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Margotta, Cassandra
(2024).
DOI: https://doi.org/10.21954/ou.ro.00099019
Abstract
Amyotrophic Lateral Sclerosis is a fatal disorder causing progressive degeneration of upper and lower motor neurons, characterized by varied rates of progression, even with a defined genetic cause. Typically appearing in mid-life, ALS relentlessly leads to muscle wasting and weakness, with respiratory muscle denervation limiting survival to 2-4 years post-onset. ALS poses a significant therapeutic challenge, with existing strategies focused on protecting motor neurons failing to counteract irreversible muscular atrophy.
Recent findings suggest retrograde neurodegeneration of motor neurons may be integral to ALS pathogenesis, with skeletal muscle pathology exacerbating motor neuron loss. Thus, we investigated skeletal muscle as early pathogenetic component, aiming to elucidate molecular mechanisms influencing distinct phenotypes and disease progression factors.
We characterized molecular differences in skeletal muscle of mice with the SOD1G93A mutation across different genetic backgrounds (C57 and 129Sv), mirroring ALS patient progression speeds. We hypothesized peripheral neuromuscular system differences may drive phenotypic variances in these mouse models. Comparative analysis of hindlimb skeletal muscles from fast and slow-progressing SOD1G93A strains revealed differences in neuromuscular junction stability and muscle regeneration. Slow-progressing mice activated compensatory mechanisms, delaying symptom onset, while fast-progressing mice experienced rapid muscle force decline due to defective muscle response.
Macrophages were found crucial in preserving skeletal muscle mass in both ALS models. Thus, we explored whether modulating macrophage muscle responses and enhancing satellite cell differentiation may promote new myofibre generation and counteract muscle dysfunction in ALS mice. Indeed, we found that IL-10 injections improved motor performance, enhanced satellite cells, and boosted muscle pro-regenerative activity, delaying muscle atrophy and motor neuron loss.
This study identifies key targets and molecular pathways indicative of fast or slow prognosis in ALS, potentially uncovering disease modifiers and offering opportunities to impede disease progression. It also lays the groundwork for a novel therapeutic approach focusing on muscle pathology in ALS, offering promise in combatting this debilitating disease.
CORE (COnnecting REpositories)
CORE (COnnecting REpositories)
