Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy

Kyrychenko, Sergii; Poláková, Eva; Kang, Chifei; Pocsai, Krisztina; Ullrich, Nina D.; Niggli, Ernst; Shirokova, Natalia

doi:10.1093/cvr/cvs425

Cited by 46 publications

(61 citation statements)

References 36 publications

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“…To establish causal relationship between cytosolic and mitochondrial pathophysiological pathways in cardiac dystrophy, we analyzed several cytosolic and mitochondrial signals: cytosolic Ca 2+ (determined in our previous work [10]) and Na + concentrations, cellular redox state (determined by us in [14]), mitochondrial redox state, mitochondrial Ca 2+ content and mitochondrial membrane potential. To follow the progression of this relationship at preclinical stages of the dystrophic cardiomyopathy, signals were monitored in cells isolated from young (1 month) and adult (3–4 months) WT and mdx mice, which do not show any sign of cardiac pathology.…”

Section: Resultsmentioning

confidence: 99%

“…stretch-activated channels and membrane ruptures [11,25]), which may also contribute to cytosolic and consequently mitochondrial Ca 2+ overload, mitochondrial depolarization and oxidation of NADH/NAD + redox couple. Further, CaMKII was found to become activated by oxidative stress during dystrophy [13,14,29] which would further amplify several Ca 2+ signaling pathways via modulation of channels and transporters (e.g. RyR2s [14,30]).…”

Section: Discussionmentioning

confidence: 99%

“…The disease is caused by a genetic defect – the lack of a functional cytoskeleton protein dystrophin [10,11] and it’s phenotype exhibits numerous cellular pathological features [12,13]. Recently we reported severe oxidative stress (resulting from overexpression of sarcolemmal NAD(P)H oxidase type II (NOX2)) and augmented intracellular Ca 2+ signaling in hearts of mdx mice well before clinical manifestations of the disease [1,14]. Our results indicated that enhanced intracellular Ca 2+ responses to mechanical challenges are associated with an increased sensitivity of sarcoplasmic (SR) Ca 2+ release channels (a.k.a.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial dysfunctions during progression of dystrophic cardiomyopathy

et al. 2015

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Duchenne muscular dystrophy (DMD) is a progressive muscle disease with severe cardiac complications. It is believed that cellular oxidative stress and augmented Ca 2+ signaling drives the development of cardiac pathology. Some mitochondrial and metabolic dysfunctions have also been reported. Here we investigate cellular mechanisms responsible for impaired mitochondrial metabolism in dystrophic cardiomyopathy at early stages of the disease. We employed electrophysiological and imaging techniques to study mitochondrial structure and function in cardiomyocytes from mdx mice, an animal model of DMD. Here we show that mitochondrial matrix was progressively oxidized in myocytes isolated from mdx mice. Moreover, an abrupt increase in workload resulted in significantly more pronounced oxidation of mitochondria in dystrophic cells. Electron micrographs revealed a gradually increased number of damaged mitochondria in mdx myocytes. Degradation in mitochondrial structure was correlated with progressive increase in mitochondrial Ca 2+ sequestration and mitochondrial depolarization, despite a substantial and persistent elevation in resting cytosolic sodium levels. Treatment of mdx cells with cyclosporine A, an inhibitor of mitochondrial permeability transition pore (mPTP), shifted both resting and workload-dependent mitochondrial redox state to the levels recorded in control myocytes. It also significantly reduced workload dependent depolarization of mitochondrial membrane in dystrophic cardiomyocytes. Overall, our studies highlight age Conflict of interest: none declared * Co-author Approval StatementThe manuscript, or part of it, has neither been published nor is currently under consideration for publication by any other journal. The co-authors have read the manuscript and approved this submission. Authors have no conflict of interests. * Conflict of Interest StatementThe manuscript, or part of it, has neither been published nor is currently under consideration for publication by any other journal. The co-authors have read the manuscript and approved this submission. Authors have no conflict of interests.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript dependent deterioration of mitochondrial function in dystrophic cardiomyocytes, which seems to be associated with excessive opening of mPTP due to oxidative stress and cellular Ca 2+ overload. Graphical Abstract KeywordsDystrophic cardiomyopathy; sodium overload; mitochondria; metabolism; oxidative stress

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial dysfunctions during progression of dystrophic cardiomyopathy

et al. 2015

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“…23) The excessive calcium influx in DMD cardiomyocytes is thought to be the result of microscopic membrane tears, 8) leakage from sarcoplasmic reticulum via "leaky" ryanodine receptor type 2, 10,11) and/or activation of stretch-activated channels 9) and TRP channels. 24,25) These hypotheses could be tested using the DMD-iPS-CM established in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have reported various abnormalities in cardiomyocytes of mdx mice such as increased susceptibility to stretch-mediated calcium overload, 8) abnormal activation in stretch-activated channels, 9) diastolic calcium leak from sarcoplasmic reticulum, 10,11) and hyperactivation of X-ROS signaling. 12) Nevertheless, mdx mice have critical limitations as a model for DMD cardiomyopathy since they do not develop heart failure.…”

