A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis.
EMBO Mol Med
; 7(5): 526-46, 2015 May.
Article
in En
| MEDLINE
| ID: mdl-25820275
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Lipid Metabolism
/
Glycolysis
/
Amyotrophic Lateral Sclerosis
/
Muscles
Limits:
Animals
Language:
En
Journal:
EMBO Mol Med
Journal subject:
BIOLOGIA MOLECULAR
Year:
2015
Type:
Article
Affiliation country:
France