title: The integrin-adhesome is required to maintain muscle structure, mitochondrial ATP production, and movement forces in Caenorhabditis elegans.
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.
authors.affiliation: *Department of Sport and Health Science, College of Life and Environmental Sciences, and College of Engineering, Mathematics and Physical Science, University of Exeter, Exeter, United Kingdom; Departments of Chemical Engineering and Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA; Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, United Kingdom; and School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom t.etheridge@exeter.ac.uk.
authors.forename: Timothy
authors.initials: T
authors.lastname: Etheridge
authors.affiliation: *Department of Sport and Health Science, College of Life and Environmental Sciences, and College of Engineering, Mathematics and Physical Science, University of Exeter, Exeter, United Kingdom; Departments of Chemical Engineering and Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA; Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, United Kingdom; and School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.
authors.forename: Mizanur
authors.initials: M
authors.lastname: Rahman
authors.affiliation: *Department of Sport and Health Science, College of Life and Environmental Sciences, and College of Engineering, Mathematics and Physical Science, University of Exeter, Exeter, United Kingdom; Departments of Chemical Engineering and Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA; Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, United Kingdom; and School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Gaffney
authors.affiliation: *Department of Sport and Health Science, College of Life and Environmental Sciences, and College of Engineering, Mathematics and Physical Science, University of Exeter, Exeter, United Kingdom; Departments of Chemical Engineering and Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA; Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, United Kingdom; and School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.
authors.forename: Debra
authors.initials: D
authors.lastname: Shaw
authors.affiliation: *Department of Sport and Health Science, College of Life and Environmental Sciences, and College of Engineering, Mathematics and Physical Science, University of Exeter, Exeter, United Kingdom; Departments of Chemical Engineering and Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA; Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, United Kingdom; and School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.
authors.forename: Freya
authors.initials: F
authors.lastname: Shephard
authors.affiliation: *Department of Sport and Health Science, College of Life and Environmental Sciences, and College of Engineering, Mathematics and Physical Science, University of Exeter, Exeter, United Kingdom; Departments of Chemical Engineering and Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA; Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, United Kingdom; and School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.
authors.forename: Jignesh
authors.initials: J
authors.lastname: Magudia
authors.affiliation: *Department of Sport and Health Science, College of Life and Environmental Sciences, and College of Engineering, Mathematics and Physical Science, University of Exeter, Exeter, United Kingdom; Departments of Chemical Engineering and Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA; Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, United Kingdom; and School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.
authors.forename: Deepak E
authors.initials: DE
authors.lastname: Solomon
authors.affiliation: *Department of Sport and Health Science, College of Life and Environmental Sciences, and College of Engineering, Mathematics and Physical Science, University of Exeter, Exeter, United Kingdom; Departments of Chemical Engineering and Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA; Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, United Kingdom; and School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Milne
authors.affiliation: *Department of Sport and Health Science, College of Life and Environmental Sciences, and College of Engineering, Mathematics and Physical Science, University of Exeter, Exeter, United Kingdom; Departments of Chemical Engineering and Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA; Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, United Kingdom; and School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Blawzdziewicz
authors.affiliation: *Department of Sport and Health Science, College of Life and Environmental Sciences, and College of Engineering, Mathematics and Physical Science, University of Exeter, Exeter, United Kingdom; Departments of Chemical Engineering and Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA; Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, United Kingdom; and School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.
authors.forename: Dumitru
authors.initials: D
authors.lastname: Constantin-Teodosiu
authors.affiliation: *Department of Sport and Health Science, College of Life and Environmental Sciences, and College of Engineering, Mathematics and Physical Science, University of Exeter, Exeter, United Kingdom; Departments of Chemical Engineering and Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA; Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, United Kingdom; and School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Greenhaff
authors.affiliation: *Department of Sport and Health Science, College of Life and Environmental Sciences, and College of Engineering, Mathematics and Physical Science, University of Exeter, Exeter, United Kingdom; Departments of Chemical Engineering and Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA; Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, United Kingdom; and School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.
authors.forename: Siva A
authors.initials: SA
authors.lastname: Vanapalli
authors.affiliation: *Department of Sport and Health Science, College of Life and Environmental Sciences, and College of Engineering, Mathematics and Physical Science, University of Exeter, Exeter, United Kingdom; Departments of Chemical Engineering and Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA; Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Ageing Research, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, United Kingdom; and School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Szewczyk
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017173:Caenorhabditis elegans / Q000033:anatomy & histology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D017238:Genes, Helminth; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D008931:Mitochondria, Muscle / Q000378:metabolism; D009068:Movement / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009132:Muscles / Q000033:anatomy & histology / Q000378:metabolism*; D010641:Phenotype; D034622:RNA Interference
chemical_list: D029742:Caenorhabditis elegans Proteins; D016023:Integrins; D009124:Muscle Proteins; D000255:Adenosine Triphosphate
keywords: calpain; dystrophy; focal adhesion; mitochondria