Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults.

Adam R Konopka,Robert V Musci,Melissa A Linden,Christopher A Wolff,Justin J Reid,Laurie M Biela,Jaime L Laurin,Benjamin F Miller,Susan M Bailey,Hayden M Schoenberg,Karyn L Hamilton,William M Castor,Oscar D Safairad

doi:10.1111/acel.12880

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.

Highlights

The declines in cardiorespiratory fitness (CRF), glucose control, and insulin sensitivity are predictors of disease, disability, and all‐cause mortality (Blair et al, 1989; Facchini, Hua, Abbasi, & Reaven, 2001; Zaslavsky, Walker, Crane, Gray, & Larson, 2016)
This study shows in older adults at risk for type 2 diabetes mellitus (T2DM), but free of chronic disease that a clinical dose of metformin inhibited the improvement in skeletal muscle mitochondrial respiration and attenuated the increase in CRF and whole‐body insulin sensitivity after aerobic exercise training (AET)
We report that the correlation between the change in complex I (CI)‐linked mitochondrial respiration and insulin sensitivity after AET was driven by the relationship in the placebo (r = 0.53) group rather than metformin (r = 0.13), which suggests that metformin may act on the mitochondria at CI to disrupt the relationship between insulin sensitivity and mitochondrial respiration

Summary

Introduction

The declines in cardiorespiratory fitness (CRF), glucose control, and insulin sensitivity are predictors of disease, disability, and all‐cause mortality (Blair et al, 1989; Facchini, Hua, Abbasi, & Reaven, 2001; Zaslavsky, Walker, Crane, Gray, & Larson, 2016). Protective caps at the ends of chromosomes, are critical features for maintaining genome integrity and stability in response to a variety of cellular stresses (e.g., cell division and oxidative stress) and lifestyle factors (e.g., nutrition and exercise). AMPK is considered an energy sensor of the cell and, in response to energetic stress, increases energy‐producing processes such as skeletal muscle mitochondrial biogenesis and insulin‐stimulated glucose uptake. In line with this notion, we and others have shown that increased skeletal muscle mitochondrial protein synthesis and respiration as well as decreased ROS emissions may contribute to improved CRF and peripheral insulin sensitivity after aerobic exercise training (AET; Konopka et al, 2015; Robinson et al, 2017)

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