Journal Article

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

Herranz Pérez, Vicente, Zufiría, Mónica, Alonso Martín, Sonia, García Verdugo, José Manuel

2024

Overview

Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicat- ing 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 physi- opathology 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 paral- lels 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.

• Publisher: Springer Berlin Heidelberg,Springer,Springer Nature B.V,Springer Verlag
• Subject: Aged / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Animals / Cell lines / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Drosophila / Ecology, environment / Energy balance / Female / Forkhead Box Protein O1 - genetics / Forkhead Box Protein O1 - metabolism / Forkhead protein / FOXO1 protein / FUS gene / Gene expression / Genetically modified organisms / Health / Health aspects / Homeostasis / Humans / Innervation / Life Sciences / Life span / Male / Medical colleges / Medicine / Medicine & Public Health / Metabolism / Middle Aged / Motor Neurons - metabolism / Motor Neurons - pathology / Muscle Development - physiology / Muscle, Skeletal - metabolism / Muscle, Skeletal - pathology / Muscles / Musculoskeletal system / Myoblasts / Myoblasts - metabolism / Myogenesis / Nerve endings / Nervous system diseases / Neurodegeneration / Neurodegenerative diseases / Neuromuscular junctions / Neurophysiology / Neurosciences / Original Paper / Pathology / Phenotypes / RNA-Binding Protein FUS - genetics / RNA-Binding Protein FUS - metabolism / Skeletal muscle / Synapses / Therapeutic targets