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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\u2010induced skeletal muscle injury. In this study, we investigated the effects of the metabolic modulator trimetazidine on skeletal muscle energy metabolism and statin\u2010associated exercise intolerance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>High\u2010fat fed apolipoprotein E knockout (ApoE<jats:sup>\u2212\/\u2212<\/jats:sup>) 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In high\u2010fat fed ApoE<jats:sup>\u2212\/\u2212<\/jats:sup> 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\u2010sectional area of muscle fibres and the proportion of slow\u2010twitch 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\u2010induced exercise intolerance and muscle damages. We also found the ability of trimetazidine in restoration of muscle fibre hypertrophy and facilitating fast\u2010to\u2010slow type shift. The energy metabolism dysfunction and oxidative stress in gastrocnemii were rescued by trimetazidine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Trimetazidine alleviated statin\u2010related skeletal muscle injury by restoration of oxidative phenotype and increasing fibre cross\u2010sectional areas in response to exercise training. Correspondingly, the exercise training adaptation were improved in high\u2010fat fed ApoE<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Moreover, trimetazidine is able to exert its positive effects without affecting the beneficial lipid\u2010lowering properties of the statins. Thus, trimetazidine could be prescribed to remedy the undesirable statins\u2010induced exercise intolerance during cardiac rehabilitation in patients with CHD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12250","type":"journal-article","created":{"date-parts":[[2017,11,20]],"date-time":"2017-11-20T02:36:38Z","timestamp":1511145398000},"page":"106-118","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Trimetazidine restores the positive adaptation to exercise training by mitigating statin\u2010induced skeletal muscle injury"],"prefix":"10.1002","volume":"9","author":[{"given":"Ming","family":"Song","sequence":"first","affiliation":[{"name":"The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang\u2010fang","family":"Chen","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi\u2010hui","family":"Li","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Wang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology Qilu Hospital of Shandong University  Jinan Shandong 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University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Zhong","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng\u2010xiong","family":"Tang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology Qilu Hospital of Shandong University  Jinan Shandong China"},{"name":"Department of Emergency Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Han","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology Qilu Hospital of Shandong University  Jinan Shandong China"},{"name":"Department of General Practice Qilu Hospital of Shandong University  Jinan Shandong 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