Association of adiponectin gene single nucleotide polymorphisms with environmental risk factors in type 2 diabetes mellitus: An updated evidence of haplotype-based analysis study.

BACKGROUND AND AIM: Adiponectin (ADIPOQ) gene is considered to be one of the promising players in deciphering the genetic bases of type 2 diabetes. This study investigated the associations between haplotype combinations of three single nucleotide polymorphisms (SNPs) of the ADIPOQ gene and two SNPs of the adiponectin receptor 1 (AdipoR1) and 2 (AdipoR2) genes with environmental risk factors for the prediction of T2DM disorder susceptibility in the Iranian population. METHODS: This case-control and cross-sectional study was conducted on 182 patients with T2DM and 155 healthy controls. Genotyping was performed using amplification refractory mutation system-PCR (ARMS-PCR) for rs17300539G/A, rs2241766T/G, and rs1501299G/T of the ADIPOQ gene, rs1342387C/T of the AdipoR1 gene, and rs10773989T/C of the AdipoR2 gene. RESULTS: All polymorphisms met the Hardy-Weinberg equilibrium (p> 0.05). The studied SNPs; rs17300539, rs2241766 of the ADIPOQ gene and rs10773989 of the AdipoR2 gene, were significantly associated with an increased risk of T2DM. Two-way ANOVA analysis indicated that GG carriers of rs2241766T/G had a significantly lower waist-to-hip ratio (P= 0.049) and body mass index (P= 0.011) and higher HbA1c (P= 0.048) compared to TT carriers, while TT genotype carriers of rs2241766T/G showed the higher plasma adiponectin concentration compared to TG and GG carriers (P= 0.009 and P= 0.013, respectively). CC carriers of rs10773989T/C displayed a significantly higher LDL level compared to the TT genotype carries (P= 0.036). Also plasma adiponectin concentrations were significantly lower in AA genotype carriers of rs17300539G/A compared to GG and GA genotypes carriers in the control group only (P= 0.005 and P= 0.016, respectively). According to Combined Haplotype ([rs17300539, rs2241766, rs1501299]/[rs17300539, rs2241766, rs1501299]) analysis, GTT-homozygote carriers displayed the highest plasma adiponectin concentration and in contrast, GGG/GTG, ATG/GTG, and GGG/GGG showed the lowest plasma adiponectin concentration in the controls (p> 0.05). CONCLUSION: The adiponectin gene haplotype combinations were associated with plasma adiponectin concentration in healthy individuals. In T2DM, adiponectin genetic variants displayed less effect on adiponectin plasma concentration.

Machine learning predicts peak oxygen uptake and peak power output for customizing cardiopulmonary exercise testing using non-exercise features.

PURPOSE: Cardiopulmonary exercise testing (CPET) is considered the gold standard for assessing cardiorespiratory fitness. To ensure consistent performance of each test, it is necessary to adapt the power increase of the test protocol to the physical characteristics of each individual. This study aimed to use machine learning models to determine individualized ramp protocols based on non-exercise features. We hypothesized that machine learning models will predict peak oxygen uptake ( V ˙ O2peak) and peak power output (PPO) more accurately than conventional multiple linear regression (MLR). METHODS: The cross-sectional study was conducted with 274 (♀168, ♂106) participants who performed CPET on a cycle ergometer. Machine learning models and multiple linear regression were used to predict V ˙ O2peak and PPO using non-exercise features. The accuracy of the models was compared using criteria such as root mean square error (RMSE). Shapley additive explanation (SHAP) was applied to determine the feature importance. RESULTS: The most accurate machine learning model was the random forest (RMSE: 6.52 ml/kg/min [95% CI 5.21-8.17]) for V ˙ O2peak prediction and the gradient boosting regression (RMSE: 43watts [95% CI 35-52]) for PPO prediction. Compared to the MLR, the machine learning models reduced the RMSE by up to 28% and 22% for prediction of V ˙ O2peak and PPO, respectively. Furthermore, SHAP ranked body composition data such as skeletal muscle mass and extracellular water as the most impactful features. CONCLUSION: Machine learning models predict V ˙ O2peak and PPO more accurately than MLR and can be used to individualize CPET protocols. Features that provide information about the participant's body composition contribute most to the improvement of these predictions. TRIAL REGISTRATION NUMBER: DRKS00031401 (6 March 2023, retrospectively registered).

