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

衰老与肌肉力量的下降比肌肉大小的下降更大，从而导致肌肉质量下降和身体功能减弱。肌肉大小和质量的综合下降也与全身新陈代谢的损害有机械上的联系。目前，改善肌肉大小和质量的最佳干预措施是阻力运动训练。不幸的是，阻力训练的合成代谢作用在老年人身上变得迟钝，使得这种形式的运动在增加老年男性和女性肌肉尺寸方面效果不佳。我的研究计划的长期目标是：1)了解男女肌肉大小、功能和质量随年龄增长而丧失的分子机制。2)通过运动和营养干预确定机制，以维持或改善老年男性和女性的肌肉大小、功能和质量。肌肉纤维周围有一层细胞外基质(ECM)，主要由胶原纤维组成，还有调节其组成的细胞，如纤维脂肪前体细胞(FAP细胞)。最近在动物模型中的研究表明，细胞外基质的特性调节力在肌肉纤维之间横向传递的方式，并可能解释与年龄相关的肌肉质量差异。其他对动物肌肉损伤和再生的研究表明，细胞外基质特性和FAP细胞功能改变了对合成代谢刺激的反应。这些观察表明，在人类中，ECM的特性可能部分解释了与年龄相关的肌肉质量差异和对运动的适应性反应。然而，对人体衰老和抵抗运动模型中的这些机制知之甚少。我的研究提案的短期目标将解决这些知识差距，同时考虑可能的性别差异。具体地说：1)确定运动后ECM周转的营养调节因素。2)了解人类衰老对细胞外基质成分和调节因子的影响。3)确定老年人阻力运动后收缩蛋白和细胞外基质蛋白周转的性别差异。4)研究高龄对急性抵抗运动后细胞外基质周转的调节作用。5)确定在慢性耐力运动训练后，衰老如何改变ECM的性质和调节因子。这些目标将使用我发展出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，基因和蛋白质丰度的测量，以及免疫组织化学。为了实现这些目标，我制定了一项计划，招募和培训一支多元化的HQP团队，他们将获得人类运动研究和一些尖端分子技术方面的技能。拟议的研究计划将有助于更好地理解年龄、性别、运动和营养如何调节人类肌肉ECM的组成和功能，并是理解人类肌肉衰老基本机制的长期努力的一部分。

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.