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Sickle cell disease (SCD) is characterized by central (cardiac) and peripheral vascular dysfunctions, significantly diminishing exercise capacity and quality of life. Although central cardiopulmonary abnormalities in SCD are known to reduce exercise capacity and quality of life; the impact of hemolysis and subsequent cell-free hemoglobin (Hb)-mediated peripheral vascular abnormalities on those outcomes are not fully understood. Despite the recognized benefits of exercise training for cardiovascular health and clinical management in chronic diseases like heart failure, there remains substantial debate on the advisability of regular physical activity for patients with SCD. This is primarily due to concerns that prolonged and/or high-intensity exercise might trigger metabolic shifts leading to vaso-occlusive crises. As a result, exercise recommendations for patients with SCD are often vague or nonexistent, reflecting a gap in knowledge about the mechanisms of exercise intolerance and the impact of exercise training on SCD-related health issues. This mini-review sheds light on recent developments in understanding how SCD affects exercise tolerance, with a special focus on the roles of hemolysis and the release of cell-free hemoglobin in altering cardiovascular and skeletal muscle function. Also highlighted here is the emerging research on the therapeutic effects and safety of exercise training in patients with SCD. In addition, the review identifies future research opportunities to fill existing gaps in our understanding of exercise (in)tolerance in SCD.

Background: We identified peripherally limited patients using cardiopulmonary exercise testing and measured skeletal muscle oxygen transport and utilization during invasive single leg exercise testing to identify the mechanisms of the peripheral limitation., Methods: Forty-five patients with heart failure with preserved ejection fraction (70±7 years, 27 females) completed seated upright cardiopulmonary exercise testing and were defined as having a (1) peripheral limitation to exercise if cardiac output/oxygen consumption (VO 2 ) was elevated (≥6) or 5 to 6 with a stroke volume reserve >50% (n=31) or (2) a central limitation to exercise if cardiac output/VO 2 slope was ≤5 or 5 to 6 with stroke volume reserve <50% (n=14). Single leg knee extension exercise was used to quantify peak leg blood flow (Doppler ultrasound), arterial-to-venous oxygen content difference (femoral venous catheter), leg VO 2 , and muscle oxygen diffusive conductance. In a subset of participants (n=36), phosphocreatine recovery time was measured by magnetic resonance spectroscopy to determine skeletal muscle oxidative capacity., Results: Peak VO 2 during cardiopulmonary exercise testing was not different between groups (central: 13.9±5.7 versus peripheral: 12.0±3.1 mL/min per kg; P =0.135); however, the peripheral group had a lower peak arterial-to-venous oxygen content difference (central: 13.5±2.0 versus peripheral: 11.1±1.6 mLO 2 /dL blood; P <0.001). During single leg knee extension, there was no difference in peak leg VO 2 ( P =0.306), but the peripherally limited group had greater blood flow/VO 2 ratio ( P =0.024), lower arterial-to-venous oxygen content difference (central: 12.3±2.5 versus peripheral: 10.3±2.2 mLO 2 /dL blood; P =0.013), and lower muscle oxygen diffusive conductance ( P =0.021). A difference in magnetic resonance spectroscopy-derived phosphocreatine recovery time was not detected ( P =0.199)., Conclusions: Peripherally limited patients with heart failure with preserved ejection fraction identified by cardiopulmonary exercise testing have impairments in oxygen transport and utilization at the level of the skeletal muscle quantified by invasive knee extension exercise testing, which includes an increased blood flow/V̇O 2 ratio and poor muscle diffusive capacity., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04068844., Competing Interests: None.

Abstract: Arroum, T, Hish, GA, Burghardt, KJ, Ghamloush, M, Bazzi, B, Mrech, A, Morse, PT, Britton, SL, Koch, LG, McCully, JD, Hüttemann, M, and Malek, MH. Mitochondria transplantation: Rescuing innate muscle bioenergetic impairment in a model of aging and exercise intolerance. J Strength Cond Res 38(7): 1189-1199, 2024-Mitochondria, through oxidative phosphorylation, are crucial for energy production. Disease, genetic impairment, or deconditioning can harm muscle mitochondria, affecting energy production. Endurance training enhances mitochondrial function but assumes mobility. Individuals with limited mobility lack effective treatments for mitochondrial dysfunction because of disease or aging. Mitochondrial transplantation replaces native mitochondria that have been damaged with viable, respiration-competent mitochondria. Here, we used a rodent model selectively bred for low-capacity running (LCR), which exhibits innate mitochondrial dysfunction in the hind limb muscles. Hence, the purpose of this study was to use a distinct breed of rats (i.e., LCR) that display hereditary skeletal muscle mitochondrial dysfunction to evaluate the consequences of mitochondrial transplantation. We hypothesized that the transplantation of mitochondria would effectively alleviate mitochondrial dysfunction in the hind limb muscles of rats when compared with placebo injections. In addition, we hypothesized that rats receiving the mitochondrial transplantation would experience an improvement in their functional capacity, as evaluated through incremental treadmill testing. Twelve aged LCR male rats (18 months old) were randomized into 2 groups (placebo or mitochondrial transplantation). One LCR rat of the same age and sex was used as the donor to isolate mitochondria from the hindlimb muscles. Isolated mitochondria were injected into both hindlimb muscles (quadriceps femoris, tibialis anterior (TA), and gastrocnemius complex) of a subset LCR (n = 6; LCR-M) rats. The remaining LCR (n = 5; LCR-P) subset received a placebo injection containing only the vehicle without the isolated mitochondria. Four weeks after mitochondrial transplantation, rodents were euthanized and hindlimb muscles harvested. The results indicated a significant (p < 0.05) increase in mitochondrial markers for glycolytic (plantaris and TA) and mixed (quadricep femoris) muscles, but not oxidative muscle (soleus). Moreover, we found significant (p < 0.05) epigenetic changes (i.e., hypomethylation) at the global and site-specific levels for a key mitochondrial regulator (transcription factor A mitochondrial) between the placebo and mitochondrial transplantation groups. To our knowledge, this is the first study to examine the efficacy of mitochondrial transplantation in a rodent model of aging with congenital skeletal muscle dysfunction., (Copyright © 2024 National Strength and Conditioning Association.)

Background: Skeletal muscle wasting is critical in patients with heart failure (HF). Whereas prior studies have employed appendicular lean mass (ALM) normalized by height squared to identify low skeletal muscle mass, the potential of ALM normalized to body mass index (ALM/BMI) remains unexplored in patients with HF. In this study, we compared the use of 2 skeletal muscle mass indices in patients with HF to examine their sex-specific correlations with measures of physical capacity, quality of life, and daily physical activity., Methods and Results: A total of 111 patients with HF underwent dual x-ray absorptiometry, physical capacity tests, and accelerometry and answered a quality-of-life questionnaire. ALM normalized by height squared and ALM/BMI indices disagreed in classifying low muscle mass (Cohen's κ, -0.008 [95% CI, -0.094 to 0.177]; P =0.93). ALM/BMI correlated well with 6-minute walking distance in women and men ( R =0.67 and 0.49; P <0.001), with maximal oxygen uptake in women and men ( R =0.41 and 0.48; P <0.05), and with maximal muscle strength in women and men ( R =0.54 and 0.43; P <0.01). Inversely, ALM normalized by height squared did not correlate significantly with 6-minute walking distance or maximal oxygen uptake and correlated with maximal muscle strength only in men ( R =0.43; P <0.001). Only ALM/BMI allowed for identification of a low-muscle-mass group characterized by poor quality of life (Minnesota Living With Heart Failure Questionnaire score of 33±21 versus 25±16; P =0.027) and less daily time spent in moderate to vigorous physical activity (8 [3-17] versus 15 [9-37] minutes; P <0.001)., Conclusions: ALM/BMI was superior for identifying clinically significant muscle dysfunction in both female and male patients with HF.

Background: Adolescents living with obesity (AlwO) can have limited exercise capacity. Exercise capacity can be predicted by a 2-factor model comprising lung function and leg muscle function, but no study has looked at cycling leg muscle function and its contribution to cycling exercise capacity in AlwO., Methods: Twenty-two nonobese adolescents and 22 AlwO (BMI > 95 percentile) were studied. Anthropometry, body composition (dual-energy X-ray absorptiometry), spirometry, 30-s isokinetic work capacity, and maximal exercise (cycle ergometry) were measured., Results: AlwO had greater total body mass, lean body mass, and lean leg mass (LLM). Lung function trended higher in AlwO. Leg 30-s work did not differ in absolute terms or per allometrically scaled LLM. Peak oxygen consumption did not differ between the groups in absolute terms or as percent predicted values (79.59 ± 14.6 vs. 82.3 ± 11.2% predicted control versus ALwO) but was lower in AlwO when expressed per kg body mass, kg lean body mass, scaled lean body mass, and LLM. Peak oxygen consumption related to both lung function and 30-s work, with no observed group effect. 30-s leg work related to the scaled LLM, with a small group effect. There was some correlation between leg work and time spent in moderate to vigorous physical activity in AlwO (r s  = 0.39, p = .07)., Conclusion: AlwO have larger LLM and preserved exercise capacity, when expressed as percentage of predicted, but not per allometrically scaled LLM. Increasing time spent in moderate to vigorous activity may benefit AlwO., (© 2024 Wiley Periodicals LLC.)

