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Exercise-induced skeletal muscle angiogenesis is a well-known physiological adaptation that occurs in humans in response to exercise training and can lead to endurance performance benefits, as well as improvements in cardiovascular and skeletal tissue health. An increase in capillary density in skeletal muscle improves diffusive oxygen exchange and waste extraction, and thus greater fatigue resistance, which has application to athletes but also to the general population. Exercise-induced angiogenesis can significantly contribute to improvements in cardiovascular and metabolic health, such as the increase in muscle glucose uptake, important for the prevention of diabetes. Recently, our understanding of the mechanisms by which angiogenesis occurs with exercise has grown substantially. This review will detail the biochemical, cellular and biomechanical signals for exercise-induced skeletal muscle angiogenesis, including recent work on extracellular vesicles and circulating angiogenic cells. In addition, the influence of age, sex, exercise intensity/duration, as well as recent observations with the use of blood flow restricted exercise, will also be discussed in detail. This review will provide academics and practitioners with mechanistic and applied evidence for optimising training interventions to promote physical performance through manipulating capillarisation in skeletal muscle.

Obesity (BMI ≥ 30 kg/m2) reduces skeletal muscle quality and impairs the myogenic response to muscle damage. The present study investigated if differences exist in myotubes from individuals with (OB) or without (LN) obesity incubated in control (bovine serum albumin [BSA]) or obesogenic (Ob) medium, at baseline or in response to cardiotoxin (CTX)‐induced damage and recovery. Differentiated, primary human myotubes from LN and OB donors were cultured in control (BSA‐DM) or (Ob‐DM) (250 µM palmitate, 250 µM oleate, 100 nM insulin, and 2.5 ng/mL tumour necrosis factor) differentiation medium (DM) for 48 h and treated with 1.0 µM CTX or vehicle control for 1 h (immediately post [IP]). Myotubes recovered in Ob (Ob‐GM) or BSA (BSA‐GM) growth medium (GM) for 3 days (3D). At baseline, myotubes (LN and OB) incubated in Ob‐DM had 5% lower fusion index (FI) and nuclei/tube than BSA‐DM. At IP post‐CTX, there were no differences in FI or membrane integrity (lactate dehydrogenase), but the reduction in cell viability was greater in OB than LN myotubes and greater in myotubes (LN and OB) incubated in Ob‐DM than BSA‐DM. At 3D post‐CTX, total nuclei, FI, and nuclei/tube were ∼15% lower in myotubes (LN and OB) incubated in Ob‐GM than BSA‐GM. Expressed as recovery (3D‐IP) post‐CTX, Ob‐GM lowered total nuclei and FI in myotubes without differences between LN and OB. In human myotubes, impaired formation and recovery following damage in obesity appear primarily due to the obesogenic environment rather than inherent, individual differences. What is the central question of this study? Obesity is associated with reduced skeletal muscle quality and impaired skeletal muscle regeneration: are decrements in skeletal muscle quality and muscle regeneration observed in obesity due to cell origin or the obesogenic environment? What is the main finding and its importance? In myotubes isolated from humans with and without obesity, some obesity associated decrements can be ascribed to cell origin, such as a reduction in mitochondrial content. However, poor recovery following injury appears to be primarily attributed to the obesogenic environment.

Skeletal muscle fibers regulate surrounding endothelial cells (EC) via secretion of numerous angiogenic factors, including extracellular vesicles (SkM-EV). Muscle fibers are broadly classified as oxidative (OXI) or glycolytic (GLY) depending on their metabolic characteristics. OXI fibers secrete more pro-angiogenic factors and have greater capillary densities than GLY fibers. OXI muscle secretes more EV than GLY, however it is unknown whether muscle metabolic characteristics regulate EV contents and signaling potential. EVs were isolated from primarily oxidative or glycolytic muscle tissue from mice. MicroRNA (miR) contents were determined and endothelial cells were treated with OXI- and GLY-EV to investigate angiogenic signaling potential. There were considerable differences in miR contents between OXI- and GLY-EV and pathway analysis identified that OXI-EV miR were predicted to positively regulate multiple endothelial-specific pathways, compared to GLY-EV. OXI-EV improved in vitro angiogenesis, which may have been mediated through nitric oxide synthase (NOS) related pathways, as treatment of endothelial cells with a non-selective NOS inhibitor abolished the angiogenic benefits of OXI-EV. This is the first report to show widespread differences in miR contents between SkM-EV isolated from metabolically different muscle tissue and the first to demonstrate that oxidative muscle tissue secretes EV with greater angiogenic signaling potential than glycolytic muscle tissue.

