Evolution and Plasticity of Muscle Metabolism

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The evolutionary aspects of muscle metabolism have not been extensively studied, despite the importance appropriate allocation of fuels for effective locomotion, shivering thermogenesis, and maintenance of metabolic homeostasis. Species variation in muscle capacity for fuel use, and the response to environmental stress, results from interactions between genotype and the plasticity of muscle phenotype occurring at physiological time scales (developmental and adult plasticity). The long-term goal of my research program is to understand how genetic adaptation and plasticity of muscle metabolism contributes to patterns of fuel use that support the dynamic energetic changes seen in this tissue. We have developed a model where exercise at % aerobic scope (oxygen available for exercise) predicts fuel use across a wide range of species. Recently, we have shown that wild mice native to high altitude deviate from this fuel use model and use a greater proportion of carbohydrate oxidation as an O2-saving strategy during locomotion. It is unknown 1) what underlying mechanisms are responsible for the common fuel use patterns in low altitude mammals, nor 2) what regulatory changes allow high altitude native fuel use to deviate from other mammals. Phenotypic plasticity in animals is related to the spatial "grain" of environmental variation, allowing animals to match physiological traits with local conditions. This plasticity is often in response to multiple influences in natural environments. However, most studies focus on single environmental stressors and do not take into account the affect of evolutionary history on the acclimation response. Over the next 5 years I will explore 3 objectives: 1. To understand the mechanisms explaining patterns of fuel use as a function of aerobic capacity. 2. To understand how developmental and physiological plasticity affect exercise fuel use in HA native mice. 3. To uncover how multiple stressors shape muscle phenotypes and how evolutionary history influences these responses.I will use two powerful animal systems to address these objectives: 1) Mice artificially selected for voluntary running that have higher aerobic capacities, exercise endurance, and rates of exercise fat oxidation than control lines. Using two different HR mice lines we have previously shown to differ in capacity for muscle fatty acid uptake, we will determine if capacity for adipose tissue fatty release and rates of muscle oxidation reflect observed differences in muscle phenotype. These data will help us understand how selection is able to increase rates of fuel use by distinct mechanisms in response to the same selection criteria. We will also explore if increased fatty acid availability or capacity for muscle FAO explain observed increases in voluntary running when HR mice are fed a diet high in fat and sugar.2) North American deer mice from populations native to high and low altitude and their F1-generation descendants. This model system gives us the unprecedented ability to determine the relative contributions of genotype and phenotypic plasticity to differences in exercise and thermogenic performance. We will explore what muscle regulatory changes occur in high altitude mice that increase reliance on CHO for exercise. We will recapitulate native environments and acclimate F1 mice to combined cold and hypoxia to explore the effect of altitude ancestry on muscle plasticity. Unlike traditional rodent models, resulting data may uncover multiple different physiological "solutions" allowing species to either sustain high rates of fuel delivery, or to provide the optimal allocation of fuel to muscle for survive in low O2 or temperature environments. This research will train 10 B.Sc, 5 M.Sc. and 3 Ph.D. students.