Background: This study aimed to determine the effect of different carbohydrate (CHO) doses on exercise capacity in patients with McArdle disease-the paradigm of "exercise intolerance", characterized by complete muscle glycogen unavailability-and to determine whether higher exogenous glucose levels affect metabolic responses at the McArdle muscle cell (in vitro) level., Methods: Patients with McArdle disease (n = 8) and healthy controls (n = 9) underwent a 12-min submaximal cycling constant-load bout followed by a maximal ramp test 15 min after ingesting a non-caloric placebo. In a randomized, double-blinded, cross-over design, patients repeated the tests after consuming either 75 g or 150 g of CHO (glucose:fructose = 2:1). Cardiorespiratory, biochemical, perceptual, and electromyographic (EMG) variables were assessed. Additionally, glucose uptake and lactate appearance were studied in vitro in wild-type and McArdle mouse myotubes cultured with increasing glucose concentrations (0.35, 1.00, 4.50, and 10.00 g/L)., Results: Compared with controls, patients showed the "classical" second-wind phenomenon (after prior disproportionate tachycardia, myalgia, and excess electromyographic activity during submaximal exercise, all p < 0.05) and an impaired endurance exercise capacity (-51% ventilatory threshold and -55% peak power output, both p < 0.001). Regardless of the CHO dose (p < 0.05 for both doses compared with the placebo), CHO intake increased blood glucose and lactate levels, decreased fat oxidation rates, and attenuated the second wind in the patients. However, only the higher dose increased ventilatory threshold (+27%, p = 0.010) and peak power output (+18%, p = 0.007). In vitro analyses revealed no differences in lactate levels across glucose concentrations in wild-type myotubes, whereas a dose-response effect was observed in McArdle myotubes., Conclusion: CHO intake exerts beneficial effects on exercise capacity in McArdle disease, a condition associated with total muscle glycogen unavailability. Some of these benefits are dose dependent., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Manipulating the amount of muscle mass engaged during exercise can noninvasively inform the contribution of central cardiovascular and peripheral vascular-oxidative functions to endurance performance. To better understand the factors contributing to exercise limitation in older and younger individuals, exercise performance was assessed during single-leg and double-leg cycling. 16 older (67 ± 5 years) and 14 younger (35 ± 5 years) individuals performed a maximal exercise using single-leg and double-leg cycling. The ratio of single-leg to double-leg cycling power (RatioPower SL/DL) was compared between age groups. The association between fitness (peak oxygen consumption, peak power output, and physical activity levels) and RatioPower SL/DL was explored. The RatioPower SL/DL was greater in older compared with younger individuals (1.14 ± 0.11 vs. 1.06 ± 0.08, p = .041). The RatioPower SL/DL was correlated with peak oxygen consumption (r = .886, p < .001), peak power output relative to body mass (r = .854, p < .001), and levels of physical activity (r = .728, p = .003) in the younger but not older subgroup. Reducing the amount of muscle mass engaged during exercise improved exercise capacity to a greater extent in older versus younger population and may reflect a greater reduction in central cardiovascular function compared with peripheral vascular-oxidative function with aging.

Purpose: Constant blood flow occlusion (BFO) superimposed on aerobic exercise can impair muscle function and exercise tolerance; however, no study has investigated the effect of intermittent BFO on the associated responses. Fourteen participants (n = 7 females) were recruited to compare neuromuscular, perceptual, and cardiorespiratory responses to shorter (5:15s, occlusion-to-release) and longer (10:30s) BFO applied during cycling to task failure., Methods: In randomized order, participants cycled to task failure (task failure 1) at 70% of peak power output with (i) shorter BFO, (ii) longer BFO, and (iii) no BFO (Control). Upon task failure in the BFO conditions, BFO was removed, and participants continued cycling until a second task failure (task failure 2). Maximum voluntary isometric knee contractions (MVC) and femoral nerve stimuli were performed along with perceptual measures at baseline, task failure 1, and task failure 2. Cardiorespiratory measures were recorded continuously across the exercises., Results: Task failure 1 was longer in Control than 5:15s and 10:30s (P < 0.001), with no differences between the BFO conditions. At task failure 1, 10:30s elicited a greater decline in twitch force compared to 5:15s and Control (P < 0.001). At task failure 2, twitch force remained lower in 10:30s than Control (P = 0.002). Low-frequency fatigue developed to a greater extent in 10:30s compared to Control and 5:15s (P < 0.047). Dyspnea and Fatigue were greater for Control than 5:15s and 10:30s at the end of task failure 1 (P < 0.002)., Conclusion: Exercise tolerance during BFO is primarily dictated by the decline in muscle contractility and accelerated development of effort and pain., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Maximal voluntary contraction force (MVC), potentiated twitch force (Q pot ), and voluntary activation (%VA) recover to baseline within 90 s following extreme-intensity exercise. However, methodological limitations mask important recovery kinetics. We hypothesized reductions in MVC, Q pot , and %VA at task failure following extreme-intensity exercise would be less than following severe-intensity exercise, and Q pot and MVC following extreme-intensity exercise would show significant recovery within 120 s but remain depressed following severe-intensity exercise. Twelve subjects (6 men) completed 2 severe-intensity (40, 50% MVC) and 2 extreme-intensity (70, 80% MVC) isometric knee-extension exercise bouts to task failure (T lim ). Neuromuscular function was measured at baseline, T lim , and through 150 s of recovery. Each intensity significantly reduced MVC and Q pot compared with baseline. MVC was greater at T lim ( p  < 0.01) and at 150 s of recovery ( p  = 0.004) following exercise at 80% MVC compared with severe-intensity exercise. Partial recovery of MVC and Q pot were detected within 150 s following T lim for each exercise intensity; Q pot recovered to baseline values within 150 s of recovery following exercise at 80% MVC. No differences in %VA were detected pre- to post-exercise or across recovery for any intensity. Although further analysis showed sex-specific differences in MVC and Q pot , future studies should closely examine sex-dependent responses to extreme-intensity exercise. It is clear, however, that these data reinforce that mechanisms limiting exercise tolerance during extreme-intensity exercise recover quickly. Novelty: Severe- and extreme-intensity exercise cause independent responses in fatigue accumulation and the subsequent recovery time courses. Recovery of MVC and Q pot occurs much faster following extreme-intensity exercise in both men and women.

Objective: Peripheral arterial disease (PAD) is characterized by intermittent claudication, which interferes with walking and leads to worsening of functional capacity. This mechanism has not been clearly defined in PAD. Thus, the aim of our study was to identify the muscular metabolism and vascular function variables using near-infrared spectroscopy (NIRS) and their possible associations with functional capacity in individuals with PAD and secondly to verify the differences in these variables between persons with PAD and diabetes mellitus (DM) and those with PAD without DM., Methods: A total of 39 participants with intermittent claudication were enrolled, 14 of whom had DM. They were assessed for functional capacity by the total distance covered in the treadmill test with the speed and grade constant and for muscle function and metabolism using near-infrared spectroscopy at rest and during the treadmill test. The Spearman correlation coefficient was computed to assess the presence of an association between the variables, and multiple linear regression analysis was performed, considering the total test distance as the dependent variable. The assessment between groups was performed using the independent t test or Mann-Whitney U test., Results: The near-infrared spectroscopy variables related to tissue oxygen saturation in the test recovery phase were correlated with the functional performance during the treadmill test. Thus, those with a longer or slower recovery time and those with greater tissue deoxygenation had walked a shorter distance. A significant difference (P = .049) was noted between those with PAD stratified by DM in the reoxygenation time required for an occlusion., Conclusions: These findings reinforce the hypothesis that peripheral factors related to vascular function and muscular metabolism can affect the walking capacity of persons with PAD and that microvascular dysfunction is more prevalent among those with PAD and DM., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

We investigated whether moderate-intensity training of horses in moderate hypoxia for 4 weeks elicits greater adaptations in exercise performance, aerobic capacity, and glycolytic/oxidative metabolism in skeletal muscle compared to normoxic training. In a randomized crossover study design, seven untrained Thoroughbred horses (5.9 ± 1.1 years, 508 ± 9 kg) completed 4 weeks (3 sessions/week) of two training protocols consisting of 3-min cantering at 70% of maximal oxygen consumption ( V ˙ O 2 max ) in hypoxia (HYP; F I O 2  = 14.7%) and normoxia (NOR; F I O 2  = 21.0%) with a 4-month washout period. Normoxic incremental exercise tests (IET) were conducted before and after training. Biopsy samples were obtained from the middle gluteal muscle before IET and monocarboxylate transporter (MCT) protein expression and glycolytic/mitochondrial enzyme activities were analyzed. Data were analyzed using mixed models (p < 0.05). Running speed was 7.9 ± 0.2 m/s in both groups and arterial oxygen saturation during training in NOR and HYP were 92.9 ± 0.9% and 75.7 ± 3.9%, respectively. Run time in HYP (+9.7%) and V ˙ O 2 max in both groups (NOR, +6.4%; HYP, +4.3%) at IET increased after 4 weeks of training. However, cardiac output, arterial-mixed venous O 2 difference, and hemoglobin concentration at exhaustion were unchanged in both conditions. While MCT1 protein and citrate synthase activity did not increase in both conditions after training, MCT4 protein (+13%), and phosphofructokinase activity (+42%) increased only in HYP. In conclusion, 4 weeks of moderate-intensity hypoxic training improves exercise performance and glycolytic capacity of skeletal muscle in horses., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

During 1-leg cycling, contralateral muscle sympathetic nerve activity (MSNA) falls in healthy adults but increases in most with reduced ejection fraction heart failure (HFrEF). We hypothesized that their peak oxygen uptake ( V̇ O 2peak ) relates inversely to their MSNA response to exercise. Twenty-nine patients (6 women; 63 ± 9 years; left ventricular ejection fraction: 30 ± 7%; V̇ O 2peak : 78 ± 23 percent age-predicted (% V̇ O 2peak ); mean ± SD) and 21 healthy adults (9 women; 58 ± 7 years; 115 ± 29% V̇ O 2peak ) performed 2 min of mild- ("loadless") and moderate-intensity ("loaded") 1-leg cycling. Heart rate, blood pressure (BP), contralateral leg MSNA and perceived exertion rate (RPE) were recorded. Resting MSNA burst frequency (BF) was higher ( p < 0.01) in HFrEF (51 ± 11 vs 44 ± 7 bursts·min -1 ). Exercise heart rate, BP and RPE responses at either intensity were similar between groups. In minute 2 of "loadless" and "loaded" cycling, group mean BF fell from baseline values in controls (-5 ± 6 and -7 ± 7 bursts·min -1 , respectively) but rose in HFrEF (+5 ± 7 and +5 ± 10 bursts·min -1 ). However, in 10 of the latter cohort, BF fell, similarly to controls. An inverse relationship between ΔBF from baseline to "loaded" cycling and % V̇ O 2peak was present in patients ( r = -0.43, p < 0.05) but absent in controls ( r = 0.07, p = 0.77). In HFrEF, ∼18% of variance in % V̇ O 2peak can be attributed to the change in BF elicited by exercise. Novelty: Unlike healthy individuals, in the majority of heart failure patients with reduced ejection fraction (HFrEF), 1-leg cycling increases muscle sympathetic nerve activity (MSNA). In HFrEF, ∼18% of age-predicted peak oxygen uptake ( V̇ O 2peak ) can be attributed to changes in MSNA elicited by low-intensity exercise. This relationship is absent in healthy adults.

