Mitochondrial‐derived peptides <scp>MOTS</scp> ‐c and humanin attenuate dexamethasone‐induced atrophy in human skeletal muscle cells

Elhusseiny, Rabie;Ihsan, Mohammed;Bellefroid, Théo;Farooq, Abdulaziz;Deldicque, Louise;et.al.
(2026) Physiological Reports — Vol. 14, n° 4, p. e70791 (2026)

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  • Elhusseiny, RabieInstitute of Neuroscience UCLouvain Louvain‐la‐Neuve Belgium
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  • Ihsan, MohammedPhysical Education Department, College of Education United Arab Emirates Université Al Ain UAE
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  • Bellefroid, ThéoInstitute of Neuroscience UCLouvain Louvain‐la‐Neuve Belgium
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  • Farooq, AbdulazizAspetar Orthopaedic and Sports Medicine Hospital Research and Scientific Support Department Doha Qatar
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  • Deldicque, Louiseorcid-logoInstitute of Neuroscience UCLouvain Louvain‐la‐Neuve Belgium
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Abstract
Glucocorticoids, such as dexamethasone (DEXA), are effective therapeutics but cause severe muscle wasting. Mitochondrial-derived peptides (MDPs) are promising countermeasures, but their effectiveness is largely unexplored. We tested the hypothesis that the MDP S14G-humanin (HNG) and the mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) mitigate DEXA-induced atrophy in human skeletal myotubes. Fully differentiated primary human myotubes were exposed to 10 μM DEXA ±10 μM HNG or 10 μM MOTS-c. DEXA decreased myotube size (area, p < 0.001) and differentiation (Fusion Index, p = 0.05). Additionally, DEXA increased both muscle ring finger protein 1 (MURF1, p < 0.001) and muscle atrophy F-box (MAFbx, p = 0.01) as well as peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α, p < 0.001). MOTS-c co-treatment with DEXA completely preserved myotube area (p < 0.001) and fusion index (p = 0.02), increased Akt phosphorylation (p = 0.0015) and blunted both MURF1 upregulation (p = 0.03) and STAT3 activation (p = 0.005) compared to DEXA alone. HNG co-treatment with DEXA preserved myotube area (p < 0.001), blunted DEXA-induced STAT3 activation (p = 0.027), but had no effect on fusion index or E3 ligase mRNA levels. Those findings suggest that MOTS-c could be an effective inhibitor of glucocorticoid-induced atrophy in human muscle, not only through selective inhibition of MURF1 but also by enhancing Akt signaling and suppressing STAT3 activation.
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Elhusseiny, R., Ihsan, M., Bellefroid, T., Farooq, A., Racinais, S., & Deldicque, L. (2026). Mitochondrial‐derived peptides <scp>MOTS</scp> ‐c and humanin attenuate dexamethasone‐induced atrophy in human skeletal muscle cells. Physiological Reports, 14(4), e70791. https://doi.org/10.14814/phy2.70791 (Original work published 2026)