TY - JOUR
T1 - MOTS-c reduces myostatin and muscle atrophy signaling
AU - Kumagai, Hiroshi
AU - Coelho, Ana Raquel
AU - Wan, Junxiang
AU - Mehta, Hemal H.
AU - Yen, Kelvin
AU - Huang, Amy
AU - Zempo, Hirofumi
AU - Fuku, Noriyuki
AU - Maeda, Seiji
AU - Oliveira, Paulo J.
AU - Cohen, Pinchas
AU - Kim, Su Jeong
N1 - Funding Information:
This work was supported by a Glenn/AFAR Postdoctoral Fellowship Program for Translational Research on Aging to S. J. Kim, by R01AG061834, P01AG034906, R56AG062693, an AFAR BIG AWARD Grants to P. Cohen, by the Fundação Luso-Americana para o Desenvolvimento (FLAD) Healthcare 2020 Grant to P. J. Oliveira, and by a PhD fellowship from Portuguese FCT (SFRH/BD/103399/2014) to A. R. Coelho.
Publisher Copyright:
© 2021 the American Physiological Society.
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
KW - FOXO1
KW - High-fat diet
KW - MOTS-c
KW - Muscle atrophy
KW - Myostatin
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U2 - 10.1152/AJPENDO.00275.2020
DO - 10.1152/AJPENDO.00275.2020
M3 - Article
C2 - 33554779
AN - SCOPUS:85103608101
SN - 0193-1849
VL - 320
SP - E680-E690
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 4
ER -