Section: Uchenne Muscular Dystrophy (Dmd) Is An X-linkedmentioning

confidence: 99%

Generation of Induced Pluripotent Stem Cells From Patients With Duchenne Muscular Dystrophy and Their Induction to Cardiomyocytes

et al. 2016

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SummaryDuchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene which encodes dystrophin protein.Dystrophin defect affects cardiac muscle as well as skeletal muscle. Cardiac dysfunction is observed in all patients with DMD over 18 years of age, but there is no curative treatment for DMD cardiomyopathy. To establish novel experimental platforms which reproduce the cardiac phenotype of DMD patients, here we established iPS cell lines from T lymphocytes donated from two DMD patients, with a protocol using Sendai virus vectors. We successfully conducted the differentiation of the DMD patient-specific iPS cells into beating cardiomyocytes. DMD patient-specific iPS cells and iPS cell-derived cardiomyocytes would be a useful in vitro experimental system with which to investigate DMD cardiomyopathy. ( DMD is caused by mutations in the DMD gene which encodes dystrophin protein. Dystrophin protein constitutes a core element of dystrophin-glycoprotein complex, and plays essential roles in transmitting force and maintaining sarcolemma stability. Lack of dystrophin protein impairs membrane integrity and causes progressive degeneration and loss of skeletal muscle. Dystrophin defect also affects cardiac muscle and cardiac dysfunction is observed in all patients with DMD over 18 years of age.2) With recent advances in the management of respiratory failure for patients with DMD, increasing attention has been paid to cardiac dysfunction since the heart failure is becoming the most frequent cause of death among adult DMD patients.3) Although medical treatments using betablockers and angiotensin converting enzyme inhibitors have been reported to delay progression of DMD cardiomyopathy, 4-6) the effects are limited. Exon skipping has been developed as a novel gene therapy for DMD and some effects have been observed in skeletal muscles, however, the recovery of dystrophin was only scarcely observed in heart muscle due to the difficulty of delivering antisense oligonucleotides to cardiomyocytes.7) Thus, we need to clarify the underlying mechanisms of DMD-associated cardiomyopathy and develop novel therapeutic strategies.To date, mdx mice have been widely used as an animal model of dystrophin gene abnormality. Recent studies have reported various abnormalities in cardiomyocytes of mdx mice such as increased susceptibility to stretch-mediated calcium overload, 8) abnormal activation in stretch-activated channels, 9) diastolic calcium leak from sarcoplasmic reticulum, 10,11) and hyperactivation of X-ROS signaling.12) Nevertheless, mdx mice have critical limitations as a model for DMD cardiomyopathy since they do not develop heart failure. 13,14) On the other hand, using both in vitro and in vivo non-genetic rat models, a recent study demonstrated that microRNA-340-5p may be involved in the progression of heart failure through the interaction with DMD gene.15) Considering these issues, novel experimental platforms that reproduce the cardiac phenotype of DMD patients is critically required for the development of new drugs a...

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The activin receptor ligand trap ActRIIB:ALK4‐Fc ameliorates cardiomyopathy induced by neuromuscular disease and diabetes

Fredericks

Tang

et al. 2022

FEBS Letters

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Cardiomyopathies are ascribed to a variety of etiologies, present with diverse clinical phenotypes, and lack disease-modifying treatments. Mounting evidence implicates dysregulated activin receptor signaling in heart disease and highlights inhibition of this pathway as a potential therapeutic target. Here, we explored the effects of activin ligand inhibition using ActRIIB:ALK4-Fc, a heterodimeric receptor fusion protein, in two mechanistically distinct murine models of cardiomyopathy. Treatment with ActRIIB:ALK4-Fc significantly improved systolic or diastolic function in cardiomyopathy induced by neuromuscular disease or diabetes mellitus. Moreover, ActRIIB:ALK4-Fc corrected Ca 2+ handling protein expression in diseased heart tissues, suggesting that activin signaling inhibition could alleviate cardiomyopathies in part by rebalancing aberrant intracellular Ca 2+ homeostasis-a common underlying pathomechanism in diverse heart diseases.

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Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy

Cited by 46 publications

References 36 publications

Mitochondrial dysfunctions during progression of dystrophic cardiomyopathy

Mitochondrial dysfunctions during progression of dystrophic cardiomyopathy

Generation of Induced Pluripotent Stem Cells From Patients With Duchenne Muscular Dystrophy and Their Induction to Cardiomyocytes

The activin receptor ligand trap ActRIIB:ALK4‐Fc ameliorates cardiomyopathy induced by neuromuscular disease and diabetes

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