Identification and functional clustering of genes regulating muscle protein degradation from amongst the known C. elegans muscle mutants.
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 uncovere...
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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0024686&type=printable |
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| author | Freya Shephard Ademola A Adenle Lewis A Jacobson Nathaniel J Szewczyk |
| author_facet | Freya Shephard Ademola A Adenle Lewis A Jacobson Nathaniel J Szewczyk |
| author_sort | Freya Shephard |
| collection | DOAJ |
| description | 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 mitochondrial morphologies are also disrupted in 19 of these 48 cases. These 48 genes appear to act via at least three sub-networks to control bulk degradation of protein in muscle cytosol. Attachment to the extracellular matrix regulates degradation via unidentified proteases and affects myofibrillar and mitochondrial morphology. Growth factor imbalance and calcium overload promote lysosome based degradation whereas calcium deficit promotes proteasome based degradation, in both cases myofibrillar and mitochondrial morphologies are largely unaffected. Our results provide a framework for effectively using RNAi to identify and functionally cluster novel regulators of degradation. This clustering allows prioritization of candidate genes/pathways for future mechanistic studies. |
| format | Article |
| id | doaj-art-fa24d9b2dff940acb8a1b797b2ecc538 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-fa24d9b2dff940acb8a1b797b2ecc5382025-08-20T02:30:58ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0169e2468610.1371/journal.pone.0024686Identification and functional clustering of genes regulating muscle protein degradation from amongst the known C. elegans muscle mutants.Freya ShephardAdemola A AdenleLewis A JacobsonNathaniel J SzewczykLoss 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 mitochondrial morphologies are also disrupted in 19 of these 48 cases. These 48 genes appear to act via at least three sub-networks to control bulk degradation of protein in muscle cytosol. Attachment to the extracellular matrix regulates degradation via unidentified proteases and affects myofibrillar and mitochondrial morphology. Growth factor imbalance and calcium overload promote lysosome based degradation whereas calcium deficit promotes proteasome based degradation, in both cases myofibrillar and mitochondrial morphologies are largely unaffected. Our results provide a framework for effectively using RNAi to identify and functionally cluster novel regulators of degradation. This clustering allows prioritization of candidate genes/pathways for future mechanistic studies.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0024686&type=printable |
| spellingShingle | Freya Shephard Ademola A Adenle Lewis A Jacobson Nathaniel J Szewczyk Identification and functional clustering of genes regulating muscle protein degradation from amongst the known C. elegans muscle mutants. PLoS ONE |
| title | Identification and functional clustering of genes regulating muscle protein degradation from amongst the known C. elegans muscle mutants. |
| title_full | Identification and functional clustering of genes regulating muscle protein degradation from amongst the known C. elegans muscle mutants. |
| title_fullStr | Identification and functional clustering of genes regulating muscle protein degradation from amongst the known C. elegans muscle mutants. |
| title_full_unstemmed | Identification and functional clustering of genes regulating muscle protein degradation from amongst the known C. elegans muscle mutants. |
| title_short | Identification and functional clustering of genes regulating muscle protein degradation from amongst the known C. elegans muscle mutants. |
| title_sort | identification and functional clustering of genes regulating muscle protein degradation from amongst the known c elegans muscle mutants |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0024686&type=printable |
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