Trimetazidine restores the positive adaptation to exercise training by mitigating statin‐induced skeletal muscle injury

Abstract

BackgroundExercise rehabilitation is demonstrated to improve the prognosis of patients with coronary heart disease (CHD). Statins, as the key medicine to lower cholesterol in CHD, result in skeletal muscle injury and impair exercise training adaptation. Energy metabolism dysfunction is identified as the potential mechanism underlying statin‐induced skeletal muscle injury. In this study, we investigated the effects of the metabolic modulator trimetazidine on skeletal muscle energy metabolism and statin‐associated exercise intolerance.MethodsHigh‐fat fed apolipoprotein E knockout (ApoE−/−) mice were given aerobic exercise and administrated simvastatin, trimetazidine, or simvastatin plus trimetazidine by gavage. Exercise capacity was evaluated at the end of the treatment by hanging grid test, forelimb grip strength, and running tolerance test. Plasma glucose, lipid, and creatine kinase concentrations were measured at the end of the treatment. After sacrifice, gastrocnemii were stored for assessment of muscle morphology and fibre type. Energy metabolism was estimated by plasma lactic acid concentration, ragged red fibres, and glycogen stores. Activities of mitochondrial complex III, citrate synthase activity, and membrane potential were measured to assess mitochondrial function. Oxidative stress was also evaluated by superoxide in mitochondria, superoxide dismutase activity, and glutathione redox state.ResultsIn high‐fat fed ApoE−/− mice, exercise training had no effect on lipid concentrations. Lower lipid concentrations with increased creatine kinase were observed with additional simvastatin treatment. Exercise capacity increased significantly in response to exercise training alone but was blunted by the addition of simvastatin. Similarly, cross‐sectional area of muscle fibres and the proportion of slow‐twitch fibres increased in the exercise group but decreased in the simvastatin plus exercise group. Additionally, simvastatin increased centronucleated fibres and induced energy metabolism dysfunction by inhibiting complex III activity and thus promoted oxidative stress in gastrocnemius. We demonstrated that trimetazidine could reverse simvastatin‐induced exercise intolerance and muscle damages. We also found the ability of trimetazidine in restoration of muscle fibre hypertrophy and facilitating fast‐to‐slow type shift. The energy metabolism dysfunction and oxidative stress in gastrocnemii were rescued by trimetazidine.ConclusionsTrimetazidine alleviated statin‐related skeletal muscle injury by restoration of oxidative phenotype and increasing fibre cross‐sectional areas in response to exercise training. Correspondingly, the exercise training adaptation were improved in high‐fat fed ApoE−/− mice. Moreover, trimetazidine is able to exert its positive effects without affecting the beneficial lipid‐lowering properties of the statins. Thus, trimetazidine could be prescribed to remedy the undesirable statins‐induced exercise intolerance during cardiac rehabilitation in patients with CHD.

Astragaloside IV reverses simvastatin‐induced skeletal muscle injury by activating the AMPK‐PGC‐1α signalling pathway

“…One study has confirmed that TMZ enhanced mitochondrial respiratory function and promoted mitochondrial biosynthesis in cardiomyocytes (Shi, Shangguan, Zhang, Li, & Li, ). A recent study also showed that TMZ attenuated SMV‐associated skeletal muscle injury in ApoE −/− mice (Song et al, ), which is an established model of atherosclerosis that develops hyperlipidaemia and atherosclerotic (Sfyri et al, ).…”

“…Statins provide great benefits to patients with coronary heart disease (Ballantyne, Corsini, & Davidson, ). However, epidemiological studies have shown that 7–29% of patients who have took statins complained about statin‐associated muscle symptoms, such as myalgia, fatigue, and spasm, which severely impair exercise tolerance (Song et al, ). A more serious effect is statin‐induced rhabdomyolysis, which can result in the death of the patient (Thompson, Clarkson, & Karas, ).…”

“…Citrate synthase (CS), a part of the mitochondrial matrix, is commonly regarded as a marker of mitochondrial oxidative capacity (de Castro Bras et al, ). SMV reduces the activity of mitochondrial complex III and mitochondrial matrix CS and impairs the mitochondrial membrane potential (Song et al, ). Studies have shown that most leaked electrons arise from the mitochondrial complex III, and these leaked electrons generate a large amount of reactive oxygen species (ROS) to further form hydrogen peroxide (Liu, , ).…”

MicroRNAs in muscle wasting

“…[32][33][34][35][36][37] Moreover, exercise mimetics such as trimetazidine are of interest in the therapy of muscle atrophy, 38 but also need companion biomarkers. [32][33][34][35][36][37] Moreover, exercise mimetics such as trimetazidine are of interest in the therapy of muscle atrophy, 38 but also need companion biomarkers.…”

“…Resistance exercise has been of particular interest in sarcopenia and also in cachexia. [32][33][34][35][36][37] Moreover, exercise mimetics such as trimetazidine are of interest in the therapy of muscle atrophy, 38 but also need companion biomarkers. MyomiRs are strongly regulated in resistance exercise, and their expression patterns in muscle as well as their plasma pattern levels may have the potential to serve as biomarkers for exercise, and regular monitoring in sarcopenic or cachectic patients could prevent detrimental over-exercise.…”