Muscle wasting is a serious complication of chronic kidney disease (CKD) because it contributes to patient's morbidity and mortality. Muscle wasting mainly reflects increased breakdown of myofibrillar proteins. Compelling evidence has shown that ubiquitin-proteasome system (UPS) is responsible for skeletal muscle protein loss. We have demonstrated that in muscle of CKD mice, depressed IGF-1/PI3 kinase/Akt signaling augments UPS activity via stimulation of the E3 ubiquitin ligases (Atrogin-1, MuRf-1) that affect UPS-mediated muscle proteolysis. Defects in the IGF-1/PI3K/p- Akt pathway stimulate caspase-3 activation and contribute to muscle wasting. We also have discovered that mitochondrial dysfunction and impaired energy metabolism contribute to muscle wasting. In this proposed project, I plan to study ROCK1 as a key molecule linked both to UPS activation and mitochondrial dysfunction. The proposed project is supported by preliminary Results: 1) in muscle of CKD mice, ROCK1 activity is increased and this change is associated with low levels of p-Akt and increased mitochondrial fission; 2) muscle-specific ROCK1 activation stimulates muscle proteolysis and causes mitochondrial dysfunction; and 3) in CKD mice, knockout of ROCK1 ameliorates muscle wasting. We hypothesize that CKD activates ROCK1 leading to both PTEN activation and mitochondria fission, ultimately resulting in muscle wasting. We will accomplish this goal by studying the following three aims Aim 1: To determine how CKD activates ROCK1 leading to depressed PI3K/Akt signaling and enhanced muscle proteolysis.
Aim 2 : To determine an association between CKD and mitochondrial dysfunction and explore how ROCK1 mediates mitochondrial fission.
Aim 3 : To determine if pharmacologic inhibition of ROCK1 and PTEN will reverse the muscle wasting caused by CKD. We propose a new pathway that regulates muscle protein and energy metabolism in CKD. Since this pathway can be manipulated pharmacologically. The results of our study might be used to define cell biologic responses that are interrupted by CKD. The results also might yield the initial steps towards designing new therapies for this dreaded complication of CKD. .
The project is directed at identifying a new mechanism for CKD -induced 'protein-energy wasting' which is frequently associated with increased morbidity and mortality. The PI has engineered transgenic mouse models specifically designed to identify the cause of protein-energy wasting. The pathway PI proposed might be manipulated pharmacologically to prevent or reverse protein-energy wasting in CKD.
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