The role of exercise-induced myokines in regulating metabolism

Exercise has beneficial effects in ameliorating metabolic disorders, and a combined therapeutic regimen of regular exercise and pharmaceutical treatment is often recommended. Exercise biology is complex and it involves various metabolic and molecular changes that translate into changes in substrate utilization, enzyme activation, and alternatively, improvement in exercise performance. Besides the effect of exercise on muscle metabolism, it has recently been discovered that contracting muscle can induce secretion of molecules called myokines. In the past few decades, a number of myokines have been discovered, such as interleukin-6, irisin, myostatin, interleukin-15, brain-derived neurotrophic factor, β-aminoisobutyric acid, meteorin-like, leukemia inhibitory factor, and secreted protein acidic and rich in cysteine, through secretome analysis. The existence of myokines has enhanced our understanding of how muscles communicate with other organs such as adipose tissue, liver, bone, and brain to exert beneficial effects of exercise at the whole body level. In this review, we focus on the role of these myokines in regulating local muscle metabolism as well as systemic metabolism in an autocrine/paracrine/endocrine fashion. The therapeutic potential of myokines and the natural or synthetic compounds known to date that regulate myokines are also discussed.     

Skeletal muscle as an immunogenic organ

During the past few years, a possible link between skeletal muscle contractile activity and immune changes has been established. This concept is based on the finding that exercise provokes an increase in a number of cytokines. We have suggested that cytokines and other peptides that are produced; expressed and released by muscle fibers and exert either paracrine or endocrine effects should be classified as 'myokines'. Human skeletal muscle has the capacity to express several myokines belonging to distinct different cytokine classes and contractile activity plays a role in regulating the expression of cytokines in skeletal muscle. In the present review, we focus on the myokines interleukin (IL)-6, IL-8 and IL-15 and their possible anti-inflammatory, immunoregulatory and metabolic roles.     

Effects of physical exercise on inflammatory markers of atherosclerosis

It is well established that physically fit individuals have a reduced risk of developing CVD (cardiovascular disease) and other age-related chronic disorders. Regular exercise is an established therapeutic intervention with an enormous range of benefits. Chronic low-grade systemic inflammation may be involved in atherosclerosis, diabetes and in pathogenesis of several chronic pathological conditions; recent findings confirm that physical activity induces an increase in the systemic levels of a number of cytokines and chemokines with anti-inflammatory properties. The possibility that regular physical exercise exerts anti-inflammation activity, being the interaction between contracting muscle and the other tissues and the circulating cells mediated through signals transmitted by "myokines" produced with muscle contractions. To date the list of myokines includes IL-6, IL-8, and IL-15. During muscle contractions are also released IL- 1receptor antagonis and sTNF-R, molecules that contribute to provide anti-inflammatory actions. Nevertheless discrepancies, analysis of available researches seem to confirm the efficacy of regular physical training as a nonpharmacological therapy having target chronic low-grade inflammation. Given this, physical exercise could be considerate a useful weapon against local vascular and systemic inflammation in atherosclerosis. Several mechanisms explain the positive effect of chronic exercise, nevertheless, these mechanisms do not fully enlighten all pathways by which exercise can decrease inflammation and endothelial dysfunction, and hence modulate the progression of the underlying disease progress.     

Roles of exercise and pharmacokinetics in cerivastatin-induced skeletal muscle toxicity.

Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are associated with adverse skeletal muscle effects, but the underlying mechanisms remain unclear. To determine whether toxicity involves the level of drug exposure in muscle tissue and to test the effect of exercise on cerivastatin (CVA)-induced skeletal muscle damage, female rats were administered vehicle or CVA at 0.1, 0.5, and 1.0 mg/kg/day by gavage for two weeks and exercised or not on treadmills for 20 min/day. Clinical chemistry and plasma and tissue pharmacokinetics were evaluated; light and transmission electron microscopy (TEM) of Type I and Type II fiber-predominant skeletal muscles were performed. Serum levels of AST, ALT, CK, and plasma lactic acid were significantly elevated dose-dependently. CVA treatment decreased psoas and quadriceps weights. At 1 mg/kg all muscles except soleus demonstrated degeneration. Exercise-exacerbated severity of CVA-induced degeneration was evident in all muscles sampled except soleus and quadriceps. Early mitochondrial involvement in toxicity is suggested by the numerous membranous whorls and degenerate mitochondria observed in muscles at 0.5 mg/kg. No significant differences in CVA concentrations between either EDL and soleus or plasma and muscle were found. We found that CVA had no effect on cleaved caspase 3. In summary, we found that treadmill exercise exacerbated the incidence and severity of CVA-induced damage in Type II fiber-predominant muscles. Tissue exposure is likely not the key factor mediating CVA-induced skeletal muscle toxicity.     

