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Key points: Females have lower fatigability than males during single limb isometric and dynamic contractions, but whether sex‐differences exist during high‐intensity whole‐body exercise remains unknown.This study shows that males and females respond similarly to repeated supramaximal whole‐body exercise, and that at task failure a large functional reserve remains in both sexes.Using post‐exercise ischaemia with repeated exercise, we have shown that this functional reserve depends on the glycolytic component of substrate‐level phosphorylation and is almost identical in both sexes.Metaboreflex activation during post‐exercise ischaemia and the O2 debt per kg of active lean mass are also similar in males and females after supramaximal exercise.Females have a greater capacity to extract oxygen during repeated supramaximal exercise and reach lower PETCO2, experiencing a larger drop in brain oxygenation than males, without apparent negative repercussion on performance.Females had no faster recovery of performance after accounting for sex differences in lean mass. The purpose of this study was to ascertain what mechanisms explain sex differences at task failure and to determine whether males and females have a functional reserve at exhaustion. Exercise performance, cardiorespiratory variables, oxygen deficit, and brain and muscle oxygenation were determined in 18 males and 18 females (21–36 years old) in two sessions consisting of three bouts of constant‐power exercise at 120% of V̇O2max until exhaustion interspaced by 20 s recovery periods. In one of the two sessions, the circulation of both legs was occluded instantaneously (300 mmHg) during the recovery periods. Females had a higher muscle O2 extraction during fatiguing supramaximal exercise than males. Metaboreflex activation, and lean mass‐adjusted O2 deficit and debt were similar in males and females. Compared to males, females reached lower PETCO2 and brain oxygenation during supramaximal exercise, without apparent negative consequences on performance. After the occlusions, males and females were able to restart exercising at 120% of V̇O2max, revealing a similar functional reserve, which depends on glycolytic component of substrate‐level phosphorylation and its rate of utilization. After ischaemia, muscle O2 extraction was increased, and muscle V̇O2 was similarly reduced in males and females. The physiological response to repeated supramaximal exercise to exhaustion is remarkably similar in males and females when differences in lean mass are considered. Both sexes fatigue with a large functional reserve, which depends on the glycolytic energy supply, yet females have higher oxygen extraction capacity, but reduced PETCO2 and brain oxygenation. Key points: Females have lower fatigability than males during single limb isometric and dynamic contractions, but whether sex‐differences exist during high‐intensity whole‐body exercise remains unknown.This study shows that males and females respond similarly to repeated supramaximal whole‐body exercise, and that at task failure a large functional reserve remains in both sexes.Using post‐exercise ischaemia with repeated exercise, we have shown that this functional reserve depends on the glycolytic component of substrate‐level phosphorylation and is almost identical in both sexes.Metaboreflex activation during post‐exercise ischaemia and the O2 debt per kg of active lean mass are also similar in males and females after supramaximal exercise.Females have a greater capacity to extract oxygen during repeated supramaximal exercise and reach lower PETCO2, experiencing a larger drop in brain oxygenation than males, without apparent negative repercussion on performance.Females had no faster recovery of performance after accounting for sex differences in lean mass. [ABSTRACT FROM AUTHOR]

Autophagy is essential for the adaptive response to exercise and physiological skeletal muscle functionality. However, the mechanisms leading to the activation of macroautophagy and chaperone-mediated autophagy in human skeletal muscle in response to high-intensity exercise remain elusive. Our findings demonstrate that macroautophagy and chaperone-mediated autophagy are stimulated by high-intensity exercise in normoxia (P I O 2 : 143 mmHg) and severe acute hypoxia (P I O 2 : 73 mmHg) in healthy humans. High-intensity exercise induces macroautophagy initiation through AMPKα phosphorylation, which phosphorylates and activates ULK1. ULK1 phosphorylates BECN1 at Ser15, eliciting the dissociation of BECN1-BCL2 crucial for phagophore formation. Besides, high-intensity exercise elevates the LC3B-II:LC3B–I ratio, reduces total SQSTM1/p62 levels, and induces p -Ser349 SQSTM1/p62 phosphorylation, suggesting heightened autophagosome degradation. PHAF1/MYTHO, a novel macroautophagy biomarker, is highly upregulated in response to high-intensity exercise. The latter is accompanied by elevated LAMP2A expression, indicating chaperone-mediated autophagy activation regardless of post-exercise HSPA8/HSC70 downregulation. Despite increased glycolytic metabolism, severe acute hypoxia does not exacerbate the autophagy signaling response. Signaling changes revert within 1 min of recovery with free circulation, while the application of immediate post-exercise ischemia impedes recovery. Our study concludes that macroautophagy and chaperone-mediated autophagy pathways are strongly activated by high-intensity exercise, regardless of PO 2 , and that oxygenation is necessary to revert these signals to pre-exercise values. PHAF1/MYTHO emerges as a pivotal exercise-responsive autophagy marker positively associated with the LC3B-II:LC3B–I ratio. [Display omitted] • It is unknown whether and how macroautophagy and chaperone-mediated autophagy are activated by exercise in human skeletal muscle. • We show that macroautophagy and chaperone-mediated autophagy are activated by acute exercise to exhaustion in normoxia and severe acute hypoxia. • Simultaneously, protein synthesis signaling is blunted. • Macroautophagy and chaperone-mediated autophagy remain activated during ischemic recovery. • MYTHO, a FOXO-regulated protein is markedly upregulated after exercise in normoxia, hypoxia, and post-exercise ischemia. [ABSTRACT FROM AUTHOR]

