Exercise performance and health: Role of GLUT4.

The glucose transporter GLUT4 is integral for optimal skeletal muscle performance during exercise, as well as for metabolic health. Physiological regulation of GLUT4 translocation during exercise and increased GLUT4 expression following exercise involves multiple, redundant signalling pathways. These include effects of reactive oxygen species (ROS). ROS contribute to GLUT4 translocation that increases skeletal muscle glucose uptake during exercise and stimulate signalling pathways that increase GLUT4 expression. Conversely, ROS can also inhibit GLUT4 translocation and expression in metabolic disease states. The opposing roles of ROS in GLUT4 regulation are ultimately linked to the metabolic state of skeletal muscle and the intricate mechanisms involved give insights into pathways critical for exercise performance and implicated in metabolic health and disease.

Lifelong physiology of a former marathon world-record holder: the pros and cons of extreme cardiac remodeling.

In a 77-year-old former world-record-holding male marathoner (2:08:33.6), this study sought to investigate the impact of lifelong intensive endurance exercise on cardiac structure, function, and the trajectory of functional capacity (determined by maximal oxygen consumption, V̇o2max) throughout the adult lifespan. As a competitive runner, our athlete (DC) reported performing up to 150-300 miles/wk of moderate-to-vigorous exercise and sustained 10-15 h/wk of endurance exercise after retirement from competition. DC underwent maximal cardiopulmonary exercise testing in 1970 (aged 27 yr), 1991 (aged 49 yr), and 2020 (aged 77 yr) to determine V̇o2max. At his evaluation in 2020, DC also underwent comprehensive cardiac assessments including resting echocardiography, and resting and exercise cardiac magnetic resonance to quantify cardiac structure and function at rest and during peak supine exercise. DC's V̇o2max showed minimal change from 27 yr (69.7 mL/kg/min) to 49 yr (68.1 mL/kg/min), although it eventually declined by 36% by the age of 77 yr (43.6 mL/kg/min). DC's V̇o2max at 77 yr, was equivalent to the 50th percentile for healthy 20- to 29-yr-old males and 2.4 times the requirement for maintaining functional independence. This was partly due to marked ventricular dilatation (left-ventricular end-diastolic volume: 273 mL), which facilitates a large peak supine exercise stroke volume (200 mL) and cardiac output (22.2 L/min). However, at the age of 78 yr, DC developed palpitations and fatigue and was found to be in atrial fibrillation requiring ablation procedures to revert his heart to sinus rhythm. Overall, this life study of a world champion marathon runner exemplifies the substantial benefits and potential side effects of many decades of intense endurance exercise.NEW & NOTEWORTHY This life study of a 77-yr-old former world champion marathon runner exemplifies the impact of lifelong high-volume endurance exercise on functional capacity (V̇o2max equivalent to a 20- to 29-yr-old), partly due to extreme ventricular remodeling that facilitates a large cardiac output during exercise despite reduced maximal heart rate. Although it is possible that this extreme remodeling may contribute to developing atrial fibrillation, the net benefits of extreme exercise throughout this athlete's lifespan favor increased health span and expected longevity.

Interactions between insulin and exercise.

The interaction between insulin and exercise is an example of balancing and modifying the effects of two opposing metabolic regulatory forces under varying conditions. While insulin is secreted after food intake and is the primary hormone increasing glucose storage as glycogen and fatty acid storage as triglycerides, exercise is a condition where fuel stores need to be mobilized and oxidized. Thus, during physical activity the fuel storage effects of insulin need to be suppressed. This is done primarily by inhibiting insulin secretion during exercise as well as activating local and systemic fuel mobilizing processes. In contrast, following exercise there is a need for refilling the fuel depots mobilized during exercise, particularly the glycogen stores in muscle. This process is facilitated by an increase in insulin sensitivity of the muscles previously engaged in physical activity which directs glucose to glycogen resynthesis. In physically trained individuals, insulin sensitivity is also higher than in untrained individuals due to adaptations in the vasculature, skeletal muscle and adipose tissue. In this paper, we review the interactions between insulin and exercise during and after exercise, as well as the effects of regular exercise training on insulin action.

Exercise and health: historical perspectives and new insights.

