Stabilizing Ryanodine Receptors Improves Left Ventricular Function in Juvenile Dogs With Duchenne Muscular Dystrophy

Cazorla, Olivier; Barthélémy, I.; Su, Jin Bo; Méli, Albano C.; Chetboul, Valérie; Scheuermann, Valérie; Gouni, Vassiliky; Anglerot, Camille; Richard, Sylvain; Blot, Stéphane; Ghaleh, Bijan; Lacampagne, Alain

doi:10.1016/j.jacc.2021.10.014

Cited by 7 publications

(21 citation statements)

References 31 publications

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“…31 Higher beat rate in DMD hiPSC-CMs was reversed by S107. These results, in addition to our previous ones on animal models, 4,5 support that targeting the SR Ca 2+ machinery, in particular RyR2, rescued hypocontractility in DMD.…”

Section: Discussionsupporting

confidence: 86%

“…We and others have reported such pathological feature of DMD‐associated DCM using hiPSC‐CMs 3,24,25,28 . More recently, we showed left ventricular dysfunction in mdx mice and GRMD dogs, a defect that is prevented by specifically stabilizing RyR2 5 . Here, we found that DMD hiPSC‐CMs display aberrant contraction cycles accompanied by lower amplitude which may reflect hypocontractility.…”

Section: Discussionsupporting

confidence: 57%

“…Importantly, the senescence observed in GRMD dogs appears to be associated with RyR2 Ca 2+ leak, further supporting the notion that RyR2 dysfunction may play a role in the senescence process. 5 It was recently shown that oxidative stress and telomere damage were the main drivers of post-mitotic senescence in cardiomyocytes. Senescent cell ablation decreased hypertrophy and fibrosis in the aging heart.…”

Section: Discussionmentioning

confidence: 99%

“…The RyR2 macromolecular complex undergoes post-translational modifications and leak, which leads to cardiac dysfunction in the DMD mouse model (mdx) 4 and GRMD. 5 We have shown that DMD patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs) exhibit abnormal ECC. 3 These findings show that sarcoplasmic reticulum (SR) Ca 2+ leak largely contributes to the pathogenesis of DMD-associated cardiac dysfunction in mouse, dog and humans.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, functional changes in intracellular Ca 2+ homeostasis in Duchenne DCM have been linked to post‐translational changes in Ca 2+ signalling proteins. The RyR2 macromolecular complex undergoes post‐translational modifications and leak, which leads to cardiac dysfunction in the DMD mouse model ( mdx ) 4 and GRMD 5 . We have shown that DMD patient‐specific hiPSC‐derived cardiomyocytes (hiPSC‐CMs) exhibit abnormal ECC 3 .…”

Section: Introductionmentioning

confidence: 99%

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Ryanodine receptor dysfunction causes senescence and fibrosis in Duchenne dilated cardiomyopathy

Souidi,

Resta,

Dridi

et al. 2024

J cachexia sarcopenia muscle

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BackgroundDuchenne muscular dystrophy (DMD) is an X‐linked disorder characterized by progressive muscle weakness due to the absence of functional dystrophin. DMD patients also develop dilated cardiomyopathy (DCM). We have previously shown that DMD (mdx) mice and a canine DMD model (GRMD) exhibit abnormal intracellular calcium (Ca2+) cycling related to early‐stage pathological remodelling of the ryanodine receptor intracellular calcium release channel (RyR2) on the sarcoplasmic reticulum (SR) contributing to age‐dependent DCM.MethodsHere, we used hiPSC‐CMs from DMD patients selected by Speckle‐tracking echocardiography and canine DMD cardiac biopsies to assess key early‐stage Duchenne DCM features.ResultsDystrophin deficiency was associated with RyR2 remodelling and SR Ca2+ leak (RyR2 Po of 0.03 ± 0.01 for HC vs. 0.16 ± 0.01 for DMD, P < 0.01), which led to early‐stage defects including senescence. We observed higher levels of senescence markers including p15 (2.03 ± 0.75 for HC vs. 13.67 ± 5.49 for DMD, P < 0.05) and p16 (1.86 ± 0.83 for HC vs. 10.71 ± 3.00 for DMD, P < 0.01) in DMD hiPSC‐CMs and in the canine DMD model. The fibrosis was increased in DMD hiPSC‐CMs. We observed cardiac hypocontractility in DMD hiPSC‐CMs. Stabilizing RyR2 pharmacologically by S107 prevented most of these pathological features, including the rescue of the contraction amplitude (1.65 ± 0.06 μm for DMD vs. 2.26 ± 0.08 μm for DMD + S107, P < 0.01). These data were confirmed by proteomic analyses, in particular ECM remodelling and fibrosis.ConclusionsWe identified key cellular damages that are established earlier than cardiac clinical pathology in DMD patients, with major perturbation of the cardiac ECC. Our results demonstrated that cardiac fibrosis and premature senescence are induced by RyR2 mediated SR Ca2+ leak in DMD cardiomyocytes. We revealed that RyR2 is an early biomarker of DMD‐associated cardiac damages in DMD patients. The progressive and later DCM onset could be linked with the RyR2‐mediated increased fibrosis and premature senescence, eventually causing cell death and further cardiac fibrosis in a vicious cycle leading to further hypocontractility as a major feature of DCM. The present study provides a novel understanding of the pathophysiological mechanisms of the DMD‐induced DCM. By targeting RyR2 channels, it provides a potential pharmacological treatment.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Ryanodine receptor dysfunction causes senescence and fibrosis in Duchenne dilated cardiomyopathy

Souidi,

Resta,

Dridi

et al. 2024

J cachexia sarcopenia muscle

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Ryanodine Receptors Matter for Cardiac Function in Duchenne Muscular Dystrophy

Kupatt

Bozoglu

2021

Journal of the American College of Cardiology

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Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders

Miotto,

Reiken,

Wronska

et al. 2024

Nat Commun

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Heart failure, the leading cause of mortality and morbidity in the developed world, is characterized by cardiac ryanodine receptor 2 channels that are hyperphosphorylated, oxidized, and depleted of the stabilizing subunit calstabin-2. This results in a diastolic sarcoplasmic reticulum Ca2+ leak that impairs cardiac contractility and triggers arrhythmias. Genetic mutations in ryanodine receptor 2 can also cause Ca2+ leak, leading to arrhythmias and sudden cardiac death. Here, we solved the cryogenic electron microscopy structures of ryanodine receptor 2 variants linked either to heart failure or inherited sudden cardiac death. All are in the primed state, part way between closed and open. Binding of Rycal drugs to ryanodine receptor 2 channels reverts the primed state back towards the closed state, decreasing Ca2+ leak, improving cardiac function, and preventing arrhythmias. We propose a structural-physiological mechanism whereby the ryanodine receptor 2 channel primed state underlies the arrhythmias in heart failure and arrhythmogenic disorders.

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Stabilizing Ryanodine Receptors Improves Left Ventricular Function in Juvenile Dogs With Duchenne Muscular Dystrophy

Cited by 7 publications

References 31 publications

Ryanodine receptor dysfunction causes senescence and fibrosis in Duchenne dilated cardiomyopathy

Ryanodine receptor dysfunction causes senescence and fibrosis in Duchenne dilated cardiomyopathy

Ryanodine Receptors Matter for Cardiac Function in Duchenne Muscular Dystrophy

Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders

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