Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults

Abstract

Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise‐induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double‐blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24‐hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole‐body insulin sensitivity and VO2max after AET. In the metformin group, there was no overall change in whole‐body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise‐mediated increase in skeletal muscle mitochondrial respiration. The change in whole‐body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET‐induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.

Mitochondrial respiration variability and simulations in human skeletal muscle: The Gene SMART study

“…This means that it would be a challenge to observe true changes in mitochondrial capacity using the OROBOROS technology, since most studies do not report such large increases following exercise training (−9% to 20%). 18,19,32,[34][35][36][37][38] We acknowledge that some of the studies have observed significant changes in mitochondrial respiration without reaching the effect sizes we presented here. This implies that although such studies were significant, the sample sizes were too low to detect the magnitude of changes they reported at 80% power.…”

Type 2 diabetes and reduced exercise tolerance: a review of the literature through an integrated physiology approach

“…Another explanation for the reduced sensitivity of VO 2peak to physical exercise in T2DM could be related to an interference of glucose lowering drugs with mitochondria. As recently shown, the ongoing treatment with metformin almost completely prevented the increase in VO 2peak induced by exercise training in T2D patients, as well as the exercise-mediated increase in skeletal muscle mitochondrial respiration [135]. However, since improvements in VO 2peak are comparable between T2D offspring and control subjects (+ 15%), it is unlikely to postulate that a different skeletal muscle mitochondria response to exercise is present before the onset of diabetes [136].…”

Improving biologic predictors of cycling endurance performance with near‐infrared spectroscopy derived measures of skeletal muscle respiration: E pluribus unum

“…More recently, metformin was shown to abolish exercise‐induced increases in skeletal muscle respiration and attenuate concomitant improvements to VO 2max and whole‐body insulin sensitivity using a randomized double‐blind placebo‐controlled design. Training‐induced changes in skeletal muscle respiration also correlated with changes in whole‐body insulin sensitivity (Konopka et al, ). The importance of skeletal muscle oxidative potential most likely extends past the relationship with endurance performance, as the whole‐body health benefits of exercise training track with improvements in exercise performance (Gabriel & Zierath, ).…”