Decreasing exercise tolerance is one of the key features related to a poor prognosis in patients with chronic obstructive pulmonary disease (COPD). Cardiopulmonary exercise testing (CPET) is useful for evaluating exercise tolerance. The present study was performed to clarify the correlation between exercise tolerance and clinical parameters, focusing especially on the cross-sectional area (CSA) of skeletal muscle. The present study investigated 69 patients with COPD who underwent CPET. The correlations between oxygen uptake ([Formula: see text]) at peak exercise and clinical parameters of COPD, including skeletal muscle area measured using single-section axial computed tomography (CT), were evaluated. The COPD assessment test score (ρ = - 0.35, p = 0.02) was weakly correlated with [Formula: see text] at peak exercise. In addition, forced expiratory volume in one second (FEV 1 ) (ρ = 0.39, p = 0.0009), FEV 1 /forced vital capacity (ρ = 0.33, p = 0.006), and the CSA of the pectoralis muscles (PMs) (ρ = 0.36, p = 0.007) and erector spinae muscles (ECMs) (ρ = 0.39, p = 0.003) were correlated with [Formula: see text] at peak exercise. Multivariate analysis adjusted by age and FEV 1 indicated that PM CSA was weakly correlated after adjustment (β value [95% confidence interval] 0.175 [0.03-0.319], p = 0.02). In addition, ECM CSA tended to be correlated, but not significantly after adjustment (0.192 [- 0.001-0.385] p = 0.052). The COPD assessment test, FEV 1 , FEV 1 /FVC, PM CSA , and ECM CSA were significantly correlated with [Formula: see text] at peak exercise., (© 2021. The Author(s).)

Muscle glycogen depletion has been proposed as one of the main causes of fatigue during exercise. However, few studies have addressed the contribution of liver glycogen to exercise performance. Using a low-intensity running protocol, here, we analyzed exercise capacity in mice overexpressing protein targeting to glycogen (PTG) specifically in the liver (PTG OE mice), which show a high concentration of glycogen in this organ. PTG OE mice showed improved exercise capacity, as determined by the distance covered and time ran in an extenuating endurance exercise, compared with control mice. Moreover, fasting decreased exercise capacity in control mice but not in PTG OE mice. After exercise, liver glycogen stores were totally depleted in control mice, but PTG OE mice maintained significant glycogen levels even in fasting conditions. In addition, PTG OE mice displayed an increased hepatic energy state after exercise compared with control mice. Exercise caused a reduction in the blood glucose concentration in control mice that was less pronounced in PTG OE mice. No changes were found in the levels of blood lactate, plasma free fatty acids, or β-hydroxybutyrate. Plasma glucagon was elevated after exercise in control mice, but not in PTG OE mice. Exercise-induced changes in skeletal muscle were similar in both genotypes. These results identify hepatic glycogen as a key regulator of endurance capacity in mice, an effect that may be exerted through the maintenance of blood glucose levels., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Impaired exercise capacity is a significant symptom of CKD and is associated with poor survival. Furthermore, there is a growing interest in applying exercise as a diagnostic tool or as therapy in CKD. However, an in-depth understanding of exercise physiology in CKD is still lacking., Methods: To evaluate the role of cardiac (central) and noncardiac (peripheral) determinants of exercise capacity in CKD, we conducted a cross-sectional study of 70 male patients with CKD (stages 2-5) without diabetes or cardiac disease, 35 healthy controls, and 25 patients with heart failure. An integrated cardiopulmonary exercise test using a CO 2 rebreathing technique was used to measure peak O 2 consumption (VO 2peak ) and peak cardiac output simultaneously, and to calculate peak peripheral O 2 extraction (C[a-v]O 2 ), the peripheral determinant (the ability of exercising skeletal muscles to extract oxygen). We performed multiple regression analysis and used Bayesian information criteria (BIC) changes to quantitatively assess the individual contribution of central and peripheral factors., Results: Compared with healthy controls, in patients with CKD, the VO 2peak was impaired proportionate to its severity. Peak cardiac output was the predominant determinant of VO 2peak in healthy controls and patients with heart failure, whereas C(a-v)O 2 played a more significant role in determining VO 2peak in CKD ( β =0.68, P <0.001) compared with cardiac output ( β =0.63, P <0.001). In addition, the magnitude of BIC reduction was greater for C(a-v)O 2 compared with cardiac output (BIC, 298.72 versus 287.68) in CKD., Conclusions: In CKD, both peak cardiac output and peak C(a-v)O 2 are independent predictors of VO 2peak , and the more significant roleplayed by peak C(a-v)O 2 highlights the importance of noncardiac factors in determining exercise capacity in CKD., (Copyright © 2021 by the American Society of Nephrology.)

Currently, little is known about the extent of interindividual variability in response to beta-alanine (BA) supplementation, nor what proportion of said variability can be attributed to external factors or to the intervention itself (intervention response). To investigate this, individual participant data on the effect of BA supplementation on a high-intensity cycling capacity test (CCT110%) were meta-analyzed. Changes in time to exhaustion (TTE) and muscle carnosine were the primary and secondary outcomes. Multilevel distributional Bayesian models were used to estimate the mean and SD of BA and placebo group change scores. The relative sizes of group SDs were used to infer whether observed variation in change scores were due to intervention or non-intervention-related effects. Six eligible studies were identified, and individual data were obtained from four of these. Analyses showed a group effect of BA supplementation on TTE (7.7, 95% credible interval [CrI] [1.3, 14.3] s) and muscle carnosine (18.1, 95% CrI [14.5, 21.9] mmol/kg DM). A large intervention response variation was identified for muscle carnosine (σIR = 5.8, 95% CrI [4.2, 7.4] mmol/kg DM) while equivalent change score SDs were shown for TTE in both the placebo (16.1, 95% CrI [13.0, 21.3] s) and BA (15.9, 95% CrI [13.0, 20.0] s) conditions, with the probability that SD was greater in placebo being 0.64. In conclusion, the similarity in observed change score SDs between groups for TTE indicates the source of variation is common to both groups, and therefore unrelated to the supplement itself, likely originating instead from external factors such as nutritional intake, sleep patterns, or training status.

The availability of dietary beta-alanine (BA) is the limiting factor in carnosine synthesis within human muscle due to its low intramuscular concentration and substrate affinity. Carnosine can accept hydrogen ions (H + ), making it an important intramuscular buffer against exercise-induced acidosis. Metabolite accumulation rate increases when exercising in hypoxic conditions, thus an increased carnosine concentration could attenuate H + build-up when exercising in hypoxic conditions. This study examined the effects of BA supplementation on high intensity cycling capacity in normoxia and hypoxia. In a double-blind design, nineteen males were matched into a BA group (n = 10; 6.4 g·d -1 ) or a placebo group (PLA; n = 9) and supplemented for 28 days, carrying out two pre- and two post-supplementation cycling capacity trials at 110% of powermax, one in normoxia and one in hypoxia (15.5% O 2 ). Hypoxia led to a 9.1% reduction in exercise capacity, but BA supplementation had no significant effect on exercise capacity in normoxia or hypoxia ( P > 0.05). Blood lactate accumulation showed a significant trial x time interaction post-supplementation ( P = 0.016), although this was not significantly different between groups. BA supplementation did not increase high intensity cycling capacity in normoxia, nor did it improve cycling capacity in hypoxia even though exercise capacity was reduced under hypoxic conditions.

Purpose: This study aimed to describe the kinetics of carnosine washout in human skeletal muscle over 16 wk., Methods: Carnosine washout kinetics were studied in 15 young, physically active omnivorous men randomly assigned to take 6.4 g·d-1 of β-alanine (n = 11) or placebo (n = 4) for 8 wk. Muscle carnosine content (M-Carn) was determined before (PRE), immediately after (POST), and 4, 8, 12, and 16 wk after supplementation. High-intensity exercise tests were performed at these same time points. Linear and exponential models were fitted to the washout data, and the leave-one-out method was used to select the model with the best fit for M-Carn decay data. Repeated-measures correlation analysis was used to assess the association between changes in M-Carn and changes in performance., Results: M-Carn increased from PRE to POST in the β-alanine group only (+91.1% ± 29.1%; placebo, +0.04% ± 10.1%; P < 0.0001). M-Carn started to decrease after cessation of β-alanine supplementation and continued to decrease until week 16 (POST4, +59% ± 40%; POST8, +35% ± 39%; POST12, +18% ± 32%; POST16, -3% ± 24% of PRE M-Carn). From week 12 onward, M-Carn was no longer statistically different from PRE. Both linear and exponential models displayed very similar fit and could be used to describe carnosine washout, although the linear model presented a slightly better fit. The decay in M-Carn was mirrored by a similar decay in high-intensity exercise tolerance; M-Carn was moderately and significantly correlated with total mechanical work done (r = 0.505; P = 0.032) and time to exhaustion (r = 0.72; P < 0.001)., Conclusions: Carnosine washout takes 12-16 wk to complete, and it can be described either by linear or exponential curves. Changes in M-Carn seem to be mirrored by changes in high-intensity exercise tolerance. This information can be used to optimize β-alanine supplementation strategies., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

