Muscle atrophy reversed by growth factor activation of satellite cells in a mouse muscle atrophy model

PLoS One. 2014 Jun 25;9(6):e100594. doi: 10.1371/journal.pone.0100594. eCollection 2014.

Abstract

Muscular dystrophies comprise a large group of inherited disorders that lead to progressive muscle wasting. We wanted to investigate if targeting satellite cells can enhance muscle regeneration and thus increase muscle mass. We treated mice with hepatocyte growth factor and leukemia inhibitory factor under three conditions: normoxia, hypoxia and during myostatin deficiency. We found that hepatocyte growth factor treatment led to activation of the Akt/mTOR/p70S6K protein synthesis pathway, up-regulation of the myognic transcription factors MyoD and myogenin, and subsequently the negative growth control factor, myostatin and atrophy markers MAFbx and MuRF1. Hypoxia-induced atrophy was partially restored by hepatocyte growth factor combined with leukemia inhibitory factor treatment. Dividing satellite cells were three-fold increased in the treatment group compared to control. Finally, we demonstrated that myostatin regulates satellite cell activation and myogenesis in vivo following treatment, consistent with previous findings in vitro. Our results suggest, not only a novel in vivo pharmacological treatment directed specifically at activating the satellite cells, but also a myostatin dependent mechanism that may contribute to the progressive muscle wasting seen in severely affected patients with muscular dystrophy and significant on-going regeneration. This treatment could potentially be applied to many conditions that feature muscle wasting to increase muscle bulk and strength.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Hypoxia / drug effects
  • Disease Models, Animal
  • Hepatocyte Growth Factor / pharmacology*
  • Hepatocyte Growth Factor / therapeutic use
  • Leukemia Inhibitory Factor / pharmacology
  • Male
  • Mice
  • Muscular Atrophy / drug therapy*
  • Muscular Atrophy / metabolism
  • Muscular Atrophy / pathology*
  • Myostatin / deficiency
  • Organ Size / drug effects
  • Protein Biosynthesis / drug effects
  • Proteolysis / drug effects
  • Satellite Cells, Skeletal Muscle / drug effects*
  • Satellite Cells, Skeletal Muscle / metabolism
  • Satellite Cells, Skeletal Muscle / pathology
  • Signal Transduction / drug effects

Substances

  • Leukemia Inhibitory Factor
  • Myostatin
  • Hepatocyte Growth Factor

Grant support

This work was supported by the Lundbeck Foundation grant #R9-A783 (http://www.lundbeckfonden.com), Aase og Ejnar Danielsen Fond #106179 (http://www.danielsensfond.dk), AP MÃ ¸ller Foundations #070126,080140 (http://www.apmollerfonde.dk), and The Research Council at Rigshospitalet. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.