Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats
Open accessAbstract
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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In rats, 10-fold lower metformin levels are needed to scavenge mitochondrial ROS than to inhibit mitochondrial complex I, without directly impacting respiratory capacity.
“it takes 10-fold lower levels of metformin to scavenge mitochondrial ROS than required to inhibit mitochondrial complex I, without directly impacting respiratory capacity as evidenced in rats”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Kane et al. 2010
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References 38 · Cited by 99
- Authors
- Kane, D. A., Anderson, E. J., Price, J. W., Woodlief, T. L., Lin, C.-T., Bikman, B. T., Cortright, R. N., & Neufer, P. D.
- Affiliations
- East Carolina University (US)
- Corresponding author
- Neufer, P. Darrell
- ORCID
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 49
- Issue
- 6
- Pages
- 1082-1087
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC2921476
- OpenAlex
- W1978277179
- Cited by
- 99
- References
- 38
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 9 · 2022: 7 · 2021: 9 · 2020: 8 · 2019: 7 · 2018: 9 · 2017: 4 · 2016: 6 · 2015: 7 · 2014: 7 · 2013: 6 · 2012: 2
- FWCI
- 2.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1r15dk061314-01a2)
- National Institute of Diabetes and Digestive and Kidney Diseases (R15 DK061314, DK075880, R01DK073488, R01DK075880, DK-073488, R01 DK061314)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- metformin, skeletal muscle, obesity, type 2 diabetes, mitochondrial respiration, complex I, reverse electron flow, Zucker fatty rats, oxidative stress
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Hydrogen Peroxide, Male, Metformin, Mitochondria, Muscle, Myofibrils, Obesity, Oxygen Consumption, Rats, Zucker, Rats, Sprague-Dawley, Muscle, Skeletal, Electron Transport Complex I, Rats, Respiratory Rate
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