Altered skeletal muscle glucose-fatty acid flux in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is characterized by the degeneration of upper and lower motor neurons, yet an increasing number ofstudies in both mouse models and patients with amyotrophic lateral sclerosis suggest that altered metabolic homeostasis is also afeature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in amyotrophiclateral sclerosis. However, the capacity to target specific metabolic pathways or mechanisms requires detailed understanding ofmetabolic dysregulation in amyotrophic lateral sclerosis. Here, using the superoxide dismutase 1, glycine to alanine substitution atamino acid 93 (SOD1G93A) mouse model of amyotrophic lateral sclerosis, we demonstrate that an increase in whole-body metabolismoccurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derivedfrom muscle of amyotrophic lateral sclerosis patients, we also show that increased dependence on fatty acid oxidation is associatedwith increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slowerdisease progression. However, within the patient cohort, there was considerable heterogeneity in whole-body metabolism and fueloxidation profiles. Thus, future studies that decipher specific metabolic changes at an individual patient level are essential for thedevelopment of treatments that aim to target metabolic pathways in amyotrophic lateral sclerosis.