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Clin Exp Nephrol. 2013 Apr;17(2):174-82. doi: 10.1007/s10157-012-0729-9. Epub 2013 Jan 5.

Mechanisms stimulating muscle wasting in chronic kidney disease: the roles of the ubiquitin-proteasome system and myostatin.

Author information

1
Nephrology Division M/S: BCM 285, Baylor College of Medicine, One Baylor Plaza, Alkek N-520, Houston, TX 77030, USA.

Abstract

Catabolic conditions including chronic kidney disease (CKD), cancer, and diabetes cause muscle atrophy. The loss of muscle mass worsens the burden of disease because it is associated with increased morbidity and mortality. To avoid these problems or to develop treatment strategies, the mechanisms leading to muscle wasting must be identified. Specific mechanisms uncovered in CKD generally occur in other catabolic conditions. These include stimulation of protein degradation in muscle arising from activation of caspase-3 and the ubiquitin-proteasome system (UPS). These proteases act in a coordinated fashion with caspase-3 initially cleaving the complex structure of proteins in muscle, yielding fragments that are substrates that are degraded by the UPS. Fortunately, the UPS exhibits remarkable specificity for proteins to be degraded because it is the major intracellular proteolytic system. Without a high level of specificity cellular functions would be disrupted. The specificity is accomplished by complex reactions that depend on recognition of a protein substrate by specific E3 ubiquitin ligases. In muscle, the specific ligases are Atrogin-1 and MuRF-1, and their expression has characteristics of a biomarker of accelerated muscle proteolysis. Specific complications of CKD (metabolic acidosis, insulin resistance, inflammation, and angiotensin II) activate caspase-3 and the UPS through mechanisms that include glucocorticoids and impaired insulin or IGF-1 signaling. Mediators activate myostatin, which functions as a negative growth factor in muscle. In models of cancer or CKD, strategies that block myostatin prevent muscle wasting, suggesting that therapies that block myostatin could prevent muscle wasting in catabolic conditions.

PMID:
23292175
PMCID:
PMC3628947
DOI:
10.1007/s10157-012-0729-9
[Indexed for MEDLINE]
Free PMC Article

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