Since ancient times, the health benefits of regular physical activity/exercise have been recognized and the classic studies of Morris and Paffenbarger provided the epidemiological evidence in support of such an association. Cardiorespiratory fitness, often measured by maximal oxygen uptake, and habitual physical activity levels are inversely related to mortality. Thus, studies exploring the biological bases of the health benefits of exercise have largely focused on the cardiovascular system and skeletal muscle (mass and metabolism), although there is increasing evidence that multiple tissues and organ systems are influenced by regular exercise. Communication between contracting skeletal muscle and multiple organs has been implicated in exercise benefits, as indeed has other interorgan "cross-talk." The application of molecular biology techniques and "omics" approaches to questions in exercise biology has opened new lines of investigation to better understand the beneficial effects of exercise and, in so doing, inform the optimization of exercise regimens and the identification of novel therapeutic strategies to enhance health and well-being.

Author Correction: Skeletal muscle energy metabolism during exercise.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Skeletal muscle energy metabolism during exercise.

The continual supply of ATP to the fundamental cellular processes that underpin skeletal muscle contraction during exercise is essential for sports performance in events lasting seconds to several hours. Because the muscle stores of ATP are small, metabolic pathways must be activated to maintain the required rates of ATP resynthesis. These pathways include phosphocreatine and muscle glycogen breakdown, thus enabling substrate-level phosphorylation ('anaerobic') and oxidative phosphorylation by using reducing equivalents from carbohydrate and fat metabolism ('aerobic'). The relative contribution of these metabolic pathways is primarily determined by the intensity and duration of exercise. For most events at the Olympics, carbohydrate is the primary fuel for anaerobic and aerobic metabolism. Here, we provide an overview of exercise metabolism and the key regulatory mechanisms ensuring that ATP resynthesis is closely matched to the ATP demand of exercise. We also summarize various interventions that target muscle metabolism for ergogenic benefit in athletic events.

Exercise adaptations: molecular mechanisms and potential targets for therapeutic benefit.

Exercise is fundamental for good health, whereas physical inactivity underpins many chronic diseases of modern society. It is well appreciated that regular exercise improves metabolism and the metabolic phenotype in a number of tissues. The phenotypic alterations observed in skeletal muscle are partly mediated by transcriptional responses that occur following each individual bout of exercise. This adaptive response increases oxidative capacity and influences the function of myokines and extracellular vesicles that signal to other tissues. Our understanding of the epigenetic and transcriptional mechanisms that mediate the skeletal muscle gene expression response to exercise as well as of their upstream signalling pathways has advanced substantially in the past 10 years. With this knowledge also comes the opportunity to design new therapeutic strategies based on the biology of exercise for a variety of chronic conditions where regular exercise might be a challenge. This Review provides an overview of the beneficial adaptive responses to exercise and details the molecular mechanisms involved. The possibility of designing therapeutic interventions based on these molecular mechanisms is addressed, using relevant examples that have exploited this approach.

Exercise and GLUT4.

The glucose transporter GLUT4 is critical for skeletal muscle glucose uptake in response to insulin and muscle contraction/exercise. Exercise increases GLUT4 translocation to the sarcolemma and t-tubule and, over the longer term, total GLUT4 protein content. Here, we review key aspects of GLUT4 biology in relation to exercise, with a focus on exercise-induced GLUT4 translocation, postexercise metabolism and muscle insulin sensitivity, and exercise effects on GLUT4 expression.

Epigenetics and Exercise.

Epigenetics can be defined as 'the structural adaptation of chromosomal regions so as to register, signal, or perpetuate altered activity states.' Increased transcription of key regulatory, metabolic, and myogenic genes is an early response to exercise and is important in mediating subsequent adaptations in skeletal muscle. DNA hypomethylation and histone hyperacetylation are emerging as important crucial events for increased transcription. The complex interactions between multiple epigenetic modifications and their regulation by metabolic changes and signaling events during exercise, with implications for enhanced understanding of the acute and chronic adaptations to exercise, are questions for further investigation.

Exercise serum increases GLUT4 in human adipocytes.

NEW FINDINGS: What is the central question of this study? Do circulating factors mediate exercise-induced effects on adipose tissue GLUT4 expression? What is the main finding and its importance? Serum (10%) obtained from human volunteers immediately after a single exercise bout increased GLUT4 protein levels in human adipocytes in culture. This result suggests that circulating factors might mediate the effects of exercise on adipose tissue GLUT4 and prompts further effort to identify the specific factor(s) and tissue(s) of origin. ABSTRACT: In this study, we tested the hypothesis that circulating factors generated during exercise increase adipose tissue GLUT4 expression. Serum was obtained from eight healthy subjects before and after 60 min of cycling exercise, and primary adipocytes were cultured from stromal vascular fractions that were isolated from subcutaneous abdominal adipose tissue samples from one healthy, male volunteer. A 48 h exposure of human primary adipocytes to 10% serum obtained after exercise increased GLUT4 protein expression, on average, by 12% compared with exposure to 10% serum obtained at rest, before exercise. GLUT4 mRNA levels were increased after 12 h of exposure to exercise serum but were unchanged after 6 and 24 h of exposure. Our results suggest that circulating factors might mediate the effects of exercise on adipose tissue GLUT4 expression and encourage further efforts to identify the potential factor(s), tissue(s) of origin and physiological relevance.

