Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue

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.

Section: Discussionsupporting

confidence: 71%

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

Song

Chen

et al. 2017

“…Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), enriched in tissues with high oxidative capacity, is a key driver of metabolic programming in skeletal muscle in health and disease regulating endurance, fibre-type switching, and insulin sensitivity. 37 Collectively, these observations support the conclusion that metabolic events occurring within myofibers condition muscle histology and performance. By inducing a moderate level of oxidative stress, physical exercise up-regulates PGC1α essential for mitochondriogenesis promoting oxidative fibre formation at the expense of glycolytic fibre formation, 32 improving exercise performance, 33 increasing muscle mass and strength and resistance to muscle wasting, 34 and augmenting early steps in the activation and proliferation of adult muscle stem cells.…”

Section: Altered Myofiber Metabolismsupporting

confidence: 58%

Cellular and molecular mechanisms of sarcopenia: the S100B perspective

Riuzzi

Sorci

Arcuri

et al. 2018

Primary sarcopenia is a condition of reduced skeletal muscle mass and strength, reduced agility, and increased fatigability and risk of bone fractures characteristic of aged, otherwise healthy people. The pathogenesis of primary sarcopenia is not completely understood. Herein, we review the essentials of the cellular and molecular mechanisms of skeletal mass maintenance; the alterations of myofiber metabolism and deranged properties of muscle satellite cells (the adult stem cells of skeletal muscles) that underpin the pathophysiology of primary sarcopenia; the role of the Ca2+‐sensor protein, S100B, as an intracellular factor and an extracellular signal regulating cell functions; and the functional role of S100B in muscle tissue. Lastly, building on recent results pointing to S100B as to a molecular determinant of myoblast–brown adipocyte transition, we propose S100B as a transducer of the deleterious effects of accumulation of reactive oxygen species in myoblasts and, potentially, myofibers concurring to the pathophysiology of sarcopenia.

“…Oxidative stress, the imbalance between pro‐oxidant generation and antioxidant defence, has been implicated in pathological conditions of skeletal muscle, including sarcopenia, denervation, and cancer cachexia . Excess levels of reactive oxygen species (ROS) impair contractile function of skeletal muscle and activate proteases that are associated with degradation of contractile machinery .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching

Ahn

Ranjit

Premkumar

et al. 2019

Background Excess reactive oxygen species (ROS) and muscle weakness occur in parallel in multiple pathological conditions. However, the causative role of skeletal muscle mitochondrial ROS (mtROS) on neuromuscular junction (NMJ) morphology and function and muscle weakness has not been directly investigated. Methods We generated mice lacking skeletal muscle‐specific manganese‐superoxide dismutase (m Sod2 KO) to increase mtROS using a cre‐Lox approach driven by human skeletal actin. We determined primary functional parameters of skeletal muscle mitochondrial function (respiration, ROS, and calcium retention capacity) using permeabilized muscle fibres and isolated muscle mitochondria. We assessed contractile properties of isolated skeletal muscle using in situ and in vitro preparations and whole lumbrical muscles to elucidate the mechanisms of contractile dysfunction. Results The m Sod2 KO mice, contrary to our prediction, exhibit a 10–15% increase in muscle mass associated with an ~50% increase in central nuclei and ~35% increase in branched fibres ( P < 0.05). Despite the increase in muscle mass of gastrocnemius and quadriceps, in situ sciatic nerve‐stimulated isometric maximum‐specific force ( N /cm 2 ), force per cross‐sectional area, is impaired by ~60% and associated with increased NMJ fragmentation and size by ~40% ( P < 0.05). Intrinsic alterations of components of the contractile machinery show elevated markers of oxidative stress, for example, lipid peroxidation is increased by ~100%, oxidized glutathione is elevated by ~50%, and oxidative modifications of myofibrillar proteins are increased by ~30% ( P < 0.05). We also find an approximate 20% decrease in the intracellular calcium transient that is associated with specific force deficit. Excess superoxide generation from the mitochondrial complexes causes a deficiency of succinate dehydrogenase and reduced complex‐II‐mediated respiration and adenosine triphosphate generation rates leading to severe exercise intolerance (~10 min vs. ~2 h in wild type, P < 0.05). Conclusions Increased skeletal muscle mtROS is sufficient to elicit NMJ disruption and contractile abnormalities, but not muscle atrophy, suggesting new roles for mitochondrial oxidative stress in maintenance of muscle mass through increased fibre branching.