Interactive effects of exercise intensity and recovery posture on postexercise hypotension.

Postexercise reduction in blood pressure, termed postexercise hypotension (PEH), is relevant for both acute and chronic health reasons and potentially for peripheral cardiovascular adaptations. We investigated the interactive effects of exercise intensity and recovery postures (seated, supine, and standing) on PEH. Thirteen normotensive men underwent a V̇o2max test on a cycle ergometer and five exhaustive constant load trials to determine critical power (CP) and the gas exchange threshold (GET). Subsequently, work-matched exercise trials were performed at two discrete exercise intensities (10% > CP and 10% < GET), with 1 h of recovery in each of the three postures. For both exercise intensities, standing posture resulted in a more substantial PEH (all P < 0.01). For both standing and seated recovery postures, the higher exercise intensity led to larger reductions in systolic [standing: -33 (11) vs. -21 (8) mmHg; seated: -34 (32) vs. -17 (37) mmHg, P < 0.01], diastolic [standing: -18 (7) vs. -8 (5) mmHg; seated: -10 (10) vs. -1 (4) mmHg, P < 0.01], and mean arterial pressures [-13 (8) vs. -2 (4) mmHg, P < 0.01], whereas in the supine recovery posture, the reduction in diastolic [-9 (9) vs. -4 (3) mmHg, P = 0.08) and mean arterial pressures [-7 (5) vs. -3 (4) mmHg, P = 0.06] was not consistently affected by prior exercise intensity. PEH is more pronounced during recovery from exercise performed above CP versus below GET. However, the effect of exercise intensity on PEH is largely abolished when recovery is performed in the supine posture.NEW & NOTEWORTHY The magnitude of postexercise hypotension is greater following the intensity above the critical power in a standing position.

Muscle abnormalities worsen after post-exertional malaise in long COVID.

A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.

The effects of high-intensity exercise training and detraining with and without active recovery on postexercise hypotension in young men.

Whether high-intensity exercise training and detraining combined with skeletal muscle pump (MP) could alter the magnitude of postexercise hypotension has not been investigated. We therefore sought to determine whether the combination of MP (unloaded back-pedaling) with 4 weeks of high-intensity exercise training and detraining could alter the magnitude of postexercise hypotension. Fourteen healthy men underwent 4 weeks of high-intensity exercise training (5 consecutive days per week for 15 min per session at 40% of the difference between the gas exchange threshold and maximal oxygen uptake [i.e., Δ40%]) followed by detraining for 4 weeks. Assessments were conducted at Pre-training (Pre), Post-training (Post) and after Detraining with (MP) and without MP (Con). The exercise test in the Pre, Post and the Detraining consisted of 15 min exercise at Δ40% followed by 1 h of recovery. At all time-points, the postexercise reduction in mean arterial pressure (MAP) was reduced in MP compared to Con (all p < 0.01). Four weeks of high-intensity exercise training resulted in a reduction in the magnitude of postexercise hypotension (i.e., the change in MAP from baseline was mitigated) across both trials (All p < 0.01) when compared to Pre and Detraining. Following Detraining, the reduction of MAP from baseline was reduced compared to Pre, but was not different from Post. We conclude that high-intensity exercise training combined with skeletal MP reduces the magnitude of postexercise hypotension, and this effect is partially retained for 4 weeks following the complete cessation of high-intensity exercise training.

Critical power is a key threshold determining the magnitude of post-exercise hypotension in non-hypertensive young males.

