title: CKD Stimulates Muscle Protein Loss Via Rho-associated Protein Kinase 1 Activation.
abstract: In patients with CKD, muscle wasting is common and is associated with morbidity and mortality. Mechanisms leading to loss of muscle proteins include insulin resistance, which suppresses Akt activity and thus stimulates protein degradation via the ubiquitin-proteasome system. However, the specific factors controlling CKD-induced suppression of Akt activity in muscle remain undefined. In mice with CKD, the reduction in Akt activity in muscle exceeded the decrease in upstream insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity, suggesting that CKD activates other pathways that suppress Akt. Furthermore, a CKD-induced increase uncovered caspase-3 activity in muscle in these mice. In C2C12 muscle cells, activated caspase-3 cleaves and activates Rho-associated protein kinase 1 (ROCK1), which enhances the activity of phosphatase and tensin homolog (PTEN) and reduces Akt activity. Notably, constitutive activation of ROCK1 also led to increased caspase-3 activity in vitro. In mice with either global ROCK1 knockout or muscle-specific PTEN knockout, CKD-associated muscle proteolysis was blunted. These results suggest ROCK1 activation in CKD and perhaps in other catabolic conditions can promote loss of muscle protein via a negative feedback loop.
authors.affiliation: Department of Internal Medicine, Nephrology Division, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas;
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas;
authors.forename: Jin
authors.initials: J
authors.lastname: Cao
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas; Renal Section, Changhai Hospital, Shanghai, China; and.
authors.forename: Rizhen
authors.initials: R
authors.lastname: Yu
authors.affiliation: Nephrology Division, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Farhad
authors.initials: F
authors.lastname: Danesh
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas;
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas;
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
authors.affiliation: Nephrology Division, University of Texas MD Anderson Cancer Center, Houston, Texas zhaoyonh@bcm.edu xuj1010@126.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas; zhaoyonh@bcm.edu xuj1010@126.com.
authors.forename: Zhaoyong
authors.initials: Z
authors.lastname: Hu
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000502:physiology; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000502:physiology; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000502:physiology*
chemical_list: D009124:Muscle Proteins; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D053148:Caspase 3
keywords: cell signaling; chronic kidney disease; metabolism