Muscular stress is equal when resistance exercise with blood flow restriction is matched in total work volume: A cross-sectional, cross-over study.

AIM: We compared muscular metabolic stress during exercise performed at multiple intensities, from very low to moderate, with blood flow restriction (BFR) adjusted by the same work volume. METHODS: Twenty-five healthy young adults performed unilateral plantar flexion at 1 repetition/2 s in a magnetic resonance system. The BFR exercise protocols were as follows: (A) exercise with 10% of one repetition maximum (1-RM) for 360 s, (B) 15% 1-RM for 240 s, (C) 20% 1-RM for 180 s, (D) 30% 1-RM for 120 s, and (E) 40% 1-RM for 90 s. All protocols had the same total work volume (load × repetitions = 1800). A high-intensity protocol at 65% 1-RM without BFR (60 s) was also performed for comparison. We used 31 P-magnetic resonance spectroscopy to evaluate the muscular metabolic stress in the subjects' calf muscle, defined as decreases in phosphocreatine and intramuscular pH. RESULTS: The phosphocreatine depletion (A: 15.6 ± 0.7, B: 14.8 ± 0.8, C: 15.2 ± 0.6, D: 14.3 ± 0.6, E: 10.9 ± 0.5 mM; no significant difference [ns]) and the intramuscular pH decrease (A: 6.82 ± 0.02, B: 6.84 ± 0.01, C: 6.83 ± 0.02, D: 6.83 ± 0.02, E: 6.77 ± 0.02; ns) at the end of each exercise were similar and greater than those produced by the 65% 1-RM without BFR. CONCLUSION: If the total work volumes are equal, the metabolic stress in exercising muscle may reach similar levels at the end of exercise with BFR and could provide similar successful training effects.

Differential effects of changes in cardiorespiratory fitness on worst- and best- school subjects.

Accumulating evidence shows a beneficial association between physical fitness and school children's academic performance. However, several other studies have failed to demonstrate such an association. We reanalyzed data of a two-year longitudinal study of the association between changes in cardiorespiratory fitness and academic performance of school children by focusing on intra-individual variability in grade points as a possible source of this discrepancy. We analyzed data from 469 junior high school students to examine if improvements in cardiorespiratory fitness had a differential effect on an individual student's worst and best grade points. Results indicated that improvements in physical fitness were associated with an improvement in the worst grade points. On the contrary, we did not observe a similar longitudinal association with the best grade points. These findings suggest that improving cardiorespiratory fitness improves the worst grade points of an individual, selectively. We suggest that intra-individual variability in grade points might moderate the association between physical fitness and academic performance changes.

Systemic oxidative stress is associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in heart failure patients.

Oxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 ± 1.1 vs. 3.4 ± 0.7 µmol/L, p < 0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.2 ± 7.1 vs. 29.4 ± 9.7 units/L, p < 0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by 31phosphorus- and 1proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.

Type 2 diabetes is an independent predictor of lowered peak aerobic capacity in heart failure patients with non-reduced or reduced left ventricular ejection fraction.

BACKGROUND: Although type 2 diabetes mellitus (T2DM) is one of the most frequent comorbidities in patients with chronic heart failure (CHF), the effects of T2DM on the exercise capacity of CHF patients are fully unknown. Here, we tested the hypothesis that the coexistence of T2DM lowers CHF patients' peak aerobic capacity. METHODS: We retrospectively analyzed the cases of 275 Japanese CHF patients with non-reduced ejection fraction (left ventricular ejection fraction [LVEF] ≥ 40%) or reduced EF (LVEF < 40%) who underwent cardiopulmonary exercise testing. We divided them into diabetic and nondiabetic groups in each CHF cohort. RESULTS: The mean peak oxygen uptake (VO2) value was 16.87 mL/kg/min in the non-reduced LVEF cohort and 15.52 mL/kg/min in the reduced LVEF cohort. The peak VO2 was lower in the diabetics versus the nondiabetics in the non-reduced LVEF cohort with the mean difference (95% confidence interval [95% CI]) of - 0.93 (- 1.82 to - 0.04) mL/kg/min and in the reduced LVEF cohort with the mean difference of - 1.05 (- 1.96 to - 0.15) mL/kg/min, after adjustment for age-squared, gender, anemia, renal function, LVEF, and log B-type natriuretic peptide (BNP). The adjusted VO2 at anaerobic threshold (AT), a submaximal aerobic capacity, was also decreased in the diabetic patients with both non-reduced and reduced LVEFs. Intriguingly, the diabetic patients had a lower adjusted peak O2 pulse than the nondiabetic patients in the reduced LVEF cohort, but not in the non-reduced LVEF cohort. A multivariate analysis showed that the presence of T2DM was an independent predictor of lowered peak VO2 in CHF patients with non-reduced LVEF and those with reduced LVEF. CONCLUSIONS: T2DM was associated with lowered peak VO2 in CHF patients with non-reduced or reduced LVEF. The presence of T2DM has a negative impact on CHF patients' exercise capacity, and the degree of impact is partly dependent on their LV systolic function.

