Muscle-Specific Nutritional Adaptations to Catabolic States

描述(申请人提供)：维持肌肉质量需要复杂的细胞反应交响乐。在肌肉萎缩过程中，激素和细胞因子的失衡通过增加泛素-蛋白酶体系统和caspase-3的活性，将调节信号通路(如PI3K/Akt)转向蛋白质降解。这些蛋白分解反应是骨骼肌独有的，尽管所有组织都暴露在相同的系统信号中。这种萎缩计划，如果不减弱，可能会导致肌肉蛋白质的有害损失。诱导两种肌肉特异性E3泛素连接酶，阿托金-1和MuRF1，已被认为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(如caspase-3)的转录，在向蛋白质降解的转变中发挥关键作用。目标1将研究FOXO如何影响肌肉细胞中的蛋白质合成和降解。Aim 2的研究将确定较高的阿托金-1水平是否会增加钙调神经磷酸酶(CaN)的降解，CaN是肌肉细胞中的一种关键磷酸酶。我们认为，CaN的减少可能提供了一种机制，通过移除能够激活(即去磷酸化)促凋亡蛋白BAD的酶来缓解浪费的严重程度；活性BAD增加caspase-3的活性(目标4)。CaN的减少可以防止caspase-3活性变得过高，而不会影响其他蛋白分解反应。目的3将证明BAD受多个信号通路调节，是肌肉中caspase-3活性的关键决定因素。我们还提出，b2-肾上腺素能激动剂的肌肉保留效应部分是由于依赖PKA的不良磷酸化增加和随后caspase-3活性的降低(目标5)。综上所述，我们认为FOXO和BAD是不同的生理刺激分别通过泛素-蛋白酶体系统和caspase-3调节蛋白质损耗的关键信号蛋白。我们的研究将提供证据，证明这两个蛋白分解系统可以独立发挥作用，并作为一个整合的途径，允许密切调节肌肉质量对生理条件的反应。有关肌肉萎缩机制的新信息可能确定治疗靶点，以降低慢性病患者的发病率和死亡率，提高他们的生活质量。

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.