15. July 2019


Cytokine expression and secretion by skeletal muscle cells: regulatory mechanisms and exercise effects.

Peake JM, Della Gatta P, Suzuki K, Nieman DC. Exerc Immunol Rev 2015 21: 8-25

Cytokines are important mediators of various aspects of health and disease, including appetite, glucose and lipid metabolism, insulin sensitivity, skeletal muscle hypertrophy and atrophy. Over the past decade or so, considerable attention has focused on the potential for regular exercise to counteract a range of disease states by modulating cytokine production. Exercise stimulates moderate to large increases in the circulating concentrations of interleukin (IL)-6, IL-8, IL- 10, IL-1 receptor antagonist, granulocyte-colony stimulating factor, and smaller increases in tumor necrosis factor-α, monocyte chemotactic protein-1, IL-1β, brain-derived neurotrophic factor, IL-12p35/p40 and IL-15. Although many of these cytokines are also expressed in skeletal muscle, not all are released from skeletal muscle into the circulation during exercise. Conversely, some cytokines that are present in the circulation are not expressed in skeletal muscle after exercise. The reasons for these discrepant cytokine responses to exercise are unclear. In this review, we address these uncertainties by summarizing the capacity of skeletal muscle cells to produce cytokines, analyzing other potential cellular sources of circulating cytokines during exercise, and discussing the soluble factors and intracellular signaling pathways that regulate cytokine synthesis (e.g., RNA-binding proteins, microRNAs, suppressor of cytokine signaling proteins, soluble receptors).

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Exercise, skeletal muscle and inflammation: ARE-binding proteins as key regulators in inflammatory and adaptive networks

Beiter T, Hoene M, Prenzler F, Mooren FC, Steinacker JM, Weigert C, Nieß AM,
Munz B. Exerc Immunol Rev 2015 21: 42-57

The role of inflammation in skeletal muscle adaptation to exercise is complex and has hardly been elucidated so far. While the acute inflammatory response to exercise seems to promote skeletal muscle training adaptation and regeneration, persistent, low-grade inflammation, as seen in a multitude of chronic diseases, is obviously detrimental. The regulation of cytokine production in skeletal muscle cells has been relatively well studied, yet little is known about the compensatory and anti-inflammatory mechanisms that resolve inflammation and restore tissue homeostasis. One important strategy to ensure sequential, timely and controlled resolution of inflammation relies on the regulated stability of mRNAs encoding pro-inflammatory mediators. Many key transcripts in early immune responses are characterized by the presence of AU-rich elements (AREs) in the 3'-untranslated regions of their mRNAs, allowing efficient fine-tuning of gene expression patterns at the post-transcriptional level. AREs exert their function by recruiting particular RNA-binding proteins, resulting, in most cases, in de-stabilization of the target transcripts. The best-characterized ARE-binding proteins are HuR, CUGBP1, KSRP, AUF1, and the three ZFP36 proteins, especially TTP/ZFP36. Here, we give a general introduction into the role of inflammation in the adaptation of skeletal muscle to exercise. Subsequently, we focus on potential roles of ARE-binding proteins in skeletal muscle tissue in general and specifically exercise-induced skeletal muscle remodeling. Finally, we present novel data suggesting a specific function of TTP/ZFP36 in exercise-induced skeletal muscle plasticity.

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The effect of exercise on obesity, body fat distribution and risk for type 2 diabetes

Goedecke JH, Micklesfield LK  Med Sport Sci 2014 60: 82-93

It is well known that obesity is a major risk factor for type 2 diabetes (T2D), while exercise is known to reduce body fatness and attenuate the risk of T2D. The aim of this chapter is to examine the interactions between exercise, obesity and body fat distribution, and the risk for T2D. Firstly, we show that body fatness, in particular visceral adipose tissue (VAT) accumulation, is associated with insulin resistance and incident T2D. We then show that aerobic exercise of sufficient intensity and volume results in a decrease in body fat and VAT. Conversely, sedentary behavior and physical inactivity are associated with increased body fat and VAT. Finally, the chapter examines the interaction between physical activity (PA), obesity and risk for T2D and shows that both obesity and PA are significant independent predictors of incident T2D, but the magnitude of risk imparted by high levels of body fat is much greater than that of low levels of PA. Further, we show that obese physically active individuals are at greater risk for incident T2D than normal-weight physically inactive individuals. The mechanisms underlying this complex interaction include the ability of exercise to increase free fatty acid oxidation to match high rates of lipolysis associated with obesity, as well as the effects of exercise on adipokine, cytokine and myokine secretion. Exercise, of sufficient volume and intensity, is therefore recommended to reduce obesity, centralization of body fat, and risk of T2D.