Development of gene delivery system into skeletal muscles by bubble liposomes and ultrasound

Skeletal muscle is a promising target tissue for the gene therapy of both muscle and non-muscle disorders. Gene transfer into muscle tissue can produce a variety of physiologically active proteins and may ultimately be applied to treatment of many diseases. A variety of methods have been studied to transfer genes into skeletal muscle, including viral and non-viral vectors. Recently, we have developed the polyethyleneglycol (PEG)-modified liposomes entrapping echo-contrast gas known as ultrasound (US) imaging gas. We have called the liposomes "Bubble liposomes" (BLs). We have further demonstrated that US-mediated eruption of BLs loaded with naked plasmid-DNA is a feasible and efficient technique for gene delivery. In this study, to assess the feasibility and the effectiveness of BLs for the gene therapy of disorders, we tried to deliver therapeutic genes (anti-inflammatory cytokine; IL-10 or anti-angiogenic factor; hK1-5) into skeletal muscles of arthritis or tumor model mice by the gene delivery system with BLs and US exposure. As a result, their disease symptom was efficiently improved by the systemic secretion of therapeutic proteins. Thus, this US-mediated BLs technique for muscle gene transfer may provide an effective noninvasive method for arthritis or cancer gene therapy in clinical use. In addition, it may be applicable for the gene therapy of other non-muscle and muscle disorders.     

Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis

Recent evidence suggests a coordinated regulation by the local renin-angiotensin system (RAS) and tissue kallikrein-kinin system (TKKS) of blood flow and substrate supply in oxidative red myofibres of skeletal muscle tissue during endurance exercise. The performance of these myofibres is dependent on the increased oxidation of substrates facilitated by augmenting nutritive blood flow and glucose uptake. Humoral factors released by the contracting fibres, such as adenosine and kinins, are suggested to be responsible for this metabolic adjustment. The considerable drain of blood volume and the enormous consumption of glucose during endurance exercise require a control mechanism for the maintenance of blood pressure (BP) and glucose homeostasis. This is achieved by the sympathetic nervous system and its subordinate RAS, which is located in the nutritive vessels and parenchyma of the red myofibres. The angiotensin-converting enzyme (ACE) is the primary enzyme responsible for kinin degradation during exercise, underscoring the important interrelationship between the RAS and the TKKS in the critical role of kinins in the multifactorial regulation of muscle bioenergetics and glucose and BP homeostasis. Importantly, overactivity of the ACE, as occurs in individuals displaying risk factors such as overweight, causes exaggerated BP response and reduced glucose disposal. If they persist over years, compensatory responses to this ACE overactivity, such as hypersecretion of insulin and compliance of the vessel walls, will inevitably be exhausted, leading ultimately to the manifestation of type 2 diabetes and hypertension. This concept also provides a unifying explanation for the beneficial effects of ACE-inhibitors and Angiotensin II receptor antagonists in the treatment of hypertension and insulin resistance.     

The influence of H1- and H2-receptor blockade on responses of resistance and capacitance vessels to noradrenaline in working skeletal muscles in cats

The effects of an H1- and H2-histamine receptor blockade upon the responses to noradrenaline (NA) of pre- and post-capillary segments of the microcirculation of the hind leg of cats were investigated. The responses to the resistance and capacitance vessels to noradrenaline injected in the coll. of femoral artery were reflected as changes in peripheral vascular resistance and in tissue volume respectively and determined during the following exercise before and after the H1 and H2-histamine receptor blockade. Muscular exercise was induced by sciatic nerve stimulation. The results show that H1- and H2-histamine receptor blockade applied together unmasked the vasodilator effects in both NA and that muscle exercise potentiated these effects in both pre- and post-capillary sections. This suggests that histamine may inhibit the response of the resistance and capacitance vessels in the working skeletal muscles to noradrenaline.     

