TY - JOUR

T1 - The integrin-adhesome is required to maintain muscle structure, mitochondrial ATP production, and movement forces in Caenorhabditis elegans

AU - Etheridge, Timothy

AU - Rahman, Mizanur

AU - Gaffney, Christopher J

AU - Shaw, Debra

AU - Shephard, Freya

AU - Magudia, Jignesh

AU - Solomon, Deepak E

AU - Milne, Thomas

AU - Blawzdziewicz, Jerzy

AU - Constantin-Teodosiu, Dumitru

AU - Greenhaff, Paul L

AU - Vanapalli, Siva A

AU - Szewczyk, Nathaniel J

N1 - © The Author(s).

PY - 2015/4

Y1 - 2015/4

N2 - 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.

AB - 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.

KW - Adenosine Triphosphate

KW - Animals

KW - Caenorhabditis elegans

KW - Caenorhabditis elegans Proteins

KW - Gene Knockdown Techniques

KW - Genes, Helminth

KW - Integrins

KW - Mechanotransduction, Cellular

KW - Mitochondria, Muscle

KW - Movement

KW - Muscle Proteins

KW - Muscles

KW - Phenotype

KW - RNA Interference

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1096/fj.14-259119

DO - 10.1096/fj.14-259119

M3 - Journal article

C2 - 25491313

VL - 29

SP - 1235

EP - 1246

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 4

ER -