Evolution and Plasticity of Muscle Metabolism

肌肉代谢的进化方面还没有得到广泛的研究，尽管适当分配燃料对于有效的运动、寒颤产热和维持代谢稳态很重要。肌肉燃料使用能力的物种差异，以及对环境应激的反应，是生理时间尺度上基因型和肌肉表型可塑性（发育可塑性和成体可塑性）之间相互作用的结果。我的研究计划的长期目标是了解肌肉代谢的遗传适应和可塑性如何有助于燃料使用模式，从而支持该组织中所见的动态能量变化。我们已经开发了一个模型，在这个模型中，在有氧范围（运动中可用的氧气）下的运动可以预测各种物种的燃料使用。最近，我们已经证明，高海拔野生小鼠偏离了这种燃料使用模式，在运动过程中使用更大比例的碳水化合物氧化作为节省o2的策略。目前尚不清楚的是：1)是什么潜在机制导致了低海拔哺乳动物的常见燃料使用模式；2)是什么调节变化使高海拔天然燃料的使用偏离了其他哺乳动物。*动物的表型可塑性与环境变异的空间“颗粒”有关，使动物的生理性状与当地条件相匹配。这种可塑性通常是对自然环境中多种影响的反应。然而，大多数研究都集中在单一的环境应激源上，没有考虑到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。了解燃料使用模式作为有氧能力函数的机制。2. 了解发育和生理可塑性如何影响HA原生小鼠的运动燃料使用。3. 揭示多重压力源如何塑造肌肉表型以及进化史如何影响这些反应。*我将使用两种强大的动物系统来实现这些目标：*1)人工选择的自愿跑步小鼠具有更高的有氧能力、运动耐力和运动脂肪氧化率。使用两种不同的HR小鼠系，我们之前已经展示了肌肉脂肪酸摄取能力的差异，我们将确定脂肪组织脂肪释放能力和肌肉氧化率是否反映了观察到的肌肉表型差异。这些数据将帮助我们理解，在相同的选择标准下，选择是如何通过不同的机制来提高燃料使用率的。我们还将探讨，当HR小鼠被喂食高脂肪和高糖饮食时，脂肪酸可用性或肌肉组织能力的增加是否可以解释观察到的自愿跑步增加。*2)北美高、低海拔原居群的鹿鼠及其f1代后代。该模型系统为我们确定基因型和表型可塑性对运动和产热性能差异的相对贡献提供了前所未有的能力。我们将探索在高海拔小鼠中发生的肌肉调节变化，这些变化增加了对CHO的依赖。我们将概括原生环境，并使F1小鼠适应寒冷和缺氧，以探索海拔祖先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多种不同的生理“解决方案”，使物种能够维持高的燃料输送率，或者为肌肉提供最佳的燃料分配，以便在低氧或低温度环境中生存。本研究将培养10名学士、5名硕士和3名博士。

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.