Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myostatin is a secreted protein that negatively regulates skeletal muscle mass determining both muscle fiber number and size. The myostatin pathway is conserved and regulates muscle mass in a number of animal species ranging from fish to humans. Inhibition of myostatin using a variety of therapeutic approaches can increase muscle mass in a number of animal models of human disease, including muscular dystrophy.
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PMID:Myostatin, a negative regulator of muscle mass: implications for muscle degenerative diseases. 1590 21

Progressive muscular dystrophy is a group of inherited disorders characterized by progressive skeletal muscle wasting and weakness, which is not of neurogenic origin. Myostatin, a new member of the TGF-beta super-family, is a negative regulator of skeletal muscle growth. To investigate the possible involvement of myostatin in the development of progressive muscular dystrophy, we cloned and sequenced myostatin cDNAs from the progressive muscular dystrophy patients by RT-PCR. Levels of myostatin mRNA and protein in the patients were analyzed by semi-quantitative RT-PCR and Western blot,respectively. We did not find any mutations in the myostatin cDNA sequences from the progressive muscular dystrophy patients in this study. However, we found that the levels of myostatin transcripts were reduced in some patients and the processing and maturation of myostatin protein were inhibited in some patients. Our data demonstrated that the pathogenesis of some types or subtypes of progressive muscular dystrophy is probably associated with the altered myostatin expression and the processing inhibition of myostatin protein.
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PMID:[Altered expression of myostatin gene in the progressive muscular dystrophy patients]. 1623 30

Dysferlin is expressed in skeletal and cardiac muscles. However, dysferlin deficiency results in skeletal muscle weakness, but spares the heart. We compared intraindividual mRNA expression profiles of cardiac and skeletal muscle in dysferlin-deficient SJL/J mice and found down-regulation of the complement inhibitor, decay-accelerating factor/CD55, in skeletal muscle only. This finding was confirmed on mRNA and protein levels in two additional dysferlin-deficient mouse strains, A/J mice and Dysf-/- mice, as well as in patients with dysferlin-deficient muscular dystrophy. In vitro, the absence of CD55 led to an increased susceptibility of human myotubes to complement attack. Evidence is provided that decay-accelerating factor/CD55 is regulated via the myostatin-SMAD pathway. In conclusion, a novel mechanism of muscle fiber injury in dysferlin-deficient muscular dystrophy is demonstrated, possibly opening therapeutic avenues in this to date untreatable disorder.
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PMID:Increased susceptibility to complement attack due to down-regulation of decay-accelerating factor/CD55 in dysferlin-deficient muscular dystrophy. 1623 20

Myostatin, or GDF-8 (growth and differentiation factor-8), was first identified through sequence identity with members of the BMP (bone morphogenetic protein)/TGF-beta (transforming growth factor-beta) superfamily. The skeletal-muscle-specific expression pattern of myostatin suggested a role in muscle development. Mice with a targeted deletion of the myostatin gene exhibit a hypermuscular phenotype. In addition, inactivating mutations in the myostatin gene have been identified in 'double muscled' cattle breeds, such as the Belgian Blue and Piedmontese, as well as in a hypermuscular child. These findings define myostatin as a negative regulator of skeletal-muscle development. Myostatin binds with high affinity to the receptor serine threonine kinase ActRIIB (activin type IIB receptor), which initiates signalling through a smad2/3-dependent pathway. In an effort to validate myostatin as a therapeutic target in a post-embryonic setting, a neutralizing antibody was developed by screening for inhibition of myostatin binding to ActRIIB. Administration of this antimyostatin antibody to adult mice resulted in a significant increase in both muscle mass and functional strength. Importantly, similar results were obtained in a murine model of muscular dystrophy, the mdx mouse. Unlike the myostatin-deficient animals, which exhibit both muscle hypertrophy and hyperplasia, the antibody-treated mice demonstrate increased musculature through a hypertrophic mechanism. These results validate myostatin inhibition as a therapeutic approach to muscle wasting diseases such as muscular dystrophy, sarcopenic frailty of the elderly and amylotrophic lateral sclerosis.
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PMID:Myostatin: a modulator of skeletal-muscle stem cells. 1624 58

Skeletal muscle is the largest organ in the human body, and plays an important role in body movement and metabolism. Skeletal muscle mass is lost in genetic disorders such as muscular dystrophy, muscle wasting and ageing. Chemicals and proteins that restore muscle mass and function are potential drugs that can improve human health and could be used in the clinic. Myostatin is a muscle-specific member of the transforming growth factor (TGF)-beta superfamily that plays an essential role in the negative regulation of muscle growth. Inhibition of myostatin activity is a promising therapeutic method for restoring muscle mass and strength. Potential inhibitors of myostatin include follistatin domain-containing proteins, myostatin propeptide, myostatin antibodies and chemical compounds. These inhibitors could be beneficial for the development of clinical drugs for the treatment of muscular disorders. Bone morphogenetic protein (BMP) plays a significant role in the development of neuromuscular architecture and its proper functions. Modulation of BMP activity could be beneficial for muscle function in muscular disorders. This review will describe the current progress in therapy for muscular disorders, emphasising the importance of myostatin as a drug target.
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PMID:The role of myostatin and bone morphogenetic proteins in muscular disorders. 1643 40