Implications of cross-talk between tumour necrosis factor and insulin-like growth factor-1 signalling in skeletal muscle

1. Inflammation, particularly the pro-inflammatory cytokine tumour necrosis factor (TNF), increases necrosis of skeletal muscle. Depletion of inflammatory cells, such as neutrophils, cromolyn blockade of mast cell degranulation or pharmacological blockade of TNF reduces necrosis of dystrophic myofibres in the mdx mouse model of the lethal childhood disease Duchenne muscular dystrophy (DMD). 2. Insulin-like growth factor-1 (IGF-1) is a very important cytokine for maintenance of skeletal muscle mass and the transgenic overexpression of IGF-1 within muscle cells reduces necrosis of dystrophic myofibres in mdx mice. Thus, IGF-1 usually has the opposite effect to TNF. 3. Activation of TNF signalling via the c-Jun N-terminal kinase (JNK) can inhibit IGF-1 signalling by phosphorylation and conformational changes in insulin receptor substrate (IRS)-1 downstream of the IGF-1 receptor. Such silencing of IGF-1 signalling in situations where inflammatory cytokines are elevated has many implications for skeletal muscle in vivo. 4. The basis for these interactions between TNF and IGF-1 is discussed with specific reference to clinical consequences for myofibre necrosis in DMD and also for the wasting (atrophy) of skeletal muscles that occurs in very old people and in cachexia associated with inflammatory disorders.     

Identifying athletes at risk of hamstring strains and how to protect them

1. One common soft-tissue injury in sports involving sprinting and kicking a ball is the hamstring strain. Strain injuries often occur while the contracting muscle is lengthened, an eccentric contraction. We have proposed that the microscopic damage to muscle fibres that routinely occurs after a period of unaccustomed eccentric exercise can lead to a more severe strain injury. 2. An indicator of susceptibility for the damage from eccentric exercise is the optimum angle for torque. When this is at a short muscle length, the muscle is more prone to eccentric damage. It is known that subjects most at risk of a hamstring strain have a previous history of hamstring strains. By means of isokinetic dynamometry, we have measured the optimum angle for torque for nine athletes with a history of unilateral hamstring strains. We also measured optimum angles for 18 athletes with no previous history of strain injuries. It was found that mean optimum angle in the previously injured muscles was at a significantly shorter length than for the uninjured muscles of the other leg and for muscles of both legs in the uninjured group. This result suggests that previously injured muscles are more prone to eccentric damage and, therefore, according to our hypothesis, more prone to strain injuries than uninjured muscles. 3. After a period of unaccustomed eccentric exercise, if the exercise is repeated 1 week later, there is much less evidence of damage because the muscle has undergone an adaptation process that protects it against further damage. We propose that for athletes considered at risk of a hamstring strain, as indicated by the optimum angle for torque, a regular programme of mild eccentric exercise should be undertaken. This approach seems to work because evidence from a group of athletes who have implemented such a programme shows a significant reduction in the incidence of hamstring strains.     

Effects of exercise on AKT/PGC1-α/FOXO3a pathway and muscle atrophy in cisplatin-administered rat skeletal muscle

Cisplatin has been reported to cause side effects such as muscle wasting in humans and rodents. The physiological mechanisms involved in preventing muscle wasting, such as the regulation of AKT, PGC1-α, and autophagy-related factor FOXO3a by MuRF 1 and Atrogin-1, remain unclear following different types of exercise and in various skeletal muscle types. Eight-week-old male Wistar rats (n = 34) were assigned to one of four groups: control (CON, n = 6), cisplatin injection (1 mg/kg) without exercise (CC, n = 8), cisplatin (1 mg/kg) + resistance exercise (CRE, n = 9) group, and cisplatin (1 mg/kg) + aerobic exercise (CAE, n = 11). The CRE group performed progressive ladder exercise (starting with 10% of body weight on a 1-m ladder with 2-cm-interval grids, at 85°) for 8 weeks. The CAE group exercised by treadmill running (20 m/min for 60 min daily, 4 times/week) for 8 weeks. Compared with the CC group, the levels of the autophagy-related factors BNIP3, Beclin 1, LC3-II/I ratio, p62, and FOXO3a in the gastrocnemius and soleus muscles were significantly decreased in the CRE and CAE groups. The CRE and CAE groups further showed significantly decreased MuRF 1 and Atrogin-1 levels and increased phosphorylation of AKT, FOXO3a, and PGC1-α. These results suggest that both ladder and aerobic exercise directly affected muscle wasting by modulating the AKT/PGC1-α/FOXO3a signaling pathways regardless of the skeletal muscle type.     

