Skeletal-Muscle Metabolic Reprogramming in ALS-SOD1G93A Mice Predates Disease Onset and Is A Promising Therapeutic Target

Silvia Scaricamazza; Illari Salvatori; Giacomo Giacovazzo; Jean Philippe Loeffler; Frederique Renè; Marco Rosina; Cyril Quessada; Daisy Proietti; Constantin Heil; Simona Rossi; Stefania Battistini; Fabio Giannini; Nila Volpi; Frederik J Steyn; Shyuan T Ngo; Elisabetta Ferraro; Luca Madaro; Roberto Coccurello; Cristiana Valle; Alberto Ferri

doi:10.1016/j.isci.2020.101087

Skeletal-Muscle Metabolic Reprogramming in ALS-SOD1^G93A Mice Predates Disease Onset and Is A Promising Therapeutic Target

iScience. 2020 May 22;23(5):101087. doi: 10.1016/j.isci.2020.101087. Epub 2020 Apr 21.

Authors

Silvia Scaricamazza¹, Illari Salvatori², Giacomo Giacovazzo², Jean Philippe Loeffler³, Frederique Renè³, Marco Rosina⁴, Cyril Quessada³, Daisy Proietti², Constantin Heil², Simona Rossi⁵, Stefania Battistini⁶, Fabio Giannini⁶, Nila Volpi⁶, Frederik J Steyn⁷, Shyuan T Ngo⁸, Elisabetta Ferraro⁹, Luca Madaro¹⁰, Roberto Coccurello¹¹, Cristiana Valle¹², Alberto Ferri¹³

Affiliations

¹ University of Rome Tor Vergata, Department of Biology, Rome, Italy; IRCCS Fondazione Santa Lucia, Rome, Italy.
² IRCCS Fondazione Santa Lucia, Rome, Italy.
³ Université de Strasbourg, UMR_S 1118, Strasbourg, France; INSERM, U1118, Central and Peripheral Mechanisms of Neurodegeneration, Strasbourg, France.
⁴ University of Rome Tor Vergata, Department of Biology, Rome, Italy.
⁵ University of Rome Tor Vergata, Department of Biology, Rome, Italy; National Research Council, Institute of Translational Pharmacology (IFT), Rome, Italy.
⁶ University of Siena, Department of Medical, Surgical and Neurological Science, Siena, Italy.
⁷ School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia; Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia.
⁸ Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
⁹ Department of Biology, University of Pisa, Pisa, Italy.
¹⁰ IRCCS Fondazione Santa Lucia, Rome, Italy; DAHFMO-Unit of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.
¹¹ IRCCS Fondazione Santa Lucia, Rome, Italy; National Research Council, Institute for Complex System (ISC), Rome, Italy.
¹² IRCCS Fondazione Santa Lucia, Rome, Italy; National Research Council, Institute of Translational Pharmacology (IFT), Rome, Italy. Electronic address: c.valle@hsantalucia.it.
¹³ IRCCS Fondazione Santa Lucia, Rome, Italy; National Research Council, Institute of Translational Pharmacology (IFT), Rome, Italy. Electronic address: alberto.ferri@cnr.it.

Abstract

Patients with ALS show, in addition to the loss of motor neurons in the spinal cord, brainstem, and cerebral cortex, an abnormal depletion of energy stores alongside hypermetabolism. In this study, we show that bioenergetic defects and muscle remodeling occur in skeletal muscle of the SOD1^G93A mouse model of ALS mice prior to disease onset and before the activation of muscle denervation markers, respectively. These changes in muscle physiology were followed by an increase in energy expenditure unrelated to physical activity. Finally, chronic treatment of SOD1^G93A mice with Ranolazine, an FDA-approved inhibitor of fatty acid β-oxidation, led to a decrease in energy expenditure in symptomatic SOD1^G93A mice, and this occurred in parallel with a robust, albeit temporary, recovery of the pathological phenotype.

Keywords: Cellular Neuroscience; Drugs; Molecular Neuroscience.