Mechanisms of activity-dependent muscle growth and repair

肌肉质量影响着我们的一生。它是骨骼强度、运动表现、职业选择、肥胖和糖尿病倾向以及老年人肌肉衰弱的主要预测指标，这通常会导致身体依赖。我们知道，由于怀孕期间影响母亲和孩子的遗传、表观遗传和环境因素，人们在出生时的肌肉量有所不同。虽然肌肉在出生后会迅速增长，但出生时的肌肉量和以后的生活有很强的相关性。肌肉是由早期胚胎中形成的几种干细胞形成的，但在产前生活中肌肉质量是如何决定的尚不清楚。这个建议的目的是通过理解基本的细胞和分子生物学过程来发现在一个简单的系统中控制肌肉组织的大小。骨骼肌接近人体质量的30-40%，这取决于性别和年龄。除了出生时的禀赋外，儿童和青少年时期的体育活动被认为会影响成年后的肌肉质量、收缩特性以及肌肉和脂肪之间的平衡，这是健康寿命的主要预测指标。肌肉/脂肪比与2型糖尿病、冠心病、中风、结肠癌、乳腺癌和其他癌症、骨关节炎、与年龄相关的肌肉萎缩，当然还有肥胖的发病率呈负相关。尽管对这些相关性的因果关系存在争议，但有一个共识，即更“运动”的体格（即更高的肌肉/脂肪比）可能会改善很大一部分人口的健康和前景，从而为整个社会带来经济和生活质量的好处。很明显，“环境”影响，如运动和食物消耗，相互作用来控制肌肉质量，但它们对早期生活中形成的组织起作用。新出现的证据表明，锻炼对全身代谢有长期影响，这不仅是因为锻炼对肌肉本身的直接影响，还因为锻炼后的肌肉释放出控制脂肪、心脏和其他组织生长的信号。因此，有必要了解肌肉质量是如何被控制的，并受到体育活动的影响。我们最近的研究结果表明，非常早期的肌肉组织需要身体活动才能正常生长，并且在一定范围内，具有调节其质量的非凡能力。我们还开发了观察肌肉形成和生长的方法，这些方法来自活体组织中几种不同的干细胞群。本研究旨在：1)了解运动控制肌肉生长的分子机制。这项研究旨在从根本上了解肌肉的发育，同时也将为老年人、运动员和一般健康人士通过训练增强肌肉的机制提供线索。通过了解活动及其产生的力量是如何调节肌肉生长的，这项工作将揭示力量是如何更普遍地控制细胞行为的。2)发现肌肉组织如何平衡干细胞的增殖和分化，以控制正确数量肌肉纤维的形成。通过了解肌肉是如何形成的，这些研究将揭示我们的基因和早期生活经历如何相互作用，以产生肌肉的“起点”，这与晚年的沧桑一起，控制着总体健康和与年龄有关的疾病的发病。3)研究肌肉组织如何在生命早期对损伤做出反应，并再生适量的肌肉。由于肌肉再生对运动员很重要，但在许多肌肉疾病的晚期和老年人中会失败，因此这项工作可能会影响临床实践，为如何最好地触发适当的肌肉再生提供见解。

Muscle mass affects us throughout our lives. It is a major predictor of bone strength, sporting performance, career choice, propensity to obesity and diabetes and the development of debilitating muscle weakening in the elderly, which often leads to physical dependency. We know that people differ in muscle mass at birth due to genetic, epigenetic and environmental factors that impinge on mother and child during pregnancy. Although muscle grows hugely after birth, there is a strong correlation between muscle mass at birth and in later life. Muscle is made from several kinds of stem cells formed in the early embryo, yet how muscle mass is determined during prenatal life is unclear. This proposal aims to find out by understanding the fundamental cell and molecular biological processes that control the size of muscle tissue in a simple system. Skeletal muscle approaches 30-40% of human body mass, depending on sex and age. In addition to one's endowment at birth, physical activity during childhood and adolescence is thought to influence adult muscle mass, contractile properties and the balance between muscle and fat, which is a major predictor of healthspan. Measures of muscle/fat ratio correlate negatively with incidence of type 2 diabetes, coronary heart disease, stroke, colon, breast and other cancers, osteoarthritis, age-related muscle wasting and, of course, obesity. Although cause and effect are debated in these correlations, there is a consensus that a more 'athletic' physique (i.e. higher muscle/fat ratio) is likely to improve the health and outlook for a significant fraction of the population, with consequent economic and quality of life benefits for society as a whole. It is clear that 'environmental' effects, like exercise and food consumption, interact to control muscle mass, but they work on the tissue formed during earlier life. Emerging evidence indicates that exercise has long-term influences on whole body metabolism not just due to direct training effects on muscle itself, but also because exercised muscle releases signals that control growth of fat, heart and other tissues. There is thus a need to understand how muscle mass is controlled and is affected by physical activity. Our recent findings show that very early muscle tissue requires physical activity for normal growth and, within limits, has a remarkable ability to regulate its mass. We have also developed methods of watching the formation and growth of muscle from several distinct populations of stem cells in the living tissue. This proposal aims: 1) To understand the molecular mechanism(s) by which physical activity controls muscle growth. This study, while aimed at fundamental insight into development, will provide clues to the mechanisms by which training builds muscle in the elderly, athletes and for general health. By understanding how activity and the force it produces regulate muscle growth, the work will shed light on how force controls cell behaviour more generally.2) To discover how muscle tissue balances proliferation and differentiation of stem cells to control formation of the correct number of muscle fibres. By providing understanding of how muscle is built, these studies will reveal how our genes and early life experience interact to generate the muscular 'starting point', which, together with the vicissitudes of later life, controls general health and the onset of age-related diseases.3) To study how muscle tissue reacts to damage in early life and regenerates the correct amount of muscle. As muscle regeneration is important in athletes and fails in the late stages of many muscle diseases and in the elderly, this work may influence clinical practice by providing insight on how best to trigger appropriate muscle regeneration.