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, a TGF-beta family member, is a negative regulator of muscle growth. Here, we generated transgenic mice that expressed myostatin mutated at its cleavage site under the control of a muscle specific promoter creating a dominant negative myostatin. These mice exhibited a significant (20-35%) increase in muscle mass that resulted from myofiber hypertrophy and not from myofiber hyperplasia. We also evaluated the role of myostatin in muscle degenerative states, such as muscular dystrophy, and found significant downregulation of myostatin. Thus, further inhibition of myostatin may permit increased muscle growth in muscle degenerative disorders.
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PMID:Dominant negative myostatin produces hypertrophy without hyperplasia in muscle. 1082 54

A human therapeutic that specifically modulates skeletal muscle growth would potentially provide a benefit for a variety of conditions including sarcopenia, cachexia, and muscular dystrophy. Myostatin, a member of the TGF-beta family of growth factors, is a known negative regulator of muscle mass, as mice lacking the myostatin gene have increased muscle mass. Thus, an inhibitor of myostatin may be useful therapeutically as an anabolic agent for muscle. However, since myostatin is expressed in both developing and adult muscles, it is not clear whether it regulates muscle mass during development or in adults. In order to test the hypothesis that myostatin regulates muscle mass in adults, we generated an inhibitory antibody to myostatin and administered it to adult mice. Here we show that mice treated pharmacologically with an antibody to myostatin have increased skeletal muscle mass and increased grip strength. These data show for the first time that myostatin acts postnatally as a negative regulator of skeletal muscle growth and suggest that myostatin inhibitors could provide a therapeutic benefit in diseases for which muscle mass is limiting.
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PMID:Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. 1255 68

More than 30 different forms of muscular dystrophy (MD) have been molecularly characterized and can be diagnosed, but progress toward treatment has been slow. Gene replacement therapy has met with great difficulty because of the large size of the defective genes and because of difficulties in delivering a gene to all muscle groups. Cell replacement therapy has also been difficult to realize. Will it even be possible to design specific therapy protocols for all MDs? Or is a more realistic goal to treat some of the secondary manifestations that are common to several forms of MD, such as membrane instability, necrosis, and inflammation, and to promote regeneration? As reviewed here, enhanced expression of a range of proteins provides a boost for degenerating dystrophic muscle in mouse models. Expression of a mini-agrin promotes basement membrane formation instead of laminin alpha2; integrin alpha7, GalNac transferase, and ADAM12 promote cell adhesion and muscle stability in the absence of dystrophin; calpastatin prevents muscle necrosis; and nitric oxide synthase prevents inflammation. ADAM12, IGF-I, and myostatin blockade promote regeneration and reduce fibrosis. One can envision numerous other candidate booster genes which encode proteins that promote survival and/or regeneration of the compromised muscle or proteins that affect post-translational modifications of critical proteins. Finally, fibrosis, which is the curse of many human diseases, may also be attacked. Once the mechanisms of the boosters are better understood, drugs may be developed to provide the boost to muscle. Some of the experiences in models of muscular dystrophy may inspire new approaches in other genetic degenerative diseases as well.
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PMID:The new frontier in muscular dystrophy research: booster genes. 1295 64

Activins and inhibins were first identified by virtue of their ability to regulate follicle-stimulating hormone (FSH) secretion from the anterior pituitary. Activins are also powerful regulators of gonadal functions. However, the physiological functions of activins are not restricted to reproductive tissues. Activins are involved in apoptosis of hepatocytes and B cells, fibrosis, inflammation and neurogenesis. Activins are regarded as novel drug targets since blocking activins would provide benefits by preventing apoptosis, fibrosis, inflammation and growth of several cancers. Activins are members of the transforming growth factor-beta (TGF-beta) family, which has numerous peptide growth and differentiation factors including activins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and TGF-betas. Among them, GDF8 is also known as myostatin and is structurally related to activins. Myostatin is specifically expressed in the skeletal muscle lineage and is a candidate for muscle chalone negatively regulating the growth of myoblasts. Myostatin is regarded as a good drug target since therapeutics that modulate skeletal muscle growth would be useful for disease conditions such as muscular dystrophy, sarcopenia, cachexia and even diabetes. Recent studies have revealed that activins and myostatin signal through activin type II receptors (ActRIIA and ActRIIB) and their activities are regulated by extracellular binding proteins, follistatins and follistatin-related gene (FLRG). Furthermore, signaling of activins, myostatin and related ligands is also controlled by intracellular receptor-interacting proteins by novel mechanisms. In this review, I would like to show the current progress in the field emphasizing the importance of activins and myostatin as novel drug targets for immune, endocrine and metabolic disorders.
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PMID:Activins, myostatin and related TGF-beta family members as novel therapeutic targets for endocrine, metabolic and immune disorders. 1518 Apr 56

Laminin alpha2 (merosin)-deficient congenital muscular dystrophy (CMD) patients show progressive muscle fiber necrosis and ineffective muscle regeneration. This is probably due to decreased formation of multi nucleated myotubes resulting from a myoblast fusion defect. When receiving a mechanical signal from muscle membranes, a cascade of RhoA, focal adhesion kinase (FAK), and serum response factor (SRF) positively regulates myogenesis and muscle hypertrophy associated with functional overload. In contrast, myostatin, a potent negative regulator of skeletal muscle hypertrophy, appears to be up-regulated in the muscles of mdx mice, an animal model for Duchenne muscular dystrophy. Using Western blot and immunohistochemical analyses, we investigated the levels of RhoA, FAK, SRF, and myostatin in the skeletal muscles of dy mice. The amount of RhoA protein was increased in the hindlimb muscles of dy mice aged 12 weeks. At 12 weeks, FAK immunoreactivity was observed in the myonuclei and/or satellite cells of normal mice, but not of dy mice. SRF protein levels decreased markedly in the gastrocnemius and rectus femoris muscles of dy mice at 2 and 12 weeks. Several muscle fibers in normal mice possessed uniform SRF immunoreactivity in the cytoplasm. An SRF immunostaining pattern in muscle was not detected in dy mice. Western blot and the densitometric analysis showed a decreased amount of myocyte enhancer factor 2C (MEF2C) in hindlimb muscles of dy mice. Although slight myostatin immunoreactivity was observed in the nuclei of some normal mice, marked myostatin immunoreactivity was observed in the cytoplasm of mature dy mice myonuclei and/or satellite cells. A low expression of FAK, SRF and MEF2C in muscles of dy mice may inhibit postnatal muscle hypertrophy by fusing satellite cells with existing fibers. Enhancing myostatin protein would result in further atrophy and degeneration of muscle fiber in dy mice.
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PMID:Marked reduction of focal adhesion kinase, serum response factor and myocyte enhancer factor 2C, but increase in RhoA and myostatin in the hindlimb dy mouse muscles. 1522 30

Recruitment determines the profile of fibre-type-specific genes expressed across the range of muscle fibres associated with slow, fast fatigue-resistant and fast fatiguable motor units. Downstream signalling pathways activated by neural signalling and mechanical load have been the focus of intensive research in past years. It is now known that Ca(2+)-dependent calcineurin-nuclear factor of activated T cells and insulin-like growth factor 1 pathways and their downstream mediators contribute to these adaptive responses. These pathways regulate gene expression through muscle-specific (myocyte-enhancing factor 2, myoblast determination protein) and non-specific (nuclear factor of activated T cell 2, GATA-2) transcription factors. Transcriptional signals activated with increased contractile activity result in altered expression of fibre-type specific genes, including the myosin heavy chain isoforms and oxidative and glycolytic enzymes and a net change in muscle fibre-type composition. In contrast, transcriptional signals activated by increased load bearing result in hypertrophy or a growth response, a component of which involves satellite cell recruitment and fusion with existing adult myofibres. Calcineurin has been identified as a key mediator in the hypertrophic response, and the current challenge has been to determine the downstream target genes of this pathway. Exciting new data have emerged, showing that myostatin, a negative regulator of muscle growth, and utrophin, a cytoskeletal protein important in maintaining membrane integrity, are downstream targets of calcineurin signalling. Increased understanding of these mediators of muscle growth may provide strategies for the development of effective therapeutics to counter muscle weakness and muscular dystrophy.
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PMID:Calcineurin and skeletal muscle growth. 1529 53