Previous work has shown that poorer mitochondrial function is associated with age-related perceived fatigability. However, whether glucose oxidation and anaerobic metabolism are intermediate factors underlying this association remains unclear. We examined the total cross-sectional association between mitochondrial function and perceived fatigability in 554 adults aged 22-99 years. Mitochondrial function was assessed by skeletal muscle oxidative capacity (kPCr) using 31P magnetic resonance spectroscopy. Perceived fatigability was measured by rating of perceived exertion after a 5-minute (0.67 m/s) treadmill walk. The intermediate role of glucose oxidation (measured by the rate of change of respiratory exchange ratio [RER change rate] during the 5-minute treadmill walk) and anaerobic metabolism (measured by ventilatory threshold [VeT] during a maximal treadmill test) was evaluated by examining their cross-sectional associations with kPCr and perceived exertion. For each 0.01/s lower kPCr, perceived fatigability was 0.47 points higher (p = .002). A 0.01/s lower kPCr was also associated with 8.3 L/min lower VeT (p < .001). Lower VeT was associated with higher fatigability at lower levels of kPCr but not at higher kPCr levels (β for interaction = 0.017, p = .002). kPCr and RER change rate were not significantly associated (p = .341), but a 0.01/min higher RER change rate was associated with 0.12-point higher fatigability (p = .001). Poorer mitochondrial function potentially contributes to higher perceived fatigability through higher glucose oxidation and higher anaerobic metabolism. Future studies to further explore the longitudinal mechanisms between these metabolic changes and fatigability are warranted., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Eccentric cycling (ECC) may be an attractive exercise method in COPD because of both low cardiorespiratory demand and perception of effort compared with conventional concentric cycling (CON) at matched mechanical loads. However, it is unknown whether ECC can be performed by individuals with COPD at an intensity able to cause sufficient metabolic stress to improve aerobic capacity., Research Question: What are the cardiopulmonary and metabolic responses to ECC in people with COPD and healthy volunteers when compared with CON at matched mechanical loads?, Study Design and Methods: Thirteen people with COPD (mean ± SD age, 64 ± 9 years; FEV 1 , 45 ± 19% predicted; BMI, 24 ± 4 kg/m 2 ; oxygen uptake at peak exercise [V̇O 2peak ], 15 ± 3 mL/kg/min) and 9 age-matched control participants (FEV 1 , 102 ± 13% predicted; BMI, 28 ± 5 kg/m 2 ; V̇O 2peak , 23 ± 5 mL/kg/min), performed up to six 4-min bouts of ECC and CON at matched mechanical loads of increasing intensity. In addition, 12 individuals with COPD underwent quadriceps muscle biopsies before and after 20 min of ECC and CON at 65% peak power., Results: At matched mechanical loads, oxygen uptake, minute ventilation, heart rate, systolic BP, respiratory exchange ratio (all P < .001), capillary lactate, perceived breathlessness, and leg fatigue (P < .05) were lower in both groups during ECC than CON. Muscle lactate content increased (P = .008) and muscle phosphocreatine decreased (P = .012) during CON in COPD, which was not evident during ECC., Interpretation: Cardiopulmonary and blood lactate responses during submaximal ECC were less compared with during CON at equivalent mechanical workloads in healthy participants and COPD patients, and this was confirmed at a muscle level in COPD patients. Submaximal ECC was well tolerated and allowed greater mechanical work at lower ventilatory cost. However, in people with COPD, a training intervention based on ECC is unlikely to stimulate cardiovascular and metabolic adaptation to the same extent as CON., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Skeletal muscle atrophy, weakness, mitochondrial loss, and dysfunction are characteristics of chronic obstructive pulmonary disease (COPD). It remains unclear whether muscle dysfunction occurs in both upper and lower limbs, because findings are inconsistent in the few studies where upper and lower limb muscle performance properties were compared within an individual. This study determined whether muscle oxidative capacity is low in upper and lower limbs of COPD patients compared with controls., Methods: Oxidative capacity of the forearm and medial gastrocnemius was measured using near-infrared spectroscopy to determine the muscle O2 consumption recovery rate constant (k, min) in 20 COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2/3/4, n = 7/7/6) and 20 smokers with normal spirometry (CON). Muscle k is linearly proportional to oxidative capacity. Steps per day and vector magnitude units per minute (VMU·min) were assessed using triaxial accelerometry. Differences between group and limb were assessed by two-way ANOVA., Results: There was a significant main effect of group (F = 11.2, ηp = 0.13, P = 0.001): k was lower in both upper and lower limb muscles in COPD (1.01 ± 0.17 and 1.05 ± 0.24 min) compared with CON (1.29 ± 0.49 and 1.54 ± 0.60 min). There was no effect on k of limb (F = 1.8, ηp = 0.02, P = 0.18) or group-limb interaction (P = 0.35). (VMU·min) was significantly lower in COPD (-38%; P = 0.042). Steps per day did not differ between COPD (4738 ± 3194) and CON (6372 ± 2107; P = 0.286), although the difference exceeded a clinically important threshold (>600-1100 steps per day)., Conclusions: Compared with CON, muscle oxidative capacity was lower in COPD in both upper (-20%) and lower (-30%) limbs. These data suggest that mitochondrial loss in COPD is not isolated to locomotor muscles.

Background: L-carnitine (LC) is used as a supplement by recreationally-active, competitive and highly trained athletes. This systematic review aims to evaluate the effect of prolonged LC supplementation on metabolism and metabolic modifications., Methods: A literature search was conducted in the MEDLINE (via PubMed) and Web of Science databases from the inception up February 2020. Eligibility criteria included studies on healthy human subjects, treated for at least 12 weeks with LC administered orally, with no drugs or any other multi-ingredient supplements co-ingestion., Results: The initial search retrieved 1024 articles, and a total of 11 studies were finally included after applying inclusion and exclusion criteria. All the selected studies were conducted with healthy human subjects, with supplemented dose ranging from 1 g to 4 g per day for either 12 or 24 weeks. LC supplementation, in combination with carbohydrates (CHO) effectively elevated total carnitine content in skeletal muscle. Twenty-four-weeks of LC supplementation did not affect muscle strength in healthy aged women, but significantly increased muscle mass, improved physical effort tolerance and cognitive function in centenarians. LC supplementation was also noted to induce an increase of fasting plasma trimethylamine-N-oxide (TMAO) levels, which was not associated with modification of determined inflammatory nor oxidative stress markers., Conclusion: Prolonged LC supplementation in specific conditions may affect physical performance. On the other hand, LC supplementation elevates fasting plasma TMAO, compound supposed to be pro-atherogenic. Therefore, additional studies focusing on long-term supplementation and its longitudinal effect on the cardiovascular system are needed.

The association between type 2 diabetes mellitus (T2DM) and heart failure (HF) is well established. Early in the course of the diabetic disease, some degree of impaired exercise capacity (a powerful marker of health status with prognostic value) can be frequently highlighted in otherwise asymptomatic T2DM subjects. However, the literature is quite heterogeneous, and the underlying pathophysiologic mechanisms are far from clear. Imaging-cardiopulmonary exercise testing (CPET) is a non-invasive, provocative test providing a multi-variable assessment of pulmonary, cardiovascular, muscular, and cellular oxidative systems during exercise, capable of offering unique integrated pathophysiological information. With this review we aimed at defying the cardiorespiratory alterations revealed through imaging-CPET that appear specific of T2DM subjects without overt cardiovascular or pulmonary disease. In synthesis, there is compelling evidence indicating a reduction of peak workload, peak oxygen assumption, oxygen pulse, as well as ventilatory efficiency. On the contrary, evidence remains inconclusive about reduced peripheral oxygen extraction, impaired heart rate adjustment, and lower anaerobic threshold, compared to non-diabetic subjects. Based on the multiparametric evaluation provided by imaging-CPET, a dissection and a hierarchy of the underlying mechanisms can be obtained. Here we propose four possible integrated pathophysiological mechanisms, namely myocardiogenic, myogenic, vasculogenic and neurogenic. While each hypothesis alone can potentially explain the majority of the CPET alterations observed, seemingly different combinations exist in any given subject. Finally, a discussion on the effects -and on the physiological mechanisms-of physical activity and exercise training on oxygen uptake in T2DM subjects is also offered. The understanding of the early alterations in the cardiopulmonary response that are specific of T2DM would allow the early identification of those at a higher risk of developing HF and possibly help to understand the pathophysiological link between T2DM and HF.

Purpose: Decline in skeletal muscle mitochondrial oxidative capacity (MOC) is associated with reduced aerobic capacity and increased risk of cardiovascular and metabolic disease. Measuring skeletal muscle MOC may be an alternative method to assess aerobic capacity, especially for individuals unable to perform a whole-body maximum oxygen uptake protocol. In this study, linear regression analysis in two leg muscles was performed to determine whether MOC values could be used to predict whole-body peak oxygen uptake., Methods: MOC was measured with near infrared spectroscopy (NIRS) in the medial gastrocnemius (MG) and vastus lateralis (VL) muscles of 26 participants (age, 27.1 ± 5.8 years old). Whole-body peak oxygen uptake (VO 2 peak) was determined by indirect calorimetry during a continuous ramp protocol on a cycle ergometer., Results: VO 2 peak values were significantly correlated with the muscle recovery rate constant (k) of the MG (kMG, r = 0.59; p < 0.01) and VL (kVL, r = 0.63; p < 0.01) muscles. Summing recovery rate constants of both muscles together (kMG + kVL) improved the strength of the correlation with VO 2 peak (r = 0.78; p < 0.0001) and could explain a majority of the variance (R 2  = 0.61) between the two measurements., Conclusion: Data suggest that NIRS can provide reliable MOC measurements on two leg muscles that correlate well with whole-body peak oxygen uptake.