The effect of different exercise intensities on the magnitude of post-exercise hypotension has not been rigorously clarified with respect to the metabolic thresholds that partition discrete exercise intensity domains (i.e., critical power and the gas exchange threshold (GET)). We hypothesized that the magnitude of post-exercise hypotension would be greater following isocaloric exercise performed above versus below critical power. Twelve non-hypertensive men completed a ramp incremental exercise test to determine maximal oxygen uptake and the GET, followed by five exhaustive constant load trials to determine critical power and W' (work available above critical power). Subsequently, criterion trials were performed at four discrete intensities matched for total work performed (i.e., isocaloric) to determine the impact of exercise intensity on post-exercise hypotension: 10% above critical power (10% > CP), 10% below critical power (10% < CP), 10% above GET (10% > GET) and 10% below GET (10% < GET). The post-exercise decrease (i.e., the minimum post-exercise values) in mean arterial (10% > CP: -12.7 ± 8.3 vs. 10% < CP: v3.5 ± 2.9 mmHg), diastolic (10% > CP: -9.6 ± 9.8 vs. 10% < CP: -1.4 ± 5.0 mmHg) and systolic (10% > CP: -23.8 ± 7.0 vs. 10% < CP: -9.9 ± 4.3 mmHg) blood pressures were greater following exercise performed 10% > CP compared to all other trials (all P < 0.01). No effects of exercise intensity on the magnitude of post-exercise hypotension were observed during exercise performed below critical power (all P > 0.05). Critical power represents a threshold above which the magnitude of post-exercise hypotension is greatly augmented. NEW FINDINGS: What is the central questions of this study? What is the influence of exercise intensity on the magnitude of post-exercise hypotension with respect to metabolic thresholds? What is the main finding and its importance? The magnitude of post-exercise hypotension is greatly increased following exercise performed above critical power. However, below critical power, there was no clear effect of exercise intensity on the magnitude of post-exercise hypotension.

How Priming Exercise Affects Oxygen Uptake Kinetics: From Underpinning Mechanisms to Endurance Performance.

The observation that prior heavy or severe-intensity exercise speeds overall oxygen uptake ([Formula: see text]O2) kinetics, termed the "priming effect", has garnered significant research attention and its underpinning mechanisms have been hotly debated. In the first part of this review, the evidence for and against (1) lactic acidosis, (2) increased muscle temperature, (3) O2 delivery, (4) altered motor unit recruitment patterns and (5) enhanced intracellular O2 utilisation in underpinning the priming effect is discussed. Lactic acidosis and increased muscle temperature are most likely not key determinants of the priming effect. Whilst priming increases muscle O2 delivery, many studies have demonstrated that an increased muscle O2 delivery is not a prerequisite for the priming effect. Motor unit recruitment patterns are altered by prior exercise, and these alterations are consistent with some of the observed changes in [Formula: see text]O2 kinetics in humans. Enhancements in intracellular O2 utilisation likely play a central role in mediating the priming effect, probably related to elevated mitochondrial calcium levels and parallel activation of mitochondrial enzymes at the onset of the second bout. In the latter portion of the review, the implications of priming on the parameters of the power-duration relationship are discussed. The effect of priming on subsequent endurance performance depends critically upon which phases of the [Formula: see text]O2 response are altered. A reduced [Formula: see text]O2 slow component or increased fundamental phase amplitude tend to increase the work performable above critical power (i.e. W´), whereas a reduction in the fundamental phase time constant following priming results in an increased critical power.

Interaction of Factors Determining Critical Power.

The physiological determinants of high-intensity exercise tolerance are important for both elite human performance and morbidity, mortality and disease in clinical settings. The asymptote of the hyperbolic relation between external power and time to task failure, critical power, represents the threshold intensity above which systemic and intramuscular metabolic homeostasis can no longer be maintained. After ~ 60 years of research into the phenomenon of critical power, a clear understanding of its physiological determinants has emerged. The purpose of the present review is to critically examine this contemporary evidence in order to explain the physiological underpinnings of critical power. Evidence demonstrating that alterations in convective and diffusive oxygen delivery can impact upon critical power is first addressed. Subsequently, evidence is considered that shows that rates of muscle oxygen utilisation, inferred via the kinetics of pulmonary oxygen consumption, can influence critical power. The data reveal a clear picture that alterations in the rates of flux along every step of the oxygen transport and utilisation pathways influence critical power. It is also clear that critical power is influenced by motor unit recruitment patterns. On this basis, it is proposed that convective and diffusive oxygen delivery act in concert with muscle oxygen utilisation rates to determine the intracellular metabolic milieu and state of fatigue within the myocytes. This interacts with exercising muscle mass and motor unit recruitment patterns to ultimately determine critical power.