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Physical activity, air pollution and the brain

Bos I, De Boever P, Int Panis L, Meeusen R. Sports Med 2014 44: 1505-1518

This review introduces an emerging research field that is focused on studying the effect of exposure to air pollution during exercise on cognition, with specific attention to the impact on concentrations of brain-derived neurotrophic factor (BDNF) and inflammatory markers. It has been repeatedly demonstrated that regular physical activity enhances cognition, and evidence suggests that BDNF, a neurotrophin, plays a key role in the mechanism. Today, however, air pollution is an environmental problem worldwide and the high traffic density, especially in urban environments and cities, is a major cause of this problem. During exercise, the intake of air pollution increases considerably due to an increased ventilation rate and particle deposition fraction. Recently, air pollution exposure has been linked to adverse effects on the brain such as cognitive decline and neuropathology. Inflammation and oxidative stress seem to play an important role in inducing these health effects. We believe that there is a need to investigate whether the well-known benefits of regular physical activity on the brain also apply when physical activity is performed in polluted air. We also report our findings about exercising in an environment with ambient levels of air pollutants. Based on the latter results, we hypothesize that traffic-related air pollution exposure during exercise may inhibit the positive effect of exercise on cognition.

Metabolic and endocrine response to exercise: sympathoadrenal integration with skeletal muscle

Ball D. J Endocrinol. 2015 224: R79-95

Skeletal muscle has the capacity to increase energy turnover by ∼1000 times its resting rate when contracting at the maximum force/power output. Since ATP is not stored in any appreciable quantity, the muscle requires a coordinated metabolic response to maintain an adequate supply of ATP to sustain contractile activity. The integration of intracellular metabolic pathways is dependent upon the cross-bridge cycling rate of myosin and actin, substrate availability and the accumulation of metabolic byproducts, all of which can influence the maintenance of contractile activity or result in the onset of fatigue. In addition, the mobilisation of extracellular substrates is dependent upon the integration of both the autonomic nervous system and endocrine systems to coordinate an increase in both carbohydrate and fat availability. The current review examines the evidence for skeletal muscle to generate power over short and long durations and discusses the metabolic response to sustain these processes. The review also considers the endocrine response from the perspective of the sympathoadrenal system to integrate extracellular substrate availability with the increased energy demands made by contracting skeletal muscle. Finally, the review briefly discusses the evidence that muscle acts in an endocrine manner during exercise and what role this might play in mobilising extracellular substrates to augment the effects of the sympathoadrenal system.

Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulation

Benatti FB, Pedersen BK. Nat Rev Rheumatol 2015 11: 86-97

Persistent systemic inflammation, a typical feature of inflammatory rheumatic diseases, is associated with a high cardiovascular risk and predisposes to metabolic disorders and muscle wasting. These disorders can lead to disability and decreased physical activity, exacerbating inflammation and the development of a network of chronic diseases, thus establishing a 'vicious cycle' of chronic inflammation. During the past two decades, advances in research have shed light on the role of exercise as a therapy for rheumatic diseases. One of the most important of these advances is the discovery that skeletal muscle communicates with other organs by secreting proteins called myokines. Some myokines are thought to induce anti-inflammatory responses with each bout of exercise and mediate long-term exercise-induced improvements in cardiovascular risk factors, having an indirect anti-inflammatory effect. Therefore, contrary to fears that physical activity might aggravate inflammatory pathways, exercise is now believed to be a potential treatment for patients with rheumatic diseases. In this Review, we discuss how exercise disrupts the vicious cycle of chronic inflammation directly, after each bout of exercise, and indirectly, by improving comorbidities and cardiovascular risk factors. We also discuss the mechanisms by which some myokines have anti-inflammatory functions in inflammatory rheumatic diseases.

