CCL5 Attenuates Palmitate-Induced Myotube Atrophy through Cytoskeletal Stabilization Rather than Proteostasis Regulation
TL;DR
CCL5 may attenuate metabolic stress–induced myotube atrophy by preserving cytoskeletal stability rather than regulating classical proteostasis pathways, highlighting a potential CCL5–CCR5–mediated mechanism for maintaining skeletal muscle structural integrity.
Abstract
Purpose
Sarcopenia is characterized by progressive skeletal muscle atrophy associated with impaired proteostasis, mitochondrial dysfunction, and chronic metabolic stress. Through transcriptomic analysis of aged skeletal muscle, CCL5 was identified as a stress-responsive immune-related factor consistently upregulated under sarcopenic conditions. This study aimed to investigate the role of CCL5 in a palmitate (PA)-induced in vitro model of sarcopenia.
Methods
Fully differentiated C2C12 myotubes were treated with PA to induce metabolic stress–associated atrophy. Morphological changes, myogenic signaling, protein turnover pathways, mitochondrial function, and apoptosis-related markers were analyzed. Candidate genes identified from transcriptomic analysis of aged skeletal muscle were validated in the PA-induced atrophy model, and the effects of exogenous recombinant CCL5 treatment were examined.
Results
PA treatment recapitulated key pathological features of muscle atrophy, including reduced myotube diameter, suppressed myogenic signaling, inhibition of the AKT–mTOR pathway, increased proteolysis, mitochondrial dysfunction, and activation of apoptosis. Among the candidate genes identified through transcriptomic analysis of aged skeletal muscle in our previous study, Ccl5 was markedly upregulated in PA-treated myotubes. Notably, exogenous CCL5 treatment partially restored myotube diameter under PA-induced stress. However, CCL5 did not significantly alter canonical regulatory pathways of muscle atrophy, including protein synthesis, protein degradation, or mitochondrial biogenesis. Instead, CCL5 selectively restored the expression of desmin, an intermediate filament protein critical for myofiber structural integrity.
Conclusions
CCL5 may attenuate metabolic stress–induced myotube atrophy by preserving cytoskeletal stability rather than regulating classical proteostasis pathways, highlighting a potential CCL5–CCR5–mediated mechanism for maintaining skeletal muscle structural integrity.