Amelioration of intracellular Ca2+ regulation by exon-45 skipping in Duchenne muscular dystrophy-induced pluripotent stem cell-derived cardiomyocytes

Sato, Mototaro; Shiba, Naoko; Miyazaki, Daigo; Shiba, Yuji; Echigoya, Yusuke; Yokota, Toshifumi; Takizawa, Hotake; Aoki, Yosuke; Takeda, Shin’ichi; Nakamura, Akinori

doi:10.1016/j.bbrc.2019.09.095

Cited by 15 publications

(20 citation statements)

References 33 publications

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“…However, DMD EHTs treated with idebenone exhibited a significantly increased contraction, whereas the combined treatment of idebenone and PTC124 improved even further the contractile function. By incubating DMD EHTs with various Ca 2+ concentrations (ranging from 0.1 to 2.5 mM), we wanted to analyze the amplitude of contraction of DMD EHTs at physiological Ca 2+ levels (1.8 mM; dotted line) and higher Ca 2+ levels (2.5 mM), mimicking the detrimental increased Ca 2+ environment, as reported in the heart from DMD patients ( 35, 44, 45 ). At physiological Ca 2+ levels, idebenone had beneficial effects on the contraction of DMD EHTs compared to untreated DMD EHTs, whereas the contractile function of DMD EHTs did not show any improvements upon idebenone administration at 2.5 mM Ca 2+ concentrations (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In consistency with these results, we found a significantly increased expression and activity of the cardiac-specific ROS-producing NOX4 isoform in DMD iPSC-CMs. Dystrophin-deficient CMs are more vulnerable to mechanical stress due to the increased membrane fragility and stretch-induced Ca 2+ influx, resulting in cell death ( 32, 35, 44, 45 ). The complexity of the DMD pathology results from the signal amplification systems, with bidirectional cross-talk and positive feed-back loops.…”

Section: Discussionmentioning

confidence: 99%

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Human iPSC-Based Model Reveals NOX4 as Therapeutic Target in Duchenne Cardiomyopathy

Duelen

Costamagna²,

Gilbert

et al. 2021

Preprint

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Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle disorder, caused by mutations in the Dystrophin gene. Cardiomyopathy is one of the major causes of early death. In this study, we used DMD patient-specific induced pluripotent stem cells (iPSCs) to model cardiomyopathic features in DMD and unravel novel pathological mechanistic insights. Cardiomyocytes (CMs) differentiated from DMD iPSCs showed enhanced premature cell death, due to significantly elevated intracellular reactive oxygen species (ROS) concentrations, as a result of depolarized mitochondria and high NADPH oxidase 4 (NOX4) protein levels. Genetic correction of Dystrophin through CRISPR/Cas9 editing restored normal ROS levels. Application of ROS reduction by N-acetyl-L-cysteine (NAC), partial Dystrophin re-expression by ataluren (PTC124) and enhancing mitochondrial electron transport chain function by idebenone improved cell survival of DMD iPSC-CMs. We show applications that could counteract the detrimental oxidative stress environment in DMD iPSC-CMs by stimulating adenosine triphosphate (ATP) production. ATP could bind to the ATP-binding domain in the NOX4 enzyme, and we demonstrate that ATP resulted in partial inhibition of the NADPH-dependent ROS production of NOX4. Considering the complexity and the early cellular stress responses in DMD cardiomyopathy, we propose to target ROS production and prevent the detrimental effects of NOX4 on DMD CMs as a promising therapeutic strategy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human iPSC-Based Model Reveals NOX4 as Therapeutic Target in Duchenne Cardiomyopathy

Duelen

Costamagna²,

Gilbert

et al. 2021

Preprint

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“…20 (Dick et al, 2013;Guan et al, 2014;Zatti et al, 2014;Lin et al, 2015;Macadangdang et al, 2015;Japp et al, 2016;Nanni et al, 2016;Young et al, 2016;Kyrychenko et al, 2017;Zhang et al, 2017;Long et al, 2018;Caluori et al, 2019;Eisen et al, 2019;Farini et al, 2019;Jelinkova et al, 2019;Min et al, 2019;Pioner et al, 2019a;Sato et al, 2019;Tsurumi et al, 2019;Moretti et al, 2020) Calcium handling abnormalities; contractile defects α-Tropomyosin (TPM1)…”