Prematurity has physical consequences, such as lower birth weight, decreased muscle mass and increased risk of adult‐onset metabolic disease. Insulin‐like growth factor 1 (IGF‐1) has therapeutic potential to improve the growth and quality of muscle and tendon in premature births, and thus attenuate some of these sequalae. We investigated the effect of IGF‐1 on extensor carpi radialis muscle and biceps brachii tendon of preterm piglets. The preterm group consisted of 19‐day‐old preterm (10 days early) piglets, treated with either IGF‐1 or vehicle. Term controls consisted of groups of 9‐day‐old piglets (D9) and 19‐day‐old piglets (D19). Muscle samples were analysed by immunofluorescence to determine the cross‐sectional area (CSA) of muscle fibres, fibre type composition, satellite cell content and central nuclei‐containing fibres in the muscle. Tendon samples were analysed for CSA, collagen content and maturation, and vascularization. Gene expression of the tendon was measured by RT‐qPCR. Across all endpoints, we found no significant effect of IGF‐1 treatment on preterm piglets. Preterm piglets had smaller muscle fibre CSA compared to D9 and D19 control group. Satellite cell content was similar across all groups. For tendon, we found an effect of age on tendon CSA, and mRNA levels of COL1A1, tenomodulin and scleraxis. Immunoreactivity for elastin and CD31, and several markers of tendon maturation, were increased in D9 compared to the preterm piglets. Collagen content was similar across groups. IGF‐1 treatment of preterm‐born piglets does not influence the growth and maturation of skeletal muscle and tendon. What is the central question of this study?Does infusion of insulin‐like growth factor‐1 in preterm piglets stimulate growth parameters of muscle and tendon?What is the main finding and its importance?IGF‐1 treatment of preterm born piglets does not influence growth and maturation of skeletal muscle and tendon. This adds to the current knowledge on the effect of IGF‐1 on muscle and tendon growth, and is relevant for future research in potential therapies for premature infants. [ABSTRACT FROM AUTHOR]

Strength training promotes a IIX‐to‐IIA shift in myosin heavy chain (MHC) composition, likely due to changes in sarcoplasmic [Ca2+] which are sensed by CaMKII. Sarcoplasmic [Ca2+] is in part regulated by sarcolipin (SLN), a small protein that when overexpressed in rodents stimulates mitochondrial biogenesis and a fast‐to‐slow fiber type shift. The purpose of this study was to determine whether CaMKII and SLN are involved in muscle phenotype and performance changes elicited by strength training. Twenty‐two men followed an 8‐week velocity‐based resistance training program using the full squat exercise while monitoring repetition velocity. Subjects were randomly assigned to two resistance training programs differing in the repetition velocity loss allowed in each set: 20% (VL20) vs 40% (VL40). Strength training caused muscle hypertrophy, improved 1RM and increased total CaMKII protein expression, particularly of the δD isoform. Phospho‐Thr287‐CaMKII δD expression increased only in VL40 (+89%), which experienced greater muscle hypertrophy, and a reduction in MHC‐IIX percentage. SLN expression was increased in VL20 (+33%) remaining unaltered in VL40. The changes in phospho‐Thr287‐CaMKII δD were positively associated with muscle hypertrophy and the number of repetitions during training, and negatively with the changes in MHC‐IIX and SLN. Most OXPHOS proteins remained unchanged, except for NDUFB8 (Complex I), which was reduced after training (−22%) in both groups. The amount of fatigue allowed in each set critically influences muscle CaMKII and SLN responses and determines muscle phenotype changes. With lower intra‐set fatigue, the IIX‐to‐IIA MHC shift is attenuated. [ABSTRACT FROM AUTHOR]

