title: Regulation of muscle protein degradation: coordinated control of apoptotic and ubiquitin-proteasome systems by phosphatidylinositol 3 kinase.
abstract: Muscle proteolysis from catabolic conditions, including chronic kidney disease, requires coordinated activation of both the apoptotic and ATP-ubiquitin-proteasome systems (Ub-P'some), including upregulation of components of the Ub-P'some system. Activation of the apoptotic system is required because caspase-3 initially cleaves myofibrils, yielding substrates for the Ub-P'some system plus a characteristic 14-kD actin fragment. The authors studied insulin deficiency, a model of accelerated muscle atrophy, to understand how regulation of the apoptotic and the Ub-P'some systems could be coordinated. As expected, phosphatidylinositol 3 kinase activity (PI3K) was suppressed in muscle; in addition to decreased insulin, the mechanism includes IRS-1 phosphorylation at serine-307. Caspase-3 activity was also increased, and the authors linked it to a low PI3K-induced activation of the apoptotic system that includes a conformational change in Bax and release of cytochrome C. Coordinated atrogin-1/MAFbx expression is required as a critical factor for Ub-P'some system-dependent muscle proteolysis in diabetes and other catabolic states. The mechanism that regulates atrogin-1/MAFbx expression is unknown. Atrogin-1/MAFbx expression increased when the authors suppressed PI3K activity in muscle cells. The forkhead transcriptional factor, a downstream substrate of PI3K, stimulated atrogin-1/MAFbx promoter transcriptional activity markedly. The authors found in diabetic muscle that mRNA of the forkhead transcriptional factor, its nuclear translocation, and binding to the atrogin-1/MAFbx promoter were increased. When PI3K activity is low, both apoptotic and Ub-P'some pathways are activated coordinately to cause muscle proteolysis. This mechanism could increase muscle atrophy in conditions with impaired insulin responsiveness.
authors.affiliation: Nephrology Division, Department of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
authors.forename: Seoung Woo
authors.initials: SW
authors.lastname: Lee
authors.forename: Guoli
authors.initials: G
authors.lastname: Dai
authors.forename: Zhaoyong
authors.initials: Z
authors.lastname: Hu
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
mesh_terms: D000199:Actins / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011487:Protein Conformation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000199:Actins; D007328:Insulin; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D025801:Ubiquitin; D012694:Serine; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D019869:Phosphatidylinositol 3-Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex