Peterson, Jennifer M; Wang, David J; Shettigar, Vikram; Roof, Steve R; Canan, Benjamin D; Bakkar, Nadine; Shintaku, Jonathan; Gu, Jin- M; Little, Sean C; Ratnam, Nivedita M; Londhe, Priya; Lu, Leina; Gaw, Christoph E; Petrosino, Jennifer M; Liyanarachchi, Sandya; Wang, Huating; Janssen, Paul M L; Davis, Jonathan P; Ziolo, Mark T; Sharma, Sudarshana M; Guttridge, Denis C
description
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-κB exacerbates DMD skeletal muscle pathology by promoting inflammation and impairing new muscle growth. Here, we show that NF-κB is activated in murine dystrophic (mdx) hearts, and that cardiomyocyte ablation of NF-κB 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-κB 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.
