Experimental modulation of metabolic flexibility in Amyotrophic Lateral Sclerosis as a new therapeutic approach

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by upper and lower motor neuron loss, muscle atrophy and resulting paralysis. Weight loss, energy store depletion and hypermetabolism as well as alterations in glucose and lipid metabolism are features shared by ALS patients and animal models. These alterations are severe clinical complications that exacerbate catabolism and sarcopenia influencing disease progression; nevertheless they are still unanswered questions about the disease aetiology. On this purpose we have explored the molecular alteration leading to hypermetabolism and the efficacy of a therapeutic strategy aimed to impinge energy dissipation in an ALS mouse model. We have studied the evolution of the metabolic alterations in ALS mice starting from early presymptomatic stages up to the terminal stage of the disease using indirect calorimetry, molecular investigations and mitochondrial bioenergetics assessments in spinal cord and skeletal muscle. In this work, we have highlighted bioenergetic defects in skeletal muscle of ALS mice long before the disease onset that lead to deep modifications of muscle physiology. Indeed, skeletal muscle of SOD1G93A mice shifts towards an oxidative phenotype with preferential use of lipids as fuel subsequently to bioenergetics defects. Muscle remodelling occurs in SOD1G93A mice before the activation of muscle denervation markers and together with a marked increase of energy expenditure unrelated to physical activity. Chronic Ranolazine treatment of symptomatic SOD1G93A mice decreases energy expenditure and this correlates with a robust, albeit temporary, recovery of pathological phenotype. This investigation sheds light on the early events that modify muscle physiology and energy expenditure in ALS mouse models. To this regard our attention has been focused on the identification of precocious biomarkers closely related to hypermetabolism, a phenomenon that possesses prognostic and diagnostic relevance. Moreover here we have demonstrated, through a pharmacological intervention aimed to stem energy dissipation, that hypermetabolism inhibition is a promising strategy to counteract pathological phenotypes in ALS.