Post-exercise cold-water immersion modulates skeletal muscle PGC-1α mRNA expression in immersed and non-immersed limbs: evidence of systemic regulation

Mechanisms mediating post-exercise cold-induced increases in PGC-1α gene expression in human skeletal muscle are yet to be fully elucidated, but may involve local cooling effects on AMPK and p38 MAPK related signalling and/or increased systemic β-adrenergic stimulation. We aimed to therefore examine whether post-exercise cold-water immersion enhancement of PGC-1α mRNA is mediated through local or systemic mechanisms. Ten subjects completed acute cycling (8x5 min at ~80% peak power output) followed by seated-rest (CON) or single-leg cold-water immersion (CWI; 10 min, 8°C). Muscle biopsies were obtained pre-, post- and 3 h post-exercise from a single limb in the CON condition but from both limbs in CWI (thereby providing tissue from a CWI and non-immersed limb, NOT). Muscle temperature decreased up to 2 h post-exercise following CWI (-5°C) in the immersed limb, with lesser changes observed in CON and NOT (-3°C; P<0.05). No differences between limbs were observed in p38MAPK phosphorylation at any time point (P<0.05), whilst a significant interaction effect was present for AMPK phosphorylation (P=0.031). Exercise (CON) increased gene expression of PGC-1α 3 h post-exercise (~5-fold; P<0.001). CWI augmented PGC-1α expression above CON in both the immersed (CWI; ~9-fold; P=0.003) and NOT limbs (~12-fold; P=0.001). Plasma Normetanephrine concentration was higher in CWI vs. CON immediately post-immersion (860 vs. 665 pmol/L; P=0.034). We report for the first time that local cooling of the immersed limb evokes transcriptional control of PGC1-α in the non-immersed limb, suggesting increased systemic β-adrenergic activation of AMPK mediates, in part, post-exercise cold-induction of PGC-1α mRNA

Polygenic mechanisms underpinning the response to exercise-induced muscle damage in humans:In vivo and in vitro evidence

We investigated whether 20 candidate single nucleotide polymorphisms (SNPs) were associated with in vivo exercise-induced muscle damage (EIMD), and with an in vitro skeletal muscle stem cell wound healing assay. Sixty-five young, untrained Caucasian adults performed 120 maximal eccentric knee-extensions on an isokinetic dynamometer to induce EIMD. Maximal voluntary isometric/isokinetic knee-extensor torque, knee joint range of motion (ROM), muscle soreness, serum creatine kinase activity and interleukin-6 concentration were assessed before, directly after and 48 h after EIMD. Muscle stem cells were cultured from vastus lateralis biopsies from a separate cohort (n = 12), and markers of repair were measured in vitro. Participants were genotyped for all 20 SNPs using real-time PCR. Seven SNPs were associated with the response to EIMD, and these were used to calculate a total genotype score, which enabled participants to be segregated into three polygenic groups: ‘preferential’ (more ‘protective’ alleles), ‘moderate’, and ‘non-preferential’. The non-preferential group was consistently weaker than the preferential group (1.93 ± 0.81 vs. 2.73 ± 0.59 N ∙ m/kg; P = 9.51 × 10−4) and demonstrated more muscle soreness (p = 0.011) and a larger decrease in knee joint ROM (p = 0.006) following EIMD. Two TTN-AS1 SNPs in linkage disequilibrium were associated with in vivo EIMD (rs3731749, p ≤ 0.005) and accelerated muscle stem cell migration into the artificial wound in vitro (rs1001238, p ≤ 0.006). Thus, we have identified a polygenic profile, linked with both muscle weakness and poorer recovery following EIMD. Moreover, we provide evidence for a novel TTN gene-cell-skeletal muscle mechanism that may help explain some of the interindividual variability in the response to EIMD.</p

Passive Heat Therapy in Sedentary Humans Increases Skeletal Muscle Capillarisation and eNOS Content but Not Mitochondrial Density or GLUT4 Content.

