Progesterone increases skeletal muscle mitochondrial H2O2 emission in nonmenopausal women

Kane DA, Lin CT, Anderson EJ, Kwak HB, Cox JH, Brophy PM, Hickner RC, Neufer PD, Cortright RN. Progesterone increases skeletal muscle mitochondrial H2O2 emission in nonmenopausal women. Am J Physiol Endocrinol Metab 300: E528-E535, 2011. First published December 28, 2010; doi:10.1152/ajpendo.00389.2010.-The luteal phase of the female menstrual cycle is associated with both 1) elevated serum progesterone (P4) and estradiol (E2), and 2) reduced insulin sensitivity. Recently, we demonstrated a link between skeletal muscle mitochondrial H2O2 emission (mE(H2O2)) and insulin resistance. To determine whether serum levels of P4 and/or E-2 are related to mitochondrial function, m(EH2O2) and respiratory O-2 flux (JO(2)) were measured in permeabilized myofibers from insulin- sensitive (IS, n = 24) and -resistant (IR, n = 8) nonmenopausal women (IR = HOMA-IR > 3.6). Succinate-supported mE(H2O2) was more than 50% greater in the IR vs. IS women (P < 0.05). Interestingly, serum P4 correlated positively with succinate-supported mE(H2O2) (r = 0. 53, P < 0.01). To determine whether P4 or E2 directly affect mitochondrial function, saponin-permeabilized vastus lateralis myofibers biopsied from five nonmenopausal women in the early follicular phase were incubated in P4 (60 nM), E2 (1.4 nM), or both. P4 alone inhibited state 3 JO(2), supported by multisubstrate combination (P < 0.01). However, E2 alone or in combination with P4 had no effect on JO(2). In contrast, during state 4 respiration, supported by succinate and glycerophosphate, m(EH2O2) was increased with P4 alone or in combination with E2 (P < 0.01). The results suggest that 1) P4 increases mE(H2O2) with or without E2; 2) P4 alone inhibits JO(2) but not when E2 is present; and 3) P4 is related to the mE(H2O2) previously linked to skeletal muscle insulin resistance.