title: A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease in adults. Numerous studies indicate that ALS is a systemic disease that affects whole body physiology and metabolic homeostasis. Using a mouse model of the disease (SOD1(G86R)), we investigated muscle physiology and motor behavior with respect to muscle metabolic capacity. We found that at 65 days of age, an age described as asymptomatic, SOD1(G86R) mice presented with improved endurance capacity associated with an early inhibition in the capacity for glycolytic muscle to use glucose as a source of energy and a switch in fuel preference toward lipids. Indeed, in glycolytic muscles we showed progressive induction of pyruvate dehydrogenase kinase 4 expression. Phosphofructokinase 1 was inhibited, and the expression of lipid handling molecules was increased. This mechanism represents a chronic pathologic alteration in muscle metabolism that is exacerbated with disease progression. Further, inhibition of pyruvate dehydrogenase kinase 4 activity with dichloroacetate delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation. In this study, we provide the first molecular basis for the particular sensitivity of glycolytic muscles to ALS pathology.
authors.affiliation: INSERM, U1118 Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France Université de Strasbourg UMRS1118, Strasbourg, France.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Palamiuc
authors.affiliation: Equipe d'Accueil 3072, Mitochondrie, Stress oxydant et Protection Musculaire, Fédération de Médecine Translationelle de Strasbourg, Université de Strasbourg, Strasbourg, France Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique Hôpitaux Universitaires, CHRU de Strasbourg, Strasbourg, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Schlagowski
authors.affiliation: School of Biomedical Sciences, The University of Queensland, St Lucia, Qld, Australia University of Queensland Centre for Clinical Research, The University of Queensland, Herston, Qld, Australia.
authors.forename: Shyuan T
authors.initials: ST
authors.lastname: Ngo
authors.affiliation: INSERM, U1118 Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France Université de Strasbourg UMRS1118, Strasbourg, France.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Vernay
authors.affiliation: INSERM, U1118 Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France Université de Strasbourg UMRS1118, Strasbourg, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dirrig-Grosch
authors.affiliation: INSERM, U1118 Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France Université de Strasbourg UMRS1118, Strasbourg, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Henriques
authors.affiliation: UMR7364 Laboratoire de Neurosciences Cognitives et Adaptatives, Faculté de Psychologie, Université de Strasbourg-CNRS, GDR CNRS 2905, Strasbourg, France.
authors.forename: Anne-Laurence
authors.initials: AL
authors.lastname: Boutillier
authors.affiliation: Equipe d'Accueil 3072, Mitochondrie, Stress oxydant et Protection Musculaire, Fédération de Médecine Translationelle de Strasbourg, Université de Strasbourg, Strasbourg, France Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique Hôpitaux Universitaires, CHRU de Strasbourg, Strasbourg, France.
authors.forename: Joffrey
authors.initials: J
authors.lastname: Zoll
authors.affiliation: INSERM, U1118 Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France Université de Strasbourg UMRS1118, Strasbourg, France Département de Neurologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Andoni
authors.initials: A
authors.lastname: Echaniz-Laguna
authors.affiliation: INSERM, U1118 Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France Université de Strasbourg UMRS1118, Strasbourg, France loeffler@unistra.fr frederique.rene@unistra.fr.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Loeffler
authors.affiliation: INSERM, U1118 Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France Université de Strasbourg UMRS1118, Strasbourg, France loeffler@unistra.fr frederique.rene@unistra.fr.
authors.forename: Frédérique
authors.initials: F
authors.lastname: René
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D006019:Glycolysis; D050356:Lipid Metabolism; D051379:Mice; D009132:Muscles / Q000378:metabolism / Q000502:physiology*
keywords: amyotrophic lateral sclerosis; exercise; glucose; lipids; muscle
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