Understanding the Matrix: Regulation of the Human Muscle Extra Cellular Matrix

与衰老相关的肌肉力量下降比尺寸下降更大，导致肌肉质量下降和身体功能减弱。这种肌肉大小和质量的综合下降也与全身代谢障碍有机械联系。目前，最好的干预措施，以提高肌肉的大小和质量是阻力运动训练。不幸的是，抗阻训练的合成代谢效果在老年人中变得迟钝，这使得这种运动形式在增加老年男性和女性的肌肉尺寸方面效果不佳。我的研究项目的长期目标是：1)了解男女中与年龄相关的肌肉大小、功能和质量损失背后的分子机制。2)通过运动和营养干预来维持或改善老年男性和女性肌肉大小、功能和质量的目标确定机制。肌肉纤维被主要由胶原纤维组成的细胞外基质（ECM）以及调节其成分的细胞（如纤维脂肪祖细胞（FAP）细胞）所包围。最近在动物模型上的研究表明，ECM的特性调节了肌肉纤维之间的横向力传递，并可能解释肌肉质量与年龄相关的差异。其他关于动物肌肉损伤和再生的研究表明，ECM特性和FAP细胞功能改变了对合成代谢刺激的反应。这些观察结果表明，在人类中，外基质的特性可能部分解释了肌肉质量和运动适应性反应的年龄相关差异。然而，在人类衰老和抗阻运动模型中，我们对这些机制知之甚少。我的研究计划的短期目标是在考虑可能的性别差异的同时解决这些知识差距。具体而言：1)确定运动后ECM转化的营养调节因子。2)了解人类衰老对ECM组成和调控因子的影响。3)确定老年人阻力运动后收缩蛋白和ECM蛋白周转的性别差异。4)研究高龄如何调节急性阻力运动后ECM的周转。5)确定年龄如何改变慢性阻力运动训练后的ECM特性和调节因子。这些目标将使用我已掌握的重要专业知识的方法来实现；例如基于稳定同位素的蛋白质周转测量，基因和蛋白质丰度测量以及免疫组织化学。为了实现这些目标，我制定了一个计划，招募和培训一个多元化的HQP团队，他们将获得人体运动研究的技能和一些尖端的分子技术。拟议的研究项目将有助于更好地了解年龄、性别、运动和营养如何调节人类肌肉ECM的组成和功能，并且是了解人类肌肉衰老基本机制的长期驱动的一部分。

Aging is associated with a greater decline in muscle strength than in size resulting in a lower muscle quality and diminished physical function. This combined decline in muscle size and quality is also mechanistically linked to impairments in whole body metabolism. Currently, the best available intervention to improve muscle size and quality is resistance exercise training. Unfortunately, the anabolic effects of resistance training are blunted in older adults making this form of exercise less effective at increasing muscle size in older men and women. The long-term goals of my research program are: 1) To understand the molecular mechanisms behind age-related loss of muscle size, function and quality in each sex. 2) Target identified mechanisms with exercise and nutritional interventions to maintain or improve muscle size, function and quality in older men and women. Muscle fibers are surrounded by an extra cellular matrix (ECM) comprised primarily of collagen fibers, along with cells that regulate its composition such as Fibro-Adipogenic Progenitors (FAP) cells. Recent work in animal models has shown that ECM properties regulate how force is transferred laterally between muscle fibers and may explain age related difference in muscle quality. Other studies of, muscle damage and regeneration in animals demonstrate that ECM properties and FAP cell function alter the response to anabolic stimuli. These observations suggest that in humans the properties of the ECM may partially explain age related differences in muscle quality and the adaptive response to exercise. However, little is known about these mechanisms in human models of aging and resistance exercise. The short-term goals of my research proposals will address these knowledge gaps while considering possible sex differences. Specifically: 1) Determine the nutritional regulators of ECM turnover following exercise. 2) Understand the effect of human aging on ECM composition and regulators. 3) Identify sex differences in the turnover of contractile and ECM proteins following resistance exercise in older adults. 4) Examine how advanced age regulates the turnover of the ECM following acute resistance exercise. 5) Determine how aging alters ECM properties and regulators following chronic resistance exercise training. These goals will be accomplished using methods in which I have developed significant expertise; such as stable isotope-based measures of protein turnover, measures of gene and protein abundance, and immunohistochemistry. In order to meet these goals, I have developed a plan to recruit and train a diverse team of HQP who will gain skills in human exercise research and a number of cutting-edge molecular techniques. The proposed program of research will lead to a better understanding of how age, sex, exercise and nutrition regulate the composition and function of the human muscle ECM and is part of a longer-term drive to understand the fundamental mechanism of human muscle aging.