title: Myostatin/activin pathway antagonism: molecular basis and therapeutic potential.
abstract: Muscle wasting is associated with a wide range of catabolic diseases. This debilitating loss of muscle mass and functional capacity reduces the quality of life and increases the risks of morbidity and mortality. Major progress has been made in understanding the biochemical mechanisms and signaling pathways regulating muscle protein balance under normal conditions and the enhanced protein loss in atrophying muscles. It is now clear that activation of myostatin/activin signaling is critical in triggering the accelerated muscle catabolism that causes muscle loss in multiple disease states. Binding of myostatin and activin to the ActRIIB receptor complex on muscle cell membrane leads to activation of Smad2/3-mediated transcription, which in turn stimulates FoxO-dependent transcription and enhanced muscle protein breakdown via ubiquitin-proteasome system and autophagy. In addition, Smad activation inhibits muscle protein synthesis by suppressing Akt signaling. Pharmacological blockade of the myostatin/activin-ActRIIB pathway has been shown to prevent or reverse the loss of muscle mass and strength in various disease models including cancer cachexia and renal failure. Moreover, it can markedly prolong the lifespan of animals with cancer-associated muscle loss. Furthermore, inhibiting myostatin/activin actions also improves insulin sensitivity, reduces excessive adiposity, attenuates systemic inflammation, and accelerates bone fracture healing in disease models. Based on these exciting advances, the potential therapeutic benefits of myostatin/activin antagonism are now being tested in multiple clinical settings. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.
authors.affiliation: Metabolic Disorders Department, Amgen, Thousand Oaks, CA, USA. hqhan@amgen.com
authors.forename: H Q
authors.initials: HQ
authors.lastname: Han
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhou
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
mesh_terms: D028341:Activins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D006801:Humans; D058990:Molecular Targeted Therapy; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055435:Myostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D055435:Myostatin; D025801:Ubiquitin; D028341:Activins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
keywords: Muscle wasting diseases; Myostatin/activin-ActRIIB signaling pathway; Protein breakdown; Ubiquitin ligases; Ubiquitin–proteasome system