Introduction: Oxygen supplementation (O 2 -Suppl) is recommended for pulmonary rehabilitation with higher exercise intensities. However, high-intensity exercise tends toward muscle damage and a greater inflammatory response. We aimed to investigate the effect of O 2 -Suppl during exercise test (EET) on CRP level and muscle damage (CPK, LDH, lactate) in non-hypoxemic COPD patients., Methods: Eleven non-depleted patients with COPD (FEV 1 65.5 ± 4.3 %) performed two EET (room-air or O 2 -Suppl-100 %), through a blind, randomized, and placebo-controlled crossover design. CPK, LDH and CRP were measured before, immediately after and 24 h after EET., Results: Exercise time was higher with O 2 -Suppl (49.9 ± 37.3 %; p = 0.001) and increases in CPK and LDH were observed compared to basal values in the O 2 -Suppl (28.4UI/L and 28.3 UI/L). The O 2 -Suppl protocol resulted in a lower increase in CRP (92.1 ± 112.4 % vs. 400.1 ± 384.9 %; p = 0.003)., Conclusions: O 2 -Suppl increases exercise-tolerance, resulting in increased muscle injury markers in COPD. However, oxygen supplementation attenuates the inflammatory response, even upon increased physical exercise., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Treatment for head and neck cancer is associated with multiple side effects, including loss of body mass, impaired physical function and reduced health-related quality of life. This study aimed to investigate the impact of treatment (radiation therapy ± concurrent chemotherapy) on (i) muscle strength, muscle cross-sectional area and patient-reported outcomes, and (ii) central and peripheral alterations during a whole-body exercise task., Methods: Ten people with head and neck cancer (4 female; 50 ± 9 years) completed a lab visit before and after (56 ± 30 days) completion of treatment. Participants performed a neuromuscular assessment (involving maximal isometric voluntary contractions in the knee extensors and electrical stimulation of the femoral nerve) before and during intermittent cycling to volitional exhaustion. Anthropometrics and patient-reported outcomes were also assessed., Results: From before to after treatment, maximal isometric muscle strength was reduced (P = 0.002, d = 0.73), as was potentiated twitch force (P < 0.001, d = 0.62), and muscle cross-sectional area (e.g., vastus lateralis: P = 0.010, d = 0.64). Exercise time was reduced (P = 0.008, d = 0.62) and peripheral processes contributed to a reduction in maximal force due to cycling. After treatment, the severity of self-reported fatigue increased (P = 0.041, r = - 0.65) and health-related quality of life decreased (P = 0.012, r = - 0.79)., Conclusion: Neuromuscular function was impaired in patients with head and neck cancer after treatment. Whole-body exercise tolerance was reduced and resulted in predominantly peripheral, rather than central, disturbances to the neuromuscular system. Future research should evaluate strength training after treatment for head and neck cancer, with the overall aim of reducing fatigue and improving health-related quality of life.

Objectives: Diffusion tensor magnetic resonance imaging (DTI) and T2 mapping enable the detection of exercise-induced changes in the skeletal muscle microenvironment. This study prospectively quantified DTI metrics and T2 relaxation times of thigh muscles in competitive triathletes at rest and following a triathlon race in comparison with sedentary controls., Methods: Twenty-two triathletes (males N = 16, females N = 6) and twenty-three controls (males N = 16, females N = 7) underwent magnetic resonance imaging (MRI) on a 3 T system at baseline (time point 1; 72 h at rest). Twelve triathletes (males N = 8, females N = 4) underwent a second scan (time point 2; 3 h of completing a triathlon race). The tensor eigenvalues (λ 1 , λ 2 , λ 3 ), mean diffusivity (MD), fractional anisotropy (FA), and T2 times were compared between controls and triathletes at time point 1 and triathletes at time points 1 and 2 using independent and paired t tests., Results: In comparison with the controls at time point 1, the T2 times of rectus femoris (RF, p < 0.02), adductor magnus (AM, p = 0.02), biceps femoris (BF, p < 0.001), semitendinosus (ST, p = 0.005), and semimembranosus (SM, p = 0.003) muscles were significantly increased in triathletes. At time point 2 in triathletes, the average tensor metrics (MD, λ 3 / λ 1 ) of BF, ST, and SM muscles increased (p < 0.05) and FA values in ST and SM muscles decreased (p < 0.03). T2 times were not significantly changed between both time points in triathletes., Conclusion: Our results indicate that this multiparametric MRI protocol allows detection and quantification of changes in the skeletal muscle microenvironment caused by endurance training and acute strenuous exercise., Key Points: • Endurance training results in changes to the skeletal microstructure, which can be quantified using MRI-based diffusion tensor imaging. • The combined application of MRI diffusion tensor imaging and T2 mapping allows the differentiation of microstructural changes caused by active exercise or endurance training. • Environmental adaptations of the skeletal muscle caused by physical training are influenced by gender.

Aims/hypothesis: The aim of this study was to compare exercise capacity, strength and skeletal muscle perfusion during exercise, and oxidative capacity between South Asians, African Caribbeans and Europeans, and determine what effect ethnic differences in the prevalence of type 2 diabetes has on these functional outcomes., Methods: In total, 708 participants (aged [mean±SD] 73 ± 7 years, 56% male) were recruited from the Southall and Brent Revisited (SABRE) study, a UK population-based cohort comprised of Europeans (n = 311) and South Asian (n = 232) and African Caribbean (n = 165) migrants. Measurements of exercise capacity using a 6 min stepper test (6MST), including measurement of oxygen consumption ([Formula: see text]) and grip strength, were performed. Skeletal muscle was assessed using near infrared spectroscopy (NIRS); measures included changes in tissue saturation index (∆TSI%) with exercise and oxidative capacity (muscle oxygen consumption recovery, represented by a time constant [τ]). Analysis was by multiple linear regression., Results: When adjusted for age and sex, in South Asians and African Caribbeans, exercise capacity was reduced compared with Europeans ([Formula: see text] [ml min -1  kg -1 ]: β = -1.2 [95% CI -1.9, -0.4], p = 0.002, and β -1.7 [95% CI -2.5, -0.8], p < 0.001, respectively). South Asians had lower and African Caribbeans had higher strength compared with Europeans (strength [kPa]: β = -9 [95% CI -12, -6), p < 0.001, and β = 6 [95% CI 3, 9], p < 0.001, respectively). South Asians had greater decreases in TSI% and longer τ compared with Europeans (∆TSI% [%]: β = -0.9 [95% CI -1.7, -0.1), p = 0.024; τ [s]: β = 11 [95% CI 3, 18], p = 0.006). Ethnic differences in [Formula: see text] and grip strength remained despite adjustment for type 2 diabetes or HbA 1c (and fat-free mass for grip strength). However, the differences between Europeans and South Asians were no longer statistically significant after adjustment for other possible mediators or confounders (including physical activity, waist-to-hip ratio, cardiovascular disease or hypertension, smoking, haemoglobin levels or β-blocker use). The difference in ∆TSI% between Europeans and South Asians was marginally attenuated after adjustment for type 2 diabetes or HbA 1c and was also no longer statistically significant after adjusting for other confounders; however, τ remained significantly longer in South Asians vs Europeans despite adjustment for all confounders., Conclusions/interpretation: Reduced exercise capacity in South Asians and African Caribbeans is unexplained by higher rates of type 2 diabetes. Poorer exercise tolerance in these populations, and impaired muscle function and perfusion in South Asians, may contribute to the higher morbidity burden of UK ethnic minority groups in older age.

Background: Inspiratory muscle training has been shown to improve exercise performance, however there is limited evidence for its effectiveness in soccer players. This study investigates the effect of inspiratory muscle training on soccer-specific fitness and exercise tolerance in adolescent male players., Methods: Thirty highly trained soccer players (16-19 y) were randomly assigned into one of three groups: experimental 1 (N.=10), experimental 2 (N.=10) and sham-control (sham, N.=10). All groups performed inspiratory muscle training twice per day and five times per week for 8 weeks. Experimental 1 performed 25-35 breaths at 55% maximal inspiratory pressure, experimental 2 performed 45-55 breaths at 40% maximal inspiratory pressure, whereas sham performed 30 breaths at 15% maximal inspiratory pressure. Measures before and after the intervention involved the Yo-Yo Intermittent Recovery test level 1, running-based anaerobic test, repeated high-intensity endurance test, maximal inspiratory pressure, and spirometry., Results: Yo-Yo Intermittent Recovery test level 1: distance increased for experimental groups 1 and 2 compared to sham (P=0.012 and P=0.031, respectively), with no difference between experimental groups. Fatigue index calculated from running-based anaerobic test improved for experimental groups 1 and 2 compared to sham (P=0.014 and P=0.011, respectively), with no difference between experimental groups. Exercise tolerance (i.e. blood lactate concentration, perceived exertion and perceived breathlessness) following the repeated high-intensity endurance test decreased in experimental groups 1 and 2 compared to sham (P <0.05), with no difference between experimental groups. Maximal inspiratory pressure increased for experimental groups 1 and 2 compared to sham (P=0.000), with no difference between experimental groups. There were no changes for the spirometry measures., Conclusions: Improvements in soccer-specific fitness and exercise tolerance can be achieved using inspiratory muscle training protocols of varying intensities and volumes.

