Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability
| العنوان: | Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability |
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| المؤلفون: | Daniel E. Michele, Anoop Gopal, Marc Witcher, Matthew D. Campbell |
| المصدر: | American Journal of Physiology-Heart and Circulatory Physiology. 310:H1140-H1150 |
| بيانات النشر: | American Physiological Society, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Cardiomyopathy, Dilated, musculoskeletal diseases, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Cell Membrane Permeability, Glycosylation, Physiology, Mutant, 030105 genetics & heredity, Biology, Transfection, medicine.disease_cause, Mechanotransduction, Cellular, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, Sarcoglycans, Physiology (medical), Internal medicine, medicine, Animals, Humans, Myocyte, Genetic Predisposition to Disease, Myocytes, Cardiac, Cells, Cultured, Genes, Dominant, Mutation, Cell Membrane, Cardiac myocyte, Dilated cardiomyopathy, musculoskeletal system, medicine.disease, Myocardial Contraction, Cell biology, Protein Transport, Sarcoglycan, Phenotype, Endocrinology, chemistry, Call for Papers, Stress, Mechanical, Cardiology and Cardiovascular Medicine, Protein Processing, Post-Translational, Limb-girdle muscular dystrophy |
| الوصف: | Delta-sarcoglycan is a component of the sarcoglycan subcomplex within the dystrophin-glycoprotein complex located at the plasma membrane of muscle cells. While recessive mutations in δ-sarcoglycan cause limb girdle muscular dystrophy 2F, dominant mutations in δ-sarcoglycan have been linked to inherited dilated cardiomyopathy (DCM). The purpose of this study was to investigate functional cellular defects present in adult cardiac myocytes expressing mutant δ-sarcoglycans harboring the dominant inherited DCM mutations R71T or R97Q. This study demonstrates that DCM mutant δ-sarcoglycans can be stably expressed in adult rat cardiac myocytes and traffic similarly to wild-type δ-sarcoglycan to the plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex. However, expression of DCM mutant δ-sarcoglycan in adult rat cardiac myocytes is sufficient to alter cardiac myocyte plasma membrane stability in the presence of mechanical strain. Upon cyclical cell stretching, cardiac myocytes expressing mutant δ-sarcoglycan R97Q or R71T have increased cell-impermeant dye uptake and undergo contractures at greater frequencies than myocytes expressing normal δ-sarcoglycan. Additionally, the R71T mutation creates an ectopic N-linked glycosylation site that results in aberrant glycosylation of the extracellular domain of δ-sarcoglycan. Therefore, appropriate glycosylation of δ-sarcoglycan may also be necessary for proper δ-sarcoglycan function and overall dystrophin-glycoprotein complex function. These studies demonstrate that DCM mutations in δ-sarcoglycan can exert a dominant negative effect on dystrophin-glycoprotein complex function leading to myocardial mechanical instability that may underlie the pathogenesis of δ-sarcoglycan-associated DCM.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/dilated-cardiomyopathy-delta-sarcoglycan-mutations-cause-cardiomyocyte-membrane-instabilityTest/ . |
| تدمد: | 1522-1539 0363-6135 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4eb48c2edf1034e2def2b31358625978Test https://doi.org/10.1152/ajpheart.00521.2015Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4eb48c2edf1034e2def2b31358625978 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15221539 03636135 |
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