Fatigue during intermittent-sprint exercise

There is a reversible decline in force production by muscles when they are contracting at or near their maximum capacity. The task-dependent nature of fatigue means that the mechanisms of fatigue may differ between different types of contractions. This paper examines how fatigue manifests during whole-body, intermittent-sprint exercise and discusses the potential muscular and neural mechanisms that underpin this fatigue. Fatigue is defined as a reversible, exercise-induced reduction in maximal power output (e.g. during cycling exercise) or speed (e.g. during running exercise), even though the task can be continued. The small changes in surface electromyogram (EMG), along with a lack of change in voluntary muscle activation (estimated from both percutaneous motor nerve stimulations and trans-cranial magnetic stimulation), indicate that there is little change in neural drive to the muscles following intermittent-sprint exercise. This, along with the observation that the decrease in EMG is much less than that which would be predicted from the decrease in power output, suggests that peripheral mechanisms are the predominant cause of fatigue during intermittent-sprint exercise. At the muscle level, limitations in energy supply, including phosphocreatine hydrolysis and the degree of reliance on anaerobic glycolysis and oxidative metabolism, and the intramuscular accumulation of metabolic by-products, such as hydrogen ions, emerge as key factors responsible for fatigue.     

Nitric oxide as a metabolic regulator during exercise: effects of training in health and disease

1. Accumulating animal and human data suggest that nitric oxide (NO) is important for both coronary and peripheral haemodynamic control and metabolic regulation during performance of exercise. 2. While still controversial, NO of endothelial origin is thought to potentiate exercise-induced hyperaemia, both in the peripheral and coronary circulations. The mechanism of release may include both acetylcholine derived from the neuromuscular junction and vascular shear stress. 3. A splice variant of neuronal nitric oxide synthase (NOS), nNOSmicro, incorporating an extra 34 amino acids, is expressed in human skeletal muscle. In addition to being a potential modulator of blood flow, skeletal muscle-derived NO is an important regulator of muscle contraction and metabolism. In particular, recent human data indicate that NO modulates muscle glucose uptake during exercise, independently of blood flow. 4. Exercise training in healthy individuals promotes adaptations in the various NO systems, which can increase NO bioavailability through a variety of mechanisms, including increased NOS enzyme expression and activity. Such adaptations likely contribute to increased exercise capacity and protection from cardiovascular events. 5. Cardiovascular risk factors, including hypercholesterolaemia, hypertension, diabetes and smoking, as well as established disease, are associated with impairment of the various NO systems. Given that NO is an important signalling mechanism during exercise, such impairment may contribute to limitations in exercise capacity through inadequate coronary or peripheral blood delivery and via metabolic effects. 6. Exercise training in individuals with elevated cardiovascular risk or established disease can increase NO bioavailability and may represent an important mechanism by which exercise training provides benefit in the setting of secondary prevention.     

Metabolic-vascular coupling in skeletal muscle: A potential role for capillary pericytes?

The matching of capillary blood flow to metabolic rate of the cells within organs and tissues is a critical microvascular function which ensures appropriate delivery of hormones and nutrients, and the removal of waste products. This relationship is particularly important in tissues where local metabolism, and hence capillary blood flow, must be regulated to avoid a mismatch between nutrient demand and supply that would compromise normal function. The consequences of a mismatch in microvascular blood flow and metabolism are acutely apparent in the brain and heart, where a sudden cessation of blood flow, for example following an embolism, acutely manifests as stroke or myocardial infarction. Even in more resilient tissues such as skeletal muscle, a short-term mismatch reduces muscle performance and exercise tolerance, and can cause intermittent claudication. In the longer-term, a microvascular-metabolic mismatch in skeletal muscle reduces insulin-mediated muscle glucose uptake, leading to disturbances in whole-body metabolic homeostasis. While the notion that capillary blood flow is fine-tuned to meet cellular metabolism is well accepted, the mechanisms that control this function and where and how different parts of the vascular tree contribute to capillary blood flow regulation remain poorly understood. Here, we discuss the emerging evidence implicating pericytes, mural cells that surround capillaries, as key mediators that match tissue metabolic demand with adequate capillary blood flow in a number of organs, including skeletal muscle.     

