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It has recently been established that myosin, the molecular motor protein, is able to exist in two conformations in relaxed skeletal muscle. These conformations are known as the super-relaxed (SRX) and disordered-relaxed (DRX) states and are finely balanced to optimize ATP consumption and skeletal muscle metabolism. Indeed, SRX myosins are thought to have a 5- to 10-fold reduction in ATP turnover compared with DRX myosins. Here, we investigated whether chronic physical activity in humans would be associated with changes in the proportions of SRX and DRX skeletal myosins. For that, we isolated muscle fibers from young men of various physical activity levels (sedentary, moderately physically active, endurance-trained, and strength-trained athletes) and ran a loaded Mant-ATP chase protocol. We observed that in moderately physically active individuals, the amount of myosin molecules in the SRX state in type II muscle fibers was significantly greater than in age-matched sedentary individuals. In parallel, we did not find any difference in the proportions of SRX and DRX myosins in myofibers between highly endurance- and strength-trained athletes. We did however observe changes in their ATP turnover time. Altogether, these results indicate that physical activity level and training type can influence the resting skeletal muscle myosin dynamics. Our findings also emphasize that environmental stimuli such as exercise have the potential to rewire the molecular metabolism of human skeletal muscle through myosin.

It has recently been established that myosin, the molecular motor protein, is able to exist in two conformations in relaxed skeletal muscle. These conformations are known as super-relaxed (SRX) and disordered-relaxed (DRX) states and are finely balanced to optimize skeletal muscle metabo-lism. Indeed, SRX myosins are thought to have a 10-fold reduction in ATP turnover compared to DRX myosins. Here, we investigated whether chronic physical activity in humans would be associated with changes in the proportions of SRX and DRX skeletal myosins. For that, we isolated mus-cle fibres from various athletic and sedentary populations and ran a loaded Mant-ATP chase proto-col. We observed that, in endurance-trained athletes, the amounts of myosin molecules in the SRX state was significantly greater than in age-matched sedentary individuals or than in strength athletes. To further assess whether this change would have an impact on the potency of a SRX-inducing pharmacological compound, Mavacamten, we performed similar analyses as above with and without the drug in muscle fibres from endurance athletes. Surprisingly, we found that 0.3 μM of Mava-camten had only marginal effects. Altogether, our results indicate that chronic endurance training-status influences resting skeletal myosin conformations, and Mavacamten potency. Our findings also emphasize that environmental stimuli such as exercise can re-wire the molecular metabolism of human skeletal muscle through myosin.SummaryLewis et al., investigate how training-status influences myosin conformations involved in the resting metabolism of skeletal muscle. They find that, in endurance-trained athletes, skeletal myosin preferentially adopts an energy-saving conformation known as super-relaxed state, lowering the metabolic rate and affecting the potency of a super-relaxed state-inducing drug, Mavacamten.

Context The maximal fat oxidation rate (MFO) is higher in aerobically fit vs unfit young men, but this training-related increase in MFO is attenuated in middle-aged men. Further, it has also been found that unfit men with obesity may have an elevated MFO compared to unfit normal-weight men. Objective Based hereupon, we aimed to investigate whether a fitness-related higher MFO were attenuated in middle-aged women compared to young women. Also, we aimed to investigate if unfit women with obesity have a higher MFO compared to unfit normal-weight women. We hypothesized that the training-related elevated MFO was attenuated in middle-aged women, but that unfit women with obesity would have an elevated MFO compared to unfit normal-weight women. Methods We recruited 70 women stratified into 6 groups: young fit (n = 12), young unfit (n = 12) middle-aged fit (n = 12), middle-aged unfit (n = 12), unfit young women with obesity (n = 12), and unfit middle-aged women with obesity (n = 10). Body composition and resting blood samples were obtained and MFO was measured by a graded exercise test on a cycle ergometer via indirect calorimetry. Subsequently, a maximal exercise test was performed to establish peak oxygen uptake (V̇O2peak). Results Young and middle-aged fit women had a higher MFO compared to age-matched unfit women, and young fit women had a higher MFO compared to fit middle-aged women. Unfit women with obesity, independent of age, had a higher MFO compared to their normal-weight and unfit counterparts. Conclusion The training-related increase in MFO seems maintained in middle-aged women, and we find that unfit women with obesity, independent of age, have a higher MFO compared to unfit normal-weight women.

