pharmacological doses have previously shown to alter the autophagic flux. Herein, we report results of administration of rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, and chloroquine, a lysosomal inhibitor which reverses autophagy by accumulating in lysosomes, responsible for blocking autophagy in 20-month old VCPR155H/+ mice. Rapamycin-treated mice demonstrated significant improvement in muscle performance, quadriceps histological analysis, and rescue of ubiquitin, and TDP-43 pathology and defective autophagy as indicated by decreased protein expression levels of LC3-I/II, p62/SQSTM1, optineurin and inhibiting the mTORC1 substrates. Conversely, chloroquine-treated VCPR155H/+ mice revealed progressive muscle weakness, cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies and increased LC3-I/II, p62/SQSTM1, and optineurin expression levels. Our in vitro patient myoblasts studies treated with rapamycin demonstrated an overall improvement in the autophagy markers. Targeting the mTOR pathway ameliorates an increasing list of disorders, and these findings suggest that VCP disease and related neurodegenerative multisystem proteinopathies can now be included as disorders that can potentially be ameliorated by rapalogs. PMID:25884947

Association between isometric muscle strength and gait joint kinetics in adolescents and young adults with cerebral palsy.

PubMed

Dallmeijer, A J; Baker, R; Dodd, K J; Taylor, N F

2011-03-01

The purpose of this study was to determine the association between isometric muscle strength of the lower limbs and gait joint kinetics in adolescents and young adults with cerebral palsy (CP). Twenty-five participants (11 males) with bilateral spastic CP, aged 14-22 years (mean: 18.9, sd: 2.0 yr) and Gross Motor Function Classification System (GMFCS) level II (n=19) and III (n=6) were tested. Hand held dynamometry was used to measure isometric strength (expressed in Nm/kg) of the hip, knee, and ankle muscles using standardized testing positions and procedures. 3D gait analysis was performed with a VICON system to calculate joint kinetics in the hip, knee and ankle during gait. Ankle peak moments exceeded by far the levels of isometric strength of the plantar flexors, while the knee and hip peak moments were just at or below maximal isometric strength of knee and hip muscles. Isometric muscle strength showed weak to moderate correlations with peak ankle and hip extension moment and power during walking. Despite considerable muscle weakness, joint moment curves were similar to norm values. Results suggest that passive stretch of the muscle-tendon complex of the triceps surae contributes to the ankle moment during walking and that muscle strength assessment may provide additional information to gait kinetics. Copyright © 2010 Elsevier B.V. All rights reserved.

Exercise capacity, muscle strength and fatigue in sarcoidosis.

PubMed

Marcellis, R G J; Lenssen, A F; Elfferich, M D P; De Vries, J; Kassim, S; Foerster, K; Drent, M

2011-09-01

The aim of this case-control study was to investigate the prevalence of exercise intolerance, muscle weakness and fatigue in sarcoidosis patients. Additionally, we evaluated whether fatigue can be explained by exercise capacity, muscle strength or other clinical characteristics (lung function tests, radiographic stages, prednisone usage and inflammatory markers). 124 sarcoidosis patients (80 males) referred to the Maastricht University Medical Centre (Maastricht, the Netherlands) were included (mean age 46.6±10.2 yrs). Patients performed a 6-min walk test (6MWT) and handgrip force (HGF), elbow flexor muscle strength (EFMS), quadriceps peak torque (QPT) and hamstring peak torque (HPT) tests. Maximal inspiratory pressure (P(I,max)) was recorded. All patients completed the Fatigue Assessment Scale (FAS) questionnaire. The 6MWT was reduced in 45% of the population, while HGF, EFMS, QPT and HPT muscle strength were reduced in 15, 12, 27 and 18%, respectively. P(I,max) was reduced in 43% of the population. The majority of the patients (81%) reported fatigue (FAS ≥22). Patients with reduced peripheral muscle strength of the upper and/or lower extremities were more fatigued and demonstrated impaired lung functions, fat-free mass, P(I,max), 6MWT and quality of life. Fatigue was neither predicted by exercise capacity, nor by muscle strength. Besides fatigue, exercise intolerance and muscle weakness are frequent problems in sarcoidosis. We therefore recommend physical tests in the multidisciplinary management of sarcoidosis patients, even in nonfatigued patients.

A prospective pilot study measuring muscle volumetric change in amyotrophic lateral sclerosis.

PubMed

Jenkins, Thomas M; Burness, Christine; Connolly, Daniel J; Rao, D Ganesh; Hoggard, Nigel; Mawson, Susan; McDermott, Christopher J; Wilkinson, Iain D; Shaw, Pamela J

2013-09-01

Our objective was to investigate the potential of muscle volume, measured with magnetic resonance (MR), as a biomarker to quantify disease progression in patients with amyotrophic lateral sclerosis (ALS). In this longitudinal pilot study, we first sought to determine the stability of volumetric muscle MR measurements in 11 control subjects at two time-points. We assessed feasibility of detecting atrophy in four patients with ALS, followed at three-month intervals for 12 months. Muscle power and MR volume were measured in thenar eminence (TEm), first dorsal interosseous (1DIO), tibialis anterior (TA) and tongue. Changes over time were assessed using linear regression models and t-tests. Results demonstrated that, in controls, no volumetric MR changes were seen (mean volume variation in all muscles < 5%, p > 0.1). In patients, between-subject heterogeneity was identified. Trends for volume loss were found in TEm (mean, - 26.84%, p = 0.056) and TA (- 8.29%, p = 0.077), but not in 1DIO (- 18.47%, p = 0.121) or tongue (< 5%, p = 0.367). In conclusion, volumetric muscle MR appears a stable measure in controls, and progressive volume loss was demonstrable in individuals with ALS in whom clinical weakness progressed. In this small study, subclinical atrophy was not demonstrable using muscle MR. Clinico-radiological discordance between muscle weakness and MR atrophy could reflect a contribution of upper motor neuron pathology.

Effects of bedding systems selected by manual muscle testing on sleep and sleep-related respiratory disturbances.

