MOTS-c partially protects against skeletal muscle loss in C26 cancer cachexia

Cancer cachexia is a debilitating metabolic syndrome characterized by progressive skeletal muscle loss, reduced function, and increased mortality, significantly impacting patient prognosis. A key underlying mechanism is mitochondrial dysfunction, which drives the muscle wasting phenotype. Current treatments are limited, highlighting an urgent need for novel therapeutic strategies. MOTS-c, a mitochondrial-derived peptide, is known to regulate metabolic homeostasis and mimic exercise signaling, making it a promising candidate to counteract cachexia by targeting mitochondrial health and muscle metabolism.

Researchers investigated MOTS-c's effects both in vitro and in vivo. In vitro, differentiated myotubes were treated with MOTS-c (50 μM) to assess intracellular signaling. For in vivo studies, male mice were inoculated with Colon-26 (C26) carcinoma cells to induce cachexia. These mice were then treated daily with MOTS-c (15 mg/kg/2x Day, i.p.) or a vehicle control. 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 significantly increased PGC-1α mRNA by +84.6% and AMPK phosphorylation by +103.1% in myotubes. In vivo, C26 tumor-bearing mice exhibited significant systemic wasting, with approximately ~9% total body weight loss. While MOTS-c did not prevent total body weight or fat loss, it remarkably preserved skeletal muscle mass. The most significant finding was:

MOTS-c rescued quadriceps weight by +12% compared to the C26 vehicle group (p < 0.05), and also showed a trend toward protecting gastrocnemius mass and EDL function. Cachexia-induced upregulation of Atrogin-1 (+8.6-fold) and MuRF1 (+16-fold) was attenuated by MOTS-c. This was accompanied by an increase in inhibitory pFOXO1 (+80%), a reduction in pFOXO3a (-39%), and a partial restoration of PGC-1α protein levels by +143%, indicating a modulation of FOXO-driven catabolic signaling and promotion of mitochondrial biogenesis.