Cellular signals activating muscle proteolysis in chronic kidney disease: a two-stage process.
Muscle atrophy is a prominent feature of catabolic conditions and in animal models of these conditions there is accelerated muscle proteolysis that is dependent on the ubiquitin-proteasome system. However, ubiquitin system cannot degrade actomyosin or myofibrils even though it rapidly degrades actin or myosin. We identified caspase-3 as the initial and potentially rate-limiting proteolytic step that cleaves actomyosin/myofibrils. In rodent models of catabolic conditions, we find that caspase-3 is activated to cleave muscle proteins and actomyosin to fragments that are rapidly degraded by the ubiquitin system. This initial proteolytic step in muscle can be recognized because it leaves a footprint of a characteristic 14-kDa actin band. Stimulation of caspase-3 activity depends on activation of phosphatidylinositol 3-kinase. When we suppressed this enzyme in muscle cells, protein breakdown increased as did the expression of caspase-3. In addition, there was increased expression of E3-ubiquitin-conjugating enzymes that are involved in muscle proteolysis, atrogin-1/MAFbx and MuRF1. Thus, when phosphatidylinositol 3-kinase activity is low in muscle cells or rat muscle, both caspase-3 and the ubiquitin-proteasome system are stimulated to degrade protein. Additional investigations will be needed to define the cell signaling processes that activate muscle proteolysis in uremia and catabolic conditions.
Nephrology Division, Baylor College of Medicine, One Baylor Plaza-BCM 285, Houston, TX 77030, USA.
Jie
J
Du
Zhaoyong
Z
Hu
William E
WE
Mitch
D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009133:Muscular Atrophy / Q000150:complications* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism
D009124:Muscle Proteins; D025801:Ubiquitin; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D046988:Proteasome Endopeptidase Complex