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Extracellular vesicles (EVs) are mediators of physiological changes that occur during physical exertion. This study examined the effects of physical exertion with and without sleep and caloric restriction on EV size, concentration, and surface proteins in men and women. Twenty participants (10 men) completed a 5-day simulated military operational stress protocol with daily physical exertion. Blood was drawn before and immediately after exertion at baseline (D1) and following 48-h of sleep and caloric restriction (D3). EV size and concentration were assessed using nanoparticle tracking analysis. EVs were identified with markers associated with exosomes (CD63), microvesicles (VAMP3), apoptotic bodies (THSD1), and skeletal muscle-derived EVs (SGCA) and quantified using imaging flow cytometry. Interactive and main effects of sex, day, and time on EVs were assessed using three-way ANOVAs. EV concentration declined pre to postexertion in women on D1 and D3 but was stable in men. EV size increased from pre to postexertion and from D1 to D3 in men and women. Physical exertion following sleep and caloric restriction increased CD63+ EV concentration, proportion of total EVs, and CD63 surface protein expression regardless of sex. The proportion of SGCA+ EVs increased in men and women following exertion and from D1 to D3 but was higher in women than in men. No differences were observed in VAMP3+ and THSD1+ EVs. This study identified sexually dimorphic EV profiles in response to various stressors. Further investigations are necessary to determine if dimorphic EV responses affect health and performance outcomes during stress. NEW & NOTEWORTHY Sex is understudied in EV research, and most studies limit EV analysis to single stress conditions such as exercise. Multistress conditions consisting of physical exertion and sleep and caloric restriction are common in real-world settings. We demonstrate that physical exertion results in sex-specific EV signatures and that EV profiles vary according to single versus multistress conditions. Our data highlight important biological and ecological characteristics that should be considered in EV research.

Simulated military operational stress (SMOS) provides a useful model to better understand resilience in humans as the stress associated with caloric restriction, sleep deficits, and fatiguing exertion degrades physical and cognitive performance. Habitual physical activity may confer resilience against these stressors by promoting favorable use-dependent neuroplasticity, but it is unclear how physical activity, resilience, and corticospinal excitability (CSE) relate during SMOS. To examine associations between corticospinal excitability, physical activity, and physical performance during SMOS. Fifty-three service members (age: 26 ± 5 yr, 13 women) completed a 5-day and -night intervention composed of familiarization, baseline, SMOS (2 nights/days), and recovery days. During SMOS, participants performed rigorous physical and cognitive activities while receiving half of normal sleep (two 2-h blocks) and caloric requirements. Lower and upper limb CSE were determined with transcranial magnetic stimulation (TMS) stimulus-response curves. Self-reported resilience, physical activity, military-specific physical performance (TMT), and endocrine factors were compared in individuals with high (HIGH) and low CSE based on a median split of lower limb CSE at baseline. HIGH had greater physical activity and better TMT performance throughout SMOS. Both groups maintained physical performance despite substantial psychophysiological stress. Physical activity, resilience, and TMT performance were directly associated with lower limb CSE. Individual differences in physical activity coincide with lower (but not upper) limb CSE. Such use-dependent corticospinal excitability directly relates to resilience and physical performance during SMOS. Future studies may use noninvasive neuromodulation to clarify the interplay among CSE, physical activity, and resilience and improve physical and cognitive performance. NEW & NOTEWORTHY We demonstrate that individual differences in physical activity levels coincide with lower limb corticospinal excitability. Such use-dependent corticospinal excitability directly relates to resilience and physical performance during a 5-day simulation of military operational stress with caloric restriction, sleep restriction and disruption, and heavy physical and cognitive exertion.

Conkright, WR, Beckner, ME, Sinnott, AM, Eagle, SR, Martin, BJ, Lagoy, AD, Proessl, F, Lovalekar, M, Doyle, TLA, Agostinelli, P, Sekel, NM, Flanagan, SD, Germain, A, Connaboy, C, and Nindl, BC. Neuromuscular performance and hormonal responses to military operational stress in men and women. J Strength Cond Res XX(X): 000-000, 2021-Women have recently been integrated into ground close combat positions; however, there are limited data in women in these roles. We aimed to test the hypothesis that there would be no sex-specific neuromuscular responses, but hormonal signaling would be differentially impacted when exposed to simulated military operational stress (SMOS). Neuromuscular performance was assessed daily using a tactical mobility test (TMT) in 54 male and 15 female military members. Blood was drawn before/after TMT. Mood states were assessed each morning. Unloaded 300-m shuttle time increased 6% in both sexes and remained 7% higher after 1 day of recovery compared with baseline (p 0.05). Growth hormone increased in men, but not women, before to after TMT (p < 0.001 vs. p = 0.086). Women experienced a greater decline in insulin-like growth factor-I across days compared with men (ηp2 = 0.778 vs. 0.209, respectively, p < 0.001). Brain-derived neurotrophic factor increased significantly in men only from before to after TMT on day 1 (men: +107% vs. women: +10%) but no difference on days 3 or 4. Cortisol increased 69% from before to after TMT when averaged by sex and day. Negative mood states (depression, tension, and anger) and altered hormonal concentrations were associated with poorer TMT performance. Acute SMOS differentially impacted circulating hormonal milieu in men and women, but no differences in physical performance responses. Unloaded 300-m shuttle was negatively impacted while other fitness domains were maintained. Relationships between performance and mood/endocrine signaling highlight the potential for self-report measures and biomarkers to serve as indicators of performance change.

