Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats

Free Radic Biol Med. 2010 Sep 15;49(6):1082-7. doi: 10.1016/j.freeradbiomed.2010.06.022. Epub 2010 Jun 28.


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 O(2) flux and H(2)O(2) 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 H(2)O(2) 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 H(2)O(2) 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 O(2) consumption in muscle from obese or lean rats. Ex vivo dose-response experiments revealed that metformin inhibits complex I-linked H(2)O(2) emission at a concentration approximately 2 orders of magnitude lower than that required to inhibit respiratory O(2) flux. These findings suggest that therapeutic concentrations of metformin normalize mitochondrial H(2)O(2) emission by blocking reverse electron flow without affecting forward electron flow or respiratory O(2) flux in skeletal muscle.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Electron Transport Complex I / metabolism
  • Hydrogen Peroxide / metabolism*
  • Male
  • Metformin / administration & dosage
  • Metformin / therapeutic use*
  • Mitochondria, Muscle / drug effects
  • Mitochondria, Muscle / metabolism
  • Mitochondria, Muscle / pathology
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Myofibrils / drug effects*
  • Myofibrils / pathology
  • Obesity
  • Oxygen Consumption / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Zucker
  • Respiratory Rate / drug effects


  • Metformin
  • Hydrogen Peroxide
  • Electron Transport Complex I