PubMed

Tsai, Ling-Ling; Liu, Hau-Min

2008-03-01

In this study, we investigated the feasibility of applying manual muscle testing (MMT) for bedding selection and examined the bedding effect on sleep. Four lay testers with limited training in MMT performed muscle tests for the selection of the bedding systems from five different mattresses and eight different pillows for 14 participants with mild sleep-related respiratory disturbances. For each participant individually, two bedding systems-one inducing stronger muscle forces and the other inducing weaker forces-were selected. The tester-participant pairs showed 85% and 100% agreement, respectively, for the selection of mattresses and pillows that induced the strongest muscle forces. The firmness of the mattress and the height of the pillow were significantly correlated with the body weight and body mass index of the participants for the selected strong bedding system but not for the weak bedding system. Finally, differences were observed between the strong and the weak bedding systems with regard to sleep-related respiratory disturbances and the percentage of slow-wave sleep. It was concluded that MMT can be performed by inexperienced testers for the selection of bedding systems.

Neurological manifestations in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis in the Amazon.

PubMed

Dias, G A S; Yoshikawa, G T; Koyama, R V L; Fujihara, S; Martins, L C S; Medeiros, R; Quaresma, J A S; Fuzii, H T

2016-02-01

A cross-sectional observational study was conducted. The aim was to analyze the clinical-functional profile of patients diagnosed with HTLV-1 (human T-lymphotropic virus type 1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in the Amazon region. Reference center for HTLV in the city of Belém, state of Pará, Brazil. Muscle strength, muscle tone, balance and the need for gait assistance among patients with HAM/TSP were evaluated. Among the 82 patients infected with HTLV-1, 27 (10 men and 17 women) were diagnosed with HAM/TSP. No statistically significant difference in muscle tone or strength was found between the lower limbs. Muscle weakness and spasticity were predominant in the proximal lower limbs. Patients with HAM/TSP are at a high risk of falls (P=0.03), and predominantly use either a cane or a crutch on one side as a gait-assistance device (P=0.02). Patients with HAM/TSP exhibit a similar clinical pattern of muscle weakness and spasticity, with a high risk of falls, requiring gait-assistance devices.

[New insights of myositis-specific and -associated autoantibodies in juvenile and adult type myositis].

PubMed

Váncsa, Andrea; Dankó, Katalin

2016-07-01

Myositis, which means inflammation of the muscles, is a general term used for inflammatory myopathies. Myositis is a rare idiopathic autoimmune disease. It is believed that environmental factors such as virus, bacteria, parasites, direct injuries, drugs side effect can trigger the immune system of genetically susceptible individuals to act against muscle tissues. There are several types of myositis with the same systemic symptoms such as muscle weakness, fatigue, muscle pain and inflammation. These include dermatomyositis, juvenile dermatomyositis, inclusion-body myositis, polymyositis, orbital myositis and myositis ossificans. Juvenile and adult dermatomyositis are chronic, immune-mediated inflammatory myopathies characterized by progressive proximal muscle weakness and typical skin symptoms. The aim of the authors was to compare the symptoms, laboratory and serological findings and disease course in children and adult patients with idiopathic inflammatory myopathy. Early diagnosis and aggressive immunosuppressive treatment improve the mortality of these patients. Myositis-specific autoantibodies have predictive and prognostic values regarding the associated overlap disease, response to treatment and disease course. The authors intend to lighten the clinical and pathogenetic significance of the new target autoantigens. Orv. Hetil., 2016, 157(29), 1179-1184.

NONBACTERIAL MYOSITIS

PubMed Central

Crum-Cianflone, Nancy F.

2010-01-01

Infectious myositis is defined as an infection of a skeletal muscle. Infectious myositis is most commonly caused by bacteria; however, a variety of viral, parasitic, and fungal agents may also cause myositis. The pathogenesis of nonbacterial infectious myositis is via direct infection of the musculature or immune mechanisms. Symptoms typically include muscular pain, tenderness, swelling, and/or weakness. The diagnosis of the specific microbe is often suggested by the presence of concordant clinical signs and symptoms, a detailed medical/travel history, and laboratory data. For example, immunocompromised hosts have a heightened risk of fungal myositis, whereas the presence of a travel history to an endemic location and/or eosinophilia may suggest a parasitic cause. Definitive diagnosis requires detecting the organism by specific laboratory testing including serologies, histopathology, and/or cultures. Treatment entails antimicrobial agents against the pathogen, with consideration for surgical drainage for focal purulent collections within the musculature. PMID:21308520

Muscle Weakness in the Empty and Full Can Tests Cannot Differentiate Rotator Cuff Tear from Cervical Spondylotic Amyotrophy: Pain Provocation is a Useful Finding.

PubMed

Iwata, Eiichiro; Shigematsu, Hideki; Inoue, Kazuya; Egawa, Takuya; Sakamoto, Yoshihiro; Tanaka, Yasuhito

2017-01-01

Rotator cuff tears and cervical spondylotic amyotrophy (CSA) are often confused as the main symptom in those with difficulty in shoulder elevation. Empty and full can tests are frequently used for the clinical diagnosis of rotator cuff tears. The aim of the present study was to investigate whether the empty and full can test results can help differentiate rotator cuff tears from CSA. Twenty-seven consecutive patients with rotator cuff tears and 25 with CSA were enrolled. We prospectively performed empty and full can tests in patients with rotator cuff tears and CSA. The following signs were considered positive: (a) muscle weakness during the empty can test, (b) muscle weakness during the full can test, (c) pain provocation during the empty can test, and (d) pain provocation during the full can test. We calculated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of rotator cuff tears for each positive finding. The sensitivity and specificity of each index were as follows (sensitivity, specificity, PPV, NPV): (a) 77.8%, 0%, 45.7%, 0%; (b) 66.7%, 4.0%, 42.9%, 10.0%; (c) 88.9%, 96.0%, 96.0%, 88.9%; and (d) 74.1%, 96.0%, 95.2%, 77.4%. There were significant differences for each index. Muscle weakness during the empty and full can tests was not useful in differentiating rotator cuff tears from CSA because of low specificity and PPV. However, pain provocation was useful in differentiating these two conditions because of high specificity and PPV.