New Findings: What is the central question of this study? Does the magnitude of neuromuscular fatigue depend on the amount of work done (W') at task failure when cycling above critical power (CP)? What is the main finding and its importance? Creatine supplementation increases W' and enhances supra-CP performance, but induces similar magnitudes of neuromuscular fatigue at task failure compared to placebo. Increased W' does not lead to higher levels of neuromuscular fatigue. This supports the notion of a critical level of neuromuscular fatigue at task failure and challenges a direct causative link between W' depletion and neuromuscular fatigue., Abstract: The present study examined the effect of creatine supplementation on neuromuscular fatigue and exercise tolerance when cycling above critical power (CP). Eleven males performed an incremental cycling test with four to five constant-load trials to task failure (TTF) to obtain asymptote (CP) and curvature constant (W') of the power-duration relationship, followed by three constant-load supra-CP trials: (1) one TTF following placebo supplementation (PLA); (2) one TTF following creatine supplementation (CRE); and (3) one trial of equal duration to PLA following creatine supplementation (ISO). Neuromuscular assessment of the right knee extensors was performed pre- and post-exercise to measure maximal voluntary contraction (MVC), twitch forces evoked by single (Q pot ) and paired high- (PS100) and low- (PS10) frequency stimulations and voluntary activation. Creatine supplementation increased TTF in CRE vs. PLA by ∼11% (P = 0.017) and work done above CP by ∼10% (P = 0.015), with no difference (P > 0.05) in reductions in MVC (-24 ± 8% vs. -20 ± 9%), Q pot (-39 ± 13% vs. -32 ± 14%), PS10 (-42 ± 14% vs. -36 ± 13%), PS100 (-25 ± 10% vs. -18 ± 12%) and voluntary activation (-7 ± 8% vs. -5 ± 7%). No significant difference was found between ISO and either PLA or CRE (P > 0.05). These findings suggest similar levels of neuromuscular fatigue can be found following supra-CP cycling despite increases in performance time and amount of work done above CP, supporting the notion of a critical level of neuromuscular fatigue and challenging a direct causative link between W' depletion and neuromuscular fatigue., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Objective: The time needed to increase oxygen utilisation to meet metabolic demand (V̇O 2 kinetics) is impaired in heart failure (HF) with reduced ejection fraction and is an independent risk factor for HF mortality. It is not known if V̇O 2 kinetics are slowed in HF with preserved ejection fraction (HFpEF). We tested the hypothesis that V̇O 2 kinetics are slowed during submaximal exercise in HFpEF and that slower V̇O 2 kinetics are related to impaired peripheral oxygen extraction., Methods: Eighteen HFpEF patients (68±7 years, 10 women) and 18 healthy controls (69±6 years, 10 women) completed submaximal and peak exercise testing. Cardiac output (acetylene rebreathing, Q̇ c ), ventilatory oxygen uptake (V̇O 2 , Douglas bags) and arterial-venous O 2 difference (a-vO 2 difference) derived from Q̇ c and V̇O 2 were assessed during exercise. Breath-by-breath O 2 uptake was measured continuously throughout submaximal exercise, and V̇O 2 kinetics was quantified as mean response time (MRT)., Results: HFpEF patients had markedly slowed V̇O 2 kinetics during submaximal exercise (MRT: control: 40.1±14.2, HFpEF: 65.4±27.7 s; p<0.002), despite no relative impairment in submaximal cardiac output (Q̇ c : control: 8.6±1.7, HFpEF: 9.7±2.2 L/min; p=0.79). When stratified by MRT, HFpEF with an MRT ≥60 s demonstrated elevated Q̇ c , and impaired peripheral oxygen extraction that was apparent during submaximal exercise compared with HFpEF with a MRT <60 s (submaximal a-vO 2 difference: MRT <60 s: 9.7±2.1, MRT ≥60 s: 7.9±1.1 mL/100 mL; p=0.03)., Conclusion: HFpEF patients have slowed V̇O 2 kinetics that are related to impaired peripheral oxygen utilisation. MRT can identify HFpEF patients with peripheral limitations to submaximal exercise capacity and may be a target for therapeutic intervention., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Signal transducer and activator of transcription 3 (STAT3) was recently found to be localized to mitochondria in a number of tissues and cell types, where it modulates oxidative phosphorylation via interactions with the electron transport proteins, complex I and complex II. Skeletal muscle is densely populated with mitochondria although whether STAT3 contributes to skeletal muscle oxidative capacity is unknown. In the present study, we sought to elucidate the contribution of STAT3 to mitochondrial and skeletal muscle function by studying mice with muscle-specific knockout of STAT3 (mKO). First, we developed a novel flow cytometry-based approach to confirm that STAT3 is present in skeletal muscle mitochondria. However, contrary to findings in other tissue types, complex I and complex II activity and maximal mitochondrial respiratory capacity in skeletal muscle were comparable between mKO mice and floxed/wild-type littermates. Moreover, there were no genotype differences in endurance exercise performance, skeletal muscle force-generating capacity, or the adaptive response of skeletal muscle to voluntary wheel running. Collectively, although we confirm the presence of STAT3 in skeletal muscle mitochondria, our data establish that STAT3 is dispensable for mitochondrial and physiological function in skeletal muscle. NEW & NOTEWORTHY Whether signal transducer and activator of transcription 3 (STAT3) can regulate the activity of complex I and II of the electron transport chain and mitochondrial oxidative capacity in skeletal muscle, as it can in other tissues, is unknown. By using a mouse model lacking STAT3 in muscle, we demonstrate that skeletal muscle mitochondrial and physiological function, both in vivo and ex vivo, is not impacted by the loss of STAT3.

Background: We assess whether the lower exercise tolerance in children with univentricular heart (UVH) after Fontan operation is associated with altered peripheral muscular and cerebral tissue oxygenation., Methods: 18 children with UVH and 20 healthy subjects performed an incremental ramp exercise test. Changes in the cerebral and muscular pattern of oxygenated (O 2 Hb) and deoxygenated hemoglobin (HHb) and local tissue oxygenation (TOI) were analyzed by means of Near Infrared Spectroscopy (NIRS). Correlations between arterial saturation during exercise and tissue oxygenation were evaluated., Results: In UVH, maximal oxygen consumption (VO 2 peak/kg, 28.9 ± 7.9 vs. 46.3 ± 11.9 ml/min/kg, P < 0.001), heart rate (HRpeak, 168 ± 13 vs. 193 ± 12 bpm, P < 0.001) and load (Ppeak, 73 ± 19 vs. 133 ± 68 W, P < 0.001) were lower, VE/VCO 2 slope was higher (34.5 ± 5.9 vs. 27.1 ± 3.9, P < 0.001). A faster and steeper course up to the same level of HHb and absent increase in O 2 Hb was seen at cerebral level in UVH; tissue oxygenation index (TOI) demonstrated a steady decrease from the start of exercise. At the muscular level, HHb curve has a similar pattern compared to controls, with an early cessation. O 2 Hb has a similar pattern, but with early discontinuation at a higher O 2 Hb-level. Muscular TOI has the same course throughout exercise, starting from a lower level. Lower arterial saturation and higher age correlated with lower VO 2 peak; higher amplitude of muscular TOI and lower amplitude cerebral TOI correlated with higher VO 2 peak., Conclusion: Children after Fontan procedure have different oxygenation mechanisms at muscular and cerebral level. This reflects a different balance between O 2 supply to O 2 demand which might contribute to the reduced exercise tolerance in this patient population., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: To examine the time course of changes in electromyographic (EMG) and mechanomyographic (MMG) amplitude (AMP) and mean power frequency (MPF) responses during cycle ergometry to exhaustion performed above (CP +10% ) and below (CP -10% ) critical power (CP) to infer motor unit activation strategies used to maintain power output., Methods: Participants performed a 3-min all out test to determine CP, and 2 randomly ordered, continuous rides to exhaustion at CP +10% and CP -10% ·V̇O 2 , EMG AMP, EMG MPF, MMG AMP, MMG MPF, and time to exhaustion (T lim ) were recorded. Responses at CP -10% and CP +10% were analyzed separately., Results: At CP -10% , EMG and MMG AMP were significantly greater than the initial 5% timepoint at 100% T lim . EMG MPF and MMG MPF reflected a downward trend that resulted in no significant difference between timepoints. At CP +10% , EMG AMP was significantly greater than the initial 5% timepoint from 60% to 100% T lim . MMG AMP was less than the initial 5% timepoint at only 50% T lim . EMG and MMG MPF were significantly less than the initial 5% timepoint at 20% T lim and 100% T lim , respectively., Conclusions: The timecourse of changes in EMG and MMG signals were different at CP -10% and CP +10% , but responses observed indicated cycle ergometry to exhaustion relies on similar motor unit activation strategies.

Objectives: To evaluate the feasibility of a 12-week progressive resistance training program for people with patellofemoral pain (PFP) targeting proximal muscle strength and power; and resulting clinical and muscle capacity outcomes., Design: Feasibility study., Setting: Clinical environment., Participants: Mixed-sex sample of people with PFP., Main Outcome Measures: Feasibility outcomes included eligibility, recruitment rate, intervention adherence, and drop-outs. Secondary outcomes included perceived recovery, physical function (AKPS and KOOS-PF), worst pain (VAS-cm), kinesiophobia (Tampa), physical activity (IPAQ), and hip strength (isometric and 10 repetition maximum) and power., Results: Eleven people, from 36 who responded to advertisements, commenced the program. One participant withdrew. Ten participants who completed the program reported improvement (3 completely recovered; 6 marked; and 1 moderate). Higher AKPS (effect size [ES] = 1.81), improved KOOS-PF (ES = 1.37), and reduced pain (ES = 3.36) occurred alongside increased hip abduction and extension dynamic strength (ES = 2.22 and 1.92, respectively) and power (ES = 0.78 and 0.77, respectively). Isometric strength improved for hip abduction (ES = 0.99), but not hip extension., Conclusion: A 12-week progressive resistance training program targeting proximal muscle strength and power is feasible and associated with moderate-large improvements in pain, function, and hip muscle capacity in people with PFP. Further research evaluating the efficacy of progressive resistance training is warranted., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The oxygen-conforming response (OCR) of skeletal muscle refers to a downregulation of muscle force for a given muscle activation when oxygen delivery (O 2 D) is reduced, which is rapidly reversed when O 2 D is restored. We tested the hypothesis that the OCR exists in voluntary human exercise and results in compensatory changes in muscle activation to maintain force output, thereby altering perception of effort. In eight men and eight women, electromyography (EMG), oxyhemoglobin (O 2 Hb) and deoxyhemoglobin (HHb), forearm blood flow (FBF), and task effort awareness (TEA) were measured. Participants completed two nonfatiguing rhythmic handgrip tests consisting of 5-min steady state (SS) followed by two bouts of 2-min brachial artery compression to reduce FBF by ~50% of SS (C1 and C2), separated by 2 min of no compression (NC1) and ending with 2 min of no compression (NC2). When FBF was compromised during C1, EMG/Force (1.58 ± 0.39) increased compared with SS (1.31 ± 0.33, P = 0.001). However, EMG/Force was not restored upon FBF restoration at NC1 (1.48 ± 0.38, P = 0.479), consistent with C1 evoking skeletal muscle fatigue. When FBF was compromised during C2, EMG/Force increased (1.73 ± 0.50) compared with NC1 (1.48 ± 0.38, P = 0.013). EMG/Force returned to NC1 levels during NC2 (1.50 ± 0.39, P = 0.016), consistent with an OCR in C2. TEA (SS 2.2 ± 2.3, C1 3.9 ± 2.5, NC1 3.4 ± 2.7, C2 4.6 ± 2.7, NC2 3.9 ± 2.8) mirrored changes in EMG. It is noteworthy that during the second compromise and then restoration of muscle oxygenation EMG and TEA were rapidly restored to precompromise levels. We interpreted these findings to support the existence of an OCR and its ability to rapidly modify perception of effort during voluntary exercise. NEW & NOTEWORTHY In healthy individuals, when force output is maintained during rhythmic handgrip exercise, muscle activation and perception of effort rapidly increase with compromised muscle oxygen delivery (O 2 D) and then return to precompromised levels when muscle O 2 D is restored. These findings suggest that an oxygen-conforming response (OCR) exists and is able to modify perception of effort during voluntary exercise. Therefore, similar to fatigue, an OCR may have implications for exercise tolerance.