No evidence of direct association between GLUT4 and glycogen in human skeletal muscle.

Previous studies have demonstrated that exercise increases whole body and skeletal muscle insulin sensitivity that is linked with increased GLUT4 at the plasma membrane following insulin stimulation and associated with muscle glycogen depletion. To assess the potential direct association between muscle glycogen and GLUT4, seven untrained, male subjects exercised for 60 min at ~75% VO2 peak, with muscle samples obtained by percutaneous needle biopsy immediately before and after exercise. Exercise reduced muscle glycogen content by ~43%. An ultracentrifugation protocol resulted in a ~2-3-fold enriched glycogen fraction from muscle samples for analysis. Total GLUT4 content was unaltered by exercise and we were unable to detect any GLUT4 in glycogen fractions, either with or without amylase treatment. In skinned muscle fiber segments, there was very little, if any, GLUT4 detected in wash solutions, except following exposure to 1% Triton X-100. Amylase treatment of single fibers did not increase GLUT4 in the wash solution and there were no differences in GLUT4 content between fibers obtained before or after exercise for any of the wash treatments. Our results indicate no direct association between GLUT4 and glycogen in human skeletal muscle, before or after exercise, and suggest that alterations in GLUT4 translocation associated with exercise-induced muscle glycogen depletion are mediated via other mechanisms.

Exercise and GLUT4 in human subcutaneous adipose tissue.

To examine the effect of acute and chronic exercise on adipose tissue GLUT4 expression, a total of 20 healthy, male subjects performed one of two studies. Ten subjects performed cycle ergometer exercise for 60 min at 73 ± 2% VO2 peak and abdominal adipose tissue samples were obtained immediately before and after exercise and after 3 h of recovery. Another 10 subjects completed 10 days of exercise training, comprising a combination of six sessions of 60 min at 75% VO2 peak and four sessions of 6 × 5 min at 90% VO2 peak, separated by 3 min at 40% VO2 peak. Abdominal adipose tissue and vastus lateralis muscle samples were obtained before training and 24 h after the last training session. A single bout of exercise did not change adipose tissue GLUT4 mRNA; however, there was a small, but significant, reduction in adipose tissue GLUT4 protein expression 3 h after exercise. There were no changes in adipose tissue GLUT4 or COX-IV expression following exercise training. In contrast, skeletal muscle GLUT4 and COX-IV were increased by 47% and 44%, respectively following exercise training. The exercise training-induced increase in GLUT4 expression was similar in both type I and type IIa single muscle fibers. Our results indicate that neither a single exercise bout, nor 10 days of exercise training, increased adipose tissue GLUT4, in contrast with the increases observed in skeletal muscle GLUT4 expression.

Exercise Metabolism: Fuels for the Fire.

During exercise, the supply of adenosine triphosphate (ATP) is essential for the energy-dependent processes that underpin ongoing contractile activity. These pathways involve both substrate-level phosphorylation, without any need for oxygen, and oxidative phosphorylation that is critically dependent on oxygen delivery to contracting skeletal muscle by the respiratory and cardiovascular systems and on the supply of reducing equivalents from the degradation of carbohydrate, fat, and, to a limited extent, protein fuel stores. The relative contribution of these pathways is primarily determined by exercise intensity, but also modulated by training status, preceding diet, age, gender, and environmental conditions. Optimal substrate availability and utilization before, during, and after exercise is critical for maintaining exercise performance. This review provides a brief overview of exercise metabolism, with expanded discussion of the regulation of muscle glucose uptake and fatty acid uptake and oxidation.

Scriptaid enhances skeletal muscle insulin action and cardiac function in obese mice.

