Effects of insulin sensitivity modulators on the mitochondrial fate of oxygen in skeletal muscle.

摘要

Increasingly, reactive oxygen species (ROS) are implicated in the development of insulin resistance. To test the hypothesis that modulators of insulin sensitivity (i.e., metformin, ovarian sex steroids and exercise training) affect the fate of oxygen in skeletal muscle, mitochondrial H2O2 emission (mEH2O2) and respiratory O2 flux (JO 2) were measured in saponin-permeabilized myofibers from rodents and women. Concommitant with improved glucose tolerance, complex Ilinked mE H2O2, but not JO2, was reduced in metformin-treated obese rats to rates near or below those in the lean animals. Ex vivo dose-response experiments revealed that metformin inhibits complex I-linked mEH2O2 at a concentration ∼2 orders of magnitude lower than that required to inhibit JO2. To determine if estradiol or progesterone directly affect mitochondrial function, saponin-permeabilized vastus lateralis myofibers biopsied from women in the menstrual cycle follicular phase were incubated breifly in luteal phase serum concentrations of estradiol, progesterone, or both. While progesterone alone inhibited respiration, the effect was absent in the presence of estradiol. Progesterone, alone or in combination with estradiol increased complex Ilinked mEH2O2. Complex I-linked mEH2O2 measured in permeabilized myofibers from insulin sensitive and resistant women correlated significantly with serum progesterone in these subjects. Moreover, mEH2O2 was more than 80% greater in the insulin resistant women. Regular exercise is known to improve insulin sensitivity. To determine the effects of exercise training on mitochondrial function, mEH2O2 and JO2 were measured in saponin-permeabilized vastus lateralis myofibers from lean (BMI 30) and obese (BMI > 30) women before (Pre) and after (Post) 8 weeks of exercise training (8WT = stationary cycling, 1 h/d, 5 d/w at heart rate corresponding to 70-75% VO2peak). Interestingly, while Pre-Post there were no changes in JO2 supported by multiple substrates or calculated ratios of respiratory control, there was a reduction in the potential for complex I-linked mEH2O2 following training in the lean women. Altogether, the results of this project support the notion that modulators of insulin sensitivity may do so through their ability to affect complex I-linked mEH2O2, but not necessarily JO 2 in skeletal muscle.