Résumé
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.