Pathophysiology and immunological profile of myasthenia gravis and its subgroups.

PubMed

Romi, Fredrik; Hong, Yu; Gilhus, Nils Erik

2017-12-01

Myasthenia gravis (MG) is an autoimmune antibody-mediated disease characterized by muscle weakness and fatigability. It is believed that the initial steps triggering humoral immunity in MG take place inside thymic tissue and thymoma. The immune response against one or several epitopes expressed on thymic tissue cells spills over to neuromuscular junction components sharing the same epitope causing humoral autoimmunity and antibody production. The main cause of MG is acetylcholine receptor antibodies. However, many other neuromuscular junction membrane protein targets, intracellular and extracellular proteins are suggested to participate in MG pathophysiology. MG should be divided into subgroups based on clinical presentation and immunology. This includes onset age, clinical characteristics, thymic pathology and antibody profile. The immunological profile of these subgroups is determined by the antibodies present. Copyright © 2017. Published by Elsevier Ltd.

An analysis of postoperative thigh symptoms after minimally invasive transpsoas lumbar interbody fusion.

PubMed

Cummock, Matthew D; Vanni, Steven; Levi, Allan D; Yu, Yong; Wang, Michael Y

2011-07-01

The minimally invasive transpsoas interbody fusion technique requires dissection through the psoas muscle, which contains the nerves of the lumbosacral plexus posteriorly and genitofemoral nerve anteriorly. Retraction of the psoas is becoming recognized as a cause of transient postoperative thigh pain, numbness, paresthesias, and weakness. However, few reports have described the nature of thigh symptoms after this procedure. The authors performed a review of patients who underwent the transpsoas technique for lumbar spondylotic disease, disc degeneration, and spondylolisthesis treated at a single academic medical center. A review of patient charts, including the use of detailed patient-driven pain diagrams performed at equal preoperative and follow-up intervals, investigated the survival of postoperative thigh pain, numbness, paresthesias, and weakness of the iliopsoas and quadriceps muscles in the follow-up period on the ipsilateral side of the surgical approach. Over a 3.2-year period, 59 patients underwent transpsoas interbody fusion surgery. Of these, 62.7% had thigh symptoms postoperatively. New thigh symptoms at first follow-up visit included the following: burning, aching, stabbing, or other pain (39.0%); numbness (42.4%); paresthesias (11.9%); and weakness (23.7%). At 3 months postoperatively, these percentages decreased to 15.5%, 24.1%, 5.6%, and 11.3%, respectively. Within the patient sample, 44% underwent a 1-level, 41% a 2-level, and 15% a 3-level transpsoas operation. While not statistically significant, thigh pain, numbness, and weakness were most prevalent after L4-5 transpsoas interbody fusion at the first postoperative follow-up. The number of lumbar levels that were surgically treated had no clear association with thigh symptoms but did correlate directly with surgical time, intraoperative blood loss, and length of hospital stay. Transpsoas interbody fusion is associated with high rates of immediate postoperative thigh symptoms. While larger, prospective studies are necessary to validate these findings, the authors found that half of the patients had symptom resolution at approximately 3 months postoperatively and more than 90% by 1 year.

Differential involvement of forearm muscles in ALS does not relate to sonographic structural nerve alterations.

PubMed

Schreiber, Stefanie; Schreiber, Frank; Debska-Vielhaber, Grazyna; Garz, Cornelia; Hensiek, Nathalie; Machts, Judith; Abdulla, Susanne; Dengler, Reinhard; Petri, Susanne; Nestor, Peter J; Vielhaber, Stefan

2018-07-01

We aimed to assess whether differential peripheral nerve involvement parallels dissociated forearm muscle weakness in amyotrophic lateral sclerosis (ALS). The analysis comprised 41 ALS patients and 18 age-, sex-, height- and weight-matched healthy controls. Strength of finger-extension and -flexion was measured using the Medical Research Council (MRC) scale. Radial, median and ulnar nerve sonographic cross-sectional area (CSA) and echogenicity, expressed by the hypoechoic fraction (HF), were determined. In ALS, finger extensors were significantly weaker than finger flexors. Sonographic evaluation revealed peripheral nerve atrophy, affecting various nerve segments in ALS. HF was unaltered. This systematic study confirmed a long-observed physical examination finding in ALS - weakness in finger-extension out of proportion to finger-flexion. This phenomenon was not related to any particular sonographic pattern of upper limb peripheral nerve alteration. In ALS, dissociated forearm muscle weakness could aid in the disease's diagnosis. Nerve ultrasound did not provide additional information on the differential involvement of finger-extension and finger-flexion strength. Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Motor polyradiculopathy during pembrolizumab treatment of metastatic melanoma.

PubMed

Sepúlveda, Maria; Martinez-Hernandez, Eugenia; Gaba, Lydia; Victoria, Ivan; Sola-Valls, Nuria; Falgàs, Neus; Casanova-Molla, Jordi; Graus, Francesc

2017-12-01

Pembrolizumab, a monoclonal antibody directed against the immune checkpoint programmed cell death-1 receptor (PD-1), has improved survival in patients with advanced melanoma. Neuromuscular immune-mediated side effects have been rarely reported. We describe a 44-year-old man with metastatic melanoma who presented with progressive muscle weakness after 23 doses of pembrolizumab. The patient developed asymmetric, proximal muscle weakness and atrophy in all four limbs. Cerebrospinal fluid examination showed albuminocytologic dissociation. MRI revealed contrast enhancement of the lumbosacral roots. Electrodiagnostic studies demonstrated widespread fibrillation potentials in all four limbs, suggesting a generalized motor polyradiculopathy. Despite pembrolizumab discontinuation and treatment with steroids and intravenous immunoglobulin, limb weakness worsened. Electrodiagnostic studies were repeated, and showed marked and diffuse axonal motor damage. Seven weeks after clinical onset the patient was treated with plasma exchanges. He showed no further deterioration. We report a severe motor polyradiculopathy associated with an anti-PD-1 agent that expands the spectrum of neuromuscular complications of this class of drugs. Muscle Nerve 56: E162-E167, 2017. © 2017 Wiley Periodicals, Inc.