Passive heat therapy (PHT) has been proposed as an alternative intervention to traditional moderate intensity continous training (MICT) in individuals who are unable or unwilling to exercise. This study aimed to make the first comparison of the effect of PHT and MICT on 1) skeletal muscle capillarisation and endothelial specific eNOS content and 2) mitochondrial density, GLUT4 and IMTG content. Twenty young sedentary males (21±1years, BMI 25±1kg.m-2) were allocated to either 6 weeks of PHT (n=10; 40-50min at 40°C in a heat chamber, 3x/wk) or MICT (n=10; time matched cycling at ~65% VO2peak). Muscle biopsies were taken from the vastus lateralis muscle pre- and post-training. Immunofluorescence microscopy was used to assess changes in skeletal muscle mitochondrial density, GLUT4 and IMTG content, capillarisation and endothelial specific eNOS content. VO2peak and whole body insulin sensitivity were also assessed. PHT and MICT both increased capillary density and capillary-fibre perimeter exchange index (P<0.05), and endothelial specific eNOS content (P<0.05). However, unlike MICT (P<0.05) PHT did not increase mitochondrial density (P=0.443), GLUT4 (P=0.217) or IMTG content (P=0.957). Both intervention improved aerobic capacity and whole body insulin sensitivity (P<0.05). 6 weeks PHT in young sedentary males increases skeletal muscle capillarisation and eNOS content to a similar extent as MICT, however, unlike MICT PHT does not affect skeletal muscle mitochondrial density, GLUT4 or IMTG content

Graded reductions in pre-exercise glycogen concentration do not augment exercise-induced nuclear AMPK and PGC-1α protein content in human muscle.

NEW FINDINGS: What is the central question of this study? What is the absolute level of pre-exercise glycogen concentration required to augment the exercise-induced signalling response regulating mitochondrial biogenesis? What is the main finding and its importance? Commencing high-intensity endurance exercise with reduced pre-exercise muscle glycogen concentrations confers no additional benefit to the early signalling responses that regulate mitochondrial biogenesis. ABSTRACT: We examined the effects of graded muscle glycogen on the subcellular location of AMPK and PGC-1α protein content and mRNA expression of genes associated with the regulation of mitochondrial biogenesis and substrate utilisation in human skeletal muscle. In a repeated measures design, eight trained male cyclists completed acute high-intensity interval (HIT) cycling (8 × 5 min at 80% peak power output) with graded concentrations of pre-exercise muscle glycogen. Following initial glycogen depleting exercise, subjects ingested  2 g kg-1  (L-CHO), 6 g kg-1  (M-CHO) or 14 g kg-1  (H-CHO) of carbohydrate during a 36 h period, such that exercise was commenced with graded (P < 0.05) muscle glycogen concentrations (H-CHO; 531 ± 83, M-CHO; 332 ± 88, L-CHO; 208 ± 79 mmol·kg-1  dw). Exercise depleted muscle glycogen to < 300 mmol·kg-1 dw in all trials (H-CHO; 270 ± 88, M-CHO; 173 ± 74, L-CHO; 100 ± 42 mmol·kg-1 dw) and induced comparable increases in nuclear AMPK protein content (∼2 fold) and PGC-1α (∼5 fold), p53 (∼1.5 fold) and CPT-1 (∼2 fold) mRNA between trials (all P < 0.05). The magnitude of increase in PGC-1α mRNA was also positively correlated with post-exercise glycogen concentration (P < 0.05). In contrast, exercise nor carbohydrate availability affected the subcellular location of PGC-1α protein or PPAR, SCO2, SIRT1, DRP1, MFN2 or CD36 mRNA. Using a sleep-low, train-low model with a high-intensity endurance exercise stimulus, we conclude that pre-exercise muscle glycogen does not modulate skeletal muscle cell signalling. This article is protected by copyright. All rights reserved

A Multidisciplinary Evaluation of a Virtually Supervised Home-Based High-Intensity Interval Training Intervention in People With Type 1 Diabetes.

