identification and functional clustering of genes regulating muscle protein degradation from amongst the known c. elegans muscle mutants鉴定和功能聚类的基因调节肌肉蛋白降解在已知的秀丽隐杆线虫肌肉突变体.pdfVIP

Identification and Functional Clustering of Genes Regulating Muscle Protein Degradation from amongst the Known C. elegans Muscle Mutants 1 1 2 1 Freya Shephard , Ademola A. Adenle , Lewis A. Jacobson , Nathaniel J. Szewczyk * 1 School of Graduate Entry Medicine and Health, University of Nottingham, Royal Derby Hospital, Derby, United Kingdom, 2 Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Abstract Loss of muscle mass via protein degradation is an important clinical problem but we know little of how muscle protein degradation is regulated genetically. To gain insight our labs developed C. elegans into a model for understanding the regulation of muscle protein degradation. Past studies uncovered novel functional roles for genes affecting muscle and/or involved in signalling in other cells or tissues. Here we examine most of the genes previously identified as the sites of mutations affecting muscle for novel roles in regulating degradation. We evaluate genomic (RNAi knockdown) approaches and combine them with our established genetic (mutant) and pharmacologic (drugs) approaches to examine these 159 genes. We find that RNAi usually recapitulates both organismal and sub-cellular mutant phenotypes but RNAi, unlike mutants, can frequently be used acutely to study gene function solely in differentiated muscle. In the majority of cases where RNAi does not produce organismal level phenotypes, sub-cellular defects can be detected; disrupted proteostasis is most commonly observed. We identify 48 genes in which mutation or RNAi knockdown causes excessive protein degradation; myofibrillar and/or mito