We recently developed a new cDNA microarray encompassing more than 5,000 genes expressed in human skeletal muscle. We successfully identified the differences at the gene expression profiles among Duchenne muscular dystrophy patients. Using our microarray, we catalogued gene expression during myogenic differentiation. The resultant expression patterns were classified into eight groups by hierarchical cluster analysis. Among them, clusters 6, 7, and 8 contain genes which show high expression level at the later differentiation stage and encode mainly sarocmere and extracellular matrix proteins. We used genes in these clusters as markers for regeneration. We identified that these regeneration-associated genes were not necessarily upregulated in Fukuyama congenital muscular dystrophy (FCMD) even though necrosis-associated genes were highly upregulated, suggesting the insufficient regenerating capability in FCMD. We have also characterized genes regulated by IGF-I simulation. We subject cascade specific inhibitors and IGF-I to human myotubes and performed gene expression profiling using our cDNA microarray. We found that PI3K/Akt-1 cascade first activates transcriptional factors such as MyoD, myogenin, and MEF2C, and then genes in clusters 6, 7, and 8, which have E-box and MEF-box where these transcriptional factors associate. We expect to develop a new therapeutic method by elucidating the molecular mechanism of muscular dystrophy and the effect of IGF-I and anti-myostatin treatments.
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PMID:[The pathomechanism and the direction of therapy development in view of cDNA microarray]. 1565 27

Myostatin is a TGF-beta family member and a negative regulator of skeletal muscle growth. It has been proposed that reduction or elimination of myostatin could be a treatment for degenerative muscle diseases such as muscular dystrophy. Laminin-deficient congenital muscular dystrophy is one of the most severe forms of muscular dystrophy. To test the possibility of ameliorating the dystrophic phenotype in laminin deficiency by eliminating myostatin, we crossed dy(W) laminin alpha2-deficient and myostatin null mice. The resulting double-deficient dy(W)/dy(W);Mstn(-/-) mice had a severe clinical phenotype similar to that of dy(W)/dy(W) mice, even though muscle regeneration was increased. Degeneration and inflammation of muscle were not alleviated. The pre-weaning mortality of dy(W)/dy(W);Mstn(-/-) mice was increased compared to dy(W)/dy(W), most likely due to significantly less brown and white fat in the absence of myostatin, and postweaning mortality was not significantly improved. These results show that eliminating myostatin in laminin-deficiency promotes muscle formation, but at the expense of fat formation, and does not reduce muscle pathology. Any future therapy based on myostatin may have undesirable side effects.
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PMID:Elimination of myostatin does not combat muscular dystrophy in dy mice but increases postnatal lethality. 1568 32

Myostatin is an endogenous inhibitor of muscle conserved across diverse species. In the absence of myostatin, there is massive muscle growth in mice, cattle, and humans. Previous studies in the mdx mouse model of muscular dystrophy demonstrate that inhibiting myostatin attenuates several features of dystrophic muscle. These findings have encouraged the development of human therapies to block myostatin. However, little is known of the long-term effects on muscle of myostatin blockade. To evaluate potential sequelae from the prolonged absence of myostatin, senescent myostatin null (mstn-/-) mice were studied. Senescent mstn-/- mice continue to have normal muscle with increased mass and strength relative to controls. Muscles of senescent mstn-/- mice regenerate robustly from both chronic and acute injury. Early markers of regeneration are enhanced in the absence of myostatin, suggesting a mechanism for the attenuation of dystrophic features found in mdx mice lacking myostatin.
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PMID:Muscle regeneration in the prolonged absence of myostatin. 1569 35

Mutations in myostatin (GDF8) cause marked increases in muscle mass, suggesting that this transforming growth factor-beta (TGF-beta) superfamily member negatively regulates muscle growth. Myostatin blockade therefore offers a strategy for reversing muscle wasting in Duchenne's muscular dystrophy (DMD) without resorting to genetic manipulation. Here, we demonstrate that pharmacological blockade using a myostatin propeptide stabilized by fusion to IgG-Fc improved pathophysiology of the mdx mouse model of DMD. Functional benefits evidenced by specific force improvement, exceeded those reported previously using myostatin antibody-mediated blockade. More importantly, use of a propeptide blockade strategy obviates possibilities of anti-idiotypic responses that could potentially limit the effectiveness of antibody-mediated myostatin blockade strategies over time. This study provides a novel pharmacological strategy for treatment of diseases associated with muscle wasting such as DMD and since it uses an endogenous inhibitor of myostatin should help circumvent technical hurdles and toxicity associated with conventional gene or cell based therapies.
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PMID:Myostatin propeptide-mediated amelioration of dystrophic pathophysiology. 1579 Oct 4


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