Clinical Applications of Myostatin Inhibitors for Neuromuscular Diseases

Hundreds of thousands of individuals suffer disability from skeletal muscle weakness associated with neuromuscular disease. Inhibition of the TGF-β family member, myostatin, may mitigate symptoms in these disorders regardless of the primary disease pathophysiology. There is substantial preclinical data that primary muscle disorders may benefit from myostatin inhibition. In particular, several mouse models of various muscular dystrophies have demonstrated amelioration of pathology and weakness with loss or inhibition of myostatin. There is also preclinical data that myostatin inhibition may increase muscle mass and strength in some denervating diseases. In addition to increasing the quantity of muscle, myostatin inhibition improves the quality of muscle by stimulating muscle regeneration and decreases muscle fibrosis in animal models. Clinical experience with myostatin inhibitors is still limited and the potential negative consequences of long term inhibition are unknown but may include replicative senescence of muscle progenitor cells, tendon shortening and off-target side effects. Clinical trials in disease populations as well as long term treatment studies in large animal models are now required to determine the appropriate clinical use of this novel therapeutic. Keywords: Myostatin, duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, limb girdle muscular dystrophy, myotonic dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, cachexia, congenital myopathies, BMD, creatine kinase, MCD1A, LGMD, Laminin 2, antibody, CAV-3 Tg, CAPN3, LGMD2A, hyperplasia, ActRIIB-mFc, TGF, necrosis, phenotype, SMBA, SOD1, snRNP, biogenesis, pre-mRNA, SMNdelta7, IGF-I, MYO-029, ACE-031, AMG-745, DEXA, neuromuscular, cytokines, tRIIB, myoblasts, myopathy, GDF11, kidney, olfactory neurons, atrophy