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起着明显的作用。然而，骨骼肌的一个未被充分认识的方面是，它是一种非常活跃的代谢组织，对我们的基础代谢率有很大贡献，而且是我们吃饭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对于降低我们患慢性疾病（如超重/肥胖、II型糖尿病）的风险，以及随着年龄的增长而出现的简单肌肉损失，是非常有保护作用的。成年期的肌肉增长被称为肥厚，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，通过经常举起重物，我们可以观察到他们肌肉的大小增加。有趣的是，这在很大程度上是由于原有肌肉细胞中新蛋白质的净增加；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就会发生。我们知道营养物质，尤其是蛋白质和举重都是MPS的有力刺激物。然而，仅仅刺激MPS是不够的，因为肌肉中的蛋白质也不断被分解以维持蛋白质的有效功能。因此，当MPS的速率超过肌肉蛋白质分解的速率时，肌肉就会生长。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氨基酸，作为MPS的有效刺激物，运动和蛋白质以及蛋白质的活性成分。然而，为了获得一个综合的观点，我们也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。我们的发现对于理解我们如何减缓肌肉损失，例如衰老，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.