Concurrent resistance and endurance exercise training (CET) has well‐studied benefits; however, inherent hormonal and genetic differences alter adaptive responses to exercise between sexes. Extracellular vesicles (EVs) are factors that contribute to adaptive signaling. Our purpose was to test if EV characteristics differ between men and women following CET. 18 young healthy participants underwent 12‐weeks of CET. Prior to and following CET, subjects performed an acute bout of heavy resistance exercise (AHRET) consisting of 6 × 10 back squats at 75% 1RM. At rest and following AHRET, EVs were isolated from plasma and characteristics and miRNA contents were analyzed. AHRET elevated EV abundance in trained men only (+51%) and AHRET‐induced changes were observed for muscle‐derived EVs and microvesicles. There were considerable sex‐specific effects of CET on EV miRNAs, highlighted by larger variation following the 12‐week program in men compared to women at rest. Pathway analysis based on differentially expressed EV miRNAs predicted that AHRET and 12 weeks of CET in men positively regulates hypertrophy and growth pathways more so than in women. This report highlights sex‐based differences in the EV response to resistance and concurrent exercise training and suggests that EVs may be important adaptive signaling factors altered by exercise training.

Military personnel experience decrements in physical fitness and psychological well‐being during training that may be attributed to allostatic load. This investigation examined the association between allostatic load measured by the allostatic load index (ALI) and physical performance and psychological responses in personnel undergoing a 10‐week training course. Thirty‐one participants (14 women) provided biochemical, questionnaire (perceived stress appraisal (PSS), sleep difficulty (SD), resilience (CD‐RISC‐25), and Physical Fitness Test (PFT; three‐mile run [3MR], pullups, Run‐Row PFT score, Push‐Pull PFT score, Crunches‐Plank PFT score, and total PFT score)) data before and after training. ALI (0–8) was calculated using biomarker components from neuroendocrine, autonomic, and immune systems. Simple linear regression analysis assessed the association between change (Δ) in ALI and responses. Backward stepwise regression identified components associated with responses (α = 0.05). In men, ΔALI was associated with Δpullups (β = −0.88, p = 0.015), Δpush‐pull PFT score (β = −2.87, p = 0.013), Δtotal PFT score (β = −3.48, p = 0.007), and ΔSD (β = −0.56, p = 0.046) with immune components explaining relationships. In women, ΔALI was associated with ΔSD (β = −1.25, p < 0.001) and ΔCD‐RISC‐25 (β = 2.65, p = 0.025) with no component explaining relationships. Increased ALI is associated with worsened physical performance in men and improved psychological outcomes in women, highlighting potential sex‐specific responses to increased allostatic load during training.

Resistance exercise augments circulating extracellular vesicle (EV) and metabolite signalling in manners that assist musculoskeletal and systemic adaptations. Women are often underrepresented in exercise research and recent attention has focused on whether hormonal fluctuations during the menstrual cycle and use of hormonal contraception (HC) impact exercise performance and adaptation. We investigated if menstrual phase (follicular and luteal) or HC usage (oral contraceptive pill and hormonal intrauterine device) impact the EV and metabolite response to exercise. Overall, we observed an exercise‐induced response across all four groups for EV microRNAs and circulating metabolites. Women in the follicular phase had baseline differences in the most abundant miRNAs and exercise‐relevant miRNAs and had the greatest miRNA response to exercise compared to other groups. Relevant metabolites were observed in EVs, but the overall response to exercise was minimally influenced by group among annotated metabolites. Multi‐omic analysis showed potential presence of molecular signatures based on circulating hormone concentrations, but trends were not differentiated enough to suggest clear phenotypic differences. Overall, our data highlights unique miRNA profiles at baseline in follicular phase women but does not support the notion that circulating EV and metabolite responses to exercise are heavily influenced by menstrual cycle phase or HC use. Trial Registration: ClinicalTrials.gov identifier: NCT06972862

This study compared the structural and cellular skeletal muscle factors underpinning adaptations in maximal strength, power, aerobic capacity, and lean body mass to a 12‐week concurrent resistance and interval training program in men and women. Recreationally active women and men completed three training sessions per week consisting of high‐intensity, low‐volume resistance training followed by interval training performed using a variety upper and lower body exercises representative of military occupational tasks. Pre‐ and post‐training vastus lateralis muscle biopsies were analyzed for changes in muscle fiber type, cross‐sectional area, capillarization, and mitochondrial biogenesis marker content. Changes in maximal strength, aerobic capacity, and lean body mass (LBM) were also assessed. Training elicited hypertrophy of type I (12.9%; p = 0.016) and type IIa (12.7%; p = 0.007) muscle fibers in men only. In both sexes, training decreased type IIx fiber expression (1.9%; p = 0.046) and increased total PGC‐1α (29.7%, p < 0.001) and citrate synthase (11.0%; p < 0.014) content, but had no effect on COX IV content or muscle capillarization. In both sexes, training increased maximal strength and LBM but not aerobic capacity. The concurrent training program was effective at increasing strength and LBM but not at improving aerobic capacity or skeletal muscle adaptations underpinning aerobic performance.

