Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis

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dc.contributor.authorZufiría García, Mónica
dc.contributor.authorPikatza-Menoio, Oihane
dc.contributor.authorGarciandia-Arcelus, Maddi
dc.contributor.authorBengoetxea, Xabier
dc.contributor.authorJiménez Zúñiga, Andrés
dc.contributor.authorElicegui, Amaia
dc.contributor.authorLevchuk, María
dc.contributor.authorArnold-García, Olatz
dc.contributor.authorOndaro, Jon
dc.contributor.authorIruzubieta, Pablo
dc.contributor.authorRodríguez-Gómez, Laura
dc.contributor.authorFernández-Pelayo, Uxoa
dc.contributor.authorMuñoz-Oreja, Mikel
dc.contributor.authorAiastui, Ana
dc.contributor.authorGarcía-Verdugo, José Manuel
dc.contributor.authorHerranz-Pérez, Vicente
dc.contributor.authorZulaica Ijurco, Miren
dc.contributor.authorPoza, Juan José
dc.contributor.authorRuiz Onandi, Rebeca
dc.contributor.authorFernández-Torrón, Roberto
dc.contributor.authorEspinal, Juan Bautista
dc.contributor.authorBonilla, Mario
dc.contributor.authorLersundi, Ana
dc.contributor.authorFernández-Eulate, Gorka
dc.contributor.authorRiancho, Javier
dc.contributor.authorVallejo-Illarramendi, Ainara
dc.contributor.authorHolt, Ian James
dc.contributor.authorSáenz, Amets
dc.contributor.authorMalfatti, Edoardo
dc.contributor.authorDuguez, Stéphanie
dc.contributor.authorBlázquez, Lorea
dc.contributor.authorLópez de Munain, Adolfo
dc.contributor.authorGerenu, Gorka
dc.contributor.authorGil Bea, Francisco Javier
dc.contributor.authorAlonso-Martín, Sonia
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2024-11-21T09:21:27Z
dc.date.available2024-11-21T09:21:27Z
dc.date.issued2024-09-16
dc.date.updated2024-11-21T09:09:20Z
dc.description.abstractAmyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.en
dc.description.sponsorshipThis research was supported by the Biodonostia Health Research Institute (Biodonostia HRI) and CIBER-Consorcio Centro de Investigación Biomédica en Red- (CB06/05/1126, Group 609), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea¿European Regional Development Fund. This work was funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union (projects P18/01066, PI19/00175, PI21/00153, PI22/00433) and by ISCIII Programa Fortalece del Ministerio de Ciencia e Innovación (FORT23/00026); by CIBERNED (CIBER de Enfermedades Neurodegenerativas, project PI2020/08-1); by the Department of Education of the Basque Country through the IKUR strategy (NEURODEGENPROT); Diputación Foral de Gipuzkoa (projects 2020-CIEN-000057-01, 2021-CIEN-000020¿01); by EiTB Maratoia (project BIO17/ND/023/BD); and by Osasun Saila, Eusko Jaurlaritzako (projects 2015111122, 2017222027, 2018111042, 2019222020, 2020111032, 2020333043, 2021333050). MZuf, OP-M, MG-A, AJ, AE, JO, LR-G, and UF-P were supported by the Department of Education of the Basque Country (PhD fellowships PRE_2015_1_0023, PRE_2019_1_0339, PRE_2020_1_0122, PRE_2020_1_0191, PRE_2020_1_0119, PRE_2018_1_0095, PRE_2021_1_0125, PRE_2018_1_0253); MM-O by Basque Country University (UPV/EHU) fellowship (PIF18/317); JMG-V and VH-P were supported by the Valencian Council for Education, Culture, University and Employment (PROMETEO/2023/053); LB by the Spanish National Plan for Scientifc and Technical Research and Innovation -Ramon y Cajal- (RYC2018-024397-I) and IKERBASQUE (RF/2019/001) research programs; GG by Juan de la Cierva-Incorporación (ISCIII, IJC2019-039965-I) and IKERBASQUE (RF/2023/010) research programs; FG-B by Roche Stop Fuga de cerebros(BIO19/ROCHE/017/BD) and IKERBASQUE (PP/2022/003) research programs; and SA-M by Gipuzkoa Fellow of Talent Attraction and Retention (2019-FELL-000010-01, 2020-FELL-000016-02-01, and 2021-FELL-000013-02-01).
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dc.identifier.citationZufiría, M., Pikatza-Menoio, O., Garciandia-Arcelus, M., Bengoetxea, X., Jiménez, A., Elicegui, A., Levchuk, M., Arnold-García, O., Ondaro, J., Iruzubieta, P., Rodríguez-Gómez, L., Fernández-Pelayo, U., Muñoz-Oreja, M., Aiastui, A., García-Verdugo, J.M., Herranz-Pérez, V., Zulaica, M., Poza, J. J., Ruiz-Onandi, R., Fernández-Torrón, R., Espinal, J. B., Bonilla, M., Lersundi, A., Fernández-Eulate, G., Riancho, J., Vallejo-Illarramendi, A., Holt, I. J., Sáenz A., Malfatti, E., Duguez, S., Blázquez, L., López de Munain, A., Gerenu, G., Gil-Bea F., Alonso-Martín, S. (2024). Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis. Acta Neuropathologica, 148(1), 1-27. https://doi.org/10.1007/s00401-024-02794-y.
dc.identifier.doi10.1007/s00401-024-02794-y
dc.identifier.issn0001-6322
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/52552
dc.language.isoeng
dc.publisherSpringer
dc.relation.ispartofActa Neuropathologica (2024), vol. 148, núm. 43
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII//P18%2F01066/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI19%2F00175/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI21%2F00153/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica, Técnica y de Innovación 2021-2023/PI22%2F00433/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII//FORT23%2F00026/
dc.relation.publisherversionhttps://doi.org/10.1007/s00401-024-02794-y
dc.rights© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License.
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAmyotrophic lateral sclerosisen
dc.subjectFOXO1en
dc.subjectFUSen
dc.subjectGlycolysisen
dc.subjectMyogenesisen
dc.subjectTDP-43en
dc.titleDysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosisen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublicationb7d8829a-1055-49d1-b2af-c051914c8ebb
relation.isAuthorOfPublication.latestForDiscoveryb7d8829a-1055-49d1-b2af-c051914c8ebb

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