Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans

Two components of integrin containing attachment complexes, UNC-97/PINCH and UNC-112/MIG-2/Kindlin-2, were recently identified as negative regulators of muscle protein degradation and as having decreased mRNA levels in response to spaceflight. Integrin complexes transmit force between the inside and...

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Main Authors:	Etheridge, Timothy, Oczypok, Elizabeth A., Lehmann, Susann, Fields, Brandon D., Shephard, Freya, Jacobson, Lewis A., Szewczyk, Nathaniel J.
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257289/

id	pubmed-3257289
recordtype	oai_dc
spelling	pubmed-32572892012-01-17 Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans Etheridge, Timothy Oczypok, Elizabeth A. Lehmann, Susann Fields, Brandon D. Shephard, Freya Jacobson, Lewis A. Szewczyk, Nathaniel J. Research Article Two components of integrin containing attachment complexes, UNC-97/PINCH and UNC-112/MIG-2/Kindlin-2, were recently identified as negative regulators of muscle protein degradation and as having decreased mRNA levels in response to spaceflight. Integrin complexes transmit force between the inside and outside of muscle cells and signal changes in muscle size in response to force and, perhaps, disuse. We therefore investigated the effects of acute decreases in expression of the genes encoding these multi-protein complexes. We find that in fully developed adult Caenorhabditis elegans muscle, RNAi against genes encoding core, and peripheral, members of these complexes induces protein degradation, myofibrillar and mitochondrial dystrophies, and a movement defect. Genetic disruption of Z-line– or M-line–specific complex members is sufficient to induce these defects. We confirmed that defects occur in temperature-sensitive mutants for two of the genes: unc-52, which encodes the extra-cellular ligand Perlecan, and unc-112, which encodes the intracellular component Kindlin-2. These results demonstrate that integrin containing attachment complexes, as a whole, are required for proper maintenance of adult muscle. These defects, and collapse of arrayed attachment complexes into ball like structures, are blocked when DIM-1 levels are reduced. Degradation is also blocked by RNAi or drugs targeting calpains, implying that disruption of integrin containing complexes results in calpain activation. In wild-type animals, either during development or in adults, RNAi against calpain genes results in integrin muscle attachment disruptions and consequent sub-cellular defects. These results demonstrate that calpains are required for proper assembly and maintenance of integrin attachment complexes. Taken together our data provide in vivo evidence that a calpain-based molecular repair mechanism exists for dealing with attachment complex disruption in adult muscle. Since C. elegans lacks satellite cells, this mechanism is intrinsic to the muscles and raises the question if such a mechanism also exists in higher metazoans. Public Library of Science 2012-01-12 /pmc/articles/PMC3257289/ /pubmed/22253611 http://dx.doi.org/10.1371/journal.pgen.1002471 Text en Etheridge et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Etheridge, Timothy Oczypok, Elizabeth A. Lehmann, Susann Fields, Brandon D. Shephard, Freya Jacobson, Lewis A. Szewczyk, Nathaniel J.
spellingShingle	Etheridge, Timothy Oczypok, Elizabeth A. Lehmann, Susann Fields, Brandon D. Shephard, Freya Jacobson, Lewis A. Szewczyk, Nathaniel J. Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans
author_facet	Etheridge, Timothy Oczypok, Elizabeth A. Lehmann, Susann Fields, Brandon D. Shephard, Freya Jacobson, Lewis A. Szewczyk, Nathaniel J.
author_sort	Etheridge, Timothy
title	Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans
title_short	Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans
title_full	Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans
title_fullStr	Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans
title_full_unstemmed	Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans
title_sort	calpains mediate integrin attachment complex maintenance of adult muscle in caenorhabditis elegans
description	Two components of integrin containing attachment complexes, UNC-97/PINCH and UNC-112/MIG-2/Kindlin-2, were recently identified as negative regulators of muscle protein degradation and as having decreased mRNA levels in response to spaceflight. Integrin complexes transmit force between the inside and outside of muscle cells and signal changes in muscle size in response to force and, perhaps, disuse. We therefore investigated the effects of acute decreases in expression of the genes encoding these multi-protein complexes. We find that in fully developed adult Caenorhabditis elegans muscle, RNAi against genes encoding core, and peripheral, members of these complexes induces protein degradation, myofibrillar and mitochondrial dystrophies, and a movement defect. Genetic disruption of Z-line– or M-line–specific complex members is sufficient to induce these defects. We confirmed that defects occur in temperature-sensitive mutants for two of the genes: unc-52, which encodes the extra-cellular ligand Perlecan, and unc-112, which encodes the intracellular component Kindlin-2. These results demonstrate that integrin containing attachment complexes, as a whole, are required for proper maintenance of adult muscle. These defects, and collapse of arrayed attachment complexes into ball like structures, are blocked when DIM-1 levels are reduced. Degradation is also blocked by RNAi or drugs targeting calpains, implying that disruption of integrin containing complexes results in calpain activation. In wild-type animals, either during development or in adults, RNAi against calpain genes results in integrin muscle attachment disruptions and consequent sub-cellular defects. These results demonstrate that calpains are required for proper assembly and maintenance of integrin attachment complexes. Taken together our data provide in vivo evidence that a calpain-based molecular repair mechanism exists for dealing with attachment complex disruption in adult muscle. Since C. elegans lacks satellite cells, this mechanism is intrinsic to the muscles and raises the question if such a mechanism also exists in higher metazoans.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257289/
_version_	1611499642660323328

Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans

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