Trimetazidine counteracts stress-induced atrophy in C2C12 myotubes and improves muscle function in mice bearing the C26 tumor and in aged mice

Purpose: The metabolic modulator Trimetazidine (TMZ) blocks fatty acid -oxidation and shifts ATP production towards glucose oxidation, resulting in improved cell energy metabolism. TMZ is commonly used to treat angina pectoris and has been found to enhance both the efficiency of myocardium metabolism and patient exercise capacity. For this reason, TMZ effects on skeletal muscle cells were investigated in the present study. Methods: In this study, the potential protective effect of TMZ against atrophy-inducing stimuli was analyzed. C2C12 myotube cultures were exposed to serum deprivation or to the proinflammatory cytokine TNFalpha. Moreover, in order to study the effectiveness of TMZ also in vivo, the drug was administered to mice bearing the C26 colon-carcinoma, a well-characterized model of cancer cachexia and to 22 months old mice as model of sarcopenia. Results: The results show that TMZ significantly prevents myotube reduction in size caused by both treatments. In addition TMZ also markedly increases MyHC expression. Such an effect is associated with: a) increased levels of phosphorylated S6-kinase, suggestive of enhanced protein synthesis, and b) activation of the PI3K-AKT-mTORC2 pathway, and reduction of muscle-specific ubiquitin ligase mRNA levels, likely inhibiting proteasome-dependent degradation. Finally, TMZ also induces autophagy in untreated myotubes. Treatment of tumor hosts with TMZ does not modify food intake, body weight and muscle mass. By contrast, muscle fiber cross-sectional area and voluntary muscle grip strength are improved by TMZ. Conclusions: On the whole, these results suggest that TMZ positively interferes with skeletal muscle cell response to stress both in vitro and in vivo, supporting a possible reappraisal of TMZ in the treatment of conditions characterized by muscle atrophy, among which cancer cachexia and sarcopenia.