Integrated mechanistic models for the study of skeletal muscle protein turnover

骨骼肌在帮助我们四处走动方面有着明显的作用。然而，骨骼肌的一个被低估的方面是，它是一个非常代谢活跃的组织，是我们基础代谢率的重要贡献者，也是我们进食后血糖的最大消耗者。因此，保持相对较大且代谢活跃的肌肉量在降低我们患慢性疾病的风险方面非常具有保护性，例如超重/肥胖，II型糖尿病以及随着年龄的增长肌肉的简单损失。成年期的肌肉生长被称为肥大，当肌肉因不得不移动沉重的外部负荷而受到压力时就会发生。最简单的实际例子是举重运动员，通过定期举起重物，我们可以观察到他们肌肉的肌肉尺寸增加。有趣的是，这在很大程度上是由于在预先存在的肌肉细胞中净增加了新的蛋白质;这是因为肌肉细胞不能分裂，因此它们必须在现有的细胞大小内积累蛋白质才能生长。因此，当制造新肌肉蛋白质的速率-肌肉蛋白质合成（MPS）-升高时，新肌肉蛋白质的净增加发生。我们知道营养素（特别是蛋白质）和举重都是MPS的有力刺激因素。然而，仅仅刺激MPS是不够的，因为肌肉内的蛋白质也不断被分解以维持有效的蛋白质功能。因此，当MPS的速率超过肌肉蛋白质分解的速率时，肌肉生长发生。在本提案中，将进行实验，以帮助了解增加肌肉大小或减缓/防止肌肉蛋白质损失的过程。我们将在培养皿中培养的细胞中使用运动和蛋白质以及蛋白质的活性成分氨基酸作为MPS的有效刺激剂。然而，为了获得一个综合的观点，我们还将用人体实验来补充细胞实验，以确定我们在细胞中看到的过程是否以类似的方式运作。我们的研究结果对于理解我们如何减缓例如衰老中的肌肉损失具有重大意义。

Skeletal muscle has an obvious role in helping us get around. However, an underappreciated aspect of skeletal muscle is that it is a very metabolically active tissue, is a large contributor to our basal metabolic rate, and is the biggest consumer of blood sugar after we have eaten. As such, maintaining a relatively large and metabolically active amount of muscle is very protective in terms of lowering our risk for development of chronic diseases such as overweight/obesity, type II diabetes, and the simple loss of muscle as we age. Muscle growth in adulthood is known as hypertrophy and occurs when muscles are stressed by having to move heavy external loads. The easiest practical example of this is a weightlifter in who, through regularly lifting heavy loads, we can observe an increase in muscle size of their muscles. Interestingly, this occurs for a large part due to the net addition of new proteins within pre-existing muscle cells; this because muscle cells cannot divide and thus they must accrue protein within their existing cellular size to grow. A net accretion of new muscle proteins occurs therefore when the rate of making new muscle proteins - muscle protein synthesis (MPS) - is elevated. We know that nutrients, in particular protein, and weightlifting are both potent stimulators of MPS. However, stimulation of MPS alone is not enough since proteins within muscles are also continually broken down to maintain efficiently functioning proteins. Thus, muscle growth occurs when the rate of MPS exceeds the rate of muscle protein breakdown. In this proposal experiments will be conducted to help understand what processes are involved in increasing muscle size or, viewed alternatively, in slowing/preventing muscle protein loss. We will use, as potent stimulators of MPS, exercise and protein as well as the active components of protein, amino acids in cells grown in petri dishes. To obtain an integrated view we will also, however, compliment the experiments in cells with experiments in humans to ascertain whether the processes we see in cells are operating in a similar fashion. Our findings have substantial implications for understanding how we might slow muscle loss in, for example, aging.