期刊
EMBO MOLECULAR MEDICINE
卷 7, 期 5, 页码 526-546出版社
WILEY
DOI: 10.15252/emmm.201404433
关键词
amyotrophic lateral sclerosis; exercise; glucose; lipids; muscle
资金
- Association pour la Recherche sur la Sclerose Laterale Amyotrophique et autres Maladies du Motoneurone
- 'Association pour la recherche et le developpement de moyens de lutte contre les maladies neurodegeneratives' (AREMANE)
- 'Andre Combat la SLA' (INSERM)
- European Community [259867]
- Motor Neurone Disease Research Institute of Australia
- University of Queensland
- Australian Academy of Science
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 65days 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.
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