Metformin suppresses the mitochondrial and transcriptional response to exercise, revealing a conserved BCL6B-associated angiogenic program.

We have previously demonstrated that the inhibitory effect of metformin on skeletal muscle mitochondrial respiration was associated with attenuated improvements in whole body insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) in older adults. To identify processes associated with the inhibitory effect of metformin on mitochondrial adaptations to AET, we evaluated the skeletal muscle transcriptome, mitochondrial respiration, and hydrogen peroxide (H(2)O(2)) emissions in 7-mo-old male C57BL6/J mice after 8 wk of nonexercise sedentary control (SED) or progressive AET with and without metformin treatment. Similar to our findings in humans, metformin diminished the improvement in whole body cardiometabolic adaptations and the increase in mitochondrial respiration in both isolated mitochondria and permeabilized muscle fibers after AET in mice. However, AET with or without metformin did not impact resting mitochondrial H(2)O(2) emissions. Metformin decreased the number of differentially expressed genes after AET by ∼50% and suppressed several transcription factors and signal transduction pathways involved in skeletal muscle proteostasis, myogenesis, oxidative capacity, and angiogenesis. A parallel analysis of human resistance exercise data revealed overlapping metformin-sensitive transcription factors and B Cell CLL/Lymphoma 6B (BCL6B)-associated signaling networks implicated in angiogenesis, suggesting a conserved regulatory axis across species and exercise modalities. Collectively, these data demonstrate that attenuation of mitochondrial respiration by metformin coincides with transcriptional repression and identify specific pathways and regulators, such as BCL6B, that may contribute to the suppression of exercise adaptations by metformin.NEW & NOTEWORTHY Metformin inhibited skeletal muscle mitochondrial respiration and transcriptional adaptations to aerobic exercise training. The findings from this study suggest BCL6B as a conserved exercise-responsive transcription factor in mice and humans that is sensitive to metformin, enriched in endothelial cells, and implicated in angiogenesis.