Aim & Methods: Extreme endurance exercise provides a valuable research model for understanding the adaptive metabolic response of older and younger individuals to intense physical activity. Here, we compare a wide range of metabolic and physiologic parameters in two cohorts of seven trained men, age 30±5years or age 65±6years, before and after the participants travelled ≈3000km by bicycle over 15days. Results: Over the 15-day exercise intervention, participants lost 2–3kg fat mass with no significant change in body weight. V̇O2max did not change in younger cyclists, but decreased (p=0.06) in the older cohort. The resting plasma FFA concentration decreased markedly in both groups, and plasma glucose increased in the younger group. In the older cohort, plasma LDL-cholesterol and plasma triglyceride decreased. In skeletal muscle, fat transporters CD36 and FABPm remained unchanged. The glucose handling proteins GLUT4 and SNAP23 increased in both groups. Mitochondrial ROS production decreased in both groups, and ADP sensitivity increased in skeletal muscle in the older but not in the younger cohort. Conclusion: In summary, these data suggest that older but not younger individuals experience a negative adaptive response affecting cardiovascular function in response to extreme endurance exercise, while a positive response to the same exercise intervention is observed in peripheral tissues in younger and older men. The results also suggest that the adaptive thresholds differ in younger and old men, and this difference primarily affects central cardiovascular functions in older men after extreme endurance exercise.

Maximal oxygen uptake (VO2max ) and muscle mass decrease with age. The loss of cardiorespiratory fitness and muscle strength is accelerated with physical inactivity and has well-documented consequences for morbidity and all-cause mortality. Participation in exercise training programs will improve one or more of the cardio-metabolic risk factors, but the long-term effects of such programs are questionable. Here, we re-examined 25 old (72 ± 4 years.) men and women who considered him/herself as "success-full agers" and were participants in a 3-month alpine skiing training program 6 years earlier. The program focused on healthy aging and included health questionnaires, measurement of lipids and glycemic parameters in blood and a VO2max test. Thirteen and 12 subjects were in the intervention (IG) and the control group (CG), respectively. In response to the training program, subjects improved their cardio-metabolic risk factors. However, after 6 years all positive effects had disappeared. Approximately 80% of the subjects had total cholesterol and LDL cholesterol above and HDL cholesterol below the recommended values, but these subjects remained the most metabolically deteriorated, including an increase in fasting glucose concentrations. We conclude that people seem to follow their individual trajectory in terms of cardio-metabolic risk factors, and participation in a relatively short lasting exercise training program with emphasis on healthy aging does not change that. Long-lasting change in lifestyle probably requires a continued attentional focus, goal setting, and feedback.

Exercise is important for prevention of sarcopenia in the elderly population. We tested two training modalities, ascending or descending stair walking, representing concentric (CON) and eccentric (ECC) exercise, respectively. We also tested the effects of additional weight during eccentric exercise (ECC+). Thirty-two healthy men and women (70 ± 3 [mean ± SE] yrs.) were randomly assigned to CON, ECC, or ECC+ (carrying +15% of body weight in a vest) in a 3 (

Aim To examine the effect of high-intensity interval training (HIIT) on glucose clearance rates in skeletal muscle and explore the mechanism within the muscle. Methods Ten males with type 2 diabetes mellitus (T2DM) and ten matched healthy subjects performed 2 weeks of one-legged HIIT (total of eight sessions, each comprised of 10 × 1 minute ergometer bicycle exercise at >80% of maximal heart rate, interspersed with one min of rest). Insulin sensitivity was assessed by an isoglycaemic, hyperinsulinaemic clamp combined with arteriovenous leg balance technique of the trained (T) and the untrained (UT) leg and muscle biopsies of both legs. Results Insulin-stimulated glucose clearance in T legs was ~30% higher compared with UT legs in both groups due to increased blood flow in T vs UT legs and maintained glucose extraction. With each training session, muscle glycogen content decreased only in the training leg, and after the training, glycogen synthase and citrate synthase activities were higher in T vs UT legs. No major changes occurred in the expression of proteins in the insulin signalling cascade. Mitochondrial respiratory capacity was similar in T2DM and healthy subjects, and unchanged by HIIT. Conclusion HIIT improves skeletal muscle insulin sensitivity. With HIIT, the skeletal muscle of patients with T2DM becomes just as insulin sensitive as untrained muscle in healthy subjects. The mechanism includes oscillations in muscle glycogen stores and a maintained ability to extract glucose from the blood in the face of increased blood flow in the trained leg.