Adaptations of skeletal muscle to prolonged, intense endurance training

1. Endurance exercise induces a variety of metabolic and morphological responses/adaptations in skeletal muscle that function to minimize cellular disturbances during subsequent training sessions. 2. Chronic adaptations in skeletal muscle are likely to be the result of the cumulative effect of repeated bouts of exercise, with the initial signalling responses leading to such adaptations occurring after each training session. 3. Recently, activation of the mitogen-activated protein kinase signalling cascade has been proposed as a possible mechanism involved in the regulation of many of the exercise-induced adaptations in skeletal muscle. 4. The protein targets of AMP-activated protein kinase also appear to be involved in both the regulation of acute metabolic responses and chronic adaptations to exercise. 5. Endurance training is associated with an increase in the activities of key enzymes of the mitochondrial electron transport chain and a concomitant increase in mitochondrial protein concentration. These morphological changes, along with increased capillary supply, result in a shift in trained muscle to a greater reliance on fat as a fuel with a concomitant reduction in glycolytic flux and tighter control of acid-base status. Taken collectively, these adaptations result in an enhanced performance capacity.     

IMPORTANCE OF THE 'CROSSOVER' CONCEPT IN EXERCISE METABOLISM

1. The ‘crossover’ concept is a model of substrate supply during exercise which makes the following predictions. 2. Lipid is the major fuel (approximatel. 60%) for non-contracting skeletal muscle and the body at rest. 3. Energy flux, as determined by exercise intensity, is the major factor in determining the balance of substrate utilization during exercise. Thus, moderate and greater exercise intensities increase contraction-induced muscle glycogenosis and glycolysis, increase recruitment of fast-twitch muscle fibres, increase sympathetic nervous system activity and down-regulate mitochondrial fatty acid uptake. 4. Glycogen and glucose utilization scales exponentially to relative exercise power output with a greater gain in glycogen than in glucose use at high power. The relationship between free fatty acid flux and power output is an inverted hyperbola. Consequently, at high power outputs, the role of lipid oxidation is diminished. 5. Factors such as endurance training, energy supply, as influenced by dietary manipulation, and prior exercise play secondary roles in determining the balance of substrate utilization durin. exercise. 6. Comparisons of the metabolic responses in subjects engaged in activities requiring vastly different metabolic rates or comparisons of subjects of different gender, age or training status require normalization of dat. to total energy flux.     

Protective effect of mitochondrial KATP activation in an isolated gracilis model of ischemia and reperfusion in dogs

Adenosine triphosphate-sensitive potassium channel (KATP) openers protect ischemic myocardium by direct protection of cardiac myocytes, which is thought to be a result of activation of mitochondrial KATP (mKATP). KATP is expressed in skeletal muscle, and the purpose of this study was to determine the effect of the mKATP opener BMS-191095 on infarct size in an isolated gracilis model of ischemia and reperfusion in dogs. The right and left gracilis muscles were isolated in anesthetized dogs except for the artery and vein supplying these muscles (pedicle). BMS-191095 (0.4 mg) or vehicle were infused directly into the artery supplying each gracilis muscle (each animal had one drug-treated and one vehicle-treated muscle). The pedicle was completely occluded for 5 hours followed by 48 hours of reperfusion, after which infarct size was determined. In the vehicle-treated gracilis muscles, significant necrosis was observed (82% +/- 3% of gracilis muscle). BMS-191095 significantly reduced the infarct size in the contralateral gracilis muscle (55% +/- 6%). Reflow into the gracilis muscle was significantly greater in BMS-191095-treated muscles. BMS-191095 appears to reduce damage in ischemic/reperfused skeletal muscle, suggesting that mKATP activation is an important protective mechanism in this tissue.     

