Muscle Activity and Growth: from Developmental Genetics to the Human Population

肌肉质量会影响我们的一生。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因素，肌肉衰弱往往导致身体依赖。我们知道，由于遗传、表观遗传和环境因素，人们在出生时的肌肉质量不同，这些因素会在怀孕期间影响母亲和孩子。虽然肌肉在出生后会长得很大，但出生时的肌肉质量与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组成的，但在产前生活中肌肉质量是如何确定的尚不清楚。该提案旨在通过了解在一个简单的系统中控制肌肉组织大小的基本细胞和分子生物学过程来找出答案。骨骼肌接近人体质量的30-40%，取决于性别和年龄。除了一个人出生时的禀赋之外，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因素。肌肉/脂肪比的测量与2型糖尿病、冠心病、中风、结肠癌、乳腺癌和其他癌症、脂肪肝、骨关节炎、年龄相关的肌肉萎缩以及肥胖的发病率呈负相关。尽管这些相关性的因果关系还在争论中，但有一个共识是，（即更高的肌肉/脂肪比例）可能会改善相当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方面的好处。很明显，“环境”效应，如运动和食物消费，有助于控制肌肉质量，但它们作用于生命早期形成的组织。新出现的证据表明，运动对全身新陈代谢有长期影响，这不仅是因为运动对肌肉本身的直接影响，还因为运动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控制和影响的身体活动，饮食等，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的正常增长，在白天和黑夜不同的增长，是受营养的影响，并在一定范围内，有一个显着的能力来调节其质量。我们还开发了观察活体动物中几种不同干细胞群体肌肉形成和生长的方法。本提案旨在：1）了解身体活动控制肌肉生长的分子机制。我们的研究，虽然旨在对发展的基本见解，也将揭示训练在老年人，运动员和一般健康中建立肌肉的机制。通过了解收缩如何调节肌肉生长，这项工作将揭示力如何更普遍地控制细胞行为。2）发现单个肌肉细胞如何形成和生长。肌肉组织平衡干细胞的增殖和分化，以控制正确数量的肌纤维的形成及其随后的生长。通过提供对肌肉是如何构建的理解，我们的研究将揭示基因和早期生活经验如何相互作用以产生肌肉的“起点”，这与晚年生活的变迁一起控制着一般健康和与年龄相关的疾病的发生。轮班工作和饮食习惯通过遗传倾向来控制肌肉生长。4）通过使用英国生物库来阐明驱动与衰老相关的肌肉衰弱的因素，将我们对简单系统中基因/环境相互作用的日益理解应用于英国人群。我们的长期目标是个性化的生活方式建议。

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, fatty-liver disease, 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, help 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 affected by physical activity, diet etc. Our recent findings show that very early muscle tissue requires physical activity for normal growth, grows differently in day and night, is influenced by nutrition 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 animal. This proposal aims:1) To understand the molecular mechanism(s) by which physical activity controls muscle growth. Our study, while aimed at fundamental insight into development, will also reveal mechanisms by which training builds muscle in the elderly, athletes and for general health. By understanding how contraction regulates muscle growth, the work will shed light on how force controls cell behaviour more generally.2) To discover how individual muscle cells are formed and grow. Muscle tissue balances proliferation and differentiation of stem cells to control formation of the correct number of muscle fibres and their subsequent growth. By providing understanding of how muscle is built, our studies will reveal how 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, in a simple model system, how lifestyle choices like exercise, shift-work and eating habits are integrated by genetic predisposition(s) to control muscle growth.4) To apply our growing understanding of the gene/environment interaction in simple systems to the UK population by using the UK Biobank to elucidate factors driving ageing-related muscle weakening. Our long-term aim is personalised lifestyle advice.