1. Academic Validation
  2. MOTS-c reduces myostatin and muscle atrophy signaling

MOTS-c reduces myostatin and muscle atrophy signaling

  • Am J Physiol Endocrinol Metab. 2021 Apr 1;320(4):E680-E690. doi: 10.1152/ajpendo.00275.2020.
Hiroshi Kumagai 1 2 Ana Raquel Coelho 3 Junxiang Wan 1 Hemal H Mehta 1 Kelvin Yen 1 Amy Huang 1 Hirofumi Zempo 2 4 Noriyuki Fuku 2 Seiji Maeda 5 Paulo J Oliveira 3 Pinchas Cohen 1 Su-Jeong Kim 1
Affiliations

Affiliations

  • 1 The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California.
  • 2 Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan.
  • 3 CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Cantanhede, Portugal.
  • 4 Department of Administrative Nutrition, Faculty of Health and Nutrition, Tokyo Seiei College, Tokyo, Japan.
  • 5 Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Abstract

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.NEW & NOTEWORTHY MOTS-c, a mitochondrial-derived peptide reduces high-fat-diet-induced muscle atrophy signaling by reducing myostatin expression. The CK2-PTEN-mTORC2-AKT-FOXO1 pathways play key roles in MOTS-c action on myostatin expression.

Keywords

FOXO1; MOTS-c; high-fat diet; muscle atrophy; myostatin.

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