Extracellular vesicles (EVs) are established mediators of adaptation to exercise. Currently, there are no published data comparing changes in EVs between men and women after resistance exercise. We tested the hypothesis that EV profiles would demonstrate a sex-specific signature following resistance exercise. Ten men and 10 women completed an acute heavy resistance exercise test for back squats using 75% of their one-repetition maximum. Blood was drawn before and immediately after exercise. EVs were isolated from plasma using size exclusion chromatography and stained with antibodies associated with exosomes (CD63), microvesicles (VAMP3), apoptotic bodies (THSD1), and a marker for skeletal muscle EVs (SGCA). CD63+ EV concentration and proportion of total EVs increased 23% ( P = 0.006) and 113% ( P = 0.005) in both sexes. EV mean size declined in men ( P = 0.020), but not in women, suggesting a relative increase in small EVs in men. VAMP3+ EV concentration and proportion of total EVs increased by 93% ( P = 0.025) and 61% ( P = 0.030) in men and women, respectively. SGCA+ EV concentration was 69% higher in women compared with men independent of time ( P = 0.007). Differences were also observed for CD63, VAMP3, and SGCA median fluorescence intensity, suggesting altered surface protein density according to sex and time. There were no significant effects of time or sex on THSD1+ EVs or fluorescence intensity. EV profiles, particularly among exosome-associated and muscle-derived EVs, exhibit sex-specific differences in response to resistance exercise which should be further studied to understand their relationship to training adaptations.

The legs of 9 men (age 21 ± 2 years, 45 ± 4 mL/(kg·min)) were randomly assigned to complete 6 sessions of high-intensity exercise training, involving either one or four 5-min bouts of counterweighted, single-leg cycling. Needle biopsies from vastus lateralis revealed that citrate synthase maximal activity increased after training in the 4-bout group (p = 0.035) but not the 1-bout group (p = 0.10), with a significant difference between groups post-training (13%, p = 0.021). Novelty Short-term training using brief intense exercise requires multiple bouts per session to increase mitochondrial content in human skeletal muscle.

We reported that supplementation with green tea extract (GTE) lowered the glycemic response to an oral glucose load following exercise, but via an unknown mechanism (Martin BJ, MacInnis MJ, Gillen JB, Skelly LE, Gibala MJ. Appl Physiol Nutr Metab 41: 1057–1063, 2016. Here we examined the effect of supplementation with GTE on plasma glucose kinetics on ingestion of a glucose beverage during exercise recovery. Eleven healthy, sedentary men (21 ± 2 yr old; body mass index = 23 ± 4 kg/m2, peak O2 uptake = 38 ± 7 ml·kg−1·min−1; means ± SD) ingested GTE (350 mg) or placebo (PLA) thrice daily for 7 days in a double-blind, crossover design. In the fasted state, a primed constant infusion of [U-13C6]glucose was started, and 1 h later, subjects performed a graded exercise test (25 W/3 min) on a cycle ergometer. Immediately postexercise, subjects ingested a 75-g glucose beverage containing 2 g of [6,6-2H2]glucose, and blood samples were collected every 10 min for 3 h of recovery. The rate of carbohydrate oxidation was lower during exercise after GTE vs. PLA (1.26 ± 0.34 vs. 1.48 ± 0.51 g/min, P = 0.04). Glucose area under the curve (AUC) was not different between treatments after drink ingestion (GTE = 1,067 ± 133 vs. PLA = 1,052 ± 91 mM/180 min, P = 0.91). Insulin AUC was lower after GTE vs. PLA (5,673 ± 2,153 vs. 7,039 ± 2,588 µIU/180 min, P = 0.05), despite similar rates of glucose appearance (GTE = 0.42 ± 0.16 vs. PLA = 0.43 ± 0.13 g/min, P = 0.74) and disappearance (GTE = 0.43 ± 0.14 vs. PLA = 0.44 ± 0.14 g/min, P = 0.57). We conclude that short-term GTE supplementation did not affect glucose kinetics following ingestion of an oral glucose load postexercise; however, GTE was associated with attenuated insulinemia. These findings suggest GTE lowers the insulin required for a given glucose load during postexercise recovery, which warrants further mechanistic studies in humans.

