Metformin Blunts Exercise‐Induced Improvements in Skeletal Muscle Mitochondrial Respiration Independent of Changes in Mitochondrial Biogenesis

Abstract

The anti‐hyperglycemic agent Metformin and exercise independently prevent the progression from prediabetes to overt type two diabetes (T2D) and are both implicated in healthspan extension. However, emerging evidence indicates the addition of Metformin to exercise may inhibit the health benefits of exercise. The purpose of the current study was to test the hypothesis that Metformin blunts the positive adaptations to exercise by inhibiting skeletal muscle mitochondrial fractional protein synthesis rates (FSR) and respiration. Older adults (n=53, 62±5 yrs) with at least one risk factor for T2D were randomized in a double‐blinded fashion to consume Metformin or placebo (1500–2000 mg/day) during 12‐weeks of aerobic exercise training (AET). VO2max and skeletal muscle mitochondrial respiration were assessed before (PRE) and after (POST) the 12‐week intervention. Skeletal muscle biopsy samples were obtained 48 hrs after the last exercise bout and 36 hrs after the last metformin dose. High‐resolution respirometry was performed on permeabilized skeletal muscle fibers to assess submaximal and maximal oxidative phosphorylation (OXPHOS; P) primarily linked to complex‐I (CIP), fatty acid oxidation (CIP&FAO), and complex II (CI+IIP&FAO). Subsequent addition of FCCP determined maximal uncoupled electron transport system (ETS) capacity. During the last four weeks of the intervention, participants consumed the stable isotope deuterium oxide (2H2O) to measure cumulative FSR (%/day) in a mitochondrial enriched skeletal muscle fraction. Compared to placebo, Metformin tended (P=0.10) to attenuate the increase in VO2max after 12 weeks of AET (Metformin: 0.06±0.02 vs. Placebo: 0.13±0.03 L/min). Congruent with these findings, Metformin abrogated (P<0.05) the exercise‐mediated increase in submaximal mitochondrial respiration, CIp, CI+IIP, and CI+IIP&FAO after AET (Metformin: −0.7 to 2.6 vs Placebo: 5.3 to 22.8 pmol/s/mg tissue). Unlike the effect of Metformin on mitochondrial respiration, mitochondrial protein synthesis rates assessed during AET were not different between Metformin and placebo (1.06±0.05 vs. 1.00±0.04 %/day; P=0.38). Here we demonstrate that metformin tended to diminish the improvement in VO2max and inhibited the increase in skeletal muscle mitochondrial respiration after AET in older adults at risk for T2D. However, the effects on mitochondrial respiration do not appear to be related to changes in mitochondrial biogenesis. Future research is warranted to determine mechanisms by which metformin influences skeletal muscle mitochondrial respiration and impacts the health benefits of exercise.Support or Funding InformationThis study was supported by the National Dairy CouncilThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.