Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower 36 motor neurons, yet an increasing number of studies in both mouse models and patients with 37 ALS suggest that altered metabolic homeostasis is a feature of disease. Pre-clinical and clinical 38 studies have shown that modulation of energy balance can be beneficial in ALS. However, our 39 capacity to target specific metabolic pathways or mechanisms requires detailed understanding 40 of metabolic dysregulation in ALS. Here, using the SOD1G93A mouse model of ALS, we 41 demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle 42 exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle 43 of ALS patients, we also show that increased dependence on fatty acid oxidation is associated 44 with increased whole-body energy expenditure. In the present study, increased fatty acid 45 oxidation was associated with slower disease progression. However, we observed considerable 46 heterogeneity in whole-body metabolism and fuel oxidation profiles across our patient cohort. 47 Thus, future studies that decipher specific metabolic changes at an individual patient level are 48 essential for the development of treatments that aim to target metabolic pathways in ALS.
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