Regulation of muscle pyruvate dehydrogenase activity and fuel use during exercise in high-altitude deer mice.

Adult, lab-reared, highland deer mice acclimate to hypoxia by increasing reliance on carbohydrates to fuel exercise. Yet neither the underlying mechanisms for this shift in fuel use nor the impact of lifetime hypoxia exposure experienced in high alpine conditions, are fully understood. Thus, we assessed the use of fuel during exercise in wild highland deer mice running in their native environment. We examined a key step in muscle carbohydrate oxidation - the regulation of pyruvate dehydrogenase (PDH) - during exercise at altitude in wild highlanders and in first generation (G1) lab-born and -raised highlanders acclimated to normoxia or hypoxia. PDH activity was also determined in the gastrocnemius of G1 highlanders using an in situ muscle preparation. We found that wild highlanders had a high reliance on carbohydrates while running in their native environment, consistent with data from hypoxia-acclimated G1 highlanders. PDH activity in the gastrocnemius was similar post exercise between G1 and wild highlanders. However, when the gastrocnemius was stimulated at a light work rate in situ, PDH activity was higher in hypoxia-acclimated G1 highlanders and was associated with lower intramuscular lactate levels. These findings were supported by lower PDH kinase 2 protein production in hypoxia-acclimated G1 mice. Our findings indicate that adult phenotypic plasticity in response to low oxygen is sufficient to increase carbohydrate reliance during exercise in highland deer mice. Additionally, variation in PDH regulation with hypoxia acclimation contributes to shifts in whole-animal patterns of fuel use and is likely to improve exercise performance via elevated energy yield per mole of O2. .

Metabolic recovery from submaximal exercise in hypoxia acclimated high altitude deer mice (Peromyscus maniculatus).

Animals living at high-altitude are faced with unremitting low oxygen availability. This can make it difficult to perform daily tasks that require increases in aerobic metabolism. An activity important for survival is aerobic locomotion, and the rapid recovery of muscle metabolism post exercise. Past work shows that hypoxia acclimated high-altitude mice (Peromyscus maniculatus) have a greater reliance on carbohydrates to power exercise than low altitude mice. However, it is unclear how quickly after aerobic exercise these mice can recovery and replenish muscle glycogen stores. The gastrocnemius muscle of high-altitude deer mice has a more aerobic phenotype and a greater capacity to oxidize lipids than low altitude deer mice. This suggests that high altitude mice may recover more rapidly from exercise than their lowland counterparts due to a greater capacity to support glycogen replenishment using intramuscular triglycerides (IMTG). To explore this possibility, we used low- and high-altitude native deer mice born and raised in common lab conditions and acclimated to chronic hypoxia. We determined changes in oxygen consumption following 15 min of aerobic exercise in 12% O2 and sampled skeletal muscles and liver at various time points during recovery to examine changes in key metabolites, including glycogen and IMTG. We found depletion in glycogen stores during exercise only in lowlanders, which returned to resting levels following 90 min of recovery. In contrast, IMTG did not change significantly with exercise or during recovery in either population. These data suggest that exercise recovery is influenced by altitude ancestry in deer mice.