OBJECTIVE: Adopt a multidisciplinary approach to evaluate a virtually supervised home-based high-intensity interval training (Home-HIT) intervention in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: Eleven individuals with type 1 diabetes (seven women; age 30 ± 3 years; VO2peak 2.5 ± 0.2 L/min; duration of diabetes 10 ± 2 years) completed 6 weeks of Home-HIT. A heart rate monitor and mobile phone application were used to provide feedback to the participants and research team on exercise intensity (compliance) and adherence. RESULTS: Training adherence was 95 ± 2%, and compliance was 99 ± 1%. Home-HIT increased VO2peak by 7% (P = 0.017) and decreased insulin dose by 13% (P = 0.012). Blood glucose concentration did not change from baseline to immediately or 1 h post Home-HIT. Qualitative perceptions of Home-HIT and the virtual-monitoring system were positive, supporting that the intervention successfully removed exercise barriers in people with type 1 diabetes. CONCLUSIONS: Virtually monitored Home-HIT resulted in high adherence alongside increased VO2peak and decreased insulin dose

Decreased Aerobic Exercise Capacity After Long-Term Remission From Cushing Syndrome: Exploration of Mechanisms.

BACKGROUND: Although major improvements are achieved after cure of Cushing syndrome (CS), fatigue and decreased quality of life persist. This is the first study to measure aerobic exercise capacity in patients in remission of CS for more than 4 years in comparison with matched controls, and to investigate whether the reduction in exercise capacity is related to alterations in muscle tissue. METHODS: Seventeen patients were included. A control individual, matched for sex, estrogen status, age, body mass index, smoking, ethnicity, and physical activity level was recruited for each patient. Maximal aerobic capacity (VO2peak) was assessed during incremental bicycle exercise to exhaustion. In 8 individually matched patients and controls, a percutaneous muscle biopsy was obtained and measures were made of cross-sectional areas, capillarization, and oxphos complex IV (COXIV) protein content as an indicator of mitochondrial content. Furthermore, protein content of endothelial nitric oxide synthase (eNOS) and eNOS phosphorylated on serine1177 and of the NAD(P)H-oxidase subunits NOX2, p47phox, and p67phox were measured in the microvascular endothelial layer. FINDINGS: Patients showed a lower mean VO2peak (SD) (28.0 [7.0] vs 34.8 [7.9] ml O2/kg bw/min, P < .01), maximal workload (SD) (176 [49] vs 212 [67] watt, P = .01), and oxygen pulse (SD) (12.0 [3.7] vs 14.8 [4.2] ml/beat, P < .01) at VO2peak. No differences were seen in muscle fiber type-specific cross-sectional area, capillarization measures, mitochondrial content, and protein content of eNOS, eNOS-P-ser1177, NOX2, p47phox, and p67phox. INTERPRETATION: Because differences in muscle fiber and microvascular outcome measures are not statistically significant, we hypothesize that cardiac dysfunction, seen in active CS, persists during remission and limits blood supply to muscles

Low-Volume High-Intensity Interval Training in a Gym Setting Improves Cardio-Metabolic and Psychological Health.

BACKGROUND: Within a controlled laboratory environment, high-intensity interval training (HIT) elicits similar cardiovascular and metabolic benefits as traditional moderate-intensity continuous training (MICT). It is currently unclear how HIT can be applied effectively in a real-world environment. PURPOSE: To investigate the hypothesis that 10 weeks of HIT, performed in an instructor-led, group-based gym setting, elicits improvements in aerobic capacity (VO2max), cardio-metabolic risk and psychological health which are comparable to MICT. METHODS: Ninety physically inactive volunteers (42±11 y, 27.7±4.8 kg.m-2) were randomly assigned to HIT or MICT group exercise classes. HIT consisted of repeated sprints (15-60 seconds, >90% HRmax) interspersed with periods of recovery cycling (≤25 min.session-1, 3 sessions.week-1). MICT participants performed continuous cycling (~70% HRmax, 30-45 min.session-1, 5 sessions.week-1). VO2max, markers of cardio-metabolic risk, and psychological health were assessed pre and post-intervention. RESULTS: Mean weekly training time was 55±10 (HIT) and 128±44 min (MICT) (p<0.05), with greater adherence to HIT (83±14% vs. 61±15% prescribed sessions attended, respectively; p<0.05). HIT improved VO2max, insulin sensitivity, reduced abdominal fat mass, and induced favourable changes in blood lipids (p<0.05). HIT also induced beneficial effects on health perceptions, positive and negative affect, and subjective vitality (p<0.05). No difference between HIT and MICT was seen for any of these variables. CONCLUSIONS: HIT performed in a real-world gym setting improves cardio-metabolic risk factors and psychological health in physically inactive adults. With a reduced time commitment and greater adherence than MICT, HIT offers a viable and effective exercise strategy to target the growing incidence of metabolic disease and psychological ill-being associated with physical inactivity

