Evolution and Plasticity of Muscle Metabolism

尽管适当的燃料底物分配对于有效的运动、产热和全身代谢稳态很重要，但肌肉代谢的进化方面尚未得到广泛研究。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。我的研究项目的长期目标是了解燃料输送和利用途径是如何进化的，并对能量和环境压力做出反应，以支持该组织中所见的动态能量变化。生活在高海拔地区的动物是研究肌肉代谢对已知低氧和低温度应激源的进化和可塑性的理想模型。因此，我们使用在普通条件下从低海拔（LA）和高海拔（HA）种群中分离的亲本种群中繁殖的鹿鼠（Peromyscus maniculatus）。这使我们能够将基因固定的特征与环境诱导的可塑性特征区分开来。先前，我们发现高海拔鹿小鼠(i)在更大程度上依赖碳水化合物氧化来进行力量运动，部分原因是与低海拔小鼠相比，高海拔鹿小鼠进化了对缺氧的表型可塑性。（ii）鹿小鼠以高脂肪酸氧化率（FAO）支持产热，HA和LA小鼠的脂肪酸氧化率更高，并表现出强大的表型可塑性。（ii）早期生活事件可以影响生存和成年表型，我们发现鹿小鼠的恒温发育方式以及出生后寒冷或低温缺氧如何影响成年产热能力的种群差异。在未来的5年里，我将确定3个目标：1。在HA运动燃料使用的进化差异的潜在机制，2。HA产热过程中FAO的调控。和3。出生后环境对成人代谢和产热能力影响的机制。我将使用我们的低海拔和高海拔鹿小鼠来解决这些问题，并使用暴露于慢性缺氧或低温缺氧来揭示次要特征可塑性的进化差异，这些差异有助于解释运动或产热表现的适应性差异。通过繁殖至第二代，我们将研究母性照料和环境对高原鹿小鼠恒温动物个体发育和产热能力发育可塑性的影响。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4名博士。

The evolutionary aspects of muscle metabolism have not been extensively studied, despite the importance of appropriate fuel substrate allocation for effective locomotion, thermogenesis, and whole-body 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 objective of my research program is to understand how fuel delivery and utilization pathways evolve and respond to energetic and environmental stress to support the dynamic energetic changes seen in this tissue. Animals who live in the high altitude (HA) are ideal models to study the evolution and plasticity of muscle metabolism to the known stressors of low oxygen and temperature. Thus, we use deer mice (Peromyscus maniculatus) bred in common conditions from separate parental stocks from populations at low altitude (LA) and HA . This allows us to distinguish genetically fixed traits from those that undergo environmental induced plasticity. Previously, we have found that high altitude deer mice (i) rely to a greater extent in carbohydrate oxidation to power exercise, in part due to evolved phenotypic plasticity to hypoxia compared to low altitude mice. (ii) Deer mice support thermogenesis with high rates of fatty acid oxidation (FAO), which is higher in HA and LA mice and shows robust phenotypic plasticity. and  (ii) Early life events can impact survival and adult phenotypes, and we uncovered population differences in how endothermy develops in deer mice but also in how postnatal cold or cold & hypoxia impact adult thermogenic capacity. In the next 5 years I will address 3 objectives to determine: 1. The underlying mechanisms of evolved differences in exercise fuel use at HA, 2. The regulation of FAO during thermogenesis at HA. and 3. The mechanisms responsible for postnatal environment impacts on adult metabolism and thermogenic capacity. I will address these objectives using our low and high altitude deer mice, and use exposures to chronic hypoxia or cold & hypoxia to uncover evolved differences in plasticity of subordinate traits that help explain adaptive differences in locomotory or thermogenic performance. Through breeding mice to the second generation we will study maternal care and environmental effects on the ontogeny of endothermy and the developmental plasticity of thermogenic capacity in high altitude deer mice. 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 4 Ph.D. students.