Therapeutic potential of HDAC8 Inhibition and SIRT1 activation in Duchenne muscular dystrophy

Duchenne Muscular Dystrophy (DMD) is a severe genetic disease causing progressive muscle degeneration, inflammation, and fibrosis. While gene and cell therapies face limitations, pharmacological approaches are showing promise. Modulating histone deacetylases (HDACs) has emerged as a key strategy. Specifically, inhibiting HDAC8 with PCI-34051 improves muscle function by stabilizing the cytoskeleton, while activating SIRT1 with SRT2104 boosts energy metabolism and muscle regeneration. In our study, we evaluated a novel combination therapy involving HDAC8 inhibition and SIRT1 activation. In dmd zebrafish embryos, the co-administration of PCI-34051 and SRT2104 showed a greater effect in reducing muscle loss and inflammation, demonstrating the synergy of this approach. Importantly, the combination therapy allowed for lower doses of each compound, maximizing therapeutic effects while minimizing potential side effects. Indeed, as evidenced by our behavioral analysis, toxic effects, including those linked to the nervous system, are mitigated by reducing the doses. These findings highlight the potential of this synergistic strategy as an innovative and effective approach for DMD therapy.