Metformin attenuates skeletal muscle transcriptional and mitochondrial respiratory adaptations to aerobic exercise training.
We have previously demonstrated that the inhibitory effect of metformin on skeletal muscle complex-I linked mitochondrial respiration was associated with attenuated improvements in whole-body insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) in older adults. However, the mechanism(s) by which metformin impacts skeletal muscle adaptations to aerobic exercise remains unclear. To understand potential mechanisms associated with the inhibitory effect of metformin on mitochondrial adaptations to AET, we evaluated the skeletal muscle transcriptome, mitochondrial respiration, and hydrogen peroxide (H2O2) emissions in 7-month-old male C57BL6/J mice after 8-weeks of non-exercise sedentary control (SED) or progressive AET with and without metformin treatment. Metformin attenuated the number of differentially expressed genes by AET (975 vs. 449). Pathway analysis suggests that metformin suppressed several signal transduction pathways involved in oxidative capacity and cellular metabolism, including VEGF, AMPK, HIF-1a, and PI3K-AKT. Notably, the addition of metformin to AET suppressed 16 downstream targets of HIF-1a and was accompanied by metformin ameliorating the increase in mitochondrial respiratory capacity and ADP sensitivity after AET. However, neither AET nor AET+MET impacted mitochondrial H2O2 emitting potential. Given the central role of HIF-1a as an upstream transcriptional regulator of mitochondrial function and biogenesis, these results suggest that suppression of HIF-1a pathway by metformin could serve as a transcriptional regulatory node associated with the inhibitory role of metformin on skeletal muscle mitochondrial adaptations to aerobic exercise training. Overall design: Mice were randomized to treatment groups (n=8-9/group) to sedentary (SED), aerobic exercise training (AET), aerobic exercise training and metformin (AET+MET). Mice allocated to AET (or AET + MET) were exercised on a 6-lane motorized treadmill (Columbus Instruments Exer 3/6 treadmill) 5 days/week, 60min/day for 8 weeks. Metformin (Cayman chemical 13118) was provided in the drinking water at 2mg/mL and replaced weekly.  Left gastrocnemius was collected and snap frozen.