Exercise in pediatric type 1 diabetes

Tran BD, Galassetti P. Pediatr Exerc Sci. 2014 26: 375-383

The beneficial effects of exercise, including reduction of cardiovascular risk, are especially important in children with type 1 diabetes (T1DM), in whom incidence of lifetime cardiovascular complications remains elevated despite good glycemic control. Being able to exercise safely is therefore a paramount concern. Dysregulated metabolism in T1DM however, causes frequent occurrence of both hypo- and hyperglycemia, the former typically associated with prolonged, moderate exercise, the latter with higher intensity, if shorter, challenges. While very few absolute contraindications to exercising exist in these children, exercise should not be started with glycemia outside the 80-250 mg/dl range. Within this glycemic range, careful adjustments in insulin administration (reduction or infusion rate via insulin pumps, or overall reduction of dosage of multiple injections) should be combined with carbohydrate ingestion before/during exercise, based on prior, individual experience with specific exercise formats. Unfamiliar exercise should always be tackled with exceeding caution, based on known responses to other exercise formats. Finally, gaining a deep understanding of other complex exercise responses, such as the modulation of inflammatory status, which is a major determinant of the cardio-protective effects of exercise, can help determine which exercise formats and which individual metabolic conditions can lead to maximally beneficial health effects.

Exercise-induced changes in inflammatory processes: Implications for thrombogenesis in cardiovascular disease

Chen YW, Apostolakis S, Lip GY. Ann Med 2014 46: 439-455

Sedentary lifestyle is a risk factor and a strong predictor for chronic disease and premature death. Low-grade inflammation has been proved a key player in the pathogenesis of cardiovascular disease. Inflammatory processes have been also involved in maintaining the balance between coagulation and fibrinolysis. In addition, an inverse linear dose-response relation between physical activity and mortality risks has also been reported. However, the favorable effects of structured exercise programs and the independent contribution of physical activity to cardiovascular risk are still under investigation. In response to heavy exercise, interleukin-6 (IL-6) is secreted by contracting skeletal muscles, followed by an acute reactant release of C-reactive protein (CRP). Both CRP and IL-6 can stimulate monocyte tissue factor production, provoke platelet hyperreactivity, promote fibrinogen biosynthesis, and enhance microparticle formation and erythrocyte aggregability, thus triggering prothrombotic state. By contrast, regular exercise and physical activity are protective against all-cause mortality through suppressing pro-inflammatory cytokine production, enhancing anti-inflammatory mediators and antioxidant development, and promoting fibrinolytic activity. Low-load resistance exercise also plays an advantageous role in thrombogenesis by reducing inflammatory processes and potentiating fibrinolytic features. In the present review article, we provide an overview of the impact of different modes and intensities of physical activity on vascular inflammation and thrombogenesis.

Skeletal muscle is an endocrine organ

Iizuka K, Machida T, Hirafuji M. J Pharmacol Sci 2014 125: 125-131

Skeletal muscle plays a key role in postural retention as well as locomotion for maintaining the physical activities of human life. Skeletal muscle has a second role as an elaborate energy production and consumption system that influences the whole body's energy metabolism. Skeletal muscle is a specific organ that engenders a physical force, and exercise training has been known to bring about multiple benefits for human health maintenance and/or improvement. The mechanisms underlying the improvement of the human physical condition have been revealed: skeletal muscle synthesizes and secretes multiple factors, and these muscle-derived factors, so-called as myokines, exert beneficial effects on peripheral and remote organs. In this short review, we focus on the third aspect of skeletal muscle function - namely, the release of multiple types of myokines, which constitute a broad network for regulating the function of remote organs as well as skeletal muscle itself. We conclusively show that skeletal muscle is one of the endocrine organs and that understanding the mechanisms of production and secretion of myokines may lead to a new pharmacological approach for treatment of clinical disorders.

The effect of physical activity on mediators of inflammation

Nimmo MA, Leggate M, Viana JL, King JA. Diabetes Obes Metab 2013 15 Suppl 3: 51-60

Being physically active and undertaking exercise on a regular basis are critical lifestyle behaviours which protect against the development of numerous chronic metabolic conditions. One of the key mechanisms by which physical activity exerts favourable health effects appears to be due to its capacity to reduce chronic low-grade inflammation. Single bouts of exercise have a potent anti-inflammatory influence with recent advances describing important effects of acute exercise on inflammatory mediators produced within skeletal muscle (myokines), adipose tissue (adipokines) and leucocytes. The accumulated effects of physical activity or exercise training on systemic inflammation have been studied widely within epidemiological research; however, information from intervention trials is still emerging. Current data suggest that the most marked improvements in the inflammatory profile are conferred with exercise performed at higher intensities, with combined aerobic and resistance exercise training potentially providing the greatest benefit. The purpose of this review is to describe recent advances in our understanding surrounding the acute and chronic effects of physical activity on key mediators of inflammation. Within this, particular attention is given to the interleukin-6 system owing to its apparent centrality in mediating the anti-inflammatory effects of exercise.