Effects of Dietary Nitrate Supplementation on Performance and Muscle Oxygenation during Resistance Exercise in Men.

The purpose of the current study was to assess the effects of acute and short-term nitrate (NO3−)-rich beetroot juice (BR) supplementation on performance outcomes and muscle oxygenation during bench press and back squat exercise. Fourteen recreationally active males were assigned in a randomized, double-blind, crossover design to supplement for 4 days in two conditions: (1) NO3−-depleted beetroot juice (PL; 0.10 mmol NO3− per day) and (2) BR (11.8 mmol NO3− per day). On days 1 and 4 of the supplementation periods, participants completed 2 sets of 2 × 70%1RM interspersed by 2 min of recovery, followed by one set of repetitions-to-failure (RTF) at 60%1RM for the determination of muscular power, velocity, and endurance. Quadriceps and pectoralis major tissue saturation index (TSI) were measured throughout exercise. Plasma [NO3−] and nitrite ([NO2−]) were higher after 1 and 4 days of supplementation with BR compared to PL (p < 0.05). Quadriceps and pectoralis major TSI were not different between conditions (p > 0.05). The number of RTF in bench press was 5% greater after acute BR ingestion compared to PL (PL: 23 ± 4 vs. BR: 24 ± 5, p < 0.05). There were no differences between BR and PL for RTF for back squat or power and velocity for back squat or bench press (p > 0.05). These data improve understanding on the ergogenic potential of BR supplementation during resistance exercise.

Altered muscle oxidative phenotype impairs exercise tolerance but does not improve after exercise training in multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) experience reduced exercise tolerance that substantially reduces quality of life. The mechanisms underpinning exercise intolerance in MS are not fully clear. This study aimed to determine the contributions of the cardiopulmonary system and peripheral muscle in MS-induced exercise intolerance before and after exercise training. METHODS: Twenty-three patients with MS (13 women) and 20 age-matched and sex-matched healthy controls (13 women) performed a cardiopulmonary exercise test. Muscle fibre type composition, size, succinate dehydrogenase (SDH) activity, capillarity, and gene expression and proteins related to mitochondrial density were determined in vastus lateralis muscle biopsies. Nine MS patients (five women) were re-examined following a 12 week exercise training programme consisting of high-intensity cycling interval and resistance training. RESULTS: Patients with MS had lower maximal oxygen uptake compared with healthy controls (V̇O2peak , 25.0 ± 8.5 vs. 35.7 ± 6.4 mL/kg/min, P < 0.001). The lower gas exchange threshold (MS: 14.5 ± 5.5 vs. controls: 19.7 ± 2.9 mL/kg/min, P = 0.01) and slope of V̇O2 versus work rate (MS: 9.5 ± 1.7 vs. controls: 10.8 ± 1.1 mL/min/W, P = 0.01) suggested an intramuscular contribution to exercise intolerance in patients with MS. Muscle SDH activity was 22% lower in MS (P = 0.004), and strongly correlated with several indices of whole-body exercise capacity in MS patients (e.g. V̇O2peak , Spearman's ρ = 0.81, P = 0.002), but not healthy controls (ρ = 0.24, P = 0.38). In addition, protein levels of mitochondrial OXPHOS complexes I (-40%, P = 0.047) and II (-45%, P = 0.026) were lower in MS patients versus controls. Muscle capillary/fibre ratio correlated with V̇O2peak in healthy controls (ρ = 0.86, P < 0.001) but not in MS (ρ = 0.35, P = 0.22), and did not differ between groups (1.41 ± 0.30 vs. 1.47 ± 0.38, P = 0.65). Expression of genes involved in mitochondrial function, such as PPARA, PPARG, and TFAM, was markedly reduced in muscle tissue samples of MS patients (all P < 0.05). No differences in muscle fibre type composition or size were observed between groups (all P > 0.05). V̇O2peak increased by 23% following exercise training in MS (P < 0.001); however, no changes in muscle capillarity, SDH activity, gene or protein expression were observed (all P > 0.05). CONCLUSIONS: Skeletal muscle oxidative phenotype (mitochondrial complex I and II content, SDH activity) is lower in patients with MS, contributing to reduced exercise tolerance. However, skeletal muscle mitochondria appeared resistant to the beneficial effects of exercise training, suggesting that other physiological systems, at least in part, drive the improvements in exercise capacity following exercise training in MS.

