Kane 2010 Free Radic Biol Med
|Kane DA, Anderson EJ, Price III JW, Woodlief TL, Lin C-T, Bikman BT, Cortright RN, Neufer PD (2010) Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats. Free Radic Biol Med 49:1082–7.|
Abstract: Metformin is a widely prescribed drug for treatment of type 2 diabetes, although no cellular mechanism of action has been established. To determine whether in vivo metformin treatment alters mitochondrial function in skeletal muscle, respiratory O2 flux and H2O2 emission were measured in saponin-permeabilized myofibers from lean and obese (fa/fa) Zucker rats treated for 4 weeks with metformin. Succinate- and palmitoylcarnitine-supported respiration generated greater than twofold higher rates of H2O2 emission in myofibers from untreated obese versus lean rats, indicative of an obesity-associated increased mitochondrial oxidant emitting potential. In conjunction with improved glycemic control, metformin treatment reduced H2O2 emission in muscle from obese rats to rates near or below those observed in lean rats during both succinate- and palmitoylcarnitine-supported respiration. Surprisingly, metformin treatment did not affect basal or maximal rates of O2 consumption in muscle from obese or lean rats. Ex vivo dose–response experiments revealed that metformin inhibits complex I-linked H2O2 emission at a concentration ~2 orders of magnitude lower than that required to inhibit respiratory O2 flux. These findings suggest that therapeutic concentrations of metformin normalize mitochondrial H2O2 emission by blocking reverse electron flow without affecting forward electron flow or respiratory O2 flux in skeletal muscle.
• Keywords: Type 2 diabetes, Zucker rats, Metformin, Reactive oxygen species, Mitochondria, Skeletal muscle, Respiration
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Diabetes Stress:Oxidative stress;RONS, Mitochondrial disease Organism: Rat Tissue;cell: Skeletal muscle
Regulation: Substrate, Fatty acid Coupling state: LEAK, OXPHOS, ET