MOTS-c reduces myostatin and muscle atrophy signaling

Hiroshi Kumagai, Ana Raquel Coelho, Junxiang Wan, Hemal H. Mehta, Kelvin Yen, Amy Huang, Hirofumi Zempo, Noriyuki Fuku, Seiji Maeda, Paulo J. Oliveira, Pinchas Cohen*, Su Jeong Kim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


Obesity and type 2 diabetes are metabolic diseases, often associated with sarcopenia and muscle dysfunction. MOTS-c, a mitochondrial- derived peptide, acts as a systemic hormone and has been implicated in metabolic homeostasis. Although MOTS-c improves insulin sensitivity in skeletal muscle, whether MOTS-c impacts muscle atrophy is not known. Myostatin is a negative regulator of skeletal muscle mass and also one of the possible mediators of insulin resistance-induced skeletal muscle wasting. Interestingly, we found that plasma MOTS-c levels are inversely correlated with myostatin levels in human subjects. We further demonstrated that MOTS-c prevents palmitic acid-induced atrophy in differentiated C2C12 myotubes, whereas MOTS-c administration decreased myostatin levels in plasma in diet-induced obese mice. By elevating AKT phosphorylation, MOTS-c inhibits the activity of an upstream transcription factor for myostatin and other muscle wasting genes, FOXO1. MOTS-c increases mTORC2 and inhibits PTEN activity, which modulates AKT phosphorylation. Further upstream, MOTS-c increases CK2 activity, which leads to PTEN inhibition. These results suggest that through inhibition of myostatin, MOTS-c could be a potential therapy for insulin resistance- induced skeletal muscle atrophy as well as other muscle wasting phenotypes including sarcopenia.

Original languageEnglish
Pages (from-to)E680-E690
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number4
Publication statusPublished - 2021 Apr
Externally publishedYes


  • FOXO1
  • High-fat diet
  • MOTS-c
  • Muscle atrophy
  • Myostatin

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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