MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia.
This study investigated whether MOTS-c, a mitochondrial-derived peptide with metabolic and exercise-mimicking properties, could attenuate skeletal muscle loss in cancer cachexia. In vitro, differentiated myotubes treated with MOTS-c showed increased PGC-1α mRNA expression (~85%) and enhanced AMPK phosphorylation (~103%), suggesting activation of mitochondrial biogenesis and energy-sensing pathways. In vivo, male mice implanted with Colon-26 (C26) carcinoma cells developed significant systemic wasting (~9% body weight loss). Daily MOTS-c treatment did not prevent total body weight loss or fat mass loss in these tumor-bearing mice, but it did significantly preserve skeletal muscle mass — notably rescuing quadriceps weight (~12% vs. C26 vehicle controls). Mechanistically, MOTS-c appeared to modulate FOXO signaling and reduce atrogene expression (MuRF1 and Atrogin-1), key mediators of muscle protein breakdown, while promoting mitochondrial biogenesis markers. The authors conclude that MOTS-c partially protects against cachexia-associated muscle deterioration. Key limitations include the exclusive use of male mice, an animal-only in vivo model, and the authors' own acknowledgment that human studies are needed to validate these findings.
Why this grade: All in vivo findings are derived from a mouse (C26 carcinoma) model with no human subjects; in vitro myotube data provides mechanistic but not clinical evidence.
Background 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. Methods 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. Results 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 Conclusion 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.
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