Transcriptomic Analysis Identifies Inflammation and Mitochondrial Dysfunction Reversed by Spermidine in SOD1-G93A Mice

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive degeneration of motor neurons and skeletal muscle. Key contributors to disease onset and progression include disrupted lipid metabolism, oxidative stress, and mitochondrial dysfunction. Spermidine has shown promise in combating neurodegeneration and muscle atrophy in vivo. In SOD1-G93A ALS mouse models, we identified altered polyamine metabolism. Gene expression analysis of spinal cord and gastrocnemius revealed a strong increase in inflammatory pathways in both the tissues and a decrease in mitochondrial gene expression and functions in gastrocnemius. We observed in gastrocnemius reduced expression of Pgc-1alpha and Ampk which was reversed by spermidine treatment. Spermidine also restored mtDNA transcription, enhanced mitochondrial bioenergetics in vitro as evidenced by Seahorse experiments, and delayed muscle weakness in vivo, improving grip strength performance. These findings suggest spermidine as a potential therapeutic strategy for ALS, offering a foundation for further research to improve patient outcomes.