# Mitochondrial‐derived peptides MOTS‐c and humanin attenuate dexamethasone‐induced atrophy in human skeletal muscle cells

## TL;DR

This study shows that mitochondrial peptides MOTS-c and humanin can reduce muscle wasting caused by dexamethasone in human muscle cells.

## Contribution

The study demonstrates that MOTS-c and humanin are effective in mitigating glucocorticoid-induced muscle atrophy in human myotubes.

## Key findings

- MOTS-c preserved myotube size and differentiation, increased Akt phosphorylation, and reduced MURF1 and STAT3 activation.
- HNG preserved myotube area and reduced STAT3 activation but did not affect fusion index or E3 ligase mRNA levels.
- DEXA caused muscle atrophy by increasing MURF1, MAFbx, and PGC1α expression in human skeletal muscle cells.

## 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.