NF-?B inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model.

ABSTRACT: Duchenne muscular dystrophy (DMD) is a neuromuscular disorder causing progressive muscle degeneration. Although cardiomyopathy is a leading mortality cause in DMD patients, the mechanisms underlying heart failure are not well understood. Previously, we showed that NF-?B exacerbates DMD skeletal muscle pathology by promoting inflammation and impairing new muscle growth. Here, we show that NF-?B is activated in murine dystrophic (mdx) hearts, and that cardiomyocyte ablation of NF-?B rescues cardiac function. This physiological improvement is associated with a signature of upregulated calcium genes, coinciding with global enrichment of permissive H3K27 acetylation chromatin marks and depletion of the transcriptional repressors CCCTC-binding factor, SIN3 transcription regulator family member A, and histone deacetylase 1. In this respect, in DMD hearts, NF-?B acts differently from its established role as a transcriptional activator, instead promoting global changes in the chromatin landscape to regulate calcium genes and cardiac function.

SUBMITTER: Peterson JM 

PROVIDER: S-EPMC6109146 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature