Ryanodine receptor dysfunction causes senescence and fibrosis in Duchenne dilated cardiomyopathy.

Autor: Souidi M; PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France., Resta J; Institute of Metabolic and Cardiovascular Diseases (I2MC), INSERM, University of Toulouse, Toulouse, France., Dridi H; Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA., Sleiman Y; PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France., Reiken S; Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA., Formoso K; Institute of Metabolic and Cardiovascular Diseases (I2MC), INSERM, University of Toulouse, Toulouse, France., Colombani S; PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France., Amédro P; PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.; Department of Pediatric and Congenital Cardiology, M3C Regional Reference CHD Centre, Clinical Investigation Centre, Montpellier University Hospital, Montpellier, France., Meyer P; PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.; Department of Pediatric Neurology, Reference Center for Neuromuscular Diseases AOC, Clinical Investigation Centre, Montpellier University Hospital, Montpellier, France., Charrabi A; PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France., Vincenti M; PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.; Department of Pediatric and Congenital Cardiology, M3C Regional Reference CHD Centre, Clinical Investigation Centre, Montpellier University Hospital, Montpellier, France., Liu Y; Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA., Soni RK; Proteomics and Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, New York, NY, USA., Lezoualc'h F; Institute of Metabolic and Cardiovascular Diseases (I2MC), INSERM, University of Toulouse, Toulouse, France., Stéphane Blot DVM; IMRB - Biology of the neuromuscular system, INSERM, UPEC, EFS, EnvA, Maisons-Alfort, France., Rivier F; PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.; Department of Pediatric Neurology, Reference Center for Neuromuscular Diseases AOC, Clinical Investigation Centre, Montpellier University Hospital, Montpellier, France., Cazorla O; PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France., Parini A; Institute of Metabolic and Cardiovascular Diseases (I2MC), INSERM, University of Toulouse, Toulouse, France., Marks AR; Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA., Mialet-Perez J; Institute of Metabolic and Cardiovascular Diseases (I2MC), INSERM, University of Toulouse, Toulouse, France.; MitoLab Team, UMR CNRS 6015, INSERM U1083, MitoVasc Institute, Angers University, Angers, France., Lacampagne A; PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France., Meli AC; PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.
Jazyk: angličtina
Zdroj: Journal of cachexia, sarcopenia and muscle [J Cachexia Sarcopenia Muscle] 2024 Apr; Vol. 15 (2), pp. 536-551. Date of Electronic Publication: 2024 Jan 14.
DOI: 10.1002/jcsm.13411
Abstrakt: Background: Duchenne 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 (Ca 2+ ) 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.
Methods: Here, 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.
Results: Dystrophin deficiency was associated with RyR2 remodelling and SR Ca 2+ 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.
Conclusions: We 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 Ca 2+ 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.
(© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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