Shephard, F and Adenle, AA and Jacobson, LA and Szewczyk, NJ
(2011)
Identification and functional clustering of genes regulating muscle protein degradation from amongst the known C. elegans muscle mutants.
PLoS ONE, 6 (9).
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 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. © 2011 Shephard et al.
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| Item Type: |
Article
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| Status: |
Published |
| Creators/Authors: |
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| Contributors: |
| Contribution | Contributors Name | Email | Pitt Username | ORCID  |
|---|
| Editor | Dupuy, Denis | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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| Date: |
27 September 2011 |
| Date Type: |
Publication |
| Journal or Publication Title: |
PLoS ONE |
| Volume: |
6 |
| Number: |
9 |
| DOI or Unique Handle: |
10.1371/journal.pone.0024686 |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Biological Sciences |
| Refereed: |
Yes |
| MeSH Headings: |
Animals; Behavior, Animal; Caenorhabditis elegans--genetics; Cluster Analysis; Gene Expression Regulation; Gene Expression Regulation, Developmental; Models, Biological; Models, Genetic; Multigene Family; Muscles--physiology; Mutation; Phenotype; RNA Interference; Signal Transduction |
| Other ID: |
NLM PMC3181249 |
| PubMed Central ID: |
PMC3181249 |
| PubMed ID: |
21980350 |
| Date Deposited: |
05 Sep 2012 20:02 |
| Last Modified: |
02 Feb 2019 15:59 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/13898 |
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