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

• DOI: 10.1007/s00401-024-02794-y
• Publication Date: 2024-09-16T12:02:35Z
• Authors: Mónica Zufiría; Oihane Pikatza-Me...; Maddi Garciandia-...; Xabier Bengoetxea; Andrés Jiménez; Amaia Elicegui; María Levchuk; Olatz Arnold-García; Jon Ondaro; Pablo Iruzubieta; Laura Rodríguez-G...; Uxoa Fernández-Pe...; Mikel Muñoz-Oreja; Ana Aiastui; José Manuel Garcí...; Vicente Herranz-P...; Miren Zulaica; Juan José Poza; Rebeca Ruiz-Onandi; Roberto Fernández...; Juan Bautista Esp...; Mario Bonilla; Ana Lersundi; Gorka Fernández-E...; Javier Riancho; Ainara Vallejo-Il...; Ian James Holt; Amets Sáenz; Edoardo Malfatti; Stéphanie Duguez; Lorea Blázquez; Adolfo López de M...; Gorka Gerenu; Francisco Gil-Bea; Sonia Alonso-Martín
• Keywords: Male; Motor Neurons; Original Paper; TDP-43; Forkhead Box Protein O1; FOXO1; Amyotrophic Lateral Sclerosis; Myogenesis; Middle Aged; Amyotrophic lateral sclerosis; Muscle Development; antropologia física; DNA-Binding Proteins; Myoblasts; Humans; Animals; RNA-Binding Protein FUS; Female; Drosophila; Muscle, Skeletal; Glycolysis; biologia; FUS; Aged

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.