Sarcolipin (SLN) is a SERCA uncoupling protein associated with exercise performance and lower adiposity in mice. To determine SLN protein expression in human skeletal muscle and its relationship with adiposity, resting energy expenditure (REE), and performance, SLN was assessed by Western blot in 199 biopsies from two previous studies. In one study, 15 overweight volunteers underwent a pretest followed by 4 days of caloric restriction and exercise (45‐minute one‐arm cranking + 8‐hour walking), and 3 days on a control diet. Muscle biopsies were obtained from the trained and non‐exercised deltoid, and vastus lateralis (VL). In another study, 16 men performed seven sessions of 4‐6 × 30‐sec all‐out sprints on the cycle ergometer with both limbs, and their VL and triceps brachii biopsied pre‐ and post‐training. SLN expression was twofold and 44% higher in the VL than in the deltoids and triceps brachii, respectively. SLN was associated with neither adiposity nor REE, and was not altered by a severe energy deficit (5500 kcal/day). SLN and cortisol changes after the energy deficit were correlated (r =.38, P =.039). SLN was not altered by low‐intensity exercise in the overweight subjects, whereas it was reduced after sprint training in the other group. The changes in SLN with sprint training were inversely associated with the changes in gross efficiency (r = −.59, P =.016). No association was observed between aerobic or anaerobic performance and SLN expression. In conclusion, sarcolipin appears to play no role in regulating the fat mass of men. Sprint training reduces sarcolipin expression, which may improve muscle efficiency. [ABSTRACT FROM AUTHOR]

Ageing, a sedentary lifestyle, and obesity are associated with increased oxidative stress, while regular exercise is associated with an increased antioxidant capacity in trained skeletal muscles. Whether a higher aerobic fitness is associated with increased expression of antioxidant enzymes and their regulatory factors in skeletal muscle remains unknown. Although oestrogens could promote a higher antioxidant capacity in females, it remains unknown whether a sex dimorphism exists in humans regarding the antioxidant capacity of skeletal muscle. Thus, the aim was to determine the protein expression levels of the antioxidant enzymes SOD1, SOD2, catalase and glutathione reductase (GR) and their regulatory factors Nrf2 and Keap1 in 189 volunteers (120 males and 69 females) to establish whether sex differences exist and how age, VO 2 max and adiposity influence these. For this purpose, vastus lateralis muscle biopsies were obtained in all participants under resting and unstressed conditions. No significant sex differences in Nrf2, Keap1, SOD1, SOD2, catalase and GR protein expression levels were observed after accounting for VO 2 max, age and adiposity differences. Multiple regression analysis indicates that the VO 2 max in mL.kg LLM−1.min−1can be predicted from the levels of SOD2, Total Nrf2 and Keap1 (R = 0.58, P < 0.001), with SOD2 being the main predictor explaining 28 % of variance in VO 2 max, while Nrf2 and Keap1 explained each around 3 % of the variance. SOD1 protein expression increased with ageing in the whole group after accounting for differences in VO 2 max and body fat percentage. Overweight and obesity were associated with increased pSer40-Nrf2, pSer40-Nrf2/Total Nrf2 ratio and SOD1 protein expression levels after accounting for differences in age and VO 2 max. Overall, at the population level, higher aerobic fitness is associated with increased basal expression of muscle antioxidant enzymes, which may explain some of the benefits of regular exercise. [Display omitted] • It remains unknown how aerobic fitness, adiposity, age and sex may influence antioxidant enzymes in human skeletal muscle. • Here we show that SOD2 is the main antioxidant enzyme associated with VO 2 max. • In young and middle-aged humans, there is no sex-dimorphism in antioxidant enzymes expression in skeletal muscle or their regulatory factors. • SOD1 protein expression is increased with ageing after accounting for differences in VO2max and body fat percentage. • Overweight and obesity are associated with increased pSer40-Nrf2, pSer40-Nrf2/Total Nrf2 ratio and SOD1 protein expression levels. [ABSTRACT FROM AUTHOR]

The study aimed to determine the levels of skeletal muscle angiotensin‐converting enzyme 2 (ACE2, the SARS‐CoV‐2 receptor) protein expression in men and women and assess whether ACE2 expression in skeletal muscle is associated with cardiorespiratory fitness and adiposity. The level of ACE2 in vastus lateralis muscle biopsies collected in previous studies from 170 men (age: 19–65 years, weight: 56–137 kg, BMI: 23–44) and 69 women (age: 18–55 years, weight: 41–126 kg, BMI: 22–39) was analyzed in duplicate by western blot. VO2max was determined by ergospirometry and body composition by DXA. ACE2 protein expression was 1.8‐fold higher in women than men (p = 0.001, n = 239). This sex difference disappeared after accounting for the percentage of body fat (fat %), VO2max per kg of legs lean mass (VO2max‐LLM) and age (p = 0.47). Multiple regression analysis showed that the fat % (β = 0.47) is the main predictor of the variability in ACE2 protein expression in skeletal muscle, explaining 5.2% of the variance. VO2max‐LLM had also predictive value (β = 0.09). There was a significant fat % by VO2max‐LLM interaction, such that for subjects with low fat %, VO2max‐LLM was positively associated with ACE2 expression while as fat % increased the slope of the positive association between VO2max‐LLM and ACE2 was reduced. In conclusion, women express higher amounts of ACE2 in their skeletal muscles than men. This sexual dimorphism is mainly explained by sex differences in fat % and cardiorespiratory fitness. The percentage of body fat is the main predictor of the variability in ACE2 protein expression in human skeletal muscle. [ABSTRACT FROM AUTHOR]