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 ( SOD 1 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, SOD 1 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. image Altered metabolic homeostasis is an early event in amyotrophic lateral sclerosis ( ALS ) manifestation. This study reveals that skeletal muscles stop using glucose as a source of energy but use lipids instead and this chronic pathologic alteration in muscles is exacerbated with disease progression. The early alteration of muscle metabolic equilibrium between glucose and lipid use impacts on the capacity for muscle to efficiently adapt to increased energetic demands in the SOD 1 G86R ALS mouse model. PDK 4 is central to these metabolic changes, being upregulated at early asymptomatic stages and increasing throughout disease progression in the SOD 1 G86R model, as well as in ALS patients. The metabolic alterations described are specific to glycolytic muscle ( TA ) in the SOD 1 G86R model. Regulation of the glycolytic pathway presents as a potential therapeutic strategy as a drug targeting of PDK 4 improves muscle function and overall metabolic status in the SOD 1 G86R model.