Fondazione Santa Lucia Clinical and Research Center - IRCCS
Published September 24, 2020 | Version v1
Journal article Open

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

Creators

  • 1. 1 School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane 4072, Australia 2 Centre for Clinical Research, The University of Queensland, Herston, Brisbane 4029, Australia 3 Department of Neurology, Royal Brisbane & Women's Hospital, Brisbane 4029, Australia 4 Wesley Medical Research, Level 8 East Wing, The Wesley Hospital, Auchenflower 4066, Australia
  • 2. The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Brisbane 4072, Australia, School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane 4072, Australia
  • 3. The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Brisbane 4072, Australia
  • 4. School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane 4072, Australia
  • 5. Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane 4072, Australia
  • 6. School of Human Movements and Nutrition Sciences, The University of Queensland, St Lucia, Brisbane 4072, Australia 8 School of Allied Health Sciences, Griffith University, Southport, Gold Coast 4222, Australia
  • 7. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
  • 8. School of Human Movements and Nutrition Sciences, The University of Queensland, St Lucia, Brisbane 4072, Australia
  • 9. IRCCS Fondazione Santa Lucia, Rome, Italy 11 National Research Council, Institute of Translational Pharmacology (IFT), Rome, Italy
  • 10. National Research Council, Institute of Translational Pharmacology (IFT), Rome, Italy 12 INSERM, U1118, Me´canismes Centraux et Pe´riphe´riques de la Neurode´ge´ne´rescence, Strasbourg, France
  • 11. Centre for Clinical Research, The University of Queensland, Herston, Brisbane 4029, Australia 3 Department of Neurology, Royal Brisbane & Women's Hospital, Brisbane 4029, Australia 4 Wesley Medical Research, Level 8 East Wing, The Wesley Hospital, Auchenflower 4066, Australia
  • 12. The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Brisbane 4072, Australia, Centre for Clinical Research, The University of Queensland, Herston, Brisbane 4029, Australia, Department of Neurology, Royal Brisbane & Women's Hospital, Brisbane 4029, Australia, Wesley Medical Research, Level 8 East Wing, The Wesley Hospital, Auchenflower 4066, Australia, Queensland Brain Institute, The University of Queensland, St Lucia, Brisbane 4072, Australia

Description

Amyotrophic lateral sclerosis is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of

studies in both mouse models and patients with amyotrophic lateral sclerosis suggest that altered metabolic homeostasis is also a

feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in amyotrophic

lateral sclerosis. However, the capacity to target specific metabolic pathways or mechanisms requires detailed understanding of

metabolic dysregulation in amyotrophic lateral sclerosis. Here, using the superoxide dismutase 1, glycine to alanine substitution at

amino acid 93 (SOD1G93A) mouse model of amyotrophic lateral sclerosis, 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 amyotrophic lateral sclerosis 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, within the patient cohort, there was considerable heterogeneity in whole-body metabolism and fuel

oxidation profiles. 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 amyotrophic lateral sclerosis.

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Additional details

Identifiers

DOI
10.1093/braincomms/fcaa154