Trimetazidine and exercise provide comparable improvements to high fat diet-induced muscle dysfunction through enhancement of mitochondrial quality control

Abstract

Obesity induces skeletal muscle dysfunction. The pathogenesis of which appears to substantially involve mitochondrial dysfunction, arising from impaired quality control. Exercise is a major therapeutic strategy against muscle dysfunction. Trimetazidine, a partial inhibitor of lipid oxidation, has been proposed as a metabolic modulator for several cardiovascular pathologies. However, the effects of Trimetazidine on regulating skeletal muscle function are largely unknown. Our present study used cell culture and obese mice models to test a novel hypothesis that Trimetazidine could improve muscle atrophy with similar results to exercise. In C2C12 cells, high palmitic acid-induced atrophy and mitochondrial dysfunction, which could be reversed by the treatment of Trimetazidine. In our animal models, with high-fat diet-induced obesity associated with skeletal muscle atrophy, Trimetazidine prevented muscle dysfunction, corrected metabolic abnormalities, and improved mitochondrial quality control and mitochondrial functions similarly to exercise. Thus, our study suggests that Trimetazidine successfully mimics exercise to enhance mitochondrial quality control leading to improved high-fat diet-induced muscle dysfunction.

Trimetazidine and exercise offer analogous improvements to the skeletal muscle insulin resistance of mice through Nrf2 signaling

“…Skeletal muscle is an important target organ in IR. We found that TMZ, similar to exercise, had a beneficial effect on skeletal muscle in healthy and obese mice by enhancing MQC 14 22. Previous studies on patients with diabetic have shown that TMZ improves glucose usage as well as reduces glycemia and glycated hemoglobin with effects comparable to exercise 20 21.…”

“…Furthermore, Fragasso et al 40 found that in patients with systolic heart failure, TMZ treatment was associated with improved left ventricular function and regulated whole-body energy metabolism. In a previous study, we found that the body composition in HFD mice significantly improved following TMZ treatment, with increased muscle mass, decreased visceral fat, and a trend for a decrease in body weight 22. These findings suggested that TMZ may bring about beneficial effects on IR.…”

“…Improvement of glucose utilization as well as the reduction of glycemia and glycated hemoglobin by the “comparable-to-exercise” effect of TMZ have also been observed in patients with diabetes 20 21. Further, our previous study indicated that TMZ and exercise both improve muscle function, increasing loaded swimming time and inverted hanging time in healthy mice and HFD-induced obese mice through enhancing MQC 14 22. Uruno et al found that specific induction of Nfr2 in skeletal muscles markedly ameliorated IR induced via a HFD, protecting mice from obesity 23…”

“…In a previous study, we found that the body composition in HFD mice significantly improved following TMZ treatment, with increased muscle mass, decreased visceral fat, and a trend for a decrease in body weight. 22 These findings suggested that TMZ may bring about beneficial effects on IR.…”

“…Fat made up 45% and 18% of total calories in the HFD and ND groups, respectively. Mice in the HFD+EX group underwent an exercise training program as previously described,13 22 whereas mice in the HFD+TMZ group were intragastrically administered TMZ (10 mg/kg/day; Schweageer Pharmaceuticals). Mice in the remaining groups were administered an equal amount of saline.…”