We examined the effects of graded muscle glycogen on exercise capacity and modulation of skeletal muscle signaling pathways associated with the regulation of mitochondrial biogenesis. In a repeated-measures design, eight men completed a sleep-low, train-low model comprising an evening glycogen-depleting cycling protocol followed by an exhaustive exercise capacity test [8 × 3 min at 80% peak power output (PPO), followed by 1-min efforts at 80% PPO until exhaustion] the subsequent morning. After glycogen-depleting exercise, subjects ingested a total of 0 g/kg (L-CHO), 3.6 g/kg (M-CHO), or 7.6 g/kg (H-CHO) of carbohydrate (CHO) during a 6-h period before sleeping, such that exercise was commenced the next morning with graded ( P < 0.05) muscle glycogen concentrations (means ± SD: L-CHO: 88 ± 43, M-CHO: 185 ± 62, H-CHO: 278 ± 47 mmol/kg dry wt). Despite differences ( P < 0.05) in exercise capacity at 80% PPO between trials (L-CHO: 18 ± 7, M-CHO: 36 ± 3, H-CHO: 44 ± 9 min), exercise induced comparable AMPK Thr172 phosphorylation (~4-fold) and PGC-1α mRNA expression (~5-fold) after exercise and 3 h after exercise, respectively. In contrast, neither exercise nor CHO availability affected the phosphorylation of p38MAPK Thr180/Tyr182 or CaMKII Thr268 or mRNA expression of p53, Tfam, CPT-1, CD36, or PDK4. Data demonstrate that when exercise is commenced with muscle glycogen < 300 mmol/kg dry wt, further graded reductions of 100 mmol/kg dry weight impair exercise capacity but do not augment skeletal muscle cell signaling. NEW & NOTEWORTHY We provide novel data demonstrating that when exercise is commenced with muscle glycogen below 300 mmol/kg dry wt (as achieved with the sleep-low, train-low model) further graded reductions in preexercise muscle glycogen of 100 mmol/kg dry wt reduce exercise capacity at 80% peak power output by 20-50% but do not augment skeletal muscle cell signaling.

Background: It is unclear to what extent an improved skeletal muscle phenotype influences maximal aerobic capacity (VO2max) when changes in cardiopulmonary function are limited. Thus, to primarily target skeletal muscle adaptations, we employed an alternating single-leg knee extension exercise training protocol and evaluated the impact on skeletal muscle morphology and whole-body exercise capacity., Methods: Eight sedentary volunteers (20±1 years; VO2max: 38.4±2.6 mL/kg/min) completed 12 weeks of progressive alternating single-leg training. Subjects performed a bilateral maximal graded exercise test on a cycle ergometer, a single-leg peak workload test on a knee extensor ergometer, knee extension muscle function testing, and a dual energy X-ray absorptiometry scan before and after training. Skeletal muscle biopsies were obtained before and after the training protocol to assess muscle fiber type, by determining myosin heavy chain isoform composition using gel electrophoresis, and fiber size using immunofluorescent staining of muscle cross sections., Results: Following training there were increases (P<0.05) in VO2max (2.53±0.25 vs. 2.76±0.20 L/min; 9±3%), the VO2 at ventilatory threshold (1.88±0.19 vs. 2.01±0.18 L/min; 8±2%), peak two-leg cycling workload (183±17 vs. 206±19 W; 13±2%), single-leg peak workload (40.0±4.4 vs. 55.3±5.1 W; 43±8%), skeletal muscle lean mass (3±1%), citrate synthase protein content (44±20%), as well as slow and fast myofiber size (13±4% and 14±4%, respectively) while there was a decrease (P<0.05) in hybrid fiber content (-33±8%)., Conclusions: These data suggest that inducing a more oxidative phenotype in skeletal muscle with isolated aerobic exercise training improves cardiopulmonary responses to maximal exercise. Additionally, the low cardiovascular burden associated with isolated single-leg exercise may be a useful training approach for clinical populations with skeletal muscle dysfunction or cardiovascular limitations to exercise.

Introduction: The phenomenon of population ageing is accompanied by increases in the number of elderly haemodialysis patients worldwide. The incidence of frailty is high in the haemodialysis population and is associated with poor clinical outcome. Although several interventions have been developed for use in general haemodialysis patients, the efficacy of such rehabilitation programmes in frail elderly patients on haemodialysis has not been elucidated. Here, we examined whether electrical muscle stimulation (EMS) would show beneficial effects in frail elderly patients on haemodialysis., Methods and Analysis: This is a randomised, two-period, controlled crossover trial, which will enrol 20 patients. Haemodialysis patients aged ≥65 years and defined as frail (ie, Short Physical Performance Battery score 4-9), will be randomly assigned to either group 1 (EMS intervention beginning in treatment period I, followed by reallocation as controls in treatment period II after a 5-week washout period) or group 2 (opposite schedule) in a 1:1 ratio. The two intervention periods will last 5 weeks each with an intervening washout period of 5 weeks. In the EMS intervention group, the treatment will be applied to the skeletal muscle of the entire lower extremity for 5 weeks, three times/week for 30-40 min during haemodialysis. The primary outcome of this study is the change in quadriceps isometric strength after the interventions. The secondary outcomes are the changes in physical function, physical activity, difficulty in activities of daily living, body composition, cognitive function, depressive symptoms, quality of life, blood test results and the clinical safety and feasibility of EMS therapy., Ethics and Dissemination: This study has been approved by the institutional review board/ethics committee of Kitasato University Allied Health Sciences. This study will be reported in peer reviewed publications and at conference presentations., Trial Registration Number: UMIN000032501., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Perturbed diurnal rhythms are becoming increasingly evident as deleterious events in the pathology of metabolic diseases. Exercise is well characterized as a crucial intervention in the prevention and treatment of individuals with metabolic diseases. Little is known, however, regarding optimizing the timing of exercise bouts in order to maximize their health benefits. Furthermore, exercise is a potent modulator of skeletal muscle metabolism, and it is clear that skeletal muscle has a strong circadian profile. In humans, mitochondrial function peaks in the late afternoon, and the circadian clock might be inherently impaired in myotubes from patients with metabolic disease. Timing exercise bouts to coordinate with an individual's circadian rhythms might be an efficacious strategy to optimize the health benefits of exercise. The role of exercise as a Zeitgeber can also be used as a tool in combating metabolic disease. Shift work is known to induce acute insulin resistance, and appropriately timed exercise might improve health markers in shift workers who are at risk of metabolic disease. In this Review, we discuss the literature regarding diurnal skeletal muscle metabolism and the interaction with exercise bouts at different times of the day to combat metabolic disease.

Muscle wasting frequently occurs in severe emphysema. Improving respiratory mechanics by bronchoscopic lung volume reduction using endobronchial valves (EBV) might prevent further loss or even increase in muscle mass. CT-derived skeletal muscle mass gain was observed in 39/49 patients 6 months after EBV. Multiple linear regression showed that gain in muscle (β=2.4; 95% CI 0.2 to 4.6; p=0.036) and intramuscular fat (β=3.1; 95% CI 0.2 to 5.9; p=0.035) is associated with improved 6 min walk distance independent of the change in residual volume. Skeletal muscle remodelling associates with improved exercise capacity after EBV, independent of hyperinflation reduction. TRIAL REGISTRATION NUMBER: Clinical trial registered with the Dutch trial register www.trialregister.nl (NTR2876), Results., Competing Interests: Competing interests: KJCS has nothing to disclose. KK reports non-financial support from ZonMW, The Hague, NL (government granting agency), during the conduct of the study; grants, personal fees, non-financial support and other from PneumRx/BTG, CA, USA, grants, personal fees, non-financial support and other from PulmonX, CA, USA, outside the submitted work. LEGWV has nothing to disclose. D-JS reports grants, personal fees, non-financial support and other from PulmonX Inc., CA, USA, outside the submitted work. AMWJS has nothing to disclose., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim of the paper was to assess indicators of muscle and intestinal damage in triathletes. The study involved 15 triathletes whose objective for the season was to start in the XTERRA POLAND 2017 event (1,500-m swimming, 36-km cycling, and 10-km mountain running). Before the 14-week preparatory period, the competitors' body composition was measured, aerobic capacity was tested (graded treadmill test) and blood samples were collected to determine markers showing the level of muscle and intestinal damage. Subsequent tests for body composition were carried out before and after the competition. Blood samples for biochemical indicators were collected the day before the competition, after the completed race, and 24 and 48 hours later. A significant decrease in body mass was observed after completing the race (-3.1±1.5%). The mean maximal oxygen uptake level among the studied athletes equalled 4.9±0.4 L·min-1, 58.8±4.5 mL·kg-1·min-1. The significant increase in concentrations of cortisol, c-reactive protein and myoglobin after the competition, significantly correlated with the significant increase in zonulin concentration (post 1h: r = 0.88, p = 0.007, r = 0,79, p = 0.001, r = 0.78, p = 0.001, and post 12h: r = 0.75, p = 0.01, r = 0.71, p = 0.011, r = 0.83, p = 0.02). No significant changes in the concentration of tumour necrosis factor alpha among the examined competitors were noted at following stages of the study. The results of our research showed that in order to monitor overload in the training of triathletes, useful markers reflecting the degree of muscle and intestinal damage include cortisol, testosterone, testosterone to cortisol ratio, c-reactive protein, myoglobin and zonulin. Changes in muscle cell damage markers strongly correlated with changes in zonulin concentration at particular stages of the study. Thus, one can expect that the concentrations of markers depicting the level of muscle cell damage after an intense and long-lasting effort will significantly influence the level of the intestinal barrier., Competing Interests: The authors have declared that no competing interests exist.

