NF-κB 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-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.

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents

“…Many molecules have been tested to target this master regulator of inflammation ( Table 3 ). In mdx myotubes or mice, several studies were performed with NF-κB inhibitors, such as NK-κB Essential MOdulator (NEMO)-Binding Domain (NBD), the antioxidant pyrrolidine dithiocarbamate (PDTC), the inhibitor of lipid peroxidation IRFI-042, and the free radical scavengers, N-acetylcysteine (NAC) and (ALA)/L-carnitine (L-Car) [ 31 , 37 , 38 , 39 , 40 , 41 , 42 ]. Unfortunately, NBD induced renal toxicity in mdx mice despite encouraging results showing decreased necrosis and increased regeneration in the diaphragm and hind limb muscles [ 37 , 43 , 44 ].…”

DMD Pluripotent Stem Cell Derived Cardiac Cells Recapitulate in vitro Human Cardiac Pathophysiology

“…Further studies in animal models showed misregulation of other ion channels such as voltage-gated Nav1.5 and L-type calcium channel (LTCC) hyperactivation (Koenig et al, 2011), as well as upregulation of inflammation-related induced nitric oxide synthase (iNOS) (Fauconnier et al, 2010;Peterson et al, 2018). Such observations remain to be validated in human DMD.…”

The SINE Compound KPT-350 Blocks Dystrophic Pathologies in DMD Zebrafish and Mice

“…17,18 Regulatory T cells have been shown to block and/or ameliorate dystrophic symptoms in mouse and canine DMD models. 7,17,[19][20][21][22][23][24][25][26] The nuclear pore functions as a key regulator of intracellular molecules such as proteins, RNA molecules, and ions. 27,28 The nuclear pore consists of various regulatory proteins called nucleoporins that together form the nuclear pore complex (NPC).…”