Alanyl-tRNA synthetase mutation in a family with dominant distal hereditary motor neuropathy

PubMed Central

Zhao, Z.; Hashiguchi, A.; Sakiyama, Y.; Okamoto, Y.; Tokunaga, S.; Zhu, L.; Shen, H.; Takashima, H.

2012-01-01

Objective: To identify a new genetic cause of distal hereditary motor neuropathy (dHMN), which is also known as a variant of Charcot-Marie-Tooth disease (CMT), in a Chinese family. Methods: We investigated a Chinese family with dHMN clinically, electrophysiologically, and genetically. We screened for the mutations of 28 CMT or related pathogenic genes using an originally designed microarray resequencing DNA chip. Results: Investigation of the family history revealed an autosomal dominant transmission pattern. The clinical features of the family included mild weakness and wasting of the distal muscles of the lower limb and foot deformity, without clinical sensory involvement. Electrophysiologic studies revealed motor neuropathy. MRI of the lower limbs showed accentuated fatty infiltration of the gastrocnemius and vastus lateralis muscles. All 4 affected family members had a heterozygous missense mutation c.2677G>A (p.D893N) of alanyl-tRNA synthetase (AARS), which was not found in the 4 unaffected members and control subjects. Conclusion: An AARS mutation caused dHMN in a Chinese family. AARS mutations result in not only a CMT phenotype but also a dHMN phenotype. PMID:22573628

Simultaneous cranioplasty and subdural-peritoneal shunting for contralateral symptomatic subdural hygroma following decompressive craniectomy.

PubMed

Lin, Muh-Shi; Chen, Tzu-Hsuan; Kung, Woon-Man; Chen, Shuo-Tsung

2015-01-01

Contralateral subdural hygroma caused by decompressive craniectomy tends to combine with external cerebral herniation, causing neurological deficits. Nine patients who underwent one-stage, simultaneous cranioplasty and contralateral subdural-peritoneal shunting were included in this study. Clinical outcome was assessed by Glasgow Outcome Scale as well as Glasgow Coma Scale, muscle power scoring system, and complications. Postoperative computed tomography scans demonstrated completely resolved subdural hygroma and reversed midline shifts, indicating excellent outcome. Among these 9 patients, 4 patients (44%) had improved GOS following the proposed surgery. Four out of 4 patients with lethargy became alert and orientated following surgical intervention. Muscle strength improved significantly 5 months after surgery in 7 out of 7 patients with weakness. Two out of 9 patients presented with drowsiness due to hydrocephalus at an average time of 65 days after surgery. Double gradient shunting is useful to eliminate the respective hydrocephalus and contralateral subdural hygroma. The described surgical technique is effective in treating symptomatic contralateral subdural hygroma following decompressive craniectomy and is associated with an excellent structural and functional outcome. However, subdural-peritoneal shunting plus cranioplasty thoroughly resolves the subdural hygroma collection, which might deteriorate the cerebrospinal fluid circulation, leading to hydrocephalus.

Exercise at Different Ages and Appendicular Lean Mass and Strength in Later Life: Results From the Berlin Aging Study II.

PubMed

Eibich, Peter; Buchmann, Nikolaus; Kroh, Martin; Wagner, Gert G; Steinhagen-Thiessen, Elisabeth; Demuth, Ilja; Norman, Kristina

2016-04-01

Excessive loss of muscle mass in advanced age is a major risk factor for decreased physical ability and falls. Physical activity and exercise training are typically recommended to maintain muscle mass and prevent weakness. How exercise in different stages of life relates to muscle mass, grip strength, and risk for weakness in later life is not well understood. Baseline data on 891 participants at least 60 years old from the Berlin Aging Study II (BASE-II) were analyzed. Linear and logistic regressions of self-reported exercise in early adulthood, old age, or both on appendicular lean mass (ALM), grip strength, and a risk indicator for weakness (ALM/ body mass index cutoff) were calculated. In addition, treatment bounds are analyzed to address potential confounding using a method proposed by Oster. Analyses indicate that for men only, continuous exercise is significantly associated with higher muscle mass (SD = 0.24, p < .001), grip strength (SD = 0.18, p < .05), and lower risk for clinically relevant low muscle mass (odds ratio = 0.36, p < .01). Exercise in early adulthood alone is not significantly associated with muscle mass or strength. No significant associations were observed for women. The results of the current study underscore the importance of health programs to promote physical activity with a focus on young adults, a group known to be affected from environmentally associated decline of physical activity, and to promote the continuation of physical exercise from early adulthood into later life in general. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice.

PubMed

Murphy, Kate T; Chee, Annabel; Gleeson, Ben G; Naim, Timur; Swiderski, Kristy; Koopman, René; Lynch, Gordon S

2011-09-01

Cancer cachexia describes the progressive skeletal muscle wasting and weakness in many cancer patients and accounts for >20% of cancer-related deaths. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the atrophy and loss of function in muscles of tumor-bearing mice. Twelve-week-old C57BL/6 mice received a subcutaneous injection of saline (control) or Lewis lung carcinoma (LLC) tumor cells. One week later, mice received either once weekly injections of saline (control, n = 12; LLC, n = 9) or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg·kg⁻¹·wk⁻¹, LLC+PF-354, n = 11) for 5 wk. Injection of LLC cells reduced muscle mass and maximum force of tibialis anterior (TA) muscles by 8-10% (P < 0.05), but the muscle atrophy and weakness were prevented with PF-354 treatment (P > 0.05). Maximum specific (normalized) force of diaphragm muscle strips was reduced with LLC injection (P < 0.05) but was not improved with PF-354 treatment (P > 0.05). PF-354 enhanced activity of oxidative enzymes in TA and diaphragm muscles of tumor-bearing mice by 118% and 89%, respectively (P < 0.05). Compared with controls, apoptosis that was not of myofibrillar or satellite cell origin was 140% higher in TA muscle cross sections from saline-treated LLC tumor-bearing mice (P < 0.05) but was not different in PF-354-treated tumor-bearing mice (P > 0.05). Antibody-directed myostatin inhibition attenuated the skeletal muscle atrophy and loss of muscle force-producing capacity in a murine model of cancer cachexia, in part by reducing apoptosis. The improvements in limb muscle mass and function highlight the therapeutic potential of antibody-directed myostatin inhibition for cancer cachexia.

