A New Muscle-Brain Axis Underlying the Cognitive Benefits of Physical Activity

描述（由申请人提供）：人类的衰老与认知功能的逐渐下降有关，其后果对受影响的个体是巨大的。任何能够延缓或预防与年龄有关的认知能力下降的科学进步都将对社会的各个层面产生深远的影响，因为人口结构正在发生变化，老年人的比例呈指数级增长，受认知能力下降影响的个人的比例也在呈指数级增长。动物模型的使用大大加快了对影响认知功能和年龄相关变化的因素的研究步伐。能够增强认知功能的最有力的干预措施之一是身体活动。这在从啮齿动物到人类的各种生物中都有体现。尽管这种干预的重要性和效力，运动增强认知活动的机制仍然难以捉摸。在这里，我们提议验证一个具有争议性的假设，即肌肉分泌一些促进神经发生和突触可塑性以维持认知功能的因素，这些因素在运动期间因肌肉活动而增加（“运动因素”）。这一假设牢牢扎根于不断扩大的肌肉研究领域

DESCRIPTION (provided by applicant): Aging in humans is associated with a progressive decline in cognitive function, the consequences of which are enormous for affected individuals. Any scientific advance that could delay or prevent age-related cognitive decline would have a profound impact at every level of society given the demographic changes that are occurring with an exponentially increasing percentage of elderly individuals and the percentage of those individuals who are affected by cognitive decline. The use of animal models has greatly accelerated the pace of research on factors that influence cognitive function and age-related changes. One of the most robust interventions that can enhance cognitive function is physical activity. This has been shown in organisms ranging from rodents to humans. Despite the importance and potency of this intervention, the mechanisms by which exercise enhances cognitive activity remain elusive. Here we propose to test the provocative hypothesis that there are factors secreted by muscle that promote neurogenesis and synaptic plasticity to maintain cognitive function and that these factors are increased by muscle activity during exercise ("exercise factors"). This hypothesis is firmly rooted in the expanding field of research on muscle as a secretory organ, participating in various endocrine networks that function to regulate physiological phenomena such as energy metabolism, angiogenesis, and bone formation. Within the context of regulation of cognitive function, we propose that a "muscle-brain" axis is an evolutionarily conserved endocrine pathway that links two primordial organ systems, with muscle-derived factors promoting maintenance of neuronal homeostasis. We will use both in vitro and in vivo approaches to explore this hypothesis in murine models of neurogenesis, neuronal function, and cognitive activity. Capitalizing on our expertise in plasma proteomics, we will characterize the muscle proteome from control muscle and muscle altered by exercise or aging. Both muscle and brain (hippocampus) will be tested for transcriptional and epigenetic changes induced by exercise, both to explore the mechanisms by which exercise modifies muscular and neuronal function and also to test for any "molecular memory" to explain any persistent effects of exercise on the brain. Direct tests of secretomes will be performed using parabiotic pairings and plasma injections, and candidate testing will include studies of neurogenesis in vitro and muscle-specific gene deletions in vivo. These multifaceted approaches will allow us to characterize the muscle-brain axis, to examine the molecular basis and regulation of that axis with exercise, and to understand the basis for the lasting effects of exercise on neuronal activity, each of which would provide an entirely new framework within which to understand the beneficial effects of physical activity on brain function and together offering a potentially revolutionary approach to the treatment of age-related cognitive decline.