Bioenergetic Mechanisms Linking V˙O2 Kinetics and Exercise Tolerance.

We hypothesize that the V˙O2 time constant (τV˙O2) determines exercise tolerance by defining the power output associated with a "critical threshold" of intramuscular metabolite accumulation (e.g., inorganic phosphate), above which muscle fatigue and work inefficiency are apparent. Thereafter, the V˙O2 "slow component" and its consequences (increased pulmonary, circulatory, and neuromuscular demands) determine performance limits.

Dissociation between exercise intensity thresholds: mechanistic insights from supine exercise.

This study tested the hypothesis that the respiratory compensation point (RCP) and breakpoint in deoxygenated [heme] [deoxy[heme]BP, assessed via near-infrared spectroscopy (NIRS)] during ramp incremental exercise would occur at the same metabolic rate in the upright (U) and supine (S) body positions. Eleven healthy men completed ramp incremental exercise tests in U and S. Gas exchange was measured breath-by-breath and time-resolved-NIRS was used to measure deoxy[heme] in the vastus lateralis (VL) and rectus femoris (RF). RCP (S: 2.56 ± 0.39, U: 2.86 ± 0.40 L·min-1, P = 0.02) differed from deoxy[heme]BP in the VL in U (3.10 ± 0.44 L·min-1, P = 0.002), but was not different in S in the VL (2.70 ± 0.50 L·min-1, P = 0.15). RCP was not different from the deoxy[heme]BP in the RF for either position (S: 2.34 ± 0.48 L·min-1, U: 2.76 ± 0.53 L·min-1, P > 0.05). However, the deoxy[heme]BP differed between muscles in both positions (P < 0.05), and changes in deoxy[heme]BP did not relate to ΔRCP between positions (VL: r = 0.55, P = 0.080, RF: r = 0.26, P = 0.44). The deoxy[heme]BP was consistently preceded by a breakpoint in total[heme], and was, in turn, itself preceded by a breakpoint in muscle surface electromyography (EMG). RCP and the deoxy[heme]BP can be dissociated across muscles and different body positions and, therefore, do not represent the same underlying physiological phenomenon. The deoxy[heme]BP may, however, be mechanistically related to breakpoints in total[heme] and muscle activity.

The ramp and all-out exercise test to determine critical power: validity and robustness to manipulations in body position.

PURPOSE: The purpose of the present study was to determine whether a contiguous ramp and all-out exercise test could accurately determine critical power (CP) in a single laboratory visit during both upright and supine cycle exercise. METHODS: Healthy males completed maximal ramp-incremental exercise on a cycle ergometer in the upright (n = 15) and supine positions (n = 8), with task failure immediately followed by a 3-min all-out phase for determination of end-test power (EP). On separate days, participants undertook four constant-power tests in either the upright or supine positions with the limit of tolerance ranging from ~ 2 to 15 min for determination of CP. RESULTS: During upright exercise, EP was highly correlated with (R2 = 0.93, P < 0.001) and not different from CP (CP = 221 ± 40 W vs. EP = 226 ± 46 W, P = 0.085, 95% limits of agreement - 30, 19 W). During supine exercise, EP was also highly correlated with (R2 = 0.94, P < 0.001) and not different from CP (CP = 140 ± 42 W vs. EP = 136 ± 40 W, P = 0.293, 95% limits of agreement - 16, 24 W). CONCLUSION: The present data suggest that EP derived from a contiguous ramp all-out exercise test is not different from the gold-standard method of CP determination during both upright and supine cycle exercise when assessed at the group level. However, the wide limits of agreement observed within the present study suggest that EP and CP should not be used interchangeably.

Impact of supine versus upright exercise on muscle deoxygenation heterogeneity during ramp incremental cycling is site specific.

PURPOSE: We tested the hypothesis that incremental ramp cycling exercise performed in the supine position (S) would be associated with an increased reliance on muscle deoxygenation (deoxy[heme]) in the deep and superficial vastus lateralis (VLd and VLs, respectively) and the superficial rectus femoris (RFs) when compared to the upright position (U). METHODS: 11 healthy men completed ramp incremental exercise tests in S and U. Pulmonary [Formula: see text]O2 was measured breath-by-breath; deoxy[heme] was determined via time-resolved near-infrared spectroscopy in the VLd, VLs and RFs. RESULTS: Supine exercise increased the overall change in deoxy[heme] from baseline to maximal exercise in the VLs (S: 38 ± 23 vs. U: 26 ± 15 µM, P < 0.001) and RFs (S: 36 ± 21 vs. U: 25 ± 15 µM, P < 0.001), but not in the VLd (S: 32 ± 23 vs. U: 29 ± 26 µM, P > 0.05). CONCLUSIONS: The present study supports that the impaired balance between O2 delivery and O2 utilization observed during supine exercise is a regional phenomenon within superficial muscles. Thus, deep muscle defended its O2 delivery/utilization balance against the supine-induced reductions in perfusion pressure. The differential responses of these muscle regions may be explained by a regional heterogeneity of vascular and metabolic control properties, perhaps related to fiber type composition.

Effect of priming exercise and body position on pulmonary oxygen uptake and muscle deoxygenation kinetics during cycle exercise.

We hypothesized that the performance of prior heavy exercise would speed pulmonary oxygen uptake (V̇o2) kinetics (i.e., as described by the time constant, [Formula: see text]) and reduce the amplitude of muscle deoxygenation (deoxy[heme]) kinetics in the supine (S) but not upright (U) body position. Seventeen healthy men completed heavy-intensity constant-work rate exercise tests in S and U consisting of two bouts of 6-min cycling separated by 6-min cycling at 20 W. Pulmonary V̇o2 was measured breath by breath; total and deoxy[heme] were determined via time-resolved near-infrared spectroscopy (NIRS) at three muscle sites. Priming exercise reduced [Formula: see text] in S (bout 1: 36 ± 10 vs. bout 2: 28 ± 10 s, P < 0.05) but not U (bout 1: 27 ± 8 s vs. bout 2: 25 ± 7 s, P > 0.05). Deoxy[heme] amplitude was increased after priming in S (bout 1: 25-28 µM vs. bout 2: 30-35 µM, P < 0.05) and U (bout 1: 13-18 µM vs. bout 2: 17-25 µM, P > 0.05), whereas baseline total[heme] was enhanced in S (bout 1: 110-179 µM vs. bout 2: 121-193 µM, P < 0.05) and U (bout 1: 123-186 µM vs. bout 2: 137-197 µM, P < 0.05). Priming exercise increased total[heme] in both S and U, likely indicating enhanced diffusive O2 delivery. However, the observation that after priming the amplitude of the deoxy[heme] response was increased in S suggests that the reduction in [Formula: see text] subsequent to priming was related to a combination of both enhanced intracellular O2 utilization and increased O2 delivery.NEW & NOTEWORTHY Here we show that oxygen uptake (V̇o2) kinetics are slower in the supine compared with upright body position, an effect that is associated with an increased amplitude of skeletal muscle deoxygenation in the supine position. After priming in the supine position, the amplitude of muscle deoxygenation remained markedly elevated above that observed during upright exercise. Hence, the priming effect cannot be solely attributed to enhanced O2 delivery, and enhancements to intracellular O2 utilization must also be contributory.