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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 1proton- and 31phosphorus 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.

We have reported that exercise capacity is reduced in high fat diet (HFD)-induced diabetic mice, and that this reduction is associated with impaired mitochondrial function in skeletal muscle (SKM). However, it remains to be clarified whether the treatment of diabetes ameliorates the reduced exercise capacity. Therefore, we examined whether an insulin sensitizing drug, pioglitazone, could improve exercise capacity in HFD mice. C57BL/6J mice were fed a normal diet (ND) or HFD, then treated with or without pioglitazone (3 mg/kg/day) to yield the following 4 groups: ND+vehicle, ND+pioglitazone, FLED I vehicle, and HFD+pioglitazone (n=10 each). After 8 weeks, body weight, plasma glucose, and insulin in the HFD+vehicle were significantly increased compared to the ND I vehicle group. Pioglitazone normalized the insulin levels in RED fed mice, but did not affect the body weight or plasma glucose. Exercise capacity determined by treadmill tests was significantly reduced in the HFD+vehicle, and this reduction was almost completely ameliorated in HFD+pioglitazone mice. ADP dependent mitochondrial respiration, complex l and Ill activities, and citrate synthase activity were significantly decreased in the SKM of the HFD+vehicle animals, and these decreases were also attenuated by pioglitazone. NAD(P)H oxidase activity was significantly increased in the HFD+vehicle compared with the ND+vehicle, and this increase was ameliorated in HFD+pioglitazone mice. Pioglitazone improved the exercise capacity in diabetic mice, which was due to the improvement in mitochondria! function and attenuation of oxidative stress in the SKM. Our data suggest that pioglitazone may be useful as an agent for the treatment of diabetes mellitus. (C) 2014 Elsevier B.V. All rights reserved.

OBJECTIVE-Systemic oxidative stress is associated with insulin resistance and obesity. We tested the hypothesis that systemic oxidative stress is linked to lower aerobic capacity and skeletal muscle dysfunction in metabolic syndrome (MetS). RESEARCH DESIGN AND METHODS-The incremental exercise testing with cycle ergometer was performed in 14 male patients with MetS and 13 age-, sex-, and activity-matched healthy subjects. Systemic lipid peroxidation was assessed by serum thiobarbituric acid reactive substances (TBARS), and systemic antioxidant defense capacity was assessed by serum total thiols and enzymatic activity of superoxide dismutase (SOD). To assess skeletal muscle energy metabolism, we measured high-energy phosphates in the calf muscle during plantar flexion exercise and intramyocellular lipid (IMCL) in the resting leg muscle, using P-31- and (1)proton-magnetic resonance spectroscopy, respectively. RESULTS-Serum TBARS were elevated (12.4 +/- 7.1 vs. 3.7 +/- 1.1 mu mol/L; P < 0.01), and serum total thiols and SOD activity were decreased (290.8 +/- 51.2 vs. 398.7 +/- 105.2 mu mol/L, P < 0.01; and 22.2 +/- 8.4 vs. 31.5 +/- 8.5 units/L, P < 0.05, respectively) in patients with MetS compared with healthy subjects. Peak VO2 and anaerobic threshold normalized to body weight were significantly lower in MetS patients by 25 and 31%, respectively, and inversely correlated with serum TBARS (r = -0.49 and r = -0.50, respectively). Moreover, muscle phosphocreatine loss during exercise was 1.4-fold greater in patients with MetS (P < 0.05), and IMCL content was 2.9-fold higher in patients with MetS (P < 0.01), indicating impaired skeletal muscle energy metabolism, and these indices positively correlated with serum TBARS (r = 0.45 and r = 0.63, respectively). CONCLUSIONS-Systemic oxidative stress was associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in patients with MetS.

Invariant natural killer T (iNKT) cells orchestrate tissue inflammation via regulating various cytokine productions. However the role of iNKT cells has not been determined in myocardial ischemia/reperfusion (I/R) injury. The purpose of this study was to examine whether the activation of iNKT cells by a-galactosylceramide (alpha-GC), which specifically activates iNKT cells, could affect myocardial I/R injury. I/R or sham operation was performed in male C57BL/6J mice. I/R mice received the injection of either alpha GC (I/R + aGC, n = 48) or vehicle (I/R + vehicle, n = 49) 30 min before reperfusion. After 24 h, infarct size/area at risk was smaller in I/R + alpha GC than in I/R + vehicle (37.8 +/- 2.7% vs. 47.1 +/- 2.5%, P < 0.05), with no significant changes in area at risk. The numbers of infiltrating myeloperoxidase- and CD3-positive cells were lower in I/R + alpha GC. Apoptosis evaluated by TUNEL staining and caspase-3 protein was also attenuated in I/R + alpha GC. Myocardial gene expression of tumor necrosis factor-a and interleukin (IL)-1 beta in I/R + alpha GC was lower to 46% and 80% of that in I/R + vehicle, respectively, whereas IL-10, IL-4, and interferon (IFN)-gamma were higher in I/R + alpha GC than I/R + vehicle by 2.0, 4.1, and 9.6 folds, respectively. The administration of anti-IL-10 receptor antibody into I/R + alpha GC abolished the protective effects of alpha GC on I/R injury (infarct size/area at risk: 53.1 +/- 5.2% vs. 37.4 +/- 3.5%, P < 0.05). In contrast, anti-IL-4 and anti-IFN-gamma antibodies did not exert such effects. In conclusion, activated iNKT cells by alpha GC play a protective role against myocardial I/R injury through the enhanced expression of IL-10. Therapies designed to activate iNKT cells might be beneficial to protect the heart from I/R injury. (C) 2013 Elsevier Ltd. All rights reserved.

Our previous study reported that intramuscular metabolic stress during low-intensity resistance exercise was significantly enhanced by combining blood flow restriction (BFR); however, they did not reach the levels achieved during high-intensity resistance exercise. That study was performed using a single set of exercise; however, usual resistance exercise consists of multiple sets with rest intervals. Therefore, we investigated the intramuscular metabolic stress during multiple-set BFR exercises, and compared the results with those during multiple-set high-intensity resistance exercise. Twelve healthy young subjects performed 3 sets of 1-min unilateral plantar flexion (30 repetitions) with 1-min intervals under 4 different conditions: low intensity (L, 20 % 1 RM) and high intensity (H, 65 % 1 RM) without BFR, and L with intermittent BFR (IBFR, only during exercise) and with continuous BFR (CBFR, during rest intervals as well as exercise). Intramuscular metabolic stress, defined as intramuscular metabolites and pH, and muscle fiber recruitment were evaluated by 31P-magnetic resonance spectroscopy. The changes of intramuscular metabolites and pH during IBFR were significantly greater than those in L but significantly lower than those in H. By contrast, those changes in CBFR were similar to those in H. Moreover, the fast-twitch fiber recruitment, evaluating by a splitting Pi peak, showed a similar level to H. In conclusion, the multiple sets of low-intensity resistance exercise with continuous BFR could achieve with the same metabolic stress as multiple sets of high-intensity resistance exercise.