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
Affiliations
Silvia Scaricamazza
University of Rome Tor Vergata, Department of Biology, Rome, Italy; IRCCS Fondazione Santa Lucia, Rome, Italy
Illari Salvatori
IRCCS Fondazione Santa Lucia, Rome, Italy
Giacomo Giacovazzo
IRCCS Fondazione Santa Lucia, Rome, Italy
Jean Philippe Loeffler
Université de Strasbourg, UMR_S 1118, Strasbourg, France; INSERM, U1118, Central and Peripheral Mechanisms of Neurodegeneration, Strasbourg, France
Frederique Renè
Université de Strasbourg, UMR_S 1118, Strasbourg, France; INSERM, U1118, Central and Peripheral Mechanisms of Neurodegeneration, Strasbourg, France
Marco Rosina
University of Rome Tor Vergata, Department of Biology, Rome, Italy
Cyril Quessada
Université de Strasbourg, UMR_S 1118, Strasbourg, France; INSERM, U1118, Central and Peripheral Mechanisms of Neurodegeneration, Strasbourg, France
Daisy Proietti
IRCCS Fondazione Santa Lucia, Rome, Italy
Constantin Heil
IRCCS Fondazione Santa Lucia, Rome, Italy
Simona Rossi
University of Rome Tor Vergata, Department of Biology, Rome, Italy; National Research Council, Institute of Translational Pharmacology (IFT), Rome, Italy
Stefania Battistini
University of Siena, Department of Medical, Surgical and Neurological Science, Siena, Italy
Fabio Giannini
University of Siena, Department of Medical, Surgical and Neurological Science, Siena, Italy
Nila Volpi
University of Siena, Department of Medical, Surgical and Neurological Science, Siena, Italy
Frederik J. Steyn
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia; Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia
Shyuan T. Ngo
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
Elisabetta Ferraro
Department of Biology, University of Pisa, Pisa, Italy
Luca Madaro
IRCCS Fondazione Santa Lucia, Rome, Italy; DAHFMO-Unit of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy
Roberto Coccurello
IRCCS Fondazione Santa Lucia, Rome, Italy; National Research Council, Institute for Complex System (ISC), Rome, Italy
Cristiana Valle
IRCCS Fondazione Santa Lucia, Rome, Italy; National Research Council, Institute of Translational Pharmacology (IFT), Rome, Italy; Corresponding author
Alberto Ferri
IRCCS Fondazione Santa Lucia, Rome, Italy; National Research Council, Institute of Translational Pharmacology (IFT), Rome, Italy; Corresponding author
Summary: 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 SOD1G93A 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 SOD1G93A mice with Ranolazine, an FDA-approved inhibitor of fatty acid β-oxidation, led to a decrease in energy expenditure in symptomatic SOD1G93A mice, and this occurred in parallel with a robust, albeit temporary, recovery of the pathological phenotype.