Correlation between Ribosome Biogenesis and the Magnitude of Hypertrophy in Overloaded Skeletal Muscle.

PubMed

Nakada, Satoshi; Ogasawara, Riki; Kawada, Shigeo; Maekawa, Takahiro; Ishii, Naokata

2016-01-01

External loads applied to skeletal muscle cause increases in the protein translation rate, which leads to muscle hypertrophy. Although some studies have demonstrated that increases in the capacity and efficiency of translation are involved in this process, it remains unclear how these two factors are related to the magnitude of muscle hypertrophy. The present study aimed to clarify the roles played by the capacity and efficiency of translation in muscle hypertrophy. We used an improved synergist ablation in which the magnitude of compensatory hypertrophy could be controlled by partial removal of synergist muscles. Male rats were assigned to four groups in which the plantaris muscle was unilaterally subjected to weak (WK), moderate (MO), middle (MI), and strong (ST) overloading by four types of synergist ablation. Fourteen days after surgery, the weight of the plantaris muscle per body weight increased by 8%, 22%, 32% and 45%, in the WK, MO, MI and ST groups, respectively. Five days after surgery, 18+28S rRNA content (an indicator of translational capacity) increased with increasing overload, with increases of 1.8-fold (MO), 2.2-fold (MI), and 2.5-fold (ST), respectively, relative to non-overloaded muscle (NL) in the WK group. rRNA content showed a strong correlation with relative muscle weight measured 14 days after surgery (r = 0.98). The phosphorylated form of p70S6K (a positive regulator of translational efficiency) showed a marked increase in the MO group, but no further increase was observed with further increase in overload (increases of 22.6-fold (MO), 17.4-fold (MI), and 18.2-fold (ST), respectively, relative to NL in the WK group). These results indicate that increases in ribosome biogenesis at the early phase of overloading are strongly dependent on the amount of overloading, and may play an important role in increasing the translational capacity for further gain of muscular size.

AT1 receptor blocker losartan protects against mechanical ventilation-induced diaphragmatic dysfunction

PubMed Central

Kwon, Oh Sung; Smuder, Ashley J.; Wiggs, Michael P.; Hall, Stephanie E.; Sollanek, Kurt J.; Morton, Aaron B.; Talbert, Erin E.; Toklu, Hale Z.; Tumer, Nihal

2015-01-01

Mechanical ventilation is a life-saving intervention for patients in respiratory failure. Unfortunately, prolonged ventilator support results in diaphragmatic atrophy and contractile dysfunction leading to diaphragm weakness, which is predicted to contribute to problems in weaning patients from the ventilator. While it is established that ventilator-induced oxidative stress is required for the development of ventilator-induced diaphragm weakness, the signaling pathway(s) that trigger oxidant production remain unknown. However, recent evidence reveals that increased plasma levels of angiotensin II (ANG II) result in oxidative stress and atrophy in limb skeletal muscles. Using a well-established animal model of mechanical ventilation, we tested the hypothesis that increased circulating levels of ANG II are required for both ventilator-induced diaphragmatic oxidative stress and diaphragm weakness. Cause and effect was determined by administering an angiotensin-converting enzyme inhibitor (enalapril) to prevent ventilator-induced increases in plasma ANG II levels, and the ANG II type 1 receptor antagonist (losartan) was provided to prevent the activation of ANG II type 1 receptors. Enalapril prevented the increase in plasma ANG II levels but did not protect against ventilator-induced diaphragmatic oxidative stress or diaphragm weakness. In contrast, losartan attenuated both ventilator-induced oxidative stress and diaphragm weakness. These findings indicate that circulating ANG II is not essential for the development of ventilator-induced diaphragm weakness but that activation of ANG II type 1 receptors appears to be a requirement for ventilator-induced diaphragm weakness. Importantly, these experiments provide the first evidence that the Food and Drug Administration-approved drug losartan may have clinical benefits to protect against ventilator-induced diaphragm weakness in humans. PMID:26359481

Respiratory muscle training increases respiratory muscle strength and reduces respiratory complications after stroke: a systematic review.

PubMed

Menezes, Kênia Kp; Nascimento, Lucas R; Ada, Louise; Polese, Janaine C; Avelino, Patrick R; Teixeira-Salmela, Luci F

2016-07-01

After stroke, does respiratory muscle training increase respiratory muscle strength and/or endurance? Are any benefits carried over to activity and/or participation? Does it reduce respiratory complications? Systematic review of randomised or quasi-randomised trials. Adults with respiratory muscle weakness following stroke. Respiratory muscle training aimed at increasing inspiratory and/or expiratory muscle strength. Five outcomes were of interest: respiratory muscle strength, respiratory muscle endurance, activity, participation and respiratory complications. Five trials involving 263 participants were included. The mean PEDro score was 6.4 (range 3 to 8), showing moderate methodological quality. Random-effects meta-analyses showed that respiratory muscle training increased maximal inspiratory pressure by 7 cmH2O (95% CI 1 to 14) and maximal expiratory pressure by 13 cmH2O (95% CI 1 to 25); it also decreased the risk of respiratory complications (RR 0.38, 95% CI 0.15 to 0.96) compared with no/sham respiratory intervention. Whether these effects carry over to activity and participation remains uncertain. This systematic review provided evidence that respiratory muscle training is effective after stroke. Meta-analyses based on five trials indicated that 30minutes of respiratory muscle training, five times per week, for 5 weeks can be expected to increase respiratory muscle strength in very weak individuals after stroke. In addition, respiratory muscle training is expected to reduce the risk of respiratory complications after stroke. Further studies are warranted to investigate whether the benefits are carried over to activity and participation. PROSPERO (CRD42015020683). [Menezes KKP, Nascimento LR, Ada L, Polese JC, Avelino PR, Teixeira-Salmela LF (2016) Respiratory muscle training increases respiratory muscle strength and reduces respiratory complications after stroke: a systematic review.Journal of Physiotherapy62: 138-144]. Copyright © 2016 Australian Physiotherapy Association. Published by Elsevier B.V. All rights reserved.

