Calcineurin signaling, PGC-1 alpha and protein-energy wasting in kidney disease

描述（由申请人提供）：蛋白质能量消耗导致慢性肾脏疾病（CKD）患者常见的虚弱和疲劳。尽管在理解导致瘦体重和蛋白质储备损失的机制方面取得了重大进展，但开发药物干预以减轻浪费的尝试一直不成功。相比之下，运动可以减少蛋白水解，并保持CKD的瘦体重，尽管其效果如何实现仍然知之甚少。我们和其他人已经报道，转录辅激活因子过氧化物酶体增殖物激活受体的水平 在CKD和其他恶病质诱导条件下，γ辅激活因子1-α（PGC-1a）降低。这是值得注意的，因为PGC-1a在正常肌肉中的表达通过运动而增加，并且PGC-1a的转基因过表达可以防止肌肉损失。PGC-1a是整合能量和蛋白质代谢的关键“主调节器”。它通过促进线粒体生物合成和减弱重要转录因子如FOXO的活性来发挥作用，FOXO上调蛋白水解系统基因。了解运动如何减少CKD患者的消耗将提高我们治疗患者疲劳和虚弱的能力。为了实现这一目标，我们必须首先了解CKD诱导的消瘦过程中PGC 1a失调的生化基础。该项目将检验以下假设：CKD和糖皮质激素相关性消瘦期间PGC-1a表达的减少是通过钙调神经磷酸酶（Cn）（一种钙激活的丝氨酸/苏氨酸磷酸酶）调节的一个或多个通路的异常信号传导所致。我们将研究肌细胞增强因子2（MEF 2）/活化T细胞的细胞质核因子（NFATc）途径，因为这两种转录因子都是调节肌细胞中PGC-1a转录的Cn底物。第三个要研究的途径是受调节CREB 1（TORC 1）/环AMP反应元件结合蛋白（CREB）通路的转导子。TORC 1是CREB的Cn激活的转录辅激活因子，其是PGC-1a表达所需的。我们的初步证据表明，TORC 1功能在恶病质期间受损。一旦PGC-1a失调的机制得到表征，我们将测试运动是否会改善CKD小鼠的Cn信号传导，从而导致PGC-1a表达增加，蛋白质降解减少和强度改善。我们研究的长期目标是改善CKD患者的治疗和康复，可能是通过开发新的运动模拟疗法。鉴于消耗综合征在广泛的衰弱性疾病中的相似性（例如，癌症，糖尿病，心脏病），我们的发现可能广泛适用于许多患者。

DESCRIPTION (provided by applicant): Protein-energy wasting contributes to the weakness and fatigue that is frequently seen in patients with chronic kidney disease (CKD). Despite significant advances in understanding the mechanisms causing the loss of lean body mass and protein reserves, attempts to develop pharmaceutical interventions to attenuate wasting have been unsuccessful. In contrast, exercise can reduce proteolysis and preserve lean body mass in CKD although how its effects are achieved remains poorly understood. We and others have reported that the level of the transcription coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) is decreased during CKD and other cachexia-inducing conditions. This is notable because PGC-1a expression in normal muscle is increased by exercise and transgenic overexpression of PGC-1a protects against muscle loss. PGC-1a is a critical "master regulator" that integrates energy and protein metabolism. It functions by promoting mitochondrial biogenesis and attenuating the activity of important transcription factors like FOXO which upregulate proteolytic system genes. Understanding how exercise decreases wasting in CKD will improve our ability to treat fatigue and weakness in patients. To accomplish this goal, we must first understand the biochemical basis for dysregulation of PGC1a during CKD-induced wasting. This project will test the hypothesis that the reduction in PGC-1a expression during CKD and glucocorticoid-related wasting results from abnormal signaling through one or more pathways that are regulated by calcineurin (Cn), a calcium-activated serine/threonine phosphatase. We will examine the myocyte enhancer factor 2 (MEF2)/cytoplasmic nuclear factor of activated T cells (NFATc) pathways because both transcription factors are Cn substrates that regulate PGC-1a transcription in muscle cells. The third pathway to be studied is the Transducer of Regulated CREB 1 (TORC1)/ cyclic AMP-responsive element-binding protein (CREB) pathway. TORC1 is a Cn-activated transcription coactivator of CREB that is required for PGC-1a expression. Our preliminary evidence suggests that TORC1 function is impaired during cachexia. Once the mechanisms of PGC-1a dysregulation are characterized, we will test whether exercise improves Cn signaling in CKD mice, thus leading to increased expression or PGC-1a, decreased protein degradation, and improvement in strength. The long-term goal of our research is to improve the treatment and rehabilitation of CKD patients, perhaps through the development of new exercise mimetic therapies. Given the similarities of the wasting syndromes in a broad range of debilitating diseases (e.g., cancer, diabetes, heart disease), our findings may be widely applicable to many patients.