Changes in metabolic regulation of the carbohydrate oxidative pathway in exercising high altitude deer mice

Abstract

Hypoxia encountered at high altitude (HA) can limit energy production via aerobic metabolism in animals. Carbohydrate oxidation (CHO) has a greater ATP yield/mole O2 than fat oxidation, and HA-native deer mice show an increased reliance on CHO during submaximal exercise after hypoxia acclimation as an O2-saving strategy. However, hypoxia acclimation does not increase glycolytic capacity in muscle. We therefore tested the hypothesis that altered metabolic regulation of the CHO pathway allows HA mice to achieve higher rates of CHO during submaximal exercise. The objective of our study was to identify the effects of hypoxia acclimation on the regulation of two key proteins in the CHO pathway and their activation with exercise. Using first generation (G1) laboratory born and raised HA deer mice acclimated to normoxia or chronic hypoxia, we examined the metabolic regulation of muscle glucose uptake by glucose transporter (GLUT) 4 and of pyruvate oxidation by pyruvate dehydrogenase (PDH). The gastrocnemius was electrically stimulated in situ under anaesthesia and acute normoxia at two submaximal workloads relative to maximal force production, which was measured using a force transducer. In frozen gastrocnemius following stimulation or rest, GLUT4 protein content was measured via Western blotting of the sarcolemmal membrane fraction and PDH activity was measured using a radiolabelled assay. We found no differences in sarcolemmal GLUT4 content with stimulation, but PDH activity was increased in hypoxia, indicating increased rates of carbohydrate breakdown at similar workloads after acclimation. These data were compared to data from wild HA deer mice sampled at their native altitude. In support of our hypothesis, these data show that the metabolic regulation of the carbohydrate oxidative pathway changes with acclimation to support higher CHO rates during submaximal exercise. These data will help uncover the mechanistic underpinnings responsible for the exercise fuel use strategies observed exclusively in HA-native mice.