Polyamine metabolism dysregulation contributes to muscle fiber 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. In spite of extensive biomedical research, no curative therapy has yet been established. One of the primary targets of ALS is skeletal muscle, which undergoes profound functional changes as the disease progresses. To better understand how altered innervation interferes with muscle homeostasis during disease progression, we generated the first spatial transcriptomics dataset of skeletal muscle in the SOD1G93A mouse model of ALS. Using this strategy, we identified polyamine (PA) metabolism as one of the main altered pathways in affected muscle fibers. By establishing a correlation between the vulnerability of muscle fibers and the dysregulation of this metabolic pathway, we show that disrupting polyamine homeostasis causes impairments similar to those seen in ALS muscle. Finally, we show that restoration of polyamine homeostasis rescues the muscle phenotype in SOD1G93A mice, opening new perspectives for the treatment of ALS. Spatial Transcriptomics of Tibialis anterior of transiently denervated mice 3 days and 30 days post-denervation, used as biological replicates for the already published samples od D'Ercole et al., 2022