Polyamine metabolism dysregulation contributes to muscle fiber vulnerability in ALS
Veronica Ruggieri,
Silvia Scaricamazza,
Andrea Bracaglia,
Chiara D’Ercole,
Cristina Parisi,
Paolo D’Angelo,
Daisy Proietti,
Chiara Cappelletti,
Alberto Macone,
Biliana Lozanoska-Ochser,
Marina Bouchè,
Lucia Latella,
Cristiana Valle,
Alberto Ferri,
Lorenzo Giordani,
Luca Madaro
Affiliations
Veronica Ruggieri
Department of Anatomical, Histological, Forensic Sciences and Orthopedics, Sapienza University of Rome, 00161 Rome, Italy; Laboratory affiliated with Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy
Silvia Scaricamazza
Laboratories of Neurochemistry and of Molecular and Cellular Neurobiology, IRCCS, Fondazione Santa Lucia, 00143 Rome, Italy; National Research Council (CNR), Institute of Translational Pharmacology (IFT), 00133 Rome, Italy
Andrea Bracaglia
Department of Anatomical, Histological, Forensic Sciences and Orthopedics, Sapienza University of Rome, 00161 Rome, Italy; Laboratory affiliated with Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy
Chiara D’Ercole
Department of Anatomical, Histological, Forensic Sciences and Orthopedics, Sapienza University of Rome, 00161 Rome, Italy; Sorbonne Université, INSERM UMRS 974, Association Institut de Myologie, Centre de Recherche en Myologie, 75013 Paris, France
Cristina Parisi
Department of Anatomical, Histological, Forensic Sciences and Orthopedics, Sapienza University of Rome, 00161 Rome, Italy; Laboratory affiliated with Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy
Paolo D’Angelo
Department of Anatomical, Histological, Forensic Sciences and Orthopedics, Sapienza University of Rome, 00161 Rome, Italy; Laboratory affiliated with Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy
Daisy Proietti
Cell Therapy for Myopathies Unit, Division of Neurosciences, San Raffaele Hospital, 20132 Milano, Italy
Chiara Cappelletti
Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
Alberto Macone
Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
Biliana Lozanoska-Ochser
Department of Medicine & Surgery LUM University, 70010 Casamassima, Italy
Marina Bouchè
Department of Anatomical, Histological, Forensic Sciences and Orthopedics, Sapienza University of Rome, 00161 Rome, Italy
Lucia Latella
National Research Council (CNR), Institute of Translational Pharmacology (IFT), 00133 Rome, Italy
Cristiana Valle
Laboratories of Neurochemistry and of Molecular and Cellular Neurobiology, IRCCS, Fondazione Santa Lucia, 00143 Rome, Italy; National Research Council (CNR), Institute of Translational Pharmacology (IFT), 00133 Rome, Italy
Alberto Ferri
Laboratories of Neurochemistry and of Molecular and Cellular Neurobiology, IRCCS, Fondazione Santa Lucia, 00143 Rome, Italy; National Research Council (CNR), Institute of Translational Pharmacology (IFT), 00133 Rome, Italy
Lorenzo Giordani
Sorbonne Université, INSERM UMRS 974, Association Institut de Myologie, Centre de Recherche en Myologie, 75013 Paris, France; Corresponding author
Luca Madaro
Department of Anatomical, Histological, Forensic Sciences and Orthopedics, Sapienza University of Rome, 00161 Rome, Italy; Laboratory affiliated with Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy; Corresponding author
Summary: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing progressive paralysis due to motor neuron degeneration with no curative therapy despite extensive biomedical research. One of the primary targets of ALS is skeletal muscle, which undergoes profound functional changes as the disease progresses. To better understand how altered innervation interferes with muscle homeostasis during disease progression, we generated a spatial transcriptomics dataset of skeletal muscle in the SOD1G93A mouse model of ALS. Using this strategy, we identified polyamine metabolism as one of the main altered pathways in affected muscle fibers. By establishing a correlation between the vulnerability of muscle fibers and the dysregulation of this metabolic pathway, we show that disrupting polyamine homeostasis causes impairments similar to those seen in ALS muscle. Finally, we show that restoration of polyamine homeostasis rescues the muscle phenotype in SOD1G93A mice, opening new perspectives for the treatment of ALS.
