title: Hypoxia Impairs Muscle Function and Reduces Myotube Size in Tissue Engineered Skeletal Muscle.
abstract: Contemporary tissue engineered skeletal muscle models display a high degree of physiological accuracy compared with native tissue, and therefore may be excellent platforms to understand how various pathologies affect skeletal muscle. Chronic obstructive pulmonary disease (COPD) is a lung disease which causes tissue hypoxia and is characterized by muscle fiber atrophy and impaired muscle function. In the present study we exposed engineered skeletal muscle to varying levels of oxygen (O2; 21-1%) for 24 h in order to see if a COPD like muscle phenotype could be recreated in vitro, and if so, at what degree of hypoxia this occurred. Maximal contractile force was attenuated in hypoxia compared to 21% O2; with culture at 5% and 1% O2causing the most pronounced effects with 62% and 56% decrements in force, respectively. Furthermore at these levels of O2, myotubes within the engineered muscles displayed significant atrophy which was not seen at higher O2levels. At the molecular level we observed increases in mRNA expression of MuRF-1 only at 1% O2whereas MAFbx expression was elevated at 10%, 5%, and 1% O2. In addition, p70S6 kinase phosphorylation (a downstream effector of mTORC1) was reduced when engineered muscle was cultured at 1% O2, with no significant changes seen above this O2level. Overall, these data suggest that engineered muscle exposed to O2levels of ≤5% adapts in a manner similar to that seen in COPD patients, and thus may provide a novel model for further understanding muscle wasting associated with tissue hypoxia. J. Cell. Biochem. 118: 2599-2605, 2017. © 2017 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc.
authors.affiliation: School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.
authors.forename: Neil R W
authors.identifier: 0000-0002-1988-047X
authors.initials: NRW
authors.lastname: Martin
authors.affiliation: School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.
authors.forename: Kathyrn
authors.initials: K
authors.lastname: Aguilar-Agon
authors.affiliation: School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.
authors.forename: George P
authors.initials: GP
authors.lastname: Robinson
authors.affiliation: School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Player
authors.affiliation: School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Turner
authors.affiliation: Department of Sport and Exercise Sciences, University of Chichester, Chichester, UK.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Myers
authors.affiliation: School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.
authors.forename: Mark P
authors.identifier: 0000-0002-8430-4479
authors.initials: MP
authors.lastname: Lewis
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D048429:Cell Size; D051379:Mice; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009124:Muscle Proteins / Q000096:biosynthesis; D010100:Oxygen / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D044843:SKP Cullin F-Box Protein Ligases / Q000096:biosynthesis; D023822:Tissue Engineering / Q000379:methods*; D000070584:Tripartite Motif Proteins / Q000096:biosynthesis; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis
chemical_list: D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D010100:Oxygen
keywords: ATROPHY; OXYGEN; UBIQUITIN-PROTEASOME; mTORC1