The integrin-adhesome is required to maintain muscle structure, mitochondrial ATP production, and movement forces in Caenorhabditis elegans

Etheridge, Timothy; Rahman, Mizanur; Gaffney, Christopher J.; Shaw, Debra; Shephard, Freya; Magudia, Jignesh; Solomon, Deepak E.; Milne, Thomas; Blawzdziewicz, Jerzy; Constantin-Teodosiu, Dumitru; Greenhaff, Paul L.; Vanapalli, Siva A.; Szewcyzk, Nathaniel

Abstract

The integrin-adhesome network, which contains >150 proteins, is mechano-transducing and located at discreet positions along the cell-cell and cell-extracellular matrix interface. A small subset of the integrin-adhesome is known to maintain normal muscle morphology. However, the importance of the entire adhesome for muscle structure and function is unknown. We used RNA interference to knock down 113 putative Caenorhabditis elegans homologs constituting most of the mammalian adhesome and 48 proteins known to localize to attachment sites in C. elegans muscle. In both cases, we found >90% of components were required for normal muscle mitochondrial structure and/or proteostasis vs. empty vector controls. Approximately half of these, mainly proteins that physically interact with each other, were also required for normal sarcomere and/or adhesome structure. Next we confirmed that the dystrophy observed in adhesome mutants associates with impaired maximal mitochondrial ATP production (P < 0.01), as well as reduced probability distribution of muscle movement forces compared with wild-type animals. Our results show that the integrin-adhesome network as a whole is required for maintaining both muscle structure and function and extend the current understanding of the full complexities of the functional adhesome in vivo.—Etheridge, T., Rahman, M., Gaffney, C. J., Shaw, D., Shephard, F., Magudia, J., Solomon, D. E., Milne, T., Blawzdziewicz, J., Constantin-Teodosiu, D., Greenhaff, P. L., Vanapalli, S. A., Szewczyk, N. J. The integrin-adhesome is required to maintain muscle structure, mitochondrial ATP production, and movement forces in Caenorhabditis elegans.

• Journal Article Type: Article
• Acceptance Date: Nov 11, 2014
• Online Publication Date: Dec 9, 2014
• Publication Date: Apr 30, 2015
• Deposit Date: Jul 24, 2018
• Publicly Available Date: Feb 8, 2019
• Print ISSN: 0892-6638
• Electronic ISSN: 1530-6860
• Publisher: Federation of American Society of Experimental Biology
• Peer Reviewed: Peer Reviewed
• Volume: 29
• Issue: 4
• Pages: 1235-1246
• DOI: https://doi.org/10.1096/fj.14-259119
• Public URL: https://nottingham-repository.worktribe.com/output/1101752
• Publisher URL: https://www.fasebj.org/doi/10.1096/fj.14-259119
• PMID: 25491313