MOTS-c promotes muscle differentiation in vitro

• Published in: Peptides (New York, N.Y. : 1980) Vol. 155; p. 170840
• Main Authors: García-Benlloch, Sandra, Revert-Ros, Francisco, Blesa, Jose Rafael, Alis, Rafael
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-09-2022
• Subjects: Atrophy; Mitochondria derived peptides; Muscle; Atrophy; Muscle; Mitochondria derived peptides
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2022.170840

MOTS-c (mitochondrial open reading frame of the 12 S rRNA-c) is a newly discovered peptide that has been shown to have a protective role in whole-body metabolic homeostasis. This could be a consequence of the effect of MOTS-c on muscle tissue. Here, we investigated the role of MOTS-c in the differentiation of human (LHCN-M2) and murine (C2C12) muscle progenitor cells. Cells were treated with peptides at the onset of differentiation or after myotubes had been formed. We identified in silico a putative Src Homology 2 (SH2) binding motif in the YIFY region of the MOTS-c sequence, and created a Y8F mutant MOTS-c peptide to explore the role of this region. In both cellular models, treatment with wild-type MOTS-c peptide increased myotube formation whereas treatment with the Y8F peptide did not. MOTS-c wild-type, but not Y8F peptide, also protected against interleukin-6 (IL-6)-induced reduction of nuclear myogenin staining in myocytes. Thus, we investigated whether MOTS-c interacts with the IL-6/Janus kinase/ Signal transducer and activator of transcription 3 (STAT3) pathway, and found that MOTS-c, but not the Y8F peptide, blocked the transcriptional activity of STAT3 induced by IL-6. Altogether, our findings suggest that, in muscle cells, MOTS-c interacts with STAT3 via the putative SH2 binding motif in the YIFY region to reduce STAT3 transcriptional activity, which enhances myotube formation. This newly discovered mechanism of action highlights MOTS-c as a potential therapeutic target against muscle-wasting in several diseases.
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•MOTS-c has a myogenic effect on myoblast differentiation in vitro.•The internal hydrophobic YIFY motif of MOTS-c is responsible for this effect.•MOTS-c seems to interact with the IL-6/JAK/STAT3 pathway to enhance muscle formation.