Open AccessMOTS-c reduces myostatin and muscle atrophy signaling
Author(s) -
Hiroshi Kumagai,
Ana R Coelho,
Junxiang Wan,
Hemal H. Mehta,
Kelvin Yen,
Amy Huang,
Hirofumi Zempo,
Noriyuki Fuku,
Seiji Maeda,
Paulo J. Oliveira,
Pinchas Cohen,
Su Jeong Kim
Publication year - 2021
Publication title -
endocrinology and metabolism/american journal of physiology: endocrinology and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.507
H-Index - 201
eISSN - 1522-1555
pISSN - 0193-1849
DOI - 10.1152/ajpendo.00275.2020
Subject(s) - myostatin , endocrinology , medicine , skeletal muscle , wasting , myogenesis , protein kinase b , sarcopenia , muscle atrophy , pten , foxo1 , insulin resistance , biology , pi3k/akt/mtor pathway , atrophy , myopathy , phosphorylation , insulin , signal transduction , microbiology and biotechnology
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.