Prominent subcutaneous oedema as a masquerading symptom of an underlying inflammatory myopathy.

PubMed

Anantharajah, Anthea; Vucic, Steve; Tarafdar, Surjit; Vongsuvanh, Roslyn; Wilcken, Nicholas; Swaminathan, Sanjay

2017-02-01

The inflammatory myopathies are a group of immune-mediated inflammatory muscle disorders that typically present with marked proximal muscle weakness. We report four cases of inflammatory myopathies with marked subcutaneous oedema as their main complaint. Three of the four patients had normal or low levels of creatine kinase, an enzyme often markedly elevated in these disorders. Magnetic resonance imaging of the muscles, followed by a muscle biopsy were used to make a definitive diagnosis. © 2017 Royal Australasian College of Physicians.

Muscle-specific kinase-antibody-positive myasthenia gravis after autologous bone marrow transplantation.

PubMed

Grover, Kavita Mohindra; Sripathi, Naganand; Elias, Stanton Bernard

2012-03-01

A 44-year-old man presented with oculobulbar weakness approximately 5 years after autologous bone marrow transplantation (BMT). His workup led to the diagnosis of muscle-specific kinase-antibody-related myasthenia gravis (MG). There has been only one case report of muscle-specific kinase-antibody-positive MG after BMT, which was allogeneic. We report the first case of autologous BMT-associated MG with muscle-specific kinase antibody. The pathogenic mechanisms of immune dysregulation leading to MG after BMT are discussed.

Impaired Organization and Function of Myofilaments in Single Muscle Fibers from a Mouse Model of Pompe Disease

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

Xu, S.; Galperin, M; Melvin, G

Pompe disease, a deficiency of lysosomal acid {alpha}-glucosidase, is a disorder of glycogen metabolism that can affect infants, children, or adults. In all forms of the disease, there is progressive muscle pathology leading to premature death. The pathology is characterized by accumulation of glycogen in lysosomes, autophagic buildup, and muscle atrophy. The purpose of the present investigation was to determine if myofibrillar dysfunction in Pompe disease contributes to muscle weakness beyond that attributed to atrophy. The study was performed on isolated myofibers dissected from severely affected fast glycolytic muscle in the {alpha}-glucosidase knockout mouse model. Psoas muscle fibers were firstmore » permeabilized, so that the contractile proteins could be directly relaxed or activated by control of the composition of the bathing solution. When normalized by cross-sectional area, single fibers from knockout mice produced 6.3 N/cm{sup 2} of maximum Ca{sup 2+}-activated tension compared with 12.0 N/cm{sup 2} produced by wild-type fibers. The total protein concentration was slightly higher in the knockout mice, but concentrations of the contractile proteins myosin and actin remained unchanged. Structurally, X-ray diffraction showed that the actin and myosin filaments, normally arranged in hexagonal arrays, were disordered in the knockout muscle, and a lower fraction of myosin cross bridges was near the actin filaments in the relaxed muscle. The results are consistent with a disruption of actin and myosin interactions in the knockout muscles, demonstrating that impaired myofibrillar function contributes to weakness in the diseased muscle fibers.« less

Human spinal cord injury: motor unit properties and behaviour.

PubMed

Thomas, C K; Bakels, R; Klein, C S; Zijdewind, I

2014-01-01

Spinal cord injury (SCI) results in widespread variation in muscle function. Review of motor unit data shows that changes in the amount and balance of excitatory and inhibitory inputs after SCI alter management of motoneurons. Not only are units recruited up to higher than usual relative forces when SCI leaves few units under voluntary control, the force contribution from recruitment increases due to elevation of twitch/tetanic force ratios. Force gradation and precision are also coarser with reduced unit numbers. Maximal unit firing rates are low in hand muscles, limiting voluntary strength, but are low, normal or high in limb muscles. Unit firing rates during spasms can exceed voluntary rates, emphasizing that deficits in descending drive limit force production. SCI also changes muscle properties. Motor unit weakness and fatigability seem universal across muscles and species, increasing the muscle weakness that arises from paralysis of units, motoneuron death and sensory impairment. Motor axon conduction velocity decreases after human SCI. Muscle contractile speed is also reduced, which lowers the stimulation frequencies needed to grade force when paralysed muscles are activated with patterned electrical stimulation. This slowing does not necessarily occur in hind limb muscles after cord transection in cats and rats. The nature, duration and level of SCI underlie some of these species differences, as do variations in muscle function, daily usage, tract control and fibre-type composition. Exploring this diversity is important to promote recovery of the hand, bowel, bladder and locomotor function most wanted by people with SCI. © 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

[Clinical features and ETFDH mutations of children with late-onset glutaric aciduria type II: a report of two cases].

PubMed

Cheng, Yan-Yang; Tang, Yue; Liu, Ao-Jie; Wei, Li; Lin, Lan; Zhang, Jing; Zhi, Liang

2017-09-01

To investigate the clinical and genetic features of two families with late-onset glutaric aciduria type II caused by ETFDH mutations. Target gene sequence capture and next generation sequencing were used for sequencing of suspected patients and their family members. The patients' clinical features were retrospectively analyzed and literature review was performed. The probands of the two families had a clinical onset at the ages of 10 years and 5.5 years respectively, with the clinical manifestations of muscle weakness and muscle pain. Laboratory examinations revealed significant increases in the serum levels of creatine kinase, creatine kinase-MB, and lactate dehydrogenase. Tandem mass spectrometry showed increases in various types of acylcarnitines. The analysis of urine organic acids showed an increase in glutaric acid. Electromyography showed myogenic damage in both patients. Gene detection showed two novel mutations in the ETFDH gene (c.1331T>C from the mother and c.824C>T from the father) in patient 1, and the patient's younger brother carried the c.1331T>C mutation but had a normal phenotype. In patient 2, there was a novel mutation (c.177insT from the father) and a known mutation (c.1474T>C from the mother) in the ETFDH gene. Several family members carried such mutations. Both patients were diagnosed with glutaric aciduria type II. Their symptoms were improved after high-dose vitamin B2 treatment. For patients with unexplained muscle weakness and pain, serum creatine kinase, acylcarnitines, and urinary organic acids should be measured, and the possibility of glutaric aciduria type II should be considered. Genetic detection is helpful to make a confirmed diagnosis.

