title: Myostatin Activates the Ubiquitin-Proteasome and Autophagy-Lysosome Systems Contributing to Muscle Wasting in Chronic Kidney Disease.
abstract: Our evidence demonstrated that CKD upregulated the expression of myostatin, TNF-α, and p-IkBa and downregulated the phosphorylation of PI3K, Akt, and FoxO3a, which were also associated with protein degradation and muscle atrophy. The autophagosome formation and protein expression of autophagy-related genes were increased in muscle of CKD rats. The mRNA level and protein expression of MAFbx and MuRF-1 were also upregulated in CKD rats, as well as proteasome activity of 26S. Moreover, activation of myostatin elicited by TNF-α induces C2C12 myotube atrophy via upregulating the expression of autophagy-related genes, including MAFbx and MuRF1 and proteasome subunits. Inactivation of FoxO3a triggered by PI3K inhibitor LY294002 prevented the myostatin-induced increase of expression of MuRF1, MAFbx, and LC3-II protein in C2C12 myotubes. The findings were further consolidated by using siRNA interference and overexpression of myostatin. Additionally, expression of myostatin was activated by TNF-α via a NF-κB dependent pathway in C2C12 myotubes, while inhibition of NF-κB activity suppressed myostatin and improved myotube atrophy. Collectively, myostatin mediated CKD-induced muscle catabolism via coordinate activation of the autophagy and the ubiquitin-proteasome systems.
authors.affiliation: Department of Nephrology, Ruikang Hospital, Guangxi University of Chinese Medicine, Nanning 530011, China.
authors.forename: Dong-Tao
authors.initials: DT
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Guangdong Key Laboratory for R&D of Natural Drug, Guangdong Medical College, Zhanjiang 524023, China.
authors.forename: Ya-Jun
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: Department of Nephrology, Ruikang Hospital, Guangxi University of Chinese Medicine, Nanning 530011, China.
authors.forename: Ren-Hua
authors.initials: RH
authors.lastname: Huang
authors.affiliation: Department of Traditional Chinese Medicine, General Hospital of Guangzhou Military Command of PLA, Guangzhou 510010, China.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D009133:Muscular Atrophy / Q000139:chemically induced* / Q000473:pathology; D055435:Myostatin / Q000009:adverse effects* / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D051436:Renal Insufficiency, Chronic; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D055435:Myostatin; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex