Ethan Green

Background: Duchenne muscular dystrophy (DMD) is a progressive X-linked neuromuscular disorder caused by mutations in the dystrophin gene, leading to muscle degeneration and cardiopulmonary complications.¹ Dilated cardiomyopathy is a major cause of mortality in DMD, but the molecular mechanisms linking dystrophin deficiency to cardiac dysfunction are not fully understood.² Inflammatory signaling pathways, such as those involving NF-κB and the NLRP3 inflammasome, have emerged as central contributors to disease progression by disrupting calcium handling and accelerating myocardial damage.^1-5

Research Objectives: This literature review investigates how NF-κB contributes to calcium dysregulation and chronic inflammation in the cardiac muscle of DMD patients. It also examines the effectiveness of emerging therapeutic strategies that inhibit NF-κB, such as optimized glucocorticoid regimens and Edasalonexent, in improving cardiac and skeletal muscle outcomes.

Search Methods: Relevant literature was identified using PubMed with keywords: “Duchenne muscular dystrophy,” “NF-κB,” “cardiomyopathy,” “calcium dysregulation,” “NLRP3 inflammasome,” and “glucocorticoids.” Key studies included human iPSC-derived cardiomyocyte models, mdx mouse experiments, and early-phase clinical trials of NF-κB inhibitors.

Results: Multiple studies demonstrate that calcium overload in dystrophin-deficient cardiomyocytes activates NF-κB signaling, suppressing genes responsible for calcium homeostasis.^3-5 In mdx mouse models, NF-κB inhibition led to increased expression of calcium-handling proteins such as NCX1 and improved ventricular relaxation and output.³ Another study found that NF-κB also drives activation of the NLRP3 inflammasome, leading to sustained IL-1β and IL-18 release.⁵ Adiponectin, a natural anti-inflammatory hormone, was shown to inhibit this axis via upregulation of miR-711 and improve muscle strength in mdx mice.⁵ Glucocorticoids suppress NF-κB transcriptional activity, but daily dosing was associated with increased expression of muscle atrophy genes, cardiac fibrosis, and muscle weakness.⁶ Weekly dosing maintained anti-inflammatory benefits while minimizing these adverse effects and preserving anabolic signaling via phosphorylated AKT.⁶ Finally, a selective NF-κB inhibitor known as Edasalonexent demonstrated a dose-dependent reduction in pro-inflammatory cytokines like IL-6 and TNF-α in a Phase 1 trial, without steroid-associated side effects.⁷ Importantly, it acts independently of the specific dystrophin mutation, making it a viable mutation-agnostic treatment for DMD.⁷

Conclusions: This review highlights NF-κB as a pivotal factor in the pathogenesis of cardiac and skeletal muscle deterioration in DMD. Therapeutic modulation of NF-κB, whether through intermittent glucocorticoid dosing or novel agents like Edasalonexent, can interrupt the harmful feedback loop of calcium dysregulation and inflammation. These strategies not only preserve muscle structure and function but also provide safer, more targeted alternatives to traditional steroid therapy. Given that NF-κB activation is common across all DMD genotypes and begins early in life, this pathway presents a highly promising target for universal and long-term therapeutic intervention. Future studies should focus on combining NF-κB inhibitors with pro-regenerative agents to enhance both muscle repair and longevity in DMD patients.

Works Cited:

1. Duan D, Goemans N, Takeda S, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021;7(1):13. Published 2021 Feb 18. doi:10.1038/s41572-021-00248-3
2. Schultz TI, Raucci FJ Jr, Salloum FN. Cardiovascular Disease in Duchenne Muscular Dystrophy: Overview and Insight Into Novel Therapeutic Targets. JACC Basic Transl Sci. 2022;7(6):608-625. Published 2022 Mar 9. doi:10.1016/j.jacbts.2021.11.004
3. Peterson JM, Wang DJ, Shettigar V, et al. NF-κB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model. Nat Commun. 2018;9(1):3431. Published 2018 Aug 24. doi:10.1038/s41467-018-05910-1
4. Tsurumi F, Baba S, Yoshinaga D, et al. The intracellular Ca2+ concentration is elevated in cardiomyocytes differentiated from hiPSCs derived from a Duchenne muscular dystrophy patient. PLoS One. 2019;14(3):e0213768. Published 2019 Mar 15. doi:10.1371/journal.pone.0213768
5. Boursereau R, Abou-Samra M, Lecompte S, Noel L, Brichard SM. Downregulation of the NLRP3 inflammasome by adiponectin rescues Duchenne muscular dystrophy. BMC Biol. 2018;16(1):33. Published 2018 Mar 20. doi:10.1186/s12915-018-0501-z
6. Quattrocelli M, Barefield DY, Warner JL, et al. Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy. J Clin Invest. 2017;127(6):2418-2432. doi:10.1172/JCI91445
7. Donovan JM, Zimmer M, Offman E, Grant T, Jirousek M. A Novel NF-κB Inhibitor, Edasalonexent (CAT-1004), in Development as a Disease-Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects. J Clin Pharmacol. 2017;57(5):627-639. doi:10.1002/jcph.842