Longitudinal relationship of favorable weight change to academic performance in children.

Although there is a growing consensus about the positive relationship between prevention of overweight/obesity and academic performance in children, relevant studies targeting the relationship between underweight and academic performance are scarce. This study aimed to examine the longitudinal relationship of favorable weight change to academic performance in schoolchildren. We analyzed 2-year longitudinal data derived from 197 seventh-grade children aged 12-13 years. Academic performance was assessed using the total grade points of five academic subjects. Body mass index (BMI) was calculated as body weight (kg)/height (m2). A significant interaction effect of baseline BMI and BMI changes over 2 years (B = -0.10, SE B = 0.03, ß = -0.40, t = -3.37, p < 0.001) was noted after controlling for confounders such as socioeconomic status, afterschool learning duration, screen time, exercise habits, and cardiorespiratory fitness. When the centered baseline BMI was outside the interval [-2.49, 3.21], the slope of the change in BMI was significant (p < 0.05). Simple slope analyses revealed a positive relationship of weight gain when baseline BMI = mean - 1 SD (B = 0.40, SE B = 0.18, ß = 0.31, t = 2.20, p = 0.03) and weight loss when baseline BMI = mean + 1 SD (B = -0.26, SE B = 0.13, ß = -0.20, t = -1.97, p = 0.05) to total grade points of five school subjects. A split-group validation was performed and robust results of original analyses were detected (i.e., significant interaction effect of baseline BMI and BMI changes over 2 years (group A: B = -0.11, SE B = 0.05, ß = -0.47, t = -2.39, p = 0.02; group B: B = -0.14, SE B = 0.05, ß = -0.47, t = -2.78, p = 0.007). Favorable changes in weight status, i.e., weight loss in children with overweight/obesity and weight gain in children with mild underweight/underweight, have a positive influence on academic performance in children independent of socioeconomic factors, learning habits, screen time, exercise habits, and cardiorespiratory fitness.

Relationship of participation in specific sports to academic performance in adolescents: A 2-year longitudinal study.

Physical activity is considered a promising behavior to improve cognitive function and academic performance in adolescents. As evidence on the relationship of specific sports activity is not conclusive, this study aimed to determine the longitudinal relationships of different sports to academic performance in adolescents and evaluate the cardiorespiratory fitness mediation effect of these sports. We focused on the demands of complex motor skills and the differences between individual sports vs team sports. Four hundred and sixty-three 7th-grade students (227 girls and 236 boys) were followed up over 2 years. Data regarding participation in sports activities, types of sports activities, academic performance, and cardiorespiratory fitness were obtained at baseline and after a 2-year follow-up. Structural equation modeling revealed that participation in all sports activity was positively associated with improvement of academic performance from baseline to follow-up, and that these associations were mediated by cardiorespiratory fitness gains. Participation in sports activities that require more complex motor skills and individual sports activity was directly associated with an improvement of academic performance from baseline to follow-up. Furthermore, quitting sports activities was negatively associated with academic performance via a reversal in cardiorespiratory fitness gains. These findings indicate that participation in specific sports may have significant benefits for academic performance in adolescents. Although these relationships are presumably mediated by cardiorespiratory fitness, sports activities that require more complex motor skills and individual sports participation may be directly related to academic performance. Considering that quitting sports activities reversed these benefits, sustained participation in sports is important for academic success.

