A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis

Autor: Lavinia Palamiuc, Anna Schlagowski, Shyuan T Ngo, Aurelia Vernay, Sylvie Dirrig‐Grosch, Alexandre Henriques, Anne‐Laurence Boutillier, Joffrey Zoll, Andoni Echaniz‐Laguna, Jean‐Philippe Loeffler, Frédérique René
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 7, Iss 5, Pp 526-546 (2015)
Druh dokumentu: article
ISSN: 1757-4684
1757-4676
DOI: 10.15252/emmm.201404433
Popis: 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 (SOD1G86R), 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, SOD1G86R 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.
Databáze: Directory of Open Access Journals
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