Short-term exposure to a clinical dose of metformin increases skeletal muscle mitochondrial H2O2 emission and production in healthy, older adults: A randomized controlled trial

Exp Gerontol. 2022 Jun 15;163:111804. doi: 10.1016/j.exger.2022.111804. Epub 2022 Apr 9.


Background and aims: Metformin is the most commonly prescribed medication to treat diabetes. Emerging evidence suggests that metformin could have off target effects that might help promote healthy muscle aging, but these effects have not been thoroughly studied in glucose tolerant older individuals. The purpose of this study was to investigate the short-term effects of metformin consumption on skeletal muscle mitochondrial bioenergetics in healthy older adults.

Methods: We obtained muscle biopsy samples from 16 healthy older adults previously naïve to metformin and treated with metformin (METF; 3F, 5M), or placebo (CON; 3F, 5M), for two weeks using a randomized and blinded study design. Samples were analyzed using high-resolution respirometry, immunofluorescence, and immunoblotting to assess muscle mitochondrial bioenergetics, satellite cell (SC) content, and associated protein markers.

Results: We found that metformin treatment did not alter maximal mitochondrial respiration rates in muscle compared to CON. In contrast, mitochondrial H2O2 emission and production were elevated in muscle samples from METF versus CON (METF emission: 2.59 ± 0.72 SE Fold, P = 0.04; METF production: 2.29 ± 0.53 SE Fold, P = 0.02). Furthermore, the change in H2O2 emission was positively correlated with the change in type 1 myofiber SC content and this was biased in METF participants (Pooled: R2 = 0.5816, P = 0.0006; METF: R2 = 0.674, P = 0.0125).

Conclusions: These findings suggest that acute exposure to metformin does not impact mitochondrial respiration in aged, glucose-tolerant muscle, but rather, influences mitochondrial-free radical and SC dynamics.

Clinical trial registration: NCT03107884,

Keywords: Aging; Complex I respiration; Free radicals; Insulin sensitizers; Metabolism; Mitochondria; Muscle stem cells.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Glucose / metabolism
  • Humans
  • Hydrogen Peroxide / metabolism
  • Metformin* / pharmacology
  • Metformin* / therapeutic use
  • Mitochondria / metabolism
  • Mitochondria, Muscle / metabolism
  • Muscle, Skeletal / metabolism


  • Metformin
  • Hydrogen Peroxide
  • Glucose

Associated data