Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats.
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.
Kane
Daniel A
DA
East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, USA.
Anderson
Ethan J
EJ
Price
Jesse W
JW
Woodlief
Tracey L
TL
Lin
Chien-Te
CT
Bikman
Benjamin T
BT
Cortright
Ronald N
RN
Neufer
P Darrell
PD
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D042967:Electron Transport Complex I / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009210:Myofibrils / Q000187:drug effects* / Q000473:pathology; D009765:Obesity; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D056152:Respiratory Rate / Q000187:drug effects
D008687:Metformin; D006861:Hydrogen Peroxide; D042967:Electron Transport Complex I