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 (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.

The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis

“…However, the shift from glycolytic to oxidative metabolism is not without risk. Our more recent studies demonstrated that glycolytic muscle from presymptomatic mutant SOD1 mice switched in fuel preference toward fatty acids but this phenomenon was accompanied by mitochondrial dysfunction and oxidative stress (87), providing further evidence of the selective vulnerability of muscles in ALS.…”

Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression

“…In rats, denervation of skeletal muscle is associated with a reduction in glucose uptake, glycogen synthesis, and insulin sensitivity [45]. Denervation atrophy in the SOD 1 mouse leads to diminished entry of pyruvate into the Krebs cycle, thus hampering glucose oxidation in skeletal muscle [46]. Moreover, muscular atrophy is associated with a reduction in the expression of glucose transporters [47,48].…”

Energy metabolism in amyotrophic lateral sclerosis: assessment of body composition and energy expenditure

“…Rat studies suggest that denervation is associated with a reduction in the expression of glucose transporters (Henriksen et al, 1991, Coderre et al, 1992 and an increased turnover of proteolipid receptors (Lunt et al, 1971) which could affect the transport of energy substrate into skeletal muscle. In line with this, altered energy substrate preference in skeletal muscle, characterized by an increase in lipid oxidation and reduction in glucose utilization, has been observed in hypermetabolic SOD1 mice (Palamiuc et al, 2015). As lipid oxidation consumes more oxygen than glucose oxidation, if this preference towards lipid metabolism in muscle occurs in a widespread fashion, it could translate into increased overall energy consumption and contribute to hypermetabolism.…”

“…In SOD1 mice, there appears to be a switch in muscle energy use towards lipid oxidation, rather than glucose utilization, resulting in glycogen accumulation (Palamiuc et al, 2015).…”

“…In rats, denervation of skeletal muscle is associated with a reduction in glucose uptake, glycogen synthesis and insulin sensitivity (Nunes and de Mello, 2005). Denervation atrophy in the SOD1 mouse leads to diminished entry of pyruvate into the Krebs cycle, thus hampering glucose oxidation in skeletal muscle (Palamiuc et al, 2015). Moreover, muscular atrophy is associated with a reduction in the expression of glucose transporters (Henriksen et al, 1991, Coderre et al, 1992.…”