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

Amyotrophic 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.

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Publication Details

Journal
Acta Neuropathologica
Published
2024-09-16
DOI
https://doi.org/10.1007/s00401-024-02794-y
Citations
7
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
2.58

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article

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

Edoardo Malfatti, Olatz Arnold-García, Stéphanie Duguez, Jon Ondaro et al.
7 citations
Acta Neuropathologica
Amyotrophic Lateral Sclerosis Research
2.58
article

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

Edoardo Malfatti, Olatz Arnold-García, Stéphanie Duguez, Jon Ondaro, Ian Holt, Ainara Vallejo‐Illarramendi, José Manuel García‐Verdugo, Mikel Muñoz‐Oreja, Maddi Garciandia-Arcelus, Javier Riancho, Lorea Blázquez, Ana Aiastui, Juan José Poza, Juan Bautista Espinal, Amets Sáenz, Pablo Iruzubieta, Rebeca Ruiz Onandi, Amaia Elicegui, Oihane Pikatza‐Menoio, Sonia Alonso‐Martín, Roberto Fernández‐Torrón, Gorka Gereñu, Miren Zulaica, Laura Rodríguez-Gómez, Mónica Zufiría, Vicente Herranz‐Pérez, Ana Lersundi, Gorka Fernández‐Eulate, Uxoa Fernández‐Pelayo, Francisco Gil-Bea, Mario Bonilla, Adolfo López de Munaín, Xabier Bengoetxea, María Levchuk, Andrés Jiménez
article en
7 citations

Abstract

Amyotrophic 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.

Acta NeuropathologicaVol. 148(1)
Ikerbasque (ES), Universidad de Cantabria (ES), Universidad de Deusto (ES), University of Ulster (GB), Inserm (FR), Universitat de València (ES), University of the Basque Country (ES), Universidad Pública de Navarra (UPNA) (ES), Université Paris-Est Créteil (FR), Université Paris Cité (FR), Parc Científic de la Universitat de València (ES), The Royal Free Hospital (GB), Instituto de Salud Carlos III (ES), Centre Hospitalier Universitaire Henri-Mondor (FR), Institut Necker Enfants Malades (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Assistance Publique – Hôpitaux de Paris (FR), Biogipuzkoa Health Research Institute (ES), Hospital Sierrallana (ES), Institut de Myologie (FR), Hospital de Galdakao (ES), Policlínica Gipuzkoa (ES), Hôpitaux Universitaires Henri-Mondor (FR), Onkologikoa (ES), National Hospital for Neurology and Neurosurgery (GB), Institut Mondor de Recherche Biomédicale (FR), University College London (GB), Universidad de Navarra (ES)
Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza, Roche España, Euskal Herriko Unibertsitatea, Ikerbasque, Basque Foundation for Science, Osasun Saila, Eusko Jaurlaritzako, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Diputación Foral de Gipuzkoa, Instituto de Salud Carlos III, Spanish National Plan for Scientific and Technical Research and Innovation
Openalex Percentile: Top 10%
Amyotrophic Lateral Sclerosis Research
2.58
DOIOpen Access PDFOpenAlex
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