Key points A classic unresolved issue in human integrative physiology involves the role of exercise intensity, duration and volume in regulating skeletal muscle adaptations to training. We employed counterweighted single-leg cycling as a unique within-subject model to investigate the role of exercise intensity in promoting training-induced increases in skeletal muscle mitochondrial content. Six sessions of high-intensity interval training performed over 2 weeks elicited greater increases in citrate synthase maximal activity and mitochondrial respiration compared to moderate-intensity continuous training matched for total work and session duration. These data suggest that exercise intensity, and/or the pattern of contraction, is an important determinant of exercise-induced skeletal muscle remodelling in humans. Abstract We employed counterweighted single-leg cycling as a unique model to investigate the role of exercise intensity in human skeletal muscle remodelling. Ten young active men performed unilateral graded-exercise tests to measure single-leg VO2, peak and peak power (Wpeak). Each leg was randomly assigned to complete six sessions of high-intensity interval training (HIIT) [4 × (5 min at 65% Wpeak and 2.5 min at 20% Wpeak)] or moderate-intensity continuous training (MICT) (30 min at 50% Wpeak), which were performed 10 min apart on each day, in an alternating order. The work performed per session was matched for MICT (143 ± 8.4 kJ) and HIIT (144 ± 8.5 kJ, P > 0.05). Post-training, citrate synthase (CS) maximal activity (10.2 ± 0.8 vs. 8.4 ± 0.9 mmol kg protein−1 min−1) and mass-specific [pmol O2•(s•mg wet weight)−1] oxidative phosphorylation capacities (complex I: 23.4 ± 3.2 vs. 17.1 ± 2.8; complexes I and II: 58.2 ± 7.5 vs. 42.2 ± 5.3) were greater in HIIT relative to MICT (interaction effects, P 0.05). In whole muscle, the protein content of COXIV (24%), NDUFA9 (11%) and mitofusin 2 (MFN2) (16%) increased similarly across groups (training effects, P 0.05). Single-leg VO2, peak was also unaffected by training (P > 0.05). In summary, single-leg cycling performed in an interval compared to a continuous manner elicited superior mitochondrial adaptations in human skeletal muscle despite equal total work.

We tested the hypothesis that ingestion of sodium bicarbonate (NaHCO3) prior to an acute session of high-intensity interval training (HIIT) would augment signaling cascades and gene expression linked to mitochondrial biogenesis in human skeletal muscle. On two occasions separated by ∼1 wk, nine men (mean ± SD: age 22 ± 2 yr, weight 78 ± 13 kg, V̇o2 peak 48 ± 8 ml·kg−1·min−1) performed 10 × 60-s cycling efforts at an intensity eliciting ∼90% of maximal heart rate (263 ± 40 W), interspersed with 60 s of recovery. In a double-blind, crossover manner, subjects ingested a total of 0.4 g/kg body weight NaHCO3 before exercise (BICARB) or an equimolar amount of a placebo, sodium chloride (PLAC). Venous blood bicarbonate and pH were elevated at all time points after ingestion ( P < 0.05) in BICARB vs. PLAC. During exercise, muscle glycogen utilization (126 ± 47 vs. 53 ± 38 mmol/kg dry weight, P < 0.05) and blood lactate accumulation (12.8 ± 2.6 vs. 10.5 ± 2.8 mmol/liter, P < 0.05) were greater in BICARB vs. PLAC. The acute exercise-induced increase in the phosphorylation of acetyl-CoA carboxylase, a downstream marker of AMP-activated protein kinase activity, and p38 mitogen-activated protein kinase were similar between treatments ( P > 0.05). However, the increase in PGC-1α mRNA expression after 3 h of recovery was higher in BICARB vs. PLAC (approximately sevenfold vs. fivefold compared with rest, P < 0.05). We conclude that NaHCO3 before HIIT alters the mRNA expression of this key regulatory protein associated with mitochondrial biogenesis. The elevated PGC-1α mRNA response provides a putative mechanism to explain the enhanced mitochondrial adaptation observed after chronic HIIT supplemented with NaHCO3 in rats.