Zebrafish muscular disease models towards drug discovery

Background: Zebrafish is an amenable vertebrate model useful for the study of development and genetics. Small molecule screenings in zebrafish have successfully identified several drugs that affect developmental process. Objective: This review covers the basics of zebrafish muscle system such as muscle development and muscle defects. It also reviews the potential use of zebrafish for chemical screening with regards to muscle disorders. Conclusion: During embryogenesis, zebrafish start to coil their body by contracting trunk muscles 17 h postfertilization, indicating that a motor circuit and skeletal muscle are functionally developed at early stages. Mutagenesis screens in zebrafish have identified many motility mutants that display morphological or functional defects in the CNS, clustering defects of acetylcholine receptors at the neuromuscular junctions or pathological defects of muscles. Most of the muscular mutants are useful as animal models of human muscle disease such as muscle dystrophy. As zebrafish live in water, pharmacological drugs are easily assayable during development, and thus zebrafish may be used to determine novel drugs that mitigate muscle disease.     

Adverse and beneficial functions of proteolytic enzymes in skeletal muscle. An overview

Proteolytic enzymes (proteases) comprise a family of enzymes which hydrolyse protein or peptide substrates in the generalised process of intracellular protein degradation, a process essential for the normal functioning of all cells. Proteases may also have a wide range of additional functions, including metabolic control of physiologically active oligopeptides or precursor protein forms, antigen presentation/recognition by the major histocompatibility complex in the cellular immune response, as well as in digestion, blood clotting, complement activation, etc. In this article, the nomenclature and classification of proteolytic enzymes in skeletal muscle, and their role in normal muscle physiological processes have been reviewed, including exercise, muscle development and ageing. Although proteases play an important role in normal muscle functioning, in pathological situations the enzymes may themselves be regarded as 'toxic agents' in terms of their damaging effects on muscle tissue. Muscle damage resulting from inappropriate activity of proteolytic enzymes in muscle wasting associated with muscular dystrophies, denervation atrophy, inflammatory myopathies, cancer, sepsis, diabetes and alcoholism have been reviewed. In addition, evidence that the adverse effects of drugs known to induce muscle wasting, such as corticosteroids, (or beneficial effects of growth promoting drugs) may be mediated via proteolytic enzymes is also reviewed.     

Effect of low-voltage electrical stimulation on angiogenic growth factors in ischaemic rat skeletal muscle

1. Low-voltage electrical stimulation (LVES) in skeletal muscle at a level far below the threshold of muscle contraction has been reported to promote local angiogenesis. However, the mechanism underlying the promotion of local angiogenesis by LVES has not been fully elucidated. In the present study, we evaluated whether angiogenic factors, such as vascular endotherial growth factor (VEGF), hepatocyte growth factor (HGF) and fibroblast growth factor (FGF), as well as other disadvantageous factors, such as inflammation (interleukin (IL)-6) and hypoxia (hypoxia-inducible factor (HIF)-1alpha), contribute to the local angiogenesis produced by LVES. 2. We completely excised bilateral femoral arteries of male Sprague-Dawley rats. After the operation, electrodes were implanted onto the centre of the fascia of the bilateral tibialis anterior (TA) muscles, tunnelled subcutaneously and exteriorized at the level of the scapulae. The right TA muscles of rats were stimulated continuously at a stimulus frequency of 50 Hz, with a 0.1 V stimulus strength and no interval, for 5 days. The left TA muscles served as controls. 3. We found that both VEGF and HGF protein were significantly increased by LVES in stimulated muscles compared with control. The VEGF level of the LVES group was 89.10 +/- 17.19 ng/g, whereas that of the control group was 65.07 +/- 12.88 ng/g, as determined by ELISA (P < 0.05). The HGF level of the LVES and control groups was 8.52 +/- 1.96 and 5.80 +/- 2.14 ng/g, respectively (P < 0.05). In contrast, there was no difference in FGF, IL-6 and HIF-1alpha between the LVES and control groups. 4. These results suggest that LVES in a hindlimb ischaemia model of rats increases not only VEGF, but also HGF, production, which may be the main mechanism responsible for the angiogenesis produced by LVES.