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

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

Daniel A Kane  1 , Ethan J Anderson, Jesse W Price 3rd, Tracey L Woodlief, Chien-Te Lin, Benjamin T Bikman, Ronald N Cortright, P Darrell Neufer
Affiliations

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

Daniel A Kane et al. Free Radic Biol Med. .

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 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.

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Figures

Fig. 1
Fig. 1
Effects of oral metformin treatment on skeletal muscle respiratory O2 flux measured in permeabilized myofibers from lean and obese Zucker rats. Respiratory O2 flux in permeabilized fiber bundles from red gastrocnemius muscle from lean and obese rats +/- metformin treatment during respiration supported by (A) complex I-linked substrates glutamate/malate (G/M, 2/1 mM) followed by additions of ADP (2 mM), succinate (+S, 3 mM), and the chemical uncoupler FCCP (2 μM + 10 μg/ml oligomycin) or (B) during respiration supported by activated fatty acid palmitoyl-carnitine and malate (P-C/M, 25 μM/1 mM) followed by additions of ADP (2 mM), glutamate (+G, 2 mM), and succinate (+S, 3 mM). The data represent means ± SEM (n = 4/group). Main effect for obesity *P < 0.05; **P < 0.01. No effect of metformin treatment on respiratory O2 flux was observed in A or B.
Fig. 2
Fig. 2
Effects of oral metformin treatment on skeletal muscle mitochondrial H2O2 emission in permeabilized myofibers from lean and obese Zucker rats. (A) H2O2 emission rates in response to titration of succinate during basal (i.e., state 4) respiration in permeabilized fiber bundles from red gastrocnemius muscle from lean and obese rats +/- metformin treatment. Data represent means ± SEM (n = 4/group). *P < 0.05 for Vmax, obese versus lean. †P <0.05, ††P < 0.01 for Vmax, metformin treated vs untreated. (B) H2O2 emission rates during basal (i.e., state 4) respiration supported by activated fatty acid palmitoyl-carnitine and malate (P-C/M, 25 μM/1 mM) followed by additions of glutamate (+G, 2 mM), and succinate (+S, 3 mM). Data represent means ± SEM (n = 4/group). †P < 0.05, ††P < 0.01 for main effect of metformin treatment. **P < 0.01, ***P < 0.001 within group effect of metformin treatment.
Fig. 3
Fig. 3
Dose-dependent effects of meformin on respiratory O2 flux and mitochondrial H2O2 emission. Parallel control permeabilized red gastrocnemius myofibers were pre-incubated in metformin (0-10 mM) for 20 min. Maximal mitochondrial H2O2 emission rates (black bars, left y-axis) during succinate (3 mM) supported respiration are plotted with maximal ADP (8 mM) stimulated respiratory O2 flux (white bars, right y-axis) during complex I (glutamate/pyruvate/malate, 5/5/2 mM) supported respiration at each concentration of metformin. **P < 0.01, ***P < 0.001 versus no metformin for H2O2 emission. †††P < 0.001 versus no metformin for O2 flux.
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