Section: Cardiac Troponin T (Tnnt2)unclassified

Advances in Stem Cell Modeling of Dystrophin-Associated Disease: Implications for the Wider World of Dilated Cardiomyopathy

et al. 2020

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Familial dilated cardiomyopathy (DCM) is mostly caused by mutations in genes encoding cytoskeletal and sarcomeric proteins. In the pediatric population, DCM is the predominant type of primitive myocardial disease. A severe form of DCM is associated with mutations in the DMD gene encoding dystrophin, which are the cause of Duchenne Muscular Dystrophy (DMD). DMD-associated cardiomyopathy is still poorly understood and orphan of a specific therapy. In the last 5 years, a rise of interest in disease models using human induced pluripotent stem cells (hiPSCs) has led to more than 50 original studies on DCM models. In this review paper, we provide a comprehensive overview on the advances in DMD cardiomyopathy disease modeling and highlight the most remarkable findings obtained from cardiomyocytes differentiated from hiPSCs of DMD patients. We will also describe how hiPSCs based studies have contributed to the identification of specific myocardial disease mechanisms that may be relevant in the pathogenesis of DCM, representing novel potential therapeutic targets.

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“…In the last few years, iPSC-CMs have been widely used to model cardiac diseases including DAC, and more than 20 original articles reported the use of iPSC-derived cells from MD patients. Starting from the first iPSC line derived from skin fibroblasts of a DMD patient in 2008 [ 341 ], numerous other iPSC cell lines derived from different somatic-cell sources obtained from DMD and BMD patients were generated and published [ 133 , 253 , 302 , 342 , 343 , 344 , 345 , 346 , 347 , 348 , 349 , 350 , 351 , 352 , 353 , 354 , 355 , 356 , 357 , 358 , 359 , 360 , 361 , 362 , 363 , 364 , 365 , 366 , 367 , 368 ]. These works demonstrated that it is possible to use iPSC-derived cells carrying specific DMD mutations to reproduce MD pathogenesis and to verify new therapeutic approaches.…”

Section: Modeling Dystrophy-associated Cardiomyopathymentioning

confidence: 99%

“…In addition to the study of DAC molecular mechanisms, the iPSC-CM platform has been widely used to test potential therapeutic strategies and, among these, genetic therapies were the most studied. Indeed, many works using iPSC-CMs demonstrated the amelioration of defects observed in DMD iPSC-CMs after restoring a truncated form of dystrophin achieved through exon skipping or delivery of micro- or minidystrophin [ 302 , 350 , 353 , 359 , 365 ]. Lin and colleagues demonstrated that treatment with the membrane sealant compound poloxamer 188 significantly decreased resting cytosolic Ca 2+ level, repressed caspase-3 activation, and consequently suppressed apoptosis in DMD iPSC-CMs [ 344 ].…”

Section: Modeling Dystrophy-associated Cardiomyopathymentioning

confidence: 99%

“Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

Rovina

Castiglioni

Niro

et al. 2020

IJMS

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The ultimate goal of precision disease modeling is to artificially recreate the disease of affected people in a highly controllable and adaptable external environment. This field has rapidly advanced which is evident from the application of patient-specific pluripotent stem-cell-derived precision therapies in numerous clinical trials aimed at a diverse set of diseases such as macular degeneration, heart disease, spinal cord injury, graft-versus-host disease, and muscular dystrophy. Despite the existence of semi-adequate treatments for tempering skeletal muscle degeneration in dystrophic patients, nonischemic cardiomyopathy remains one of the primary causes of death. Therefore, cardiovascular cells derived from muscular dystrophy patients’ induced pluripotent stem cells are well suited to mimic dystrophin-associated cardiomyopathy and hold great promise for the development of future fully effective therapies. The purpose of this article is to convey the realities of employing precision disease models of dystrophin-associated cardiomyopathy. This is achieved by discussing, as suggested in the title echoing William Shakespeare’s words, the settlements (or “leagues”) made by researchers to manage the constraints (“betwixt mine eye and heart”) distancing them from achieving a perfect precision disease model.

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Amelioration of intracellular Ca2+ regulation by exon-45 skipping in Duchenne muscular dystrophy-induced pluripotent stem cell-derived cardiomyocytes

Cited by 15 publications

References 33 publications

Human iPSC-Based Model Reveals NOX4 as Therapeutic Target in Duchenne Cardiomyopathy

Human iPSC-Based Model Reveals NOX4 as Therapeutic Target in Duchenne Cardiomyopathy

Advances in Stem Cell Modeling of Dystrophin-Associated Disease: Implications for the Wider World of Dilated Cardiomyopathy

“Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

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