NF-\u03baB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model

James W Peterson ,David J Wang,Jonathan P Davis,Sudarshana M Sharma,Nivedita M Ratnam,Steve Roof ,Priya Londhe,Christopher E Gaw,Mark T Ziolo,Nadine Bakkar,Jonathan Shintaku,Vikram Shettigar,Paul M.l Janssen ,Benjamin D Canan,Leina Lu,Huating Wang,Sean C Little,Jing Gu ,Jennifer M Petrosino,Sandya Liyanarachchi,Denis C Guttridge

doi:10.1038/s41467-018-05910-1

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-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.

Highlights

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder causing progressive muscle degeneration
Histological abnormalities are apparent by 7 months[27], and by 10–12 months, dysfunction in vivo is detectable by echocardiogram[28,29,30]
These results indicate that NF-κB is active prior to the onset of mdx cardiomyopathy, and persists throughout the disease process

Summary

Introduction

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder causing progressive muscle degeneration. 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 the Golden Retriever DMD model (GRMD), NBD administration improved hind-limb function, posture, and skeletal muscle histopathology[23] While encouraged that such results might translate to improved ambulation and respiratory function in DMD patients, we realized that further development of an NF-κB inhibitor would require investigation into its effects on dystrophic cardiac muscle. We showed that NBD administration rescued in vitro cardiac function in the severe dystrophin/utrophin double knockout murine DMD model[24] These results indicated that NF-κB contributes to dystrophic cardiac disease, but how it promotes this pathology remains unknown

Methods

Results

Conclusion