Trimetazidine combined with exercise improves exercise capacity and anti-fatal stress ability through enhancing mitochondrial quality control

Abstract

AimsTo explore the effects of trimetazidine combined with exercise on EC and anti-fatal stress ability, and illustrate the underlying mechanism. MethodsC57BL/6 mice were randomly assigned to four groups (n = 11 in each group): the control, exercise, trimetazidine and trimetazidine + exercise (TE) groups. Mice were accordingly given saline (ig), Aerobic exercise (AE), trimetazidine (ig), or a combination of trimetazidine (ig) and AE for five weeks. After the intervention, each group was randomly subdivided into rest and exhaustive exercise (EE) subgroups. The mice in the control-EE and TE-EE subgroups underwent fatal stress experiments. EC and anti-fatal stress ability were assessed respectively. Mitochondrial quality control (MQC) in skeletal muscle were measured at the protein level and the organelle level. Key findingsA significantly increased exhaustive swimming time was observed in exercise (39.10 ± 12.58 min vs 14.18 ± 4.37 min), trimetazidine (33.73 ± 8.45 min vs 14.18 ± 4.37 min) and TE groups (73.78 ± 18.95 min vs 14.18 ± 4.37 min) compared with that in the control group, and a synergistic effect was detected (P < 0.05). Fatal stress experiments successfully induced skeletal muscle damage, including increased creatine kinase activity, myofibrosis, and impaired antioxidative enzyme system, all those were significantly alleviated by trimetazidine supplementation combined with AE precondition (P < 0.05). Meanwhile, AE and trimetazidine alone or combined, significantly enhanced the MQC in normal mice by activating mitochondrial biogenesis, dynamics and mitophagy, and that in mice underwent fatal stress stimulus (P < 0.05). SignificanceThis study for the first time found that trimetazidine and AE have synergistic effects on improving EC. Moreover, the combination of both interventions enhances anti-fatal stress ability. Enhancing MQC may be a key mechanism of AE combined with trimetazidine that improves EC and anti-fatal stress ability.