Myostatin/activin pathway antagonism: molecular basis and therapeutic potential

Int J Biochem Cell Biol. 2013 Oct;45(10):2333-47. doi: 10.1016/j.biocel.2013.05.019. Epub 2013 May 28.


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.

Keywords: Muscle wasting diseases; Myostatin/activin-ActRIIB signaling pathway; Protein breakdown; Ubiquitin ligases; Ubiquitin–proteasome system.

Publication types

  • Review

MeSH terms

  • Activins / antagonists & inhibitors*
  • Activins / metabolism
  • Animals
  • Humans
  • Molecular Targeted Therapy
  • Muscle Proteins / antagonists & inhibitors
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Diseases / drug therapy*
  • Muscular Diseases / metabolism
  • Muscular Diseases / pathology
  • Myostatin / antagonists & inhibitors*
  • Myostatin / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Signal Transduction
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism


  • Muscle Proteins
  • Myostatin
  • Ubiquitin
  • Activins
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex