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 Bausela, Xabier
dc.contributor.authorJiménez Zúñiga, Andrés
dc.contributor.authorElicegui, Amaia
dc.contributor.authorLevchuk, María
dc.contributor.authorArnold García, Olatz
dc.contributor.authorOndaro Ezkurra, Jon
dc.contributor.authorIruzubieta Agudo, Pablo
dc.contributor.authorRodríguez Gómez, Laura
dc.contributor.authorFernández Pelayo, Uxoa
dc.contributor.authorMuñoz Oreja, Mikel
dc.contributor.authorAiastui Pujana, Ana
dc.contributor.authorGarcía Verdugo, Jose Manuel
dc.contributor.authorHerranz Pérez, Vicente
dc.contributor.authorZulaica, Miren
dc.contributor.authorPoza Aldea, Juan José
dc.contributor.authorRuiz Onandi, Rebeca
dc.contributor.authorFernández Torrón, Roberto
dc.contributor.authorEspinal Valencia, Juan Bautista
dc.contributor.authorBonilla Zagala, Mario
dc.contributor.authorLersundi Artamendi, Ana
dc.contributor.authorFernández-Eulate, Gorka
dc.contributor.authorRiancho Zarrabeitia, 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 García, Lorea
dc.contributor.authorLópez de Munain Arregui, Adolfo
dc.contributor.authorGereñu Lopetegi, Gorka
dc.contributor.authorGil Bea, Francisco Javier
dc.contributor.authorAlonso-Martin, Sonia
dc.date.accessioned2025-07-10T08:46:37Z
dc.date.available2025-07-10T08:46:37Z
dc.date.issued2024-09-16
dc.date.updated2025-07-10T08:46:37Z
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 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 Scientific 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)en
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., et al. (2024). Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis. Acta Neuropathologica, 148(1). https://doi.org/10.1007/S00401-024-02794-Y
dc.identifier.doi10.1007/S00401-024-02794-Y
dc.identifier.eissn1432-0533
dc.identifier.issn0001-6322
dc.identifier.urihttps://hdl.handle.net/20.500.14454/3192
dc.language.isoeng
dc.publisherSpringer Science and Business Media Deutschland GmbH
dc.rights© The Author(s) 2024
dc.subject.otherAmyotrophic lateral sclerosis
dc.subject.otherFOXO1
dc.subject.otherFUS
dc.subject.otherGlycolysis
dc.subject.otherMyogenesis
dc.subject.otherTDP-43
dc.titleDysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosisen
dc.typejournal article
dcterms.accessRightsopen access
oaire.citation.issue1
oaire.citation.titleActa Neuropathologica
oaire.citation.volume148
oaire.licenseConditionhttps://creativecommons.org/licenses/by/4.0/
oaire.versionVoR
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