Microvascular responses during reactive hyperemia assessed by near-infrared spectroscopy and arterial stiffness in young, middle-aged, and older women.

We investigated the effects of age on microvascular responses during reactive hyperemia and arterial stiffness in 13 young (22 ± 1 years), 12 middle-aged (42 ± 5 years), and 15 older (63 ± 2 years) women. During the vascular occlusion test (VOT), forearm tissue oxygen saturation (StO2) was measured using near-infrared spectroscopy (NIRS). During reperfusion, the area under the curve (AUC) during hyperemia in young women (1123 ± 208% s) was significantly greater than that in middle-aged (771 ± 445% s, P = 0.024) and older women (619 ± 356% s, P = 0.001) with no differences between middle-aged and older women (P = 0.265). Cardio-ankle vascular index (CAVI) as an indicator of arterial stiffness was assessed using four-limb oscillometry. CAVI significantly increased with age (8.1 ± 0.7 in the older group, 6.0 ± 0.8 in the middle-aged group, and 5.8 ± 0.4 in the young group), with significant differences between older women and women in the other groups (P < 0.001); however, no differences in CAVI between young and middle-aged women (P = 0.484) were found. When the data of all groups were pooled, the AUC or upslope was associated with CAVI or body mass index or mean arterial pressure (all P < 0.05). To conclude, the AUC derived by NIRS measures of StO2 during the reperfusion phase can be used as one of the evaluations of microvascular function, followed by the development of atherosclerosis in middle-aged and older women.

Resistance training with interval blood flow restriction effectively enhances intramuscular metabolic stress with less ischemic duration and discomfort.

Increases in muscle size and strength similar to those obtained with high resistance load can be achieved by combining lower loads with continuous blood flow restriction (BFR). However, high ratings for distress have been reported for continuous BFR. Therefore, we investigated the efficacy (metabolic stress) of BFR applied only during intervals in resistance exercise. Seven healthy men performed three 1-min sets of plantar flexion (30 reps/min) with 1-min rest intervals under 4 conditions: low-load resistance exercise (L, 20% 1-repetition maximum (1RM)) without BFR (L-noBFR), L with BFR during exercise sets (L-exBFR), L with BFR during rest intervals (L-intBFR), and L with continuous BFR during both exercise and rest intervals (L-conBFR). Based on the results of the first experiment, we performed additional protocols using a moderate load (M, 40% 1RM) with intermittent (exercise or rest intervals) BFR (M-exBFR and M-intBFR). Intramuscular metabolic stress, defined as decreases in phosphocreatine and intramuscular pH, was evaluated by 31P magnetic resonance spectroscopy. Rated perceived exertion (RPE) was also assessed. At the end of exercise, total decreases in phosphocreatine and intramuscular pH were similar among L-noBFR, L-intBFR, and L-exBFR and significantly less than those in L-conBFR (p < 0.05). In contrast, changes in these variables in M-intBFR but not in M-exBFR were similar to those in L-conBFR. Nevertheless, RPE was lower in M-intBFR than in both M-exBFR and L-conBFR (p < 0.05). The effect of intermittent BFR during exercise might be insufficient to induce metabolic stress when using a low load. However, effective metabolic stress for muscle adaptation could be obtained by moderate-load resistance exercise with BFR during intervals with less ischemic duration and discomfort.

Impact of High Respiratory Exchange Ratio During Submaximal Exercise on Adverse Clinical Outcome in Heart Failure.

