Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition

Elizabeth M. MacDonald, Eva Andres-Mateos, Rebeca Mejias, Jessica L. Simmers, Ruifa Mi, Jae Sung Park, Stephanie Ying, Ahmet Hoke, Se Jin Lee, Ronald D. Cohn

Research output: Contribution to journalArticlepeer-review

Abstract

The purpose of our study was to compare two acquired muscle atrophies and the use of myostatin inhibition for their treatment. Myostatin naturally inhibits skeletal muscle growth by binding to ActRIIB, a receptor on the cell surface of myofibers. Because blocking myostatin in an adult wild-type mouse induces profound muscle hypertrophy, we applied a soluble ActRIIB receptor to models of disuse (limb immobilization) and denervation (sciatic nerve resection) atrophy. We found that treatment of immobilized mice with ActRIIB prevented the loss of muscle mass observed in placebo-treated mice. Our results suggest that this protection from disuse atrophy is regulated by serum and glucocorticoid-induced kinase (SGK) rather than by Akt. Denervation atrophy, however, was not protected by ActRIIB treatment, yet resulted in an upregulation of the pro-growth factors Akt, SGK and components of the mTOR pathway. We then treated the denervated mice with the mTOR inhibitor rapamycin and found that, despite a reduction in mTOR activation, there is no alteration of the atrophy phenotype. Additionally, rapamycin prevented the denervation-induced upregulation of the mTORC2 substrates Akt and SGK. Thus, our studies show that denervation atrophy is not only independent from Akt, SGK and mTOR activation but also has a different underlying pathophysiological mechanism than disuse atrophy.

Original languageEnglish (US)
Pages (from-to)471-481
Number of pages11
JournalDMM Disease Models and Mechanisms
Volume7
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • Denervation atrophy
  • Muscle atrophy pathophysiology
  • Myostatin
  • Skeletal muscle
  • TGF-β signaling

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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