Plasticity and evolution of muscle metabolism

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Understanding the regulation of muscle metabolism is valuable due to the wide diversity amongst species in ability to exercise & in adjusting their muscles to function when subjected to environmental & energetic changes (stress). I study the ability to regulate fat (FAO) & carbohydrate oxidation (CHO) as an important mechanism to conserve muscle function. My group will address several questions regarding muscle metabolism: 1) What are the key regulators that determine FAO & CHO between tissues, species & in response to stress? 2) What regulates the interaction between aerobic & anaerobic metabolism in muscles with hypoxia? 3) How do animals deal with multiple stressors (cold & hypoxia)? & 4) What are true metabolic adaptations to hypoxia at altitude? Mainly we will concentrate on 2 steps in metabolism that determine the ability of mitochondria to oxidize fat (carnitine palmitoyltransferase, CPTI) or carbohydrates (pyruvate dehydrogenase, PDH). Using trout will allow us to capitalize on the fact that fish have separate fast (white) & slow (red) muscle masses & may have multiple forms of important proteins involved in FAO. We will examine populations of mitochondria specializing in FAO & examine the expression & function of proteins that regulate FAO. In mice we aim to define exercise fuel use in normal & low oxygen conditions. We will also explore decades-old observations that CHO is preferred & blood lactate levels are lower in chronic low oxygen. This may involve a pathway shown in cancer cells to regulate aerobic & anaerobic metabolism in low oxygen. Finally, we are working with a group of mouse species in Peru that live at different altitudes & therefore experience low oxygen for generations. This will give us the opportunity to define a true adaptation to low oxygen at the level of muscle metabolism. We will provide unique insight into vertebrate muscle remodeling from alternate models demonstrating conserved & divergent methods of regulating FAO & CHO. Genetically-based physiological mechanisms used by animals to live in low oxygen environments represent biological solutions applicable to human disease.