The cyclooxygenase (COX) pathway regulates vascular tone and, therefore, local O2 delivery‐utilization matching. The two main isoforms, COX‐1 and COX‐2, may promote opposing effects on contracting muscle O2 transport in health by inducing vasoconstriction and vasodilatation, respectively. Whether COX‐2 and its main vasodilatory product (prostacyclin, PGI2) modulate microvascular O2 transport to skeletal muscle and thus exercise tolerance is unknown. We tested the hypothesis that acute selective COX‐2 inhibition (SC2I) would impair cardiorespiratory and skeletal muscle microvascular responses from rest to exercise, thereby reducing exercise tolerance in healthy adults. Twelve individuals participated in a randomized, double‐blind, crossover study to receive SC2I (200 mg celecoxib) or placebo (control, CON). Moderate and severe intensity cycling were performed with measurements of heart rate, arterial blood pressure, pulmonary oxygen uptake (V̇O2 ${\\dot V_{{{\\mathrm{O}}_2}}}$ ), leg muscle microvascular oxygenation (StO2 ${S_{{\\mathrm{t}}{{\\mathrm{O}}_2}}}$ ; near‐infrared spectroscopy) and time to exhaustion. Leg muscle StO2 ${S_{{\\mathrm{t}}{{\\mathrm{O}}_2}}}$was also assessed during cuff occlusion protocols. SC2I decreased the plasma concentration of the stable PGI2 metabolite 6‐keto prostaglandin F1α (CON: 203 (54) pg/mL; SC2I: 108 (54) pg/mL; P = 0.002). There was no difference in exercise tolerance (CON: 278 (55) s; SC2I: 298 (75) s), arterial blood pressure, heart rate, pulmonary V̇O2 ${\\dot V_{{{\\mathrm{O}}_2}}}$or leg muscle StO2 ${S_{{\\mathrm{t}}{{\\mathrm{O}}_2}}}$from rest to moderate or severe exercise between conditions (P > 0.05 for all). Moreover, there was no significant difference in StO2 ${S_{{\\mathrm{t}}{{\\mathrm{O}}_2}}}$during cuff occlusion protocols between conditions. Contrary to our hypothesis, these data indicate that COX‐2 is not obligatory for the regulation of skeletal muscle microvascular oxygenation at rest or during moderate or severe intensity exercise, and therefore does not modulate exercise tolerance in healthy adults. What is the central question of this study? What are the effects of acute selective cyclooxygenase‐2 (COX‐2) inhibition via oral celecoxib on cardiorespiratory and skeletal muscle microvascular function at rest and during moderate and severe intensity exercise in healthy young individuals? What is the main finding and its importance? Selective COX‐2 inhibition reduced plasma prostacyclin metabolites but had no effect on central or peripheral determinants of oxygen transport, peak oxygen uptake or exercise tolerance. These findings indicate that COX‐2 is not obligatory for skeletal muscle oxygen delivery–utilization matching at rest or during contractions in healthy adults.

Abstract Context Optimizing bone mass accrual early in life is a strategy for mitigating fracture risk in older age. Objective This study aimed to identify factors associated with lower than expected bone mass in healthy young adult men. Methods Data from 39 male participants (21 areal bone mineral density [aBMD] Z scores <−1.0 at either the total hip, femoral neck, or lumbar spine [Lower]; 18 Z scores ≥1.0, but not <−1.0 at any site [controls; Con]) were analyzed from a larger study. aBMD and body composition were assessed by dual-energy x-ray absorptiometry (DXA), and bone quality was evaluated at the tibia using high resolution–peripheral quantitative computed tomography (HR-pQCT). Fasted concentrations of bone turnover markers, testosterone, estradiol, parathyroid hormone (PTH), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-1 binding protein 5 (IGFBP-5) were measured via enzyme-linked immunosorbent assays. Results The Lower group was older (age in years: Lower 25 [6]; Con 21 [5]; P = .037), shorter (m; Lower 1.74 [0.10]; Con 1.79 [0.10]; P = .024), and had less lean mass than Con (kg; Lower 54.2 [6.2]; Con 60.3 [6.9]; P = .018). Tibial bone microarchitecture (trabecular number 1/mm; Lower 1.7 [0.2]; Con 1.9 [0.2]; P = .004; trabecular separation mm; Lower 0.6 [0.1]; Con 0.5 [0.1]; P = .002) and strength (stiffness kN/mm Lower 207.7 [43.3]; Con 274.7 [39.7] and failure load kN Lower 11.3 [2.2]; Con 14.8 [2.0]; P < .001) were compromised in Lower. Alkaline phosphatase was greater (Lower 1528.2 [933.8]; Con 605.4 [624.1]; P = .003), and IGF-1 (Lower 265.5 [93.6]; Con 340.4 [106.5]; P = .027) was lower in Lower. Osteoblast activity (P ≥ .361) and gene expression were similar between groups (P ≥ .451). Conclusion Men with relatively lower than expected aBMD demonstrated compromised bone microarchitecture and lower lean mass, indicating the importance of targeted intervention for lean mass accrual during young adulthood.