Strategies for suppressing muscle atrophy in chronic kidney disease: mechanisms activating distinct proteolytic systems.
Loss of protein and lean body mass occurs commonly in patients with chronic kidney disease (CKD). CKD or conditions associated with CKD will stimulate muscle loss, but the cellular mechanisms by which these conditions cause muscle atrophy are largely undefined. In animal models of uremia and other catabolic conditions or in peritoneal dialysis patients, there is evidence that the ubiquitin-proteasome proteolytic system is activated to degrade actomyosin and myofibrillar proteins in muscle. Before the ubiquitin system can degrade muscle proteins, however, an initial cleavage of actomyosin and myofibrils must occur. Caspase-3 performs this initial cleavage of actomyosin and leaves a footprint of its activity, accumulation of a 14-kDa actin fragment in muscle. A critical step in stimulating the ubiquitin-proteasome system in muscle was recently discovered, the activation of a specific E3 ubiquitin-conjugating enzyme, atrogin-1. Both caspase-3 and the ubiquitin system, including atrogin-1, are activated when insulin signaling is impaired, and specifically when phosphatidylinositol 3 kinase activity is suppressed. Strategies that prevent a decrease in phosphatidylinositol 3 kinase activity or inhibit caspase-3 activity could lead to treatments that prevent muscle wasting in CKD patients.
Mitch
William E
WE
Department of Medicine, University of Texas Medical Branch, Galveston, TX, USA. wmitch@utmb.edu <wmitch@utmb.edu>
Hu
Zhaoyong
Z
Lee
Seoung Woo
SW
Du
Jie
J
D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D005938:Glucocorticoids / Q000502:physiology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications*; D009124:Muscle Proteins / Q000378:metabolism*; D009133:Muscular Atrophy / Q000209:etiology / Q000517:prevention & control*; D009210:Myofibrils / Q000737:chemistry; D010447:Peptide Hydrolases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism
D005938:Glucocorticoids; D009124:Muscle Proteins; D025801:Ubiquitin; D000205:Actomyosin; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D010447:Peptide Hydrolases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D046988:Proteasome Endopeptidase Complex