AIM: To determine the effect of Scriptaid, a compound that can replicate aspects of the exercise adaptive response through disruption of the class IIa histone deacetylase (HDAC) corepressor complex, on muscle insulin action in obesity. MATERIALS AND METHODS: Diet-induced obese mice were administered Scriptaid (1 mg/kg) via daily intraperitoneal injection for 4 weeks. Whole-body and skeletal muscle metabolic phenotyping of mice was performed, in addition to echocardiography, to assess cardiac morphology and function. RESULTS: Scriptaid treatment had no effect on body weight or composition, but did increase energy expenditure, supported by increased lipid oxidation, while food intake was also increased. Scriptaid enhanced the expression of oxidative genes and proteins, increased fatty acid oxidation and reduced triglycerides and diacylglycerides in skeletal muscle. Furthermore, ex vivo insulin-stimulated glucose uptake by skeletal muscle was enhanced. Surprisingly, heart weight was reduced in Scriptaid-treated mice and was associated with enhanced expression of genes involved in oxidative metabolism in the heart. Scriptaid also improved indices of both diastolic and systolic cardiac function. CONCLUSION: These data show that pharmacological targeting of the class IIa HDAC corepressor complex with Scriptaid could be used to enhance muscle insulin action and cardiac function in obesity.

An evaluation of physical activity training in Australian medical school curricula.

OBJECTIVES: To evaluate the current level of physical activity (PA) training provided to Australian medical students. DESIGN: Individual interviews were completed via phone interview or online survey from June-October 2015. METHODS: Program leaders from Australian medical schools, who were knowledgeable about their curriculum content, were invited to participate in the study. The number of programs, hours of PA training instruction, institutional attitude towards offering PA, barriers experienced, and content areas in which PA training was offered, were explored. RESULTS: Seventeen of the 19 (89%) Australian medical schools participated in the study. Among the responding schools, 15 (88.2%) reported providing specific PA training to medical students. Thirteen of these 15 schools (86.7%) taught the national aerobic guidelines while only seven (46.7%) taught the national strength training recommendations. Four, five, and six year programs reported providing an average of 6.6, 5.0, and 12.3h of PA training, respectively, across their entire curriculum. Only 42.9% of the schools that had PA training reported that it was sufficient for their medical students. Nearly half (41.2%) of the respondents reported no barriers to implementing PA training into their medical curricula. CONCLUSIONS: Most Australian medical schools reported including some PA training in their medical curriculum. Key topics, such as the national strength recommendations, however, were not taught by most schools. Given the importance of PA for the prevention and treatment of numerous mental and physical health outcomes, it is unlikely that the attention it currently receives adequately prepares medical students to treat patients.

Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation.

Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase) transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex. Adaptations include increased metabolic gene expression, mitochondrial capacity, and lipid oxidation. An existing HDAC inhibitor, Scriptaid, had similar phenotypic effects through disruption of the class IIa HDAC corepressor complex. Acute Scriptaid administration to mice increased the expression of metabolic genes, which required an intact class IIa HDAC corepressor complex. Chronic Scriptaid administration increased exercise capacity, whole-body energy expenditure and lipid oxidation, and reduced fasting blood lipids and glucose. Therefore, compounds that disrupt class IIa HDAC function could be used to enhance metabolic health in chronic diseases driven by physical inactivity.

Heat shock proteins and exercise adaptations. Our knowledge thus far and the road still ahead.

By its very nature, exercise exerts a challenge to the body's cellular homeostatic mechanisms. This homeostatic challenge affects not only the contracting skeletal muscle but also a number of other organs and results over time in exercise-induced adaptations. Thus it is no surprise that heat shock proteins (HSPs), a group of ancient and highly conserved cytoprotective proteins critical in the maintenance of protein and cellular homeostasis, have been implicated in exercise/activity-induced adaptations. It has become evident that HSPs such as HSP72 are induced or activated with acute exercise or after chronic exercise training regimens. These observations have given scientists an insight into the protective mechanisms of these proteins and provided an opportunity to exploit their protective role to improve health and physical performance. Although our knowledge in this area of physiology has improved dramatically, many questions still remain unanswered. Further understanding of the role of HSPs in exercise physiology may prove beneficial for therapeutic targeting in diseased patient cohorts, exercise prescription for disease prevention, and training strategies for elite athletes.

Exercise and Gene Expression.

Acute and transient changes in gene transcription following a single exercise bout, if reinforced by repeated exercise stimuli, result in the longer lasting effects on protein expression and function that form the basis of skeletal muscle training adaptations. Changes in skeletal muscle gene expression occur in response to multiple stimuli associated with skeletal muscle contraction, various signaling kinases that respond to these stimuli, and numerous downstream pathways and targets of these kinases. In addition, DNA methylation, histone acetylation and phosphorylation, and micro-RNAs can alter gene expression via epigenetic mechanisms. Contemporary studies rely upon "big omics data," in combination with computational and systems biology, to interrogate, and make sense of, the complex interactions underpinning exercise adaptations. The exciting potential is a greater understanding of the integrative biology of exercise.