Myostatin Activates the Ubiquitin-Proteasome and Autophagy-Lysosome Systems Contributing to Muscle Wasting in Chronic Kidney Disease

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-relate...

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Published in:Oxidative medicine and cellular longevity 2015-01, Vol.2015 (2015), p.1-18
Main Authors: Zhang, Zhi-Hua, Huang, Ren-Hua, Yang, Yajun, Wang, Dongtao, Lin, Xin
Format: Article
Language:English
Subjects:
Animals
Autophagy
Autophagy - genetics
Care and treatment
Chinese medicine
Complications and side effects
Development and progression
Health aspects
Hospitals
Inflammation
Kidney diseases
Kinases
Lysosomes - metabolism
Male
Mortality
Muscular Atrophy - chemically induced
Muscular Atrophy - pathology
Musculoskeletal system
Myostatin
Myostatin - adverse effects
Myostatin - pharmacology
Nephrology
Phosphorylation
Proteasome Endopeptidase Complex - metabolism
Protein synthesis
Proteins
Rats
Renal Insufficiency, Chronic
Signal Transduction
Studies
Transcription factors
Ubiquitin - metabolism
Ubiquitin-proteasome system
Wasting syndrome
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Summary: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.
ISSN:1942-0900
1942-0994
DOI:10.1155/2015/684965