dMyc suppresses CTG-induced cytotoxicity in the Drosophila model of DM1 by reducing autophagy and cell death.

Myotonic Dystrophy Type 1 (DM1) is a complex, genetic, and multisystemic disorder caused by the expansion of CTG trinucleotide repeats in the Dystrophia Myotonica Protein Kinase gene, leading to the formation of toxic RNA foci, which finally result in progressive muscle weakness, myotonia, and systemic complications affecting almost every organ system of the body. Despite its severity and high prevalence, effective therapeutic strategies remain elusive. Our study aims to identify a genetic modifier with therapeutic potential. We used transgenic flies expressing pathogenic CTG250 and CTG270 repeats as a Drosophila model of DM1, which recapitulated the hallmark features: formation of RNA foci, muscle fibre degeneration, impaired locomotor activity, and shortened lifespan. Drosophila Myc (dMyc), also known as diminutive, is a highly conserved transcription factor that plays a crucial role in cellular growth, metabolism, and autophagy. We found that targeted overexpression of dMyc significantly ameliorated disease phenotypes, including improved muscle integrity, enhanced motor function, extended lifespan, and reduced RNA foci. Our findings also revealed that dMyc expression is significantly reduced in flies with disease caused by abnormal CTG expansion. Overexpression of dMyc led to a marked decrease in autophagy and apoptosis. Our findings highlight impaired dMyc expression in CTG-mediated pathogenesis in the DM1 model and suggest that modulation of Myc expression could be a promising therapeutic intervention for DM1.