Green tea extract (GTE) ingestion improves glucose homeostasis in healthy and diabetic humans, but the interactive effect of GTE and exercise is unknown. The present study examined the effect of short-term GTE supplementation on the glycemic response to an oral glucose load at rest and following an acute bout of exercise, as well as substrate oxidation during exercise. Eleven sedentary, overweight men with fasting plasma glucose (FPG) ≥5.6 mmol·L−1 (age, 34 ± 13 years; body mass index = 32 ± 5 kg·m−2; FPG = 6.8 ± 1.0; mean ± SD) ingested GTE (3× per day, 1050 mg·day–1 total) or placebo (PLA) for 7 days in a double-blind, crossover design. The effects of a 75-g glucose drink were assessed on 4 occasions during both GTE and PLA treatments: On days 1 and 5 at rest, and again following an acute bout of exercise on days 3 and 8. The glycemic response was assessed via an indwelling continuous glucose monitor (CGM) and venous blood draws. At rest, 1-h CGM glucose area under the curve was not different (P > 0.05), but the postexercise response was lower after GTE versus PLA (330 ± 53 and 393 ± 65 mmol·L−1·min−1, main effect of treatment, P < 0.05). The 1-h postprandial peaks in venous blood glucose (8.6 ± 1.6 and 9.8 ± 2.2 mmol·L−1) and insulin (96 ± 59 and 124 ± 68 μIU·ml−1) were also lower postexercise with GTE versus PLA (time × treatment interactions, P < 0.05). In conclusion, short-term GTE supplementation did not affect postprandial glucose at rest; however, GTE was associated with an attenuated glycemic response following a postexercise oral glucose load. These data suggest that GTE might alter skeletal muscle glucose uptake in humans.

Background ‘Healthy’ aging drives structural and functional changes in the heart including maladaptive electrical remodeling, fibrosis and inflammation, which lower the threshold for cardiovascular diseases such as heart failure (HF) and atrial fibrillation (AF). Despite mixed results in recent clinical trials, Relaxin-therapy for 2-days could reduce mortality by 37% at 180-days post-treatment, in patients with acute decompensated HF. Relaxin’s short life-span (hours) but long-lasting protective actions led us to test the hypothesis that relaxin acts at a genomic level to reverse maladaptive remodeling in aging and HF. Methods and results Young (9-month) and aged (24-month), male and female F-344/Brown Norway rats were treated with relaxin (0.4 mg/kg/day) for 2-weeks delivered by subcutaneous osmotic mini-pumps or with sodium acetate (controls). The genomic effects of aging and relaxin were evaluated by extracting RNA from the left ventricles and analyzing genomic changes by RNA-sequencing, Ingenuity Pathway Analysis, MetaCore and tissue immunohistochemistry. We found that aging promotes a native inflammatory response with distinct sex-differences and relaxin suppresses transcription of multiple genes and signaling pathways associated with inflammation and HF in both genders. In addition, aging significantly increased: macrophage infiltration and atrial natriuretic peptide levels in female ventricles, and activation of the complement cascade, whereas relaxin reversed these age-related effects. Conclusion These data support the hypothesis that relaxin alters gene transcription and suppresses inflammatory pathways and genes associated with HF and aging. Relaxin’s suppression of inflammation and fibrosis supports its potential as a therapy for cardiovascular and inflammation-related diseases, such as HF, AF and diabetes.

Subjects performed high-intensity interval training (HIIT) and continuous moderate-intensity training (END) to evaluate 24-h oxygen consumption. Oxygen consumption during HIIT was lower versus END; however, total oxygen consumption over 24 h was similar. These data demonstrate that HIIT and END induce similar 24-h energy expenditure, which may explain the comparable changes in body composition reported despite lower total training volume and time commitment.

We investigated whether a training protocol that involved 3 min of intense intermittent exercise per week — within a total training time commitment of 30 min including warm up and cool down — could increase skeletal muscle oxidative capacity and markers of health status. Overweight/obese but otherwise healthy men and women (n = 7 each; age = 29±9 y; BMI = 29.8±2.7 kg/m2) performed 18 training sessions over 6 wk on a cycle ergometer. Each session began with a 2 min warm-up at 50 W, followed by 3×20 s “all-out” sprints against 5.0% body mass (mean power output: ∼450–500 W) interspersed with 2 min of recovery at 50 W, followed by a 3 min cool-down at 50 W. Peak oxygen uptake increased by 12% after training (32.6±4.5 vs. 29.1±4.2 ml/kg/min) and resting mean arterial pressure decreased by 7% (78±10 vs. 83±10 mmHg), with no difference between groups (both p