Background: PRKAG2 mutations cause glycogen-storage cardiomyopathy, ventricular preexcitation, and conduction system degeneration. A genetic approach that utilizes a binary inducible transgenic system was used to investigate the disease mechanism and to assess preventability and reversibility of disease features in a mouse model of glycogen-storage cardiomyopathy.
Methods And Results: Transgenic (Tg) mice expressing a human N488I PRKAG2 cDNA under control of the tetracycline-repressible alpha-myosin heavy chain promoter underwent echocardiography, ECG, and in vivo electrophysiology studies. Transgene suppression by tetracycline administration caused a reduction in cardiac glycogen content and was initiated either prenatally (Tg(OFF(E-8 weeks))) or at different time points during life (Tg(OFF(4-16 weeks)), Tg(OFF(8-20 weeks)), and Tg(OFF(>20 weeks))). One group never received tetracycline, expressing transgene throughout life (Tg(ON)). Tg(ON) mice developed cardiac hypertrophy followed by dilatation, ventricular preexcitation involving multiple accessory pathways, and conduction system disease, including sinus and atrioventricular node dysfunction.
Conclusions: Using an externally modifiable transgenic system, cardiomyopathy, cardiac dysfunction, and electrophysiological disorders were demonstrated to be reversible processes in PRKAG2 disease. Transgene suppression during early postnatal development prevented the development of accessory electrical pathways but not cardiomyopathy or conduction system degeneration. Taken together, these data provide insight into mechanisms of cardiac PRKAG2 disease and suggest that glycogen-storage cardiomyopathy can be modulated by lowering glycogen content in the heart.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957811 | PMC |
| http://dx.doi.org/10.1161/CIRCULATIONAHA.107.726752 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
A novel CD71 Centyrin:Gys1 siRNA conjugate reduces glycogen synthesis and glycogen levels in a mouse model of Pompe disease.
Mol Ther
January 2025
Center for Medical Education, Ball State University, Muncie, IN 47306, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-Muncie, Muncie, IN 47303, USA. Electronic address:
Article Synopsis
- Pompe disease results from a deficiency in acid alpha-glucosidase, leading to muscle weakness, respiratory issues, and cardiomyopathy in infants; the only current treatment is enzyme replacement therapy (ERT).
- A new approach using a Centyrin protein-conjugated short interfering RNA (siRNA) targets the transferrin receptor (CD71) and the GYS1 enzyme to inhibit glycogen synthesis, potentially restoring glycogen balance instead of just degrading it.
- In tests on a Pompe mouse model, this novel siRNA conjugate effectively reduced GYS1 levels and glycogen accumulation, improving exercise performance, indicating its promise as a therapy for late-onset Pompe disease or in combination with ERT for infants.
Catheter Ablation of Atrial Fibrillation in Infiltrative Cardiomyopathies: A Narrative Review.
J Cardiovasc Electrophysiol
January 2025
Department of Medicine, Division of Cardiology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA.
Atrial and ventricular arrhythmias are common in patients with Infiltrative heart diseases. This review discusses ablative techniques for arrhythmias in amyloidosis, sarcoidosis, hemochromatosis, and glycogen storage disorders, primarily focusing on atrial fibrillation (AF). A thorough literature review was conducted on the MEDLINE database to synthesize current knowledge and propose future research directions.
View Article and Find Full Text PDFHistory and Perspective of LAMP-2 Deficiency (Danon Disease).
Biomolecules
October 2024
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-8551, Japan.
Danon disease, an X-linked dominant vacuolar cardiomyopathy and skeletal myopathy, is caused by a primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). This disease is one of the autophagy-related muscle diseases. Male patients present with the triad of cardiomyopathy, myopathy, and intellectual disability, while female patients present with cardiomyopathy.
View Article and Find Full Text PDFClinical and Genetic Profile of Chinese Children With Danon Disease: A Single-Center Retrospective Cohort Study.
Can J Cardiol
January 2025
Department of Cardiology, Shanghai Children's Medical Centre, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Clinical Research Centre for Rare Pediatric Diseases, Shanghai Clinical Research Centre for Rare Pediatric Diseases, Shanghai Children's Medical Centre, National Children's Medical Centre, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address:
Background: Danon disease (DD) is a rare X-linked dominant lysosomal storage disorder. Studies on DD pediatric patients are limited owing to the small number of cases and challenges in early detection.
Methods: We retrospectively analysed clinical and genetic data of 29 pediatric patients who visited our hospital for treatment or genetic counselling for DD from July 2014 to December 2023.
Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs).
Biomolecules
September 2024
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem 9112001, Israel.
Article Synopsis
- - Glycogen storage disorders (GSDs) are genetic metabolic conditions caused by enzyme defects that affect glycogen metabolism, leading to mitochondrial dysfunction and issues like oxidative stress and impaired cell metabolism.
- - Specific GSD types, such as Pompe disease and Cori disease, demonstrate how enzyme deficiencies lead to glycogen accumulation, which disrupts normal mitochondrial function, causing issues like muscle weakness and liver enlargement.
- - Addressing mitochondrial dysfunction through treatments like antioxidants, enhancing mitochondrial growth, and gene therapy may offer new ways to alleviate symptoms and complications associated with GSDs, including cardiac and cognitive issues.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!