Difference between revisions of "Kane 2010 Free Radic Biol Med"
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|year=2010 | |year=2010 | ||
|journal=Free Radical Biol. Med. | |journal=Free Radical 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<sub>2</sub> flux and H<sub>2</sub>O<sub>2</sub> 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<sub>2</sub>O<sub>2</sub> 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<sub>2</sub>O<sub>2</sub> 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<sub>2</sub> consumption in muscle from obese or lean rats. Ex vivo dose–response experiments revealed that metformin inhibits complex I-linked H<sub>2</sub>O<sub>2</sub> emission at a concentration ~2 orders of magnitude lower than that required to inhibit respiratory O<sub>2</sub> flux. These findings suggest that therapeutic concentrations of metformin normalize mitochondrial H<sub>2</sub>O<sub>2</sub> emission by blocking reverse electron flow without affecting forward electron flow or respiratory O<sub>2</sub> flux in skeletal muscle. | |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<sub>2</sub> flux and H<sub>2</sub>O<sub>2</sub> 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<sub>2</sub>O<sub>2</sub> 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<sub>2</sub>O<sub>2</sub> 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<sub>2</sub> consumption in muscle from obese or lean rats. Ex vivo dose–response experiments revealed that metformin inhibits complex I-linked H<sub>2</sub>O<sub>2</sub> emission at a concentration ~2 orders of magnitude lower than that required to inhibit respiratory O<sub>2</sub> flux. These findings suggest that therapeutic concentrations of metformin normalize mitochondrial H<sub>2</sub>O<sub>2</sub> emission by blocking reverse electron flow without affecting forward electron flow or respiratory O<sub>2</sub> flux in skeletal muscle. | ||
|mipnetlab=US_NC Greenville_NeuferPD, CA Antigonish_Kane DA | |||
|discipline=Mitochondrial Physiology, Biomedicine | |||
}} | }} | ||
{{Labeling | {{Labeling | ||
| | |instruments=Oxygraph-2k | ||
|injuries=RONS; Oxidative Stress, Mitochondrial Disease; Degenerative Disease and Defect | |injuries=RONS; Oxidative Stress, Mitochondrial Disease; Degenerative Disease and Defect | ||
|organism=Rat | |organism=Rat | ||
|tissues=Skeletal Muscle | |tissues=Skeletal Muscle | ||
|topics=Respiration; OXPHOS; ETS Capacity, Substrate; Glucose; TCA Cycle, Fatty Acid | |topics=Respiration; OXPHOS; ETS Capacity, Substrate; Glucose; TCA Cycle, Fatty Acid | ||
|additional=Obesity, Diabetes-2 | |additional=Obesity, Diabetes-2 | ||
|discipline=Mitochondrial Physiology, Biomedicine | |||
}} | }} | ||
Revision as of 12:00, 11 August 2011
| 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 Radical Biol. Med. 49: 1082–1087. |
Kane DA, Anderson EJ, Price III JW, Woodlief TL, Lin CT, Bikman BT, Cortright RN, Neufer PD (2010) Free Radical 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 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.
• O2k-Network Lab: US_NC Greenville_NeuferPD, CA Antigonish_Kane DA
Labels:
Stress:RONS; Oxidative Stress"RONS; Oxidative Stress" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property., Mitochondrial Disease; Degenerative Disease and Defect"Mitochondrial Disease; Degenerative Disease and Defect" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property. Organism: Rat Tissue;cell: Skeletal Muscle"Skeletal Muscle" is not in the list (Heart, Skeletal muscle, Nervous system, Liver, Kidney, Lung;gill, Islet cell;pancreas;thymus, Endothelial;epithelial;mesothelial cell, Blood cells, Fat, ...) of allowed values for the "Tissue and cell" property.
Regulation: Respiration; OXPHOS; ETS Capacity"Respiration; OXPHOS; ETS Capacity" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property., Substrate; Glucose; TCA Cycle"Substrate; Glucose; TCA Cycle" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property., Fatty Acid"Fatty Acid" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property.
HRR: Oxygraph-2k
Obesity, Diabetes-2
