Improving the effects of HDAC8 inhibition by combining the activation of SIRT1 in a zebrafish model of Duchenne muscular dystrophy

Despite the challenges that hinder the application of gene and cell therapies for Duchenne Muscular Dystrophy (DMD), pharmacological treatments that mitigate skeletal muscle loss, inflammation, and fibrosis offer a promising and immediate approach. Among these treatments, histone deacetylase inhibitors (HDACi) are being investigated extensively, with the pan-HDACi givinostat recently gaining FDA approval for DMD patients. Our previous research demonstrated that inhibiting HDAC8, an enzyme overexpressed in DMD patients, restored normal muscle function in DMD zebrafish by remodeling the cytoskeleton. In the mdx mice, we found that activating SIRT1, a NAD+ dependent class III HDAC, enhanced muscle performance by promoting fatty acid oxidation and fiber type switch towards a more oxidative phenotype. This study evaluated a novel combination therapy for DMD patients that involves HDAC8 inhibition using the HDAC8-selective inhibitor PCI-34051 and SIRT1 activation, through SRT2104 administration. Our data show that DMD zebrafish embryos treated with PCI-34051 and SRT2104 exhibited reduced muscle loss and inflammation. Notably, the combination therapy allowed for lower doses of each drug, maximizing the effects of the single treatment and minimizing possible side effects. In parallel, since it has been shown that HDAC8 inhibition might influence the proliferation and differentiation of zebrafish neurons and murine neural stem cells, we excluded the toxicity of PCI-34051 and SRT2104 on the neural system. In conclusion, our findings support the potential benefits of combining HDAC8 inhibition with SIRT1 activation, demonstrating a synergistic approach to target modulation in DMD treatment.