Muscle-Specific Nutritional Adaptations to Catabolic States

描述（由申请人提供）：肌肉质量的维持需要细胞反应的复杂交响乐。在肌肉萎缩期间，激素和细胞因子的不平衡改变了调节信号通路（例如，PI 3 K/Akt）通过增加泛素-蛋白酶体系统和半胱天冬酶-3的活性而朝向蛋白质降解。这些蛋白水解反应是骨骼肌独有的，尽管所有组织都暴露于相同的全身信号。这种萎缩程序，如果不减弱，可能会导致有害的肌肉蛋白质损失。已经提出两种肌肉特异性E3泛素连接酶atrogin-1和MuRF 1的诱导是萎缩反应的关键部分。FOXO转录因子似乎通过增加这些E3和可能的其他蛋白水解酶（例如，caspase-3）。目的1将研究FOXO如何影响肌肉细胞中的蛋白质合成和降解。目标2中的研究将确定较高的atrogin-1水平是否会增加钙调神经磷酸酶（CaN）的降解，钙调神经磷酸酶是肌肉细胞中的一种关键磷酸酶。我们提出，CaN的减少可能提供了一种机制，通过去除一种可以激活（即，使促凋亡蛋白BAD去磷酸化;活性BAD增加半胱天冬酶-3活性（Aim 4）。CaN的减少可以防止caspase-3活性变得过度，而不影响其他蛋白水解反应。目的3将证明BAD受多种信号通路调节，并且是肌肉中caspase-3活性的关键决定因素。我们还提出，β 2-肾上腺素能激动剂的肌肉保护作用部分是由于BAD磷酸化的PKA依赖性增加和随后caspase-3活性的降低（目的5）。总之，我们认为FOXO和BAD是关键的信号传导蛋白，不同的生理刺激分别通过泛素-蛋白酶体系统和胱天蛋白酶-3调节蛋白质消耗。我们的研究将提供证据表明，这两个蛋白水解系统可以独立地发挥作用，并作为一个集成的途径，允许密切调节肌肉质量，以响应生理条件。关于肌肉萎缩机制的新信息可能会确定治疗靶点，以降低慢性病患者的发病率和死亡率，并改善他们的生活质量。

DESCRIPTION (provided by applicant): The maintenance of muscle mass requires a complex symphony of cellular responses. During muscle atrophy, an imbalance of hormones and cytokines shifts regulatory signaling pathways (e.g., PI3K/Akt) towards protein degradation by increasing the activities of the ubiquitin-proteasome system and caspase-3. These proteolytic responses are unique to skeletal muscle, despite the fact that all tissues are exposed to the same systemic signals. This atrophy program, if unabated, could result in a deleterious loss of muscle proteins. Induction of two muscle -specific E3 ubiquitin ligases, atrogin-1 and MuRF1, has been proposed to be a key part of the atrophy response. The FOXO transcription factors appear to play a key role in the shift towards protein degradation by increasing the transcription of these E3s and possible other proteolytic enzymes (e.g., caspase-3). Aim 1 will examine how the FOXOs affect protein sythesis and degradation in muscle cells. Studies in Aim 2 will determine if higher atrogin-1 levels increase the degradation of calcineurin (CaN), a key phosphatase in muscle cells. We propose that the decrease in CaN may provide a mechanism to moderate the severity of wasting by removing an enzyme that can activate (i.e., dephosphorylate) the proapoptotic protein BAD; active BAD increases caspase-3 activity (Aim 4). The decrease in CaN could prevent caspase-3 activity from becoming excessive without affecting other proteolytic responses. Aim 3 will demonstrate that BAD is regulated by multiple signaling pathways and is a critical determinant of caspase-3 activity in muscle. We also propose that the muscle-sparing effects of b2- adrenergic agonists result, in part, from a PKA-dependent increase in BAD phosphorylation and a subsequent reduction in caspase-3 activity (Aim 5). In summary, we believe that FOXO and BAD are key signaling proteins through which diverse physiologic stimuli regulate protein attrition via the ubiquitin- proteasome system and caspase-3, respectively. Our studies will provide evidence that these two proteolytic systems can function independently and as an integrated pathway that allows for close regulation of muscle mass in response to physiologic conditions. New information regarding the mechanisms of muscle atrophy may identify therapeutic targets to reduce morbidity and mortality of chronically ill patients and improve their quality of life.