New Zealand blackcurrant extract enhances fat oxidation during prolonged cycling in endurance-trained females.

PURPOSE: New Zealand blackcurrant (NZBC) extract has previously been shown to increase fat oxidation during prolonged exercise, but this observation is limited to males. We examined whether NZBC intake also increases fat oxidation during prolonged exercise in females, and whether this was related to greater concentrations of circulating fatty acids. METHODS: In a randomised, crossover, double-blind design, 16 endurance-trained females (age: 28 ± 8 years, BMI: 21.3 ± 2.1 kg·m-2, VO2max: 43.7 ± 1.1 ml·kg-1·min-1) ingested 600 mg·day-1NZBC extract (CurraNZ™) or placebo (600 mg·day-1microcrystalline cellulose) for 7 days. On day 7, participants performed 120 min cycling at 65% VO2max, using online expired air sampling with blood samples collected at baseline and at 15 min intervals throughout exercise for analysis of glucose, NEFA and glycerol. RESULTS: NZBC extract increased mean fat oxidation by 27% during 120 min moderate-intensity cycling compared to placebo (P = 0.042), and mean carbohydrate oxidation tended to be lower (P = 0.063). Pre-exercise, plasma NEFA (P = 0.034) and glycerol (P = 0.051) concentrations were greater following NZBC intake, although there was no difference between conditions in the exercise-induced increase in plasma NEFA and glycerol concentrations (P > 0.05). Mean fat oxidation during exercise was moderately associated with pre-exercise plasma NEFA concentrations (r = 0.45, P = 0.016). CONCLUSIONS: Intake of NZBC extract for 7 days elevated resting concentrations of plasma NEFA and glycerol, indicative of higher lipolytic rates, and this may underpin the observed increase in fat oxidation during prolonged cycling in endurance-trained females

Increased muscle blood supply and transendothelial nutrient and insulin transport induced by food intake and exercise: effect of obesity and ageing.

This review concludes that a sedentary lifestyle, obesity and ageing impair the vasodilator response of the muscle microvasculature to insulin, exercise and VEGF-A and reduce microvascular density. Both impairments contribute to the development of insulin resistance, obesity and chronic age-related diseases. A physically active lifestyle keeps both the vasodilator response and microvascular density high. Intravital microscopy has shown that microvascular units (MVUs) are the smallest functional elements to adjust blood flow in response to physiological signals and metabolic demands on muscle fibres. The luminal diameter of a common terminal arteriole (TA) controls blood flow through up to 20 capillaries belonging to a single MVU. Increases in plasma insulin and exercise/muscle contraction lead to recruitment of additional MVUs. Insulin also increases arteriolar vasomotion. Both mechanisms increase the endothelial surface area and therefore transendothelial transport of glucose, fatty acids (FAs) and insulin by specific transporters, present in high concentrations in the capillary endothelium. Future studies should quantify transporter concentration differences between healthy and at risk populations as they may limit nutrient supply and oxidation in muscle and impair glucose and lipid homeostasis. An important recent discovery is that VEGF-B produced by skeletal muscle controls the expression of FA transporter proteins in the capillary endothelium and thus links endothelial FA uptake to the oxidative capacity of skeletal muscle, potentially preventing lipotoxic FA accumulation, the dominant cause of insulin resistance in muscle fibres