Predictive Values of the New Sarcopenia Index by the Foundation for the National Institutes of Health Sarcopenia Project for Mortality among Older Korean Adults.

PubMed

Moon, Joon Ho; Kim, Kyoung Min; Kim, Jung Hee; Moon, Jae Hoon; Choi, Sung Hee; Lim, Soo; Lim, Jae-Young; Kim, Ki Woong; Park, Kyong Soo; Jang, Hak Chul

2016-01-01

We evaluated the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project's recommended criteria for sarcopenia's association with mortality among older Korean adults. We conducted a community-based prospective cohort study which included 560 (285 men and 275 women) older Korean adults aged ≥65 years. Muscle mass (appendicular skeletal muscle mass-to-body mass index ratio (ASM/BMI)), handgrip strength, and walking velocity were evaluated in association with all-cause mortality during 6-year follow-up. Both the lowest quintile for each parameter (ethnic-specific cutoff) and FNIH-recommended values were used as cutoffs. Forty men (14.0%) and 21 women (7.6%) died during 6-year follow-up. The deceased subjects were older and had lower ASM, handgrip strength, and walking velocity. Sarcopenia defined by both low lean mass and weakness had a 4.13 (95% CI, 1.69-10.11) times higher risk of death, and sarcopenia defined by a combination of low lean mass, weakness, and slowness had a 9.56 (3.16-28.90) times higher risk of death after adjusting for covariates in men. However, these significant associations were not observed in women. In terms of cutoffs of each parameter, using the lowest quintile showed better predictive values in mortality than using the FNIH-recommended values. Moreover, new muscle mass index, ASM/BMI, provided better prognostic values than ASM/height2 in all associations. New sarcopenia definition by FNIH was better able to predict 6-year mortality among Korean men. Moreover, ethnic-specific cutoffs, the lowest quintile for each parameter, predicted the higher risk of mortality than the FNIH-recommended values.

Predictive Values of the New Sarcopenia Index by the Foundation for the National Institutes of Health Sarcopenia Project for Mortality among Older Korean Adults

PubMed Central

Kim, Jung Hee; Moon, Jae Hoon; Choi, Sung Hee; Lim, Soo; Lim, Jae-Young; Kim, Ki Woong; Park, Kyong Soo; Jang, Hak Chul

2016-01-01

Objective We evaluated the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project’s recommended criteria for sarcopenia’s association with mortality among older Korean adults. Methods We conducted a community-based prospective cohort study which included 560 (285 men and 275 women) older Korean adults aged ≥65 years. Muscle mass (appendicular skeletal muscle mass-to-body mass index ratio (ASM/BMI)), handgrip strength, and walking velocity were evaluated in association with all-cause mortality during 6-year follow-up. Both the lowest quintile for each parameter (ethnic-specific cutoff) and FNIH-recommended values were used as cutoffs. Results Forty men (14.0%) and 21 women (7.6%) died during 6-year follow-up. The deceased subjects were older and had lower ASM, handgrip strength, and walking velocity. Sarcopenia defined by both low lean mass and weakness had a 4.13 (95% CI, 1.69–10.11) times higher risk of death, and sarcopenia defined by a combination of low lean mass, weakness, and slowness had a 9.56 (3.16–28.90) times higher risk of death after adjusting for covariates in men. However, these significant associations were not observed in women. In terms of cutoffs of each parameter, using the lowest quintile showed better predictive values in mortality than using the FNIH-recommended values. Moreover, new muscle mass index, ASM/BMI, provided better prognostic values than ASM/height2 in all associations. Conclusions New sarcopenia definition by FNIH was better able to predict 6-year mortality among Korean men. Moreover, ethnic-specific cutoffs, the lowest quintile for each parameter, predicted the higher risk of mortality than the FNIH-recommended values. PMID:27832145

The effect of bedding system selected by manual muscle testing on sleep-related cardiovascular functions.

PubMed

Kuo, Terry B J; Li, Jia-Yi; Lai, Chun-Ting; Huang, Yu-Chun; Hsu, Ya-Chuan; Yang, Cheryl C H

2013-01-01

Different types of mattresses affect sleep quality and waking muscle power. Whether manual muscle testing (MMT) predicts the cardiovascular effects of the bedding system was explored using ten healthy young men. For each participant, two bedding systems, one inducing the strongest limb muscle force (strong bedding system) and the other inducing the weakest limb force (weak bedding system), were identified using MMT. Each bedding system, in total five mattresses and eight pillows of different firmness, was used for two continuous weeks at the participant's home in a random and double-blind sequence. A sleep log, a questionnaire, and a polysomnography were used to differentiate the two bedding systems. Heart rate variability and arterial pressure variability analyses showed that the strong bedding system resulted in decreased cardiovascular sympathetic modulation, increased cardiac vagal activity, and increased baroreceptor reflex sensitivity during sleep as compared to the weak bedding system. Different bedding systems have distinct cardiovascular effects during sleep that can be predicted by MMT.

The Effect of Bedding System Selected by Manual Muscle Testing on Sleep-Related Cardiovascular Functions

PubMed Central

Kuo, Terry B. J.; Li, Jia-Yi; Lai, Chun-Ting; Huang, Yu-Chun; Hsu, Ya-Chuan; Yang, Cheryl C. H.

