ArticleCardiovascular research2013
Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy.
Article in Cardiovascular research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 50 citations in OpenAlex.
- Review
- Remodeled connexin 43 hemichannels alter cardiac excitability and promote arrhythmias.The Journal of general physiology · 2023Article
- Ion Channels of the Sarcolemma and Intracellular Organelles in Duchenne Muscular Dystrophy: A Role in the Dysregulation of Ion Homeostasis and a Possible Target for Therapy.International journal of molecular sciences · 2023Review
- Post-translational Modification in Muscular Dystrophies.Advances in experimental medicine and biology · 2022Article
- Calcium handling maturation and adaptation to increased substrate stiffness in human iPSC-derived cardiomyocytes: The impact of full-length dystrophin deficiency.Frontiers in physiology · 2022Article
- Cardiomyocyte-produced miR-339-5p mediates pathology in Duchenne muscular dystrophy cardiomyopathy.Human molecular genetics · 2021Article
- Disrupted Calcium Homeostasis in Duchenne Muscular Dystrophy: A Common Mechanism behind Diverse Consequences.International journal of molecular sciences · 2021Review
- Duchenne muscular dystrophy.Nature reviews. Disease primers · 2021Review
- Apocynin Treatment Prevents Cardiac Connexin 43 Hemichannels Hyperactivity by Reducing Nitroso-Redox Stress in Mdx Mice.International journal of molecular sciences · 2020Article
- Increased RyR2 activity is exacerbated by calcium leak-induced mitochondrial ROS.Basic research in cardiology · 2020Article
- S-nitrosylation of connexin43 hemichannels elicits cardiac stress-induced arrhythmias in Duchenne muscular dystrophy mice.JCI insight · 2019Article
- Article
- Endoplasmic reticulum stress alters ryanodine receptor function in the murine pancreatic β cell.The Journal of biological chemistry · 2019Article
- Exosomes exert cardioprotection in dystrophin-deficient cardiomyocytes via ERK1/2-p38/MAPK signaling.Scientific reports · 2018Article
- Oxidized CaMKII (CaCirculation. Arrhythmia and electrophysiology · 2018Article
- Pharmacological Modulation of Mitochondrial CaFrontiers in physiology · 2018Article
- Deficit in PINK1/PARKIN-mediated mitochondrial autophagy at late stages of dystrophic cardiomyopathy.Cardiovascular research · 2018Article
- Functional correction of dystrophin actin binding domain mutations by genome editing.JCI insight · 2017Article
- Dystrophic Cardiomyopathy: Complex Pathobiological Processes to Generate Clinical Phenotype.Journal of cardiovascular development and disease · 2017Review
- Reversible redox modifications of ryanodine receptor ameliorate ventricular arrhythmias in the ischemic-reperfused heart.American journal of physiology. Heart and circulatory physiology · 2016Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
aimsDuchenne muscular dystrophy (DMD) is a muscle disease with serious cardiac complications. Changes in Ca(2+) homeostasis and oxidative stress were recently associated with cardiac deterioration, but the cellular pathophysiological mechanisms remain elusive. We investigated whether the activity of ryanodine receptor (RyR) Ca(2+) release channels is affected, whether changes in function are cause or consequence and which post-translational modifications drive disease progression. METHODS AND
resultsElectrophysiological, imaging, and biochemical techniques were used to study RyRs in cardiomyocytes from mdx mice, an animal model of DMD. Young mdx mice show no changes in cardiac performance, but do so after ∼8 months. Nevertheless, myocytes from mdx pups exhibited exaggerated Ca(2+) responses to mechanical stress and 'hypersensitive' excitation-contraction coupling, hallmarks of increased RyR Ca(2+) sensitivity. Both were normalized by antioxidants, inhibitors of NAD(P)H oxidase and CaMKII, but not by NO synthases and PKA antagonists. Sarcoplasmic reticulum Ca(2+) load and leak were unchanged in young mdx mice. However, by the age of 4-5 months and in senescence, leak was increased and load was reduced, indicating disease progression. By this age, all pharmacological interventions listed above normalized Ca(2+) signals and corrected changes in ECC, Ca(2+) load, and leak.
conclusionOur findings suggest that increased RyR Ca(2+) sensitivity precedes and presumably drives the progression of dystrophic cardiomyopathy, with oxidative stress initiating its development. RyR oxidation followed by phosphorylation, first by CaMKII and later by PKA, synergistically contributes to cardiac deterioration.
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