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

Jennifer M. Peterson, David J. Wang, Vikram Shettigar, Steve R. Roof, Benjamin D. Canan, Nadine Bakkar, Jonathan Shintaku, Jin-Mo Gu, Sean C. Little, Nivedita M. Ratnam, Priya Londhe, Leina Lu, Christopher E. Gaw, Jennifer M. Petrosino, Sandya Liyanarachchi, Huating Wang, Paul M. L. Janssen, Jonathan P. Davis, Mark T. Ziolo, Sudarshana M. Sharma and Denis C. Guttridge ()
Additional contact information
Jennifer M. Peterson: Department of Cancer Biology and Genetics
David J. Wang: Department of Cancer Biology and Genetics
Vikram Shettigar: Center for Muscle Health and Neuromuscular Disorders
Steve R. Roof: Center for Muscle Health and Neuromuscular Disorders
Benjamin D. Canan: Center for Muscle Health and Neuromuscular Disorders
Nadine Bakkar: Department of Cancer Biology and Genetics
Jonathan Shintaku: Department of Cancer Biology and Genetics
Jin-Mo Gu: Department of Cancer Biology and Genetics
Sean C. Little: Center for Muscle Health and Neuromuscular Disorders
Nivedita M. Ratnam: Department of Cancer Biology and Genetics
Priya Londhe: Department of Cancer Biology and Genetics
Leina Lu: The Chinese University of Hong Kong
Christopher E. Gaw: The Ohio State University Medical Center
Jennifer M. Petrosino: Center for Muscle Health and Neuromuscular Disorders
Sandya Liyanarachchi: Department of Cancer Biology and Genetics
Huating Wang: The Chinese University of Hong Kong
Paul M. L. Janssen: Center for Muscle Health and Neuromuscular Disorders
Jonathan P. Davis: Center for Muscle Health and Neuromuscular Disorders
Mark T. Ziolo: Center for Muscle Health and Neuromuscular Disorders
Sudarshana M. Sharma: Medical University of South Carolina
Denis C. Guttridge: Department of Cancer Biology and Genetics

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05910-1

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