2013-01-01

Background. Different types of mattresses affect sleep quality and waking muscle power. Whether manual muscle testing (MMT) predicts the cardiovascular effects of the bedding system was explored using ten healthy young men. Methods. For each participant, two bedding systems, one inducing the strongest limb muscle force (strong bedding system) and the other inducing the weakest limb force (weak bedding system), were identified using MMT. Each bedding system, in total five mattresses and eight pillows of different firmness, was used for two continuous weeks at the participant's home in a random and double-blind sequence. A sleep log, a questionnaire, and a polysomnography were used to differentiate the two bedding systems. Results and Conclusion. Heart rate variability and arterial pressure variability analyses showed that the strong bedding system resulted in decreased cardiovascular sympathetic modulation, increased cardiac vagal activity, and increased baroreceptor reflex sensitivity during sleep as compared to the weak bedding system. Different bedding systems have distinct cardiovascular effects during sleep that can be predicted by MMT. PMID:24371836

MUSCLE WEAKNESS, FATIGUE, AND TORQUE VARIABILITY: EFFECTS OF AGE AND MOBILITY STATUS

PubMed Central

KENT-BRAUN, JANE A.; CALLAHAN, DAMIEN M.; FAY, JESSICA L.; FOULIS, STEPHEN A.; BUONACCORSI, JOHN P.

2013-01-01

Introduction Whereas deficits in muscle function, particularly power production, develop in old age and are risk factors for mobility impairment, a complete understanding of muscle fatigue during dynamic contractions is lacking. We tested hypotheses related to torque-producing capacity, fatigue resistance, and variability of torque production during repeated maximal contractions in healthy older, mobility-impaired older, and young women. Methods Knee extensor fatigue (decline in torque) was measured during 4 min of dynamic contractions. Torque variability was characterized using a novel 4-component logistic regression model. Results Young women produced more torque at baseline and during the protocol than older women (P < 0.001). Although fatigue did not differ between groups (P = 0.53), torque variability differed by group (P = 0.022) and was greater in older impaired compared with young women (P = 0.010). Conclusions These results suggest that increased torque variability may combine with baseline muscle weakness to limit function, particularly in older adults with mobility impairments. PMID:23674266

Decreased bone mineral density in experimental myasthenia gravis in C57BL/6 mice.

PubMed

Oshima, Minako; Iida-Klein, Akiko; Maruta, Takahiro; Deitiker, Philip R; Atassi, M Zouhair

2017-09-01

Experimental autoimmune myasthenia gravis (EAMG), an animal model of myasthenia gravis (MG), can be induced in C57BL/6 (B6, H-2  b ) mice by 2-3 injections with Torpedo californica AChR (tAChR) in complete Freund's adjuvant. Some EAMG mice exhibit weight loss with muscle weakness. The loss in body weight, which is closely associated with bone structure, is particularly evident in EAMG mice with severe muscle weakness. However, the relationship between muscle weakness and bone loss in EAMG has not been studied before. Recent investigations on bone have shed light on association of bone health and immunological states. It is possible that muscle weakness in EAMG developed by anti-tAChR immune responses might accompany bone loss. We determined whether reduced muscle strength associates with decreased bone mineral density (BMD) in EAMG mice. EAMG was induced by two injections at 4-week interval of tAChR and adjuvants in two different age groups. The first tAChR injection was either at age 8 weeks or at 15 weeks. We measured BMD at three skeletal sites, including femur, tibia, and lumbar vertebrae, using dual energy X-ray absorptiometry. Among these bone areas, femur of EAMG mice in both age groups showed a significant decrease in BMD compared to control adjuvant-injected and to non-immunized mice. Reduction in BMD in induced EAMG at a later-age appears to parallel the severity of the disease. The results indicate that anti-tAChR autoimmune response alone can reduce bone density in EAMG mice. BMD reduction was also observed in adjuvant-injected mice in comparison to normal un-injected mice, suggesting that BMD decrease can occur even when muscle activity is normal. Decreased BMD observed in both tAChR-injected and adjuvant-injected mice groups were discussed in relation to innate immunity and bone-related immunology involving activated T cells and tumour necrosis factor-related cytokines that trigger osteoclastogenesis and bone loss.

Molecular and cell-based therapies for muscle degenerations: a road under construction.

PubMed

Berardi, Emanuele; Annibali, Daniela; Cassano, Marco; Crippa, Stefania; Sampaolesi, Maurilio

2014-01-01

Despite the advances achieved in understanding the molecular biology of muscle cells in the past decades, there is still need for effective treatments of muscular degeneration caused by muscular dystrophies and for counteracting the muscle wasting caused by cachexia or sarcopenia. The corticosteroid medications currently in use for dystrophic patients merely help to control the inflammatory state and only slightly delay the progression of the disease. Unfortunately, walkers and wheel chairs are the only options for such patients to maintain independence and walking capabilities until the respiratory muscles become weak and the mechanical ventilation is needed. On the other hand, myostatin inhibition, IL-6 antagonism and synthetic ghrelin administration are examples of promising treatments in cachexia animal models. In both dystrophies and cachectic syndrome the muscular degeneration is extremely relevant and the translational therapeutic attempts to find a possible cure are well defined. In particular, molecular-based therapies are common options to be explored in order to exploit beneficial treatments for cachexia, while gene/cell therapies are mostly used in the attempt to induce a substantial improvement of the dystrophic muscular phenotype. This review focuses on the description of the use of molecular administrations and gene/stem cell therapy to treat muscular degenerations. It reviews previous trials using cell delivery protocols in mice and patients starting with the use of donor myoblasts, outlining the likely causes for their poor results and briefly focusing on satellite cell studies that raise new hope. Then it proceeds to describe recently identified stem/progenitor cells, including pluripotent stem cells and in relationship to their ability to home within a dystrophic muscle and to differentiate into skeletal muscle cells. Different known features of various stem cells are compared in this perspective, and the few available examples of their use in animal models of muscular degeneration are reported. Since non coding RNAs, including microRNAs (miRNAs), are emerging as prominent players in the regulation of stem cell fates we also provides an outline of the role of microRNAs in the control of myogenic commitment. Finally, based on our current knowledge and the rapid advance in stem cell biology, a prediction of clinical translation for cell therapy protocols combined with molecular treatments is discussed.