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Although considered to be a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single targeted drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi\u2010target drug used to treatment of coronary artery disease, trimetazidine, in SOD1<jats:sup>G93A<\/jats:sup>mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>As a metabolic modulator, trimetazidine improves glucose metabolism. Furthermore, trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti\u2010inflammatory and antioxidant effect. We orally treated SOD1<jats:sup>G93A<\/jats:sup>mice with trimetazidine, solubilized in drinking water at a dose of 20\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup>, from disease onset. We assessed the impact of trimetazidine on disease progression by studying metabolic parameters, grip strength and histological alterations in skeletal muscle, peripheral nerves and the spinal cord.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Trimetazidine administration delays motor function decline, improves muscle performance and metabolism, and significantly extends overall survival of SOD1<jats:sup>G93A<\/jats:sup>mice (increased median survival of 16\u2009days and 12.5\u2009days for male and female respectively). Moreover, trimetazidine prevents the degeneration of neuromuscular junctions, attenuates motor neuron loss and reduces neuroinflammation in the spinal cord and in peripheral nerves.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>In SOD1<jats:sup>G93A<\/jats:sup>mice, therapeutic effect of trimetazidine is underpinned by its action on mitochondrial function in skeletal muscle and spinal cord.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15738","type":"journal-article","created":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T09:51:57Z","timestamp":1637056317000},"page":"1732-1752","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Repurposing of Trimetazidine for amyotrophic lateral sclerosis: A study in SOD1<sup>G93A<\/sup>mice"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7177-9459","authenticated-orcid":false,"given":"Silvia","family":"Scaricamazza","sequence":"first","affiliation":[{"name":"Division of Experimental Neuroscience IRCCS Fondazione Santa Lucia Via del Fosso di Fiorano 64 Rome 00143 Italy"},{"name":"Department of Biology University of Rome \u201cTor Vergata\u201d Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9700-1269","authenticated-orcid":false,"given":"Illari","family":"Salvatori","sequence":"additional","affiliation":[{"name":"Division of Experimental Neuroscience IRCCS Fondazione Santa Lucia Via del Fosso di Fiorano 64 Rome 00143 Italy"},{"name":"Department of Experimental Medicine University of Roma \u201cLa Sapienza\u201d Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9266-4597","authenticated-orcid":false,"given":"Susanna","family":"Amadio","sequence":"additional","affiliation":[{"name":"Division of Experimental Neuroscience IRCCS Fondazione Santa Lucia Via del Fosso di Fiorano 64 Rome 00143 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Nesci","sequence":"additional","affiliation":[{"name":"Division of Experimental Neuroscience IRCCS Fondazione Santa Lucia Via del Fosso di Fiorano 64 Rome 00143 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9436-8783","authenticated-orcid":false,"given":"Alessio","family":"Torcinaro","sequence":"additional","affiliation":[{"name":"National Council of Research (CNR) Institute of Cell Biology and Neurology (IBCN) Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7430-2835","authenticated-orcid":false,"given":"Giacomo","family":"Giacovazzo","sequence":"additional","affiliation":[{"name":"Division of Experimental Neuroscience IRCCS Fondazione Santa Lucia Via del Fosso di Fiorano 64 Rome 00143 Italy"},{"name":"Department of Biology University of Rome \u201cTor Vergata\u201d Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9415-9175","authenticated-orcid":false,"given":"Aniello","family":"Primiano","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biochemistry and Molecular Biology Clinic Universit\u00e0 Cattolica del Sacro Cuore Rome Italy"},{"name":"Department of Chemistry, Biochemistry and Molecular Biology Clinic Fondazione Policlinico Universitario A. 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