Altered skeletal muscle glucose-fatty acid flux in amyotrophic lateral sclerosis (ALS) [article]

Frederik Jacobus Steyn, Siobhan E Kirk, Tesfaye W Tefera, Teresa Y Xie, Timothy J Tracey, Dean Kelk, Elyse Wimberger, Fleur C Garton, Llion Roberts, Sarah E Chapman, Jeff S Coombes, W Matthew Leevy (+7 others)
2020 bioRxiv   pre-print
Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with ALS suggest that altered metabolic homeostasis is a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in ALS. However, our capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in ALS.
more » ... Here, using the SOD1G93A mouse model of ALS, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of ALS patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, we observed considerable heterogeneity in whole-body metabolism and fuel oxidation profiles across our patient cohort. Thus, future studies that decipher specific metabolic changes at an individual patient level are essential for the development of treatments that aim to target metabolic pathways in ALS.
doi:10.1101/2020.04.02.021238 fatcat:latvlt6vazdtzal5m6rrqneg2y