Combination therapy targeting HDAC8 and SIRT1 improves muscle integrity in a dmd zebrafish model

Duchenne Muscular Dystrophy (DMD) is a severe genetic disease that causes progressive muscle degeneration, inflammation, and fibrosis. Gene and cell therapies now offer promising therapeutic avenues, although their complexity makes pharmacological approaches complementary and more accessible. Histone deacetylases (HDACs) are a family of epigenetic regulators found deregulated in DMD patients and their modulation has emerged as a key strategy in DMD with Givinostat, a pan-HDAC inhibitor, recently approved by the FDA. However, the chronic use of pan inhibitors might be associated with side effects; while the treatment with selective compounds might reduce off-targets effects, maintaining the therapeutic ones. Our evidence demonstrated that the modulation of two HDACs , HDAC8 and SIRT1, was able to restore muscle function, acting on the stabilization of the cytoskeleton, and muscle energy metabolism, improving mitochondrial functioning . In dmd zebrafish embryos, the co-administration of the HDAC8 inhibitor PCI-34051, and the SIRT1 activator SRT2104, restores muscle loss and reduces inflammation. Importantly, this novel combination therapy allowed for lower doses of each compound, maximizing therapeutic effects and minimizing potential side effects. Moreover, we performed the acetylation profile of HDAC8 inhibited and SIRT1 activated zebrafish embryos to identify the respective acetylation targets. The identification of new targets holds significant potential for advancing therapeutic strategies. This approach not only provides opportunities to refine existing treatments but also opens the door to developing entirely new strategies that may synergize with current interventions. Ultimately, these efforts aim to broaden the arsenal of pharmacological tools available for the treatment of DMD and similar conditions, offering improved outcomes for affected individuals.