Polyamine Dysregulation Contributes to Muscle Fibers Vulnerability in ALS

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive paralysis due to primary and secondary degeneration of motor neurons. Despite the incredible effort of biomedical research, no curative therapy for this disease has yet been established. Given the direct interaction with neurons through neuromuscular junction (NMJ) stabilization, skeletal muscle appears to be a primary target of ALS, causing profound alteration in its function. Here we generated the first spatial transcriptomics dataset of SOD1G93A skeletal muscle as a mouse model for ALS. Using this strategy, we identified polyamine (PA) metabolism as one of the main altered pathways in affected muscle fibers. By identifying PA balance as a key factor in fiber vulnerability during disease progression, we show that perturbation of PA balance in muscle resembles disease features observed in ALS-affected muscle. Finally, we show that restoration of PA flux rescues the muscle phenotype of SOD1G93A mice, opening new perspectives in the treatment of ALS. Spatial Transcriptomics analysis of wildtype and SOD1G93A (B6.Cg-Tg(SOD1 G93A)1Gur/J) murine Tibialis Anterior and Extensor digitorum longus at 75 and 150 days of age