Stat3 Activation Links a C/EBPδ to Myostatin Pathway to Stimulate Loss of Muscle Mass

Cell Metab. 2013 Sep 3;18(3):368-79. doi: 10.1016/j.cmet.2013.07.012.

Abstract

Catabolic conditions like chronic kidney disease (CKD) cause loss of muscle mass by unclear mechanisms. In muscle biopsies from CKD patients, we found activated Stat3 (p-Stat3) and hypothesized that p-Stat3 initiates muscle wasting. We created mice with muscle-specific knockout (KO) that prevents activation of Stat3. In these mice, losses of body and muscle weights were suppressed in models with CKD or acute diabetes. A small-molecule that inhibits Stat3 activation produced similar responses, suggesting a potential for translation strategies. Using CCAAT/enhancer-binding protein δ (C/EBPδ) KO mice and C2C12 myotubes with knockdown of C/EBPδ or myostatin, we determined that p-Stat3 initiates muscle wasting via C/EBPδ, stimulating myostatin, a negative muscle growth regulator. C/EBPδ KO also improved survival of CKD mice. We verified that p-Stat3, C/EBPδ, and myostatin were increased in muscles of CKD patients. The pathway from p-Stat3 to C/EBPδ to myostatin and muscle wasting could identify therapeutic targets that prevent muscle wasting.

Publication types

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

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-delta / antagonists & inhibitors
  • CCAAT-Enhancer-Binding Protein-delta / genetics
  • CCAAT-Enhancer-Binding Protein-delta / metabolism*
  • Cell Line
  • Cytokines / metabolism
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Humans
  • Interleukin-6 / metabolism
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / physiology
  • Myostatin / antagonists & inhibitors
  • Myostatin / genetics
  • Myostatin / metabolism*
  • Phosphorylation
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Renal Insufficiency, Chronic / metabolism
  • Renal Insufficiency, Chronic / pathology
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / deficiency
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction

Substances

  • Cytokines
  • Interleukin-6
  • Myostatin
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • CCAAT-Enhancer-Binding Protein-delta