HDAC11 deficiency improves muscle phenotype in a Duchenne muscular dystrophy murine model by reducing inflammation and fibrosis.

Abstract

Duchenne muscular dystrophy (DMD) is a devastating genetic disorder caused by mutations in the dystrophin gene, which encodes for an essential protein to maintain muscle integrity. Loss of dystrophin leads to progressive muscle degeneration, chronic inflammation and replacement of muscle by fibroadipose tissue. To date there is no cure for DMD and the identification of novel molecular targets involved in disease progression is needed to design new therapies to slow DMD progression and prolong survival. Here, we show for the first time that genetic deficiency of HDAC11 in a mouse model of DMD has a positive impact in dystrophic phenotype by reducing muscle damage and fibrosis, which results in improved muscle function. In addition, HDAC11dystrophic muscles show diminished inflammation and changes in the inflammatory environment that positively affect regeneration. Importantly, a partial reduction in HDAC11 levels also improved the dystrophic phenotype, and this therapeutic impact was also observed in old mice. Dystrophic FAPs deficient for HDAC11 underwent more apoptosis, limiting their expansion, and produced less collagen. Single cell RNA sequencing data identified distinct FAP subpopulations, which differ between genotypes. These results were in agreement with the reduced inflammation observed in dKO mice, and suggest changes in the FAPs plasticity. Overall, our results show unequivocally that the total or partial reduction of HDAC11 levels improves the dystrophic phenotype, both histologically and functionally, in young and old mice, therefore HDAC11 could be envisioned as a new potential therapeutic target to ameliorate DMD pathology.