Background: Changes in circulatory physiology are common in Fontan patients due to suboptimal cardiac output, which may reduce the peripheral blood flow and impair the skeletal muscle. The objective of this study was to investigate the forearm blood flow (FBF), cross-sectional area (CSA) of the thigh and functional capacity in asymptomatic clinically stable patients undergoing Fontan surgery., Methods: Thirty Fontan patients and 27 healthy subjects underwent venous occlusion plethysmography, magnetic resonance imaging of the thigh musculature and maximal cardiopulmonary exercise testing. Muscle sympathetic nerve activity (MSNA), norepinephrine measures, cardiovascular magnetic resonance, handgrip strength and 6-minute walk test were also performed., Results: Fontan patients have blunted FBF (1.59 ± 0.33 vs 2.17 ± 0.52 mL/min/100 mL p < 0.001) and forearm vascular conductance (FVC) (1.69 ± 0.04 vs 2.34 ± 0.62 units p < 0.001), reduced CSA of the thigh (81.2 ± 18.6 vs 116.3 ± 26.4 cm 2 p < 0.001), lower peak VO 2 (29.3 ± 6 vs 41.5 ± 9 mL/kg/min p < 0.001), walked distance (607 ± 60 vs 701 ± 58 m p < 0.001) and handgrip strength (21 ± 9 vs 30 ± 8 kgf p < 0.001). The MSNA (30 ± 4 vs 22 ± 3 bursts/min p < 0.001) and norepinephrine concentration [265 (236-344) vs 222 (147-262) pg/mL p = 0.006] were also higher in Fontan patients. Multivariate linear regression showed FVC (β = 0.653; CI = 0.102-1.205; p = 0.022) and stroke volume (β = 0.018; CI = 0.007-0.029; p = 0.002) to be independently associated with reduced CSA of the thigh adjusted for body mass index. The CSA of the thigh adjusted for body mass index (β = 5.283; CI = 2.254-8.312; p = 0.001) was independently associated with reduced peak VO 2 ., Conclusion: Patients with Fontan operation have underdeveloped skeletal muscle with reduced strength that is associated with suboptimal peripheral blood supply and diminished exercise capacity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: Changes in heart failure (HF) patients' body composition may be associated with reduced exercise capacity. The aim of the present study was to determine the overlap in wasting syndromes in HF (cachexia and sarcopenia) and to compare their functional impact., Methods and Results: We prospectively enrolled 207 ambulatory male patients with clinically stable chronic HF. All patients underwent a standardized protocol examining functional capacity, body composition, and quality of life (QoL). Cachexia was present in 39 (18.8%) of 207 patients, 14 of whom also fulfilled the characteristics of sarcopenia (sarcopenia + cachexia group, 6.7%), whereas 25 did not (cachectic HF group, 12.1%). Sarcopenia without cachexia was present in 30 patients (sarcopenic HF group, 14.4%). A total of 44 patients (21.3%) presented with sarcopenia; however, 138 patients showed no signs of wasting (no wasting group, 66%). Patients with sarcopenia had lower strength and exercise capacity than both the no wasting and the cachectic HF group. Handgrip strength, quadriceps strength, peak oxygen uptake (VO 2 ), distance in the 6-minute walk test (6MWT), and QoL results were lowest in the sarcopenia + cachexia group vs. the no wasting group (P < 0.05 for all). Likewise, the sarcopenic HF group showed lower handgrip strength, quadriceps strength, 6MWT, peak VO 2 , and QoL results vs. the no wasting group (P < 0.05 for all)., Conclusion: Losing muscle with or without weight loss appears to have a more pronounced role than weight loss alone with regard to functional capacity and QoL among male patients with chronic HF., Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01872299., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

This laboratory study examined human stair ascending capacity and constraining factors including legs' local muscle fatigue (LMF) and cardiorespiratory capacity. Twenty-five healthy volunteers, with mean age 35.3 years, maximal oxygen uptake (VO 2max ) of 46.7 mL·min -1 ·kg -1 and maximal heart rate (HR) of 190 bpm, ascended on a stair machine at 60 and 75% (3 min each) and 90% of VO 2max (5 min or until exhaustion). The VO 2 , maximal heart rate (HR max ) and electromyography (EMG) of the leg muscles were measured. The average VO 2highest reached 43.9 mL·min -1 ·kg -1 , and HR highest peaked at 185 bpm at 90% of VO 2max step rate (SR). EMG amplitudes significantly increased at all three levels, p < .05, and median frequencies decreased mostly at 90% of VO 2max SR evidencing leg LMF. Muscle activity interpretation squares were developed and effectively used to observe changes over time, confirming LMF. The combined effects of LMF and cardiorespiratory constraints reduced ascending tolerance and constrained the duration to 4.32 min. Practitioner Summary: To expedite ascending evacuation from high-rise buildings and deep underground structures, it is necessary to consider human physical load. This study investigated the limiting physiological factors and muscle activity rate changes (MARC) used in the muscle activity interpretation squares (MAIS) to evaluate leg local muscle fatigue (LMF). LMF and cardiorespiratory capacity significantly constrain human stair ascending capacities at high, constant step rates.

Objectives: This study sought to test the hypothesis that older obese patients with heart failure with preserved ejection fraction (HFpEF) have significantly greater abdominal, cardiac, and intermuscular fat than healthy, age-matched controls, out of proportion to total body fat, and that these abnormalities are associated with objective measurements of physical function., Background: Recent studies indicate that excess total body adipose tissue contributes to exercise intolerance in patients with HFpEF. However, the impact of the pattern of regional (abdominal, cardiac, intermuscular) adipose deposition on exercise intolerance in patients with HFpEF is unknown., Methods: We measured total body adiposity (using dual-energy x-ray absorptiometry) and regional adiposity (using cardiac magnetic resonance), peak oxygen uptake (Vo 2 ), 6-min walk distance (6MWD), short physical performance battery (SPPB), and leg press power in 100 older obese patients with HFpEF and 61 healthy controls (HCs) and adjusted for age, sex, race, and body surface area., Results: Peak Vo 2 (15.7 ± 0.4 ml/kg/min vs. 23.0 ± 0.6 ml/kg/min, respectively; p < 0.001), 6MWD (427 ± 7 m vs. 538 ± 10 m, respectively; p < 0.001), SPPB (10.3 ± 0.2 vs. 10.9 ± 0.2, respectively; p < 0.05), and leg power (117 ± 5 W vs. 152 ± 9 W, respectively; p = 0.004) were significantly lower in patients with HFpEF than HCs. Total fat mass, total percent fat, abdominal subcutaneous fat, intra-abdominal fat, and thigh intermuscular fat were significantly higher, whereas epicardial fat was significantly lower in patients with HFpEF than in HC. After we adjusted for total body fat, intra-abdominal fat remained significantly higher, while epicardial fat remained significantly lower in patients with HFpEF. Abdominal subcutaneous fat, thigh subcutaneous fat, and thigh intermuscular fat:skeletal muscle ratio were inversely associated, whereas epicardial fat was directly associated with peak Vo 2 , 6MWD, SPPB, and leg power. Using multiple stepwise regression, we found intra-abdominal fat was the strongest independent predictor of peak Vo 2 and 6MWD., Conclusions: In metabolic obese HFpEF, the pattern of regional adipose deposition may have important adverse consequences beyond total body adiposity. Interventions targeting intra-abdominal and intermuscular fat could potentially improve exercise intolerance. (Exercise Intolerance in Elderly Patients With Diastolic Heart Failure [SECRET]; NCT00959660)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Impaired skeletal muscle oxygenation potentially contributes to reduced exercise capacity in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients during early recovery and may explain altered hemoglobin responses to exercise following allo-HSCT. We investigated whether skeletal muscle oxygenation parameters and hemoglobin parameters in the tibialis anterior decreased following allo-HSCT, and whether these results were associated with declines in exercise capacity., Methods: We used near-infrared spectroscopy during and following a repeated isometric contraction task at 50% of maximal voluntary contraction in 18 patients before and after allo-HSCT., Results: The rate of decrease in the muscle oxy-hemoglobin saturation (SmO 2 ; an index of skeletal muscle oxygenation) was significantly lower after allo-HSCT (P < 0.01). In contrast, total hemoglobin (an index of hemoglobin) was not different after allo-HSCT. Furthermore, SmO 2 during and following exercise was associated with exercise capacity (r = 0.648; P = 0.004 vs. r = 0.632; P = 0.005)., Conclusion: The results of this study reveal that although the peripheral hemoglobin response was not altered by allo-HSCT, skeletal muscle oxygenation was decreased following allo-HSCT. Furthermore, the decrease in skeletal muscle oxygenation was associated with a reduction in exercise capacity.

Aims: This study aimed to describe a method of peripheral muscle training with resistance bands in patients with chronic heart failure (CHF) and to evaluate its effects on the 6 min walk test and quality of life up to 12 months using a home-based programme., Methods and Results: Twenty-two patients with stable CHF (19 men and 3 women), mean age 63.2 years (SD 8.1), New York Heart Association class II-III were randomized to individual home-based training (HT group), or home-based training with a group-based start-up in a hospital setting (GT group). A 6 min walk test, the Minnesota Living with Heart Failure Questionnaire (MLHFQ), and Short Form with 36 items (SF-36) were administered at baseline and after 3, 6, 9, and 12 months. Exercise training resulted in statistically significant increased walking distance in both groups. The HT group increased on average 107 (80) m from baseline to 12 months, and the GT group by 100 (96) m. Health-related quality of life, measured with MLHFQ and SF-36, reached statistically significant improvements in both groups but at different time points. There were no statistically significant differences between groups on any parameters or follow-ups., Conclusions: Long-term home-based peripheral muscle training in patients with CHF, with or without an introductory period in a hospital setting, can be used for initial improvement and retention of walking distance and health-related quality of life., (© 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

This study was conducted to determine the effects of inspiratory muscle training (IMT) on respiratory and peripheral muscles oxygenation during a maximal exercise tolerance test and on repeated-sprint ability (RSA) performance in professional women football players. Eighteen athletes were randomly assigned to one of the following groups: SHAM (n = 8) or IMT (n = 10). After a maximal incremental exercise test, all participants performed (on a different day) a time-to-exhaustion (Tlim) test. Peripheral and respiratory muscles oxygenation by near-infrared spectroscopy, breath-by-breath ventilatory and metabolic variables, and blood lactate concentration were measured. The RSA test was performed on a grass field. After a 6 week intervention, all athletes were reevaluated. Both groups showed increases in inspiratory muscles strength, exercise tolerance and RSA performance, however only the IMT group presented lower deoxyhemoglobin and total hemoglobin blood concentrations on intercostal muscles concomitantly to an increased oxyhemoglobin and total hemoglobin blood concentrations on vastus lateralis muscle during Tlim. In conclusion, these results may indicate the potential role of IMT to attenuate inspiratory muscles metaboreflex and consequently improve oxygen and blood supply to limb muscles during high-intensity exercise, with a potential impact on inspiratory muscle strength, exercise tolerance and sprints performance in professional women football players.