title: Genetic ablation of 12/15-lipoxygenase but not 5-lipoxygenase protects against denervation-induced muscle atrophy.
abstract: Skeletal muscle atrophy is a debilitating outcome of a number of chronic diseases and conditions associated with loss of muscle innervation by motor neurons, such as aging and neurodegenerative diseases. We previously reported that denervation-induced loss of muscle mass is associated with activation of cytosolic phospholipase A2 (cPLA2), the rate-limiting step for the release of arachidonic acid from membrane phospholipids, which then acts as a substrate for metabolic pathways that generate bioactive lipid mediators. In this study, we asked whether 5- and 12/15-lipoxygenase (LO) lipid metabolic pathways downstream of cPLA2 mediate denervation-induced muscle atrophy in mice. Both 5- and 12/15-LO were activated in response to surgical denervation; however, 12/15-LO activity was increased ~2.5-fold versus an ~1.5-fold increase in activity of 5-LO. Genetic and pharmacological inhibition of 12/15-LO (but not 5-LO) significantly protected against denervation-induced muscle atrophy, suggesting a selective role for the 12/15-LO pathway in neurogenic muscle atrophy. The activation of the 12/15-LO pathway (but not 5-LO) during muscle atrophy increased NADPH oxidase activity, protein ubiquitination, and ubiquitin-proteasome-mediated proteolytic degradation. In conclusion, this study reveals a novel pathway for neurogenic muscle atrophy and suggests that 12/15-LO may be a potential therapeutic target in diseases associated with loss of innervation and muscle atrophy.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA. Electronic address: bhattacharya@uthscsa.edu.
authors.forename: Arunabh
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Hamilton
authors.affiliation: Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Jernigan
authors.affiliation: Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA; Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
authors.forename: Marian
authors.initials: M
authors.lastname: Sabia
authors.affiliation: Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA; Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Md M
authors.initials: MM
authors.lastname: Rahman
authors.affiliation: Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
authors.forename: Rochelle
authors.initials: R
authors.lastname: Wei
authors.affiliation: Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA; Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Geriatric Research Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
authors.forename: Asish
authors.initials: A
authors.lastname: Chaudhuri
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA; Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Geriatric Research Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency* / Q000235:genetics; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency* / Q000235:genetics; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology; D005449:Fluorenes / Q000494:pharmacology; D017353:Gene Deletion; D015870:Gene Expression; D015316:Genetic Therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000294:innervation / Q000503:physiopathology / Q000601:surgery; D009133:Muscular Atrophy / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C475064:12-15-lipoxygenase; C106248:6,11-dihydro-5-thia-11-aza-benzo(a)-fluorene; D004791:Enzyme Inhibitors; D044950:Flavanones; D005449:Fluorenes; C006680:baicalein; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase; D019255:NADPH Oxidases; D046988:Proteasome Endopeptidase Complex
keywords: 12/15-Lipoxygenase; 5-Lipoxygenase; Denervation; Free radicals; Muscle atrophy; NADPH oxidase