Over the past decade, signalling cascades have been characterised that control key features of muscle growth, including the proliferation, differentiation of muscle precursors, the control cell size (hypertrophy) and cell death. In this review we highlight how two differing signalling molecules, Insulin-like Growth Factor-1 (IGF-1) and myostatin, regulate key steps during muscle development. We discuss how IGF-1 and myostatin signalling cascades can be manipulated to stimulate muscle growth. We summarise experimental data from mdx mouse, the animal model for Duchenne muscular dystrophy, that suggest a therapeutic value of these strategies for patients suffering from muscular dystrophy without redressing the primary cause of the lesion.
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PMID:Molecular mechanisms involving IGF-1 and myostatin to induce muscle hypertrophy as a therapeutic strategy for Duchenne muscular dystrophy. 1662 58

Myostatin (MSTN) is a muscle-specific secreted peptide that functions to limit muscle growth through an autocrine regulatory feedback loop. Loss of MSTN activity in cattle, mice, and humans leads to a profound phenotype of muscle overgrowth, associated with more and larger fibers and enhanced regenerative capacity. Deletion of MSTN in the mdx mouse model of Duchenne muscular dystrophy enhances muscle mass and reduces disease severity. In contrast, loss of MSTN activity in the dyW/dyW mouse model of laminin-deficient congenital muscular dystrophy, a much more severe and lethal disease model, does not improve all aspects of muscle pathology. Here we examined disease severity associated with myostatin (mstn-/-) deletion in mice nullizygous for delta-sarcoglycan (scgd-/-), a model of limb-girdle muscular dystrophy. Early loss of MSTN activity achieved either by monoclonal antibody administration or by gene deletion each improved muscle mass, regeneration, and reduced fibrosis in scgd-/- mice. However, antibody-mediated inhibition of MSTN in late-stage dystrophic scgd-/- mice did not improve disease. These findings suggest that MSTN inhibition may benefit muscular dystrophy when instituted early or if disease is relatively mild but that MSTN inhibition in severely affected or late-stage disease may be ineffective.
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PMID:Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdle muscular dystrophy. 1672 94

The transforming growth factor-beta (TGF-beta) superfamily includes TGF-betas, activin, myostatin and bone morphogenetic proteins. Misregulation of the activity of TGF-beta family members is involved in pathogenesis of cancer, muscular dystrophy, obesity and bone and tooth remodeling. Natural inhibitors for the TGF-beta superfamily regulate fine-tuning of activity of TGF-beta family in vivo. In addition to natural inhibitors for the TGF-beta family, soluble forms of receptors for the TGF-beta family, blocking monoclonal antibodies and small chemical TGF-beta inhibitors have been developed. In this review, we summarize recent advances in our understanding of inhibitors for the TGF-beta superfamily and their medical applications.
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PMID:Inhibitors of the TGF-beta superfamily and their clinical applications. 1710 Jun 37

Skeletal muscles become atrophied by muscular disorders such as muscular dystrophy, wasting and even aging. In addition to muscle atrophy, progressive muscle damage, inflammation and replacement of muscle fibers with fibrous and fatty tissues are observed in muscular dystrophy. Neuronal innervation is required for skeletal muscle, and muscles become atrophic when motor neurons are affected by neurodegenerative disorders such as amyotrophic lateral sclerosis. Restoring muscle mass and function lost by diseases such as muscular dystrophy and neurodegenerative disorders is important. There are three rational therapies for muscular dystrophy and related diseases: gene therapy, cell therapy and drug therapy. Gene therapies to replace the defective genes have been tried with various degrees of effectiveness. Multiple myogenic stem cells including satellite cells, bone marrow cells, muscle side population cells, muscle-derived stem cells and mesoangioblast have been characterized. Cell therapies using these stem cells are one of the promising therapies for neuromuscular diseases causing muscle atrophy. As pharmacological drug therapies, increasing skeletal muscle mass by myostatin inhibition is quite promising and will be applied clinically in the near future.
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PMID:[Development of therapies against neuromuscular diseases causing muscle atrophy]. 1724 Aug 49

Myostatin is a negative regulator of muscle growth. Loss of myostatin has been shown to cause increase in skeletal muscle size and improve skeletal muscle function and fibrosis in the dystrophin-deficient mdx muscular dystrophy mouse model. We evaluated whether lack of myostatin has an impact on cardiac muscle growth and fibrosis in vivo. Using genetically modified mice we assessed whether myostatin absence induces similar beneficial effects on cardiac function and fibrosis. Cardiac mass and ejection fraction were measured in wild-type, myostatin-null, mdx and double mutant mdx/myostatin-null mice by high resolution echocardiography. Heart mass, myocyte area and extent of cardiac fibrosis were determined post mortem. Myostatin-null mice do not demonstrate ventricular hypertrophy when compared to wild-type mice as shown by echocardiography (ventricular mass 0.69+/-0.01 vs. 0.69+/-0.018 g) and morphometric analyses including heart/body weight ratio (5.39+/-0.45 vs. 5.62+/-0.58 mg/g) and cardiomyocyte area 113.67+/-1.5, 116.85+/-1.9 microm(2)). Moreover, absence of myostatin does not attenuate cardiac fibrosis in the dystrophin-deficient mdx mouse (12.2% vs. 12%). The physiological role of myostatin in cardiac muscle appears significantly different than that in skeletal muscle as it does not induce cardiac hypertrophy and does not modulate cardiac fibrosis in mdx mice.
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PMID:Myostatin does not regulate cardiac hypertrophy or fibrosis. 1733 25


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