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.

Details

Title
NF-κB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model
Author
Peterson, Jennifer M 1 ; Wang, David J 2 ; Shettigar, Vikram 3 ; Roof, Steve R 4 ; Canan, Benjamin D 3 ; Bakkar, Nadine 5 ; Shintaku, Jonathan 6   VIAFID ORCID Logo  ; Jin-Mo, Gu 7 ; Little, Sean C 8 ; Ratnam, Nivedita M 9 ; Londhe, Priya 10 ; Lu, Leina 11 ; Gaw, Christopher E 12   VIAFID ORCID Logo  ; Petrosino, Jennifer M 13 ; Liyanarachchi, Sandya 9 ; Wang, Huating 14 ; Janssen, Paul M L 3 ; Davis, Jonathan P 3 ; Ziolo, Mark T 3 ; Sharma, Sudarshana M 15   VIAFID ORCID Logo  ; Guttridge, Denis C 16 

1  Department of Cancer Biology and Genetics, Columbus, OH, USA; Center for Muscle Health and Neuromuscular Disorders, Columbus, OH, USA; The Ohio State University Medical Center, Columbus, OH, USA; Department of Pharmacy and Pharmaceutical Sciences, SUNY Binghamton University, Binghamton, NY, USA 
2  Department of Cancer Biology and Genetics, Columbus, OH, USA; The Ohio State University Medical Center, Columbus, OH, USA; Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA 
3  Center for Muscle Health and Neuromuscular Disorders, Columbus, OH, USA; The Ohio State University Medical Center, Columbus, OH, USA; Department of Physiology and Cell Biology, The Ohio State University Medical Center, Columbus, Ohio, USA 
4  Center for Muscle Health and Neuromuscular Disorders, Columbus, OH, USA; The Ohio State University Medical Center, Columbus, OH, USA; Department of Physiology and Cell Biology, The Ohio State University Medical Center, Columbus, Ohio, USA; Q Test Labs, Columbus, OH, USA 
5  Department of Cancer Biology and Genetics, Columbus, OH, USA; Center for Muscle Health and Neuromuscular Disorders, Columbus, OH, USA; The Ohio State University Medical Center, Columbus, OH, USA; Department of Neurobiology, St Joseph’s Hospital and Medical Center-Barrow Neurological Institute, Phoenix, AZ, USA 
6  Department of Cancer Biology and Genetics, Columbus, OH, USA; Center for Muscle Health and Neuromuscular Disorders, Columbus, OH, USA; The Ohio State University Medical Center, Columbus, OH, USA; Department of Neurology, Columbia University Medical Center, New York, NY, USA 
7  Department of Cancer Biology and Genetics, Columbus, OH, USA; Center for Muscle Health and Neuromuscular Disorders, Columbus, OH, USA; The Ohio State University Medical Center, Columbus, OH, USA; Department of Biomedical Engineering and Pediatrics, Emory University, Decatur, GA, USA 
8  Center for Muscle Health and Neuromuscular Disorders, Columbus, OH, USA; The Ohio State University Medical Center, Columbus, OH, USA; Department of Physiology and Cell Biology, The Ohio State University Medical Center, Columbus, Ohio, USA; Bristol-Myers Squibb, Wallingford, CT, USA 
9  Department of Cancer Biology and Genetics, Columbus, OH, USA; The Ohio State University Medical Center, Columbus, OH, USA 
10  Department of Cancer Biology and Genetics, Columbus, OH, USA; Center for Muscle Health and Neuromuscular Disorders, Columbus, OH, USA; The Ohio State University Medical Center, Columbus, OH, USA; Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA 
11  Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA 
12  The Ohio State University Medical Center, Columbus, OH, USA; Children’s Hospital of Philadelphia, Philadelphia, PA, USA 
13  Center for Muscle Health and Neuromuscular Disorders, Columbus, OH, USA; The Ohio State University Medical Center, Columbus, OH, USA 
14  Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China 
15  Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA 
16  Department of Cancer Biology and Genetics, Columbus, OH, USA; Center for Muscle Health and Neuromuscular Disorders, Columbus, OH, USA; The Ohio State University Medical Center, Columbus, OH, USA; Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA 
Pages
1-14
Publication year
2018
Publication date
Aug 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-05910-1
ProQuest document ID
2092839551
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.