Inactivation of Sirt6 ameliorates muscular dystrophy in mdx mice by releasing suppression of utrophin expression

Abstract

The NAD+-dependent SIRT1-7 family of protein deacetylases plays a vital role in various molecular pathways related to stress response, DNA repair, aging and metabolism. Increased activity of individual sirtuins often exerts beneficial effects in pathophysiological conditions whereas reduced activity is usually associated with disease conditions. Here, we demonstrate that SIRT6 deacetylates H3K56ac in myofibers to suppress expression of utrophin, a dystrophin-related protein stabilizing the sarcolemma in absence of dystrophin. Inactivation of Sirt6 in dystrophin-deficient mdx mice reduced damage of myofibers, ameliorated dystrophic muscle pathology, and improved muscle function, leading to attenuated activation of muscle stem cells (MuSCs). ChIP-seq and locus-specific recruitment of SIRT6 using a CRISPR-dCas9/gRNA approach revealed that SIRT6 is critical for removal of H3K56ac at the Downstream utrophin Enhancer (DUE), which is indispensable for utrophin expression. We conclude that epigenetic manipulation of utrophin expression is a promising approach for the treatment of Duchenne Muscular Dystrophy (DMD).