BACKGROUND: Oxygen uptake (V̇O2) at peak workload and anaerobic threshold (AT) workload are often used for grading heart failure (HF) severity and predicting all-cause mortality. The clinical relevance of respiratory exchange ratio (RER) during exercise, however, is unknown. Methods and Results: We retrospectively studied 295 HF patients (57±15 years, NYHA class I-III) who underwent cardiopulmonary exercise testing. RER was measured at rest; at AT workload; and at peak workload. Peak V̇O2 had an inverse correlation with RER at AT workload (r=-0.256), but not at rest (r=-0.084) or at peak workload (r=0.090). Using median RER at AT workload, we divided the patients into high RER (≥0.97) and low RER (<0.97) groups. Patients with high RER at AT workload were characterized by older age, lower body mass index, anemia, and advanced NYHA class. After propensity score matching, peak V̇O2 tended to be lower in the high-RER than in the low-RER group (14.9±4.5 vs. 16.1±5.0 mL/kg/min, P=0.06). On Kaplan-Meier analysis, HF patients with a high RER at AT workload had significantly worse clinical outcomes, including all-cause mortality and rate of readmission due to HF worsening over 3 years (29% vs. 15%, P=0.01). CONCLUSIONS: High RER during submaximal exercise, particularly at AT workload, is associated with poor clinical outcome in HF patients.

Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure.

BACKGROUND: Exercise intolerance is a common clinical feature and is linked to poor prognosis in patients with heart failure (HF). Skeletal muscle dysfunction, including impaired energy metabolism in the skeletal muscle, is suspected to play a central role in this intolerance, but the underlying mechanisms remain elusive. Lysine acetylation, a recently identified post-translational modification, has emerged as a major contributor to the derangement of mitochondrial metabolism. We thus investigated whether mitochondrial protein acetylation is associated with impaired skeletal muscle metabolism and lowered exercise capacity in both basic and clinical settings of HF. METHODS: We first conducted a global metabolomic analysis to determine whether plasma acetyl-lysine is a determinant factor for peak oxygen uptake (peak VO2 ) in HF patients. We then created a murine model of HF (n = 11) or sham-operated (n = 11) mice with or without limited exercise capacity by ligating a coronary artery, and we tested the gastrocnemius tissues by using mass spectrometry-based acetylomics. A causative relationship between acetylation and the activity of a metabolic enzyme was confirmed in in vitro studies. RESULTS: The metabolomic analysis verified that acetyl-lysine was the most relevant metabolite that was negatively correlated with peak VO2 (r = -0.81, P < 0.01). At 4 weeks post-myocardial infarction HF, a treadmill test showed lowered work (distance × body weight) and peak VO2 in the HF mice compared with the sham-operated mice (11 ± 1 vs. 23 ± 1 J, P < 0.01; 143 ± 5 vs. 159 ± 3 mL/kg/min, P = 0.01; respectively). As noted, the protein acetylation of gastrocnemius mitochondria was 48% greater in the HF mice than the sham-operated mice (P = 0.047). Acetylproteomics identified the mitochondrial enzymes involved in fatty acid ß-oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (ß-hydroxyacyl CoA dehydrogenase) activity and fatty acid-driven mitochondrial respiration were reduced in the HF mice. This alteration was associated with a decreased expression of mitochondrial deacetylase, Sirtuin 3, because silencing of Sirtuin 3 in cultured skeletal muscle cells resulted in increased mitochondrial acetylation and reduced ß-hydroxyacyl CoA dehydrogenase activity. CONCLUSIONS: Enhanced mitochondrial protein acetylation is associated with impaired FAO in skeletal muscle and reduced exercise capacity in HF. Our results indicate that lysine acetylation is a crucial mechanism underlying deranged skeletal muscle metabolism, suggesting that its modulation is a potential approach for exercise intolerance in HF.

Modeling relationships of achievement motivation and physical fitness with academic performance in Japanese schoolchildren: Moderation by gender.

The aim of this study was to determine, using structural equation modeling, the comprehensive relationships of achievement motivation (self-fulfillment achievement motivation [SFAM] and competitive achievement motivation [CAM]), daily behaviors (exercise habits, screen time, and learning duration), body mass index [BMI], and cardiorespiratory fitness [CRF]) with academic performance among schoolchildren. Three hundred twenty-five schoolchildren (172 males and 153 females; 12-13 years old) were recruited. Academic performance was assessed using the total grade points in 8 academic subjects (GP8); CRF using the 20-m shuttle run; and achievement motivation, daily behaviors, and socioeconomic status using questionnaires. Socioeconomic status was included as a control variable. In males, two cascade associations of achievement motivation to GP8 were detected: (1) SFAM → screen time/learning duration → GP8, and (2) CAM → exercise habit → CRF → GP8 (χ2 = 8.72, p = .19, AGFI = .92). In females, two cascade associations were also detected: (1) SFAM → screen time/learning habit → GP8, and (2) exercise habit → BMI2 → GP8 (χ2 = 6.17, p = .41, AGFI = .93). Our results suggest that greater achievement motivation is associated with academic success via various physiological/behavioral factors, and that these associations differ by gender.

