Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease

FASEB J. 2011 May;25(5):1653-63. doi: 10.1096/fj.10-176917. Epub 2011 Jan 31.


Chronic kidney disease (CKD) and several other catabolic conditions are characterized by increased circulating inflammatory cytokines, defects in IGF-1 signaling, abnormal muscle protein metabolism, and progressive muscle atrophy. In these conditions, no reliable treatments successfully block the development of muscle atrophy. In mice with CKD, we found a 2- to 3-fold increase in myostatin expression in muscle. Its pharmacological inhibition by subcutaneous injections of an anti-myostatin peptibody into CKD mice (IC(50) ∼1.2 nM) reversed the loss of body weight (≈5-7% increase in body mass) and muscle mass (∼10% increase in muscle mass) and suppressed circulating inflammatory cytokines vs. results from CKD mice injected with PBS. Pharmacological myostatin inhibition also decreased the rate of protein degradation (16.38 ± 1.29%; P<0.05), increased protein synthesis in extensor digitorum longus muscles (13.21 ± 1.09%; P<0.05), markedly enhanced satellite cell function, and improved IGF-1 intracellular signaling. In cultured muscle cells, TNF-α increased myostatin expression via a NF-κB-dependent pathway, whereas muscle cells exposed to myostatin stimulated IL-6 production via p38 MAPK and MEK1 pathways. Because IL-6 stimulates muscle protein breakdown, we conclude that CKD increases myostatin through cytokine-activated pathways, leading to muscle atrophy. Myostatin antagonism might become a therapeutic strategy for improving muscle growth in CKD and other conditions with similar characteristics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Insulin-Like Growth Factor I / metabolism
  • Interleukin-6 / metabolism
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / immunology
  • Muscular Atrophy / drug therapy*
  • Muscular Atrophy / metabolism
  • Myostatin / antagonists & inhibitors*
  • Myostatin / metabolism*
  • NF-kappa B / metabolism
  • Polymerase Chain Reaction
  • Recombinant Fusion Proteins / therapeutic use
  • Signal Transduction / drug effects


  • Interleukin-6
  • Myostatin
  • NF-kappa B
  • Recombinant Fusion Proteins
  • Insulin-Like Growth Factor I