Defining the contribution of skeletal muscle pyruvate dehydrogenase alpha 1 (Pdha1) to exercise performance and insulin action.

The pyruvate dehydrogenase complex (PDC) converts pyruvate to acetyl-CoA and is an important control-point for carbohydrate (CHO) oxidation. However, the importance of the PDC and CHO oxidation to muscle metabolism and exercise performance, particularly during prolonged or high-intensity exercise, has not been fully defined, especially in mature skeletal muscle. To this end, we determined whether skeletal muscle-specific loss of pyruvate dehydrogenase alpha 1 (Pdha1), which is a critical subunit of the PDC, impacts resting energy metabolism, exercise performance or metabolic adaptation to high-fat diet (HFD) feeding. For this, we generated a tamoxifen (TMX)-inducible Pdha1 knockout (PDHmKO) mouse, in which PDC activity is temporally and specifically ablated in adult skeletal muscle. We assessed energy expenditure, ex vivo muscle contractile performance and endurance exercise capacity in PDHmKO mice and wild-type (WT) littermates. Additionally, we studied glucose homeostasis and insulin sensitivity in muscle after 12 weeks HFD feeding. TMX administration largely ablated PDHα in skeletal muscle of adult PDHmKO mice, but did not impact energy expenditure, muscle contractile function or low-intensity exercise performance. Additionally, there were no differences in muscle insulin sensitivity or body composition in PDHmKO mice fed a control or HFD, as compared to WT mice. However, exercise capacity during high-intensity exercise was severely impaired in PDHmKO mice, in parallel with a large increase in plasma lactate concentration. In conclusion, while skeletal muscle PDC is not a major contributor to resting energy expenditure or long-duration, low-intensity exercise performance, it is necessary for optimal performance during high-intensity exercise.