Deletion of NAD(P)H Oxidase 2 Prevents Angiotensin II-Induced Skeletal Muscle Atrophy.

Skeletal muscle atrophy is induced by an imbalance between protein synthesis and degradation. Our previous studies reported that angiotensin II (AII) directly induced muscle atrophy in mice. This study investigated the role of NAD(P)H oxidase 2 (Nox2) activation by AII in the induction of skeletal muscle atrophy. For 4 weeks, either saline (vehicle: V) or AII (1000 ng kg-1 min-1) was infused into male wild-type (WT) and Nox2 knockout (KO) mice via osmotic minipumps. Experiments were performed in the following 4 groups: WT + V, KO + V, WT + AII, and KO + AII. Body weight, muscle weight, and myocyte cross-sectional area were significantly decreased in WT + AII compared to WT + V mice, and these changes were not observed in KO + AII mice. Akt phosphorylation of Ser473 and p70S6K of Thr389 was decreased, gene expression levels of MuRF-1 and atrogin-1 were increased in WT + AII compared to WT + V, and these changes were significantly attenuated in KO + AII mice. The deletion of Nox2 prevented AII-induced skeletal muscle atrophy via improving the balance between protein synthesis and degradation. Therefore, Nox2 may be a therapeutic target for AII-induced skeletal muscle atrophy.

Direct and indirect relationships of physical fitness, weight status, and learning duration to academic performance in Japanese schoolchildren.

The purpose of this study was to determine, using structural equation modelling (SEM), the direct and indirect influence of daily behaviours (i.e. exercise/learning durations), weight status, and physical fitness on academic performance among seventh-grade schoolchildren, after controlling for socioeconomic status. We analysed cross-sectional data from 274 schoolchildren (159 males and 115 females; 12-13 years old). Academic performance was assessed using the total grade points in eight academic subjects. Physical fitness was evaluated using the total score of eight physical fitness tests and weight status using body mass index. The daily behaviours and socioeconomic status were assessed by the questionnaire. The SEM showed an adequate fit to the data (χ2 = 0.684, p = .710, RMSEA = .000). Physical fitness and learning durations had direct effects on academic performance (ß = .301, p < .001; ß = .132, p = .037, respectively) after controlling for confounders. Healthy weight status and exercise habits positively indirectly influenced academic performance via physical fitness. These findings suggest that, independent of socioeconomic status and learning durations, exercise habits and maintaining healthy weight status may indirectly contribute to academic success via better physical fitness in children.

Jump training with blood flow restriction has no effect on jump performance.

This study investigated whether jump training with blood flow restriction (BFR) improves jump performance compared to jump training without BFR under similar exercise intensity in healthy young humans. The participants were twenty healthy males who were assigned to either jump training with BFR (n = 10) or jump training without BFR [control (CON); n = 10] groups. All subjects completed five sets of 10 repetitions with one-minute intervals of half-squat jumps (SJ) at maximal effort, four days a week for four weeks. In the BFR group, circulatory occlusion around both thigh muscles was applied at a pressure of 200 mmHg, and physical characteristics, muscle strength and jump performance were evaluated before and after training. A significant main effect of training period on lean body mass, percentage of body fat and leg circumference in both groups was observed (P < 0.05). For jump training with BFR, only knee flexion strength increased (P < 0.05), while in the CON group, both knee extension and flexion strength increased (P < 0.05). BFR training did not improve SJ or counter-movement jumps (CMJ) (P > 0.05), whereas training without BFR (CON) improved the performance of both jumps (SJ: pre 35.7 ± 5.1 vs. post 38.9 ± 4.1 cm, P = 0.002: CMJ: pre 41.6 ± 3.6 vs. post 44.6 ± 3.8 cm, P < 0.001). These results indicate that jump training with BFR may not be an effective strategy for improving jump performance.

