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

Palamiuc, Lavinia, Schlagowski, Anna, Ngo, Shyuan T., Vernay, Aurelia, Dirrig-Grosch, Sylvie, Henriques, Alexandre, Boutillier, Anne-Laurence, Zoll, Joffrey, Echaniz-Laguna, Andoni, Loeffler, Jean-Philippe and René, Frédérique (2015) A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Molecular Medicine, 7 5: 526-546. doi:10.15252/emmm.201404433


Author Palamiuc, Lavinia
Schlagowski, Anna
Ngo, Shyuan T.
Vernay, Aurelia
Dirrig-Grosch, Sylvie
Henriques, Alexandre
Boutillier, Anne-Laurence
Zoll, Joffrey
Echaniz-Laguna, Andoni
Loeffler, Jean-Philippe
René, Frédérique
Title A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis
Journal name EMBO Molecular Medicine   Check publisher's open access policy
ISSN 1757-4684
Publication date 2015-05-01
Year available 2015
Sub-type Article (original research)
DOI 10.15252/emmm.201404433
Open Access Status DOI
Volume 7
Issue 5
Start page 526
End page 546
Total pages 21
Place of publication Weinheim, Germany
Publisher Wiley - V C H Verlag GmbH & Co. KGaA
Collection year 2016
Language eng
Formatted 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.
Keyword Amyotrophic lateral sclerosis
Exercise
Glucose
Lipids
Muscle
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2016 Collection
School of Biomedical Sciences Publications
 
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