MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia.

Cancer cachexia is a multifactorial metabolic syndrome marked by progressive skeletal muscle loss, reduced function, and increased mortality.

Mitochondrial dysfunction is a key driver of this phenotype.

MOTS-c, a mitochondrial-derived peptide that regulates metabolic homeostasis and mimics exercise signaling, may counteract cachexia, but its role remains largely unexplored, and human studies using MOTS-c in subjects with cancer cachexia are needed.

Differentiated myotubes were treated with MOTS-c (50 μM) to assess intracellular signaling.

In vivo , male mice were inoculated with Colon-26 (C26) carcinoma cells and treated daily with MOTS-c (15 mg/kg/2x Day, i.p.) or vehicle.

Body weight was monitored daily.

At euthanasia, organ and skeletal muscle masses were measured.

Molecular analyses focused on FOXO signaling, atrogene expression (MuRF1, Atrogin-1), and mitochondrial biogenesis markers, including PGC-1α.

In vitro , MOTS-c increased PGC-1α mRNA (+84.6%) and AMPK phosphorylation (+103.1%).

C26 tumor-bearing mice exhibited significant systemic wasting (~9% body weight loss).

Although MOTS-c did not prevent total body weight or fat loss, it significantly preserved skeletal muscle mass, rescuing quadriceps weight (+12% vs.

C26 vehicle; p &#x202f;<&#x202f;0.05) and trending toward protection of gastrocnemius mass and EDL function.

Cachexia-induced upregulation of Atrogin-1 (+8.6-fold) and MuRF1 (+16-fold) was attenuated by MOTS-c, accompanied by increased inhibitory pFOXO1 (+80%), reduced pFOXO3a (-39%), and partial restoration of PGC-1&#x3b1; protein (+143%).

Our findings demonstrate that MOTS-c partially protects against skeletal muscle loss in C26 cachexia by modulating FOXO-driven catabolic signaling and promoting mitochondrial biogenesis, supporting its therapeutic potential in cancer cachexia..