Arm-Cranking Exercise Training Reduces Plasminogen Activator Inhibitor 1 in People With Spinal Cord Injury.

OBJECTIVE: To investigate the effects of arm-cranking exercise training on plasminogen activator inhibitor 1 (PAI-1) as a risk factor of deep vein thrombosis, along with general physical parameters such as muscle strength, aerobic capacity, and hemodynamics, in individuals with spinal cord injury (SCI) and control subjects. DESIGN: Longitudinal study. SETTING: Community-based supervised intervention. PARTICIPANTS: Participants (N=17) comprised individuals with SCI (n=9) who volunteered for this study, and able-bodied individuals (n=8) matched for age, height, and body mass index who were assessed at baseline only. INTERVENTION: The arm-cranking exercise program was performed for 10 weeks with 4 sessions per week. Sessions consisted of 2 sets of warmup (5min) and arm crank exercises (25min) with a 10-minute recovery at an intensity of 50% to 70% of heart rate reserve. MAIN OUTCOME MEASURES: Body mass (BM), waist circumference (WC), aerobic capacity (peak oxygen consumption [Vo2peak]), PAI-1, blood pressure, glucose metabolism, and lipids. RESULTS: PAI-1, BM, WC, systolic blood pressure, and triglycerides (TG) decreased, and Vo2peak increased after training (P<.05, respectively). Spearman rank-order analysis revealed that changes in PAI-1 were related to changes in Vo2peak, BM, WC, TG, and high-density lipoprotein cholesterol. Multiple linear regression analysis revealed that WC was the most sensitive factor for predicting changes in PAI-1 (P=.038). CONCLUSIONS: These results suggest that 10 weeks of arm-cranking exercise training for people with SCI may help to reduce the risk factors of cardiovascular disease. In addition, changes in abdominal fat may be related to changes in PAI-1 in the SCI population.

Pioglitazone improves whole-body aerobic capacity and skeletal muscle energy metabolism in patients with metabolic syndrome.

AIMS/INTRODUCTION: Low aerobic capacity is a strong and independent predictor of all-cause mortality in patients with metabolic syndrome (MetS). Here, we investigated the effects of pioglitazone treatment on whole-body aerobic capacity and skeletal muscle energy metabolism in MetS patients. MATERIALS AND METHODS: A total of 14 male patients with MetS received oral pioglitazone 15 mg/day for 4 months. To assess whole-body aerobic capacity, exercise testing with a bicycle ergometer was carried out before and after pioglitazone treatment. To assess skeletal muscle energy metabolism, intramyocellular lipid in the resting leg and high-energy phosphates in the calf muscle during plantar-flexion exercise were measured using 1 proton- and 31 phosphorus magnetic resonance spectroscopy, respectively. RESULTS: Pioglitazone significantly increased peak oxygen uptake (25.1 ± 4.9 mL/kg/min pretreatment vs 27.2 ± 3.9 mL/kg/min post- treatment, P < 0.05) and anaerobic threshold (12.7 ± 1.9 mL/kg/min pretreatment vs 13.6 ± 1.6 mL/kg/min post-treatment, P < 0.05), although daily physical activity was comparable before and after the treatment. Intramyocellular lipid content was significantly reduced after pioglitazone treatment by 26%, indicating improved skeletal muscle fatty acid metabolism. Pioglitazone also significantly decreased the muscle phosphocreatine loss during exercise by 13%, indicating improved skeletal muscle high-energy phosphate metabolism. Notably, the increase in anaerobic threshold; that is, submaximal aerobic capacity, closely correlated with the decrease in intramyocellular lipid content after pioglitazone treatment. CONCLUSIONS: Pioglitazone significantly improved the MetS patients' whole-body aerobic capacity and skeletal muscle energy metabolism. The beneficial effect of pioglitazone on whole-body aerobic capacity might be at least in part through improved fatty acid metabolism in the skeletal muscle.