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

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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.