Vaibhavi Joshi

Background: Duchenne Muscular Dystrophy (DMD) is a debilitating neuromuscular disorder characterized by the loss of functional dystrophin protein due to mutations in the dystrophin gene. Dystrophin is a key cytoskeletal structural protein, and its loss results in sarcolemma membrane instability, initiation of cellular repair, muscle tissue degeneration, and progressive muscular weakness.¹ One life-threatening complication in patients with DMD is cardiomyopathies, leading to heart failure. The most prevalent is dilated cardiomyopathy (DCM), in which the chambers of the heart are stretched and become dilated, impairing the heart’s ability to pump adequate blood.¹

Objective: In this narrative review, I reviewed molecular mechanisms behind sarcolemma membrane instability, explored the role of increased cytosolic Ca²⁺ levels as a pathological mechanism for muscle atrophy and cardiomyopathy, and evaluated restoring physiological Ca²⁺ levels as potential therapy for DMD.

Search Methods: Online search in the PubMed database from 2017-2023 using these keywords: “Duchenne muscular dystrophy”, “dilated cardiomyopathy”, “gene therapy”, “elevated calcium ion”

Results: A lack of dystrophin can lead to sarcolemma membrane instability, which results in altered expression of membrane-associated proteins and micro-tears in the membrane. A multiomic study found that mice with DMD (mdx/mTR) showed changes in the transcriptome, proteome, and metabolome, regarding proteins, contractile elements, extracellular matrix, and increased glycolic metabolites.³ In a proteomic study, mice with DMD (mdx-4cv) showed a decrease in dystrophin, its glycoproteins, intermediate filament synemin, metabolic enzymes, and proteins involved in membrane and cytoskeletal repair. Additionally, proteins involved in cell metabolism, contraction, protein synthesis, Ca²⁺ balance, membrane potential, the innate immune response, and inflammation were found to be elevated in the mdx-4cv mice. Furthermore, a decrease in voltage-gated L-type calcium channels and sarcalumenin, and an increase in ryanodine receptor Ca²⁺-release channels (RYR2) and sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) pumps were found in the DMD mice. These variations lead to atypical calcium influx and increase cytosolic Ca²⁺ levels, which initiate proteolytic degradation, diminish the lumen’s ability to stabilize Ca²⁺ levels, and cause muscle necrosis.⁴ Comparing myocardial tissue in patients with hypertrophic cardiomyopathy and DCM with healthy patients further demonstrated the pathogenic role of increased cytosolic Ca²⁺ in DMD. An elevated expression of FKBP1A was found, which can increase RYR1 calcium channel activity, leading to increased intracellular Ca²⁺ and muscle damage, and subsequently, TGF-β receptor activation, which could lead to fibrosis in muscle tissue.⁵ Human induced pluripotent stem cell-derived cardiomyocytes from male DMD patients showed RyR2 channel remodeling and Ca²⁺ leak, which are early markers of DMD and lead to cardiac hypertrophy and fibrosis, decreased cardiac contractility, sarcomere disorganization, and senescence.⁶ Delivering SERCA2a calcium pump via adeno-associated virus into 3-month-old mdx mice allowed for improved uptake of calcium, forelimb grip strength, and treadmill running, normal ECG readings and ejection fraction, and prevention of myocardial fibrosis and left ventricle dilation.⁷

Conclusion: Many advances have been made in gene therapies upregulating the expression of dystrophin, but challenges include difficulty working with the large dystrophin gene and immune recognition of new dystrophin as a foreign antigen. Newer approaches involving restoring normal cytosolic Ca²⁺ via stabilizing RyR channels and increasing SERCA activity are more promising, as they may mitigate the negative effects of elevated Ca²⁺ and may delay or prevent DCM in patients with DMD.

Works Cited:

1. Babbs A, Chatzopoulou M, Edwards B, et al. From diagnosis to therapy in Duchenne muscular dystrophy. Biochemical Soc Trans. 2020;48(3):813-821. doi:https://doi.org/10.1042/BST20190282
2. Saad FA, Siciliano G, Angelini C. Advances in Dystrophinopathy Diagnosis and Therapy. Biomolecules. 2023;13(9):1319. Published 2023 Aug 28. doi:10.3390/biom13091319
3. Van Pelt DW, Kharaz YA, Sarver DC, et al. Multiomics analysis of the mdx/mTR mouse model of Duchenne muscular dystrophy. Connect Tissue Res. 2021;621:24-39. doi:10.1080/03008207.2020.1791103
4. Murphy S, Zweyer M, Henry M, et al. Proteomic analysis of the sarcolemma-enriched fraction from dystrophic mdx-4cv skeletal muscle. J Proteomics. 2019;191:212-227. doi:10.1016/j.jprot.2018.01.015
5. Yang W, Zhu Y, Tang F, Jian Z, Xiao Y. Cardiac proteomic profiling suggests that hypertrophic and dilated cardiomyopathy share a common pathogenetic pathway of the calcium signalling pathway. Eur J Clin Invest. 2023;53(11):e14051. doi:10.1111/eci.14051
6. Wasala NB, Yue Y, Lostal W, et al. Single SERCA2a Therapy Ameliorated Dilated Cardiomyopathy for 18 Months in a Mouse Model of Duchenne Muscular Dystrophy. Mol Ther. 2020;28(3):845-854. doi:10.1016/j.ymthe.2019.12.011
7. Souidi M, Resta J, Dridi H, et al. Ryanodine receptor dysfunction causes senescence and fibrosis in Duchenne dilated cardiomyopathy. J Cachexia Sarcopenia Muscle. 2024;15(2):536-551. doi:10.1002/jcsm.13411