title: Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise.
abstract: During submaximal exercise fatty acids are a predominant energy source for muscle contractions. An important regulator of fatty acid oxidation is acetyl-CoA carboxylase (ACC), which exists as two isoforms (ACC1 and ACC2) with ACC2 predominating in skeletal muscle. Both ACC isoforms regulate malonyl-CoA production, an allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT-1); the primary enzyme controlling fatty acyl-CoA flux into mitochondria for oxidation. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is activated during exercise or by pharmacological agents such as metformin and AICAR. In resting muscle the activation of AMPK with AICAR leads to increased phosphorylation of ACC (S79 on ACC1 and S221 on ACC2), which reduces ACC activity and malonyl-CoA; effects associated with increased fatty acid oxidation. However, whether this pathway is vital for regulating skeletal muscle fatty acid oxidation during conditions of increased metabolic flux such as exercise/muscle contractions remains unknown. To examine this we characterized mice lacking AMPK phosphorylation sites on ACC2 (S212 in mice/S221 in humans-ACC2-knock-in [ACC2-KI]) or both ACC1 (S79) and ACC2 (S212) (ACC double knock-in [ACCD-KI]) during submaximal treadmill exercise and/or ex vivo muscle contractions. We find that surprisingly, ACC2-KI mice had normal exercise capacity and whole-body fatty acid oxidation during treadmill running despite elevated muscle ACC2 activity and malonyl-CoA. Similar results were observed in ACCD-KI mice. Fatty acid oxidation was also maintained in muscles from ACC2-KI mice contracted ex vivo. These findings indicate that pathways independent of ACC phosphorylation are important for regulating skeletal muscle fatty acid oxidation during exercise/muscle contractions.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia Faculty of Health Sciences and Medicine, Bond Institute of Health and Sport, Bond University, Robina, Queensland, Australia.
authors.forename: Hayley M
authors.identifier: http://orcid.org/0000-0002-8386-217X
authors.initials: HM
authors.lastname: O'Neill
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: James S
authors.initials: JS
authors.lastname: Lally
authors.affiliation: Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Galic
authors.affiliation: Department of Pediatrics, Faculty of Medicine and Dentistry, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pulinilkunnil
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Ford
authors.affiliation: Department of Pediatrics, Faculty of Medicine and Dentistry, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.affiliation: Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Bryce J
authors.initials: BJ
authors.lastname: van Denderen
authors.affiliation: Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia gsteinberg@mcmaster.ca.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
keywords: AMP‐activated protein kinase; Acetyl‐CoA carboxylase 2; exercise; fatty acid/metabolism; knock‐in mice; malonyl‐CoA