Evolution and Plasticity of Muscle Metabolism

肌肉新陈代谢的进化方面还没有得到广泛的研究，尽管燃料的适当分配对于有效的运动、颤抖的产热和维持代谢平衡非常重要。肌肉燃料使用能力和对环境压力的反应的物种差异，是由于在生理时间尺度上发生的肌肉表型的可塑性(发育和成体可塑性)与基因之间的相互作用所致。我的研究计划的长期目标是了解肌肉新陈代谢的遗传适应和可塑性如何有助于燃料使用模式，以支持在该组织中看到的动态能量变化。我们已经开发了一个模型，在这个模型中，有氧范围内的运动(可用于运动的氧气)预测了各种物种的燃料使用量。最近，我们发现生活在高海拔地区的野生小鼠背离了这种燃料使用模式，并在运动过程中使用更大比例的碳水化合物氧化作为一种节省氧气的策略。目前尚不清楚1)是什么潜在机制导致了低海拔哺乳动物的共同燃料使用模式，2)是什么监管变化允许高海拔本地燃料使用偏离其他哺乳动物。 动物的表型可塑性与环境变化的空间“谷粒”有关，允许动物将生理特征与当地条件相匹配。这种可塑性通常是对自然环境中多种影响的反应。然而，大多数研究侧重于单一的环境应激源，而没有考虑进化史对适应反应的影响。在接下来的5年里，我将探索3个目标：1.理解作为有氧能力函数的燃料使用模式的解释机制。2.了解发育可塑性和生理可塑性对HA小鼠运动燃料使用的影响。3.揭示多重应激源如何塑造肌肉表型，以及进化史如何影响这些反应。 我将使用两个强大的动物系统来解决这些目标： 1)人工选择自愿跑步的小鼠，其有氧能力、运动耐力和运动脂肪氧化率高于对照品系。使用两个不同的HR小鼠品系，我们之前已经证明了肌肉摄取脂肪酸的能力不同，我们将确定脂肪组织脂肪释放能力和肌肉氧化速率是否反映了观察到的肌肉表型的差异。这些数据将帮助我们理解选择如何能够根据相同的选择标准，通过不同的机制增加燃料使用率。我们还将探索粮农组织是否可以解释当给HR小鼠喂食高脂肪和高糖的饮食时，自愿跑步的增加是否可以解释脂肪酸供应或肌肉能力的增加。 2)原产于高、低海拔地区的北美鹿鼠及其F1代后代。这个模型系统给了我们前所未有的能力来确定基因和表型可塑性对运动和产热性能差异的相对贡献。我们将探索在高原小鼠中发生了哪些肌肉调节变化，从而增加了对CHO运动的依赖。我们将总结自然环境，并使F1小鼠适应寒冷和低氧的组合，以探讨海拔血统对肌肉可塑性的影响。与传统的啮齿动物模型不同，由此产生的数据可能会揭示出多种不同的生理“解决方案”，使物种要么维持高速率的燃料输送，要么为肌肉提供最佳的燃料分配，以便在低氧气或温度环境中生存。本研究将培养10名理科学士、5名理科硕士。和3名博士生。

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.