Subcellular Localization of Dystrophin Isoforms in Cardiomyocytes and Phenotypic Analysis of Dystrophin-deficient Mice Reveal Cardiac Myopathy is Predominantly Caused by a Deficiency in Full-length Dystrophin

Masubuchi, Nami; Shidoh, Yuichi; Kondo, Shunzo; Takatoh, Jun; Hanaoka, Kazunori

doi:10.1538/expanim.62.211

Cited by 18 publications

(17 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At cell edges dystrophin domains appeared in line with Z-bands with matching periodicity. This is similar to previous observations in wild-type mice, 27 suggesting codependence in forming costameric regions. These findings also support the idea that costameres are hotspots during early stages of hiPSC-CM maturation, similar to human foetal ventricular tissue.…”

Section: Discussionsupporting

confidence: 92%

Absence of full-length dystrophin impairs normal maturation and contraction of cardiomyocytes derived from human-induced pluripotent stem cells

Pioner

Guan

Klaiman

et al. 2019

Cardiovascular Research

View full text Add to dashboard Cite

Heart failure invariably affects patients with various forms of muscular dystrophy (MD), but the onset and molecular sequelae of altered structure and function resulting from full-length dystrophin (Dp427) deficiency in MD heart tissue are poorly understood. To better understand the role of dystrophin in cardiomyocyte development and the earliest phase of Duchenne muscular dystrophy (DMD) cardiomyopathy, we studied human cardiomyocytes differentiated from induced pluripotent stem cells (hiPSC-CMs) obtained from the urine of a DMD patient.

show abstract

Section: Discussionsupporting

confidence: 92%

Absence of full-length dystrophin impairs normal maturation and contraction of cardiomyocytes derived from human-induced pluripotent stem cells

Pioner

Guan

Klaiman

et al. 2019

Cardiovascular Research

View full text Add to dashboard Cite

show abstract

“…One may speculate that, because dystrophin expression is lost at an earlier time point in mdx 5cv than in MHC-Cre + mice, Na v 1.5 is not yet affected in MHC-Cre + mice. In addition, an increase in utrophin expression may compensate for the dystrophin down-regulation, which has already been reported in previous studies [20][21][22] . Importantly, in a recent study, the presence of more than 600 loxP like sites in the genome of C57Bl/6 mice has been reported 3 .…”

Section: Discussionsupporting

confidence: 72%

Dystrophin and calcium current are decreased in cardiomyocytes expressing Cre enzyme driven by αMHC but not TNT promoter

Gillet

Guichard

Essers

et al. 2019

Preprint

View full text Add to dashboard Cite

Background:The Cre/lox system is a potent technology to control gene expression in mouse tissues. However, cardiac alterations following cardiac-specific Cre enzyme expression in non-loxP-flanked genome heart have been reported. Recently, many loxP like sites have been identified in the wild-type mouse genome. Interestingly one of them is localized in the Dmd gene encoding the dystrophin protein known to be crucial for stabilization of cardiac voltage-gated ion channels Na v 1.5 and Ca v 1.2. Aim: Here, we studied the potential alteration of dystrophin expression in adult alpha-myosin heavy chain (MHC)-Cre mice, which are extensively used for cardiac-specific recombination, and investigated Troponin T (TNT)-Cre mice as a potential alternative. Methods: Cardiac-specific MHC-Cre and TNT-Cre mouse lines expressing Cre recombinase under the control of the cardiac-specific alpha-myosin-heavy chain, and rat cardiac troponin T2 promoter respectively were used. Western blots, quantitative RT-PCR, immunostainings, and patch-clamp experiments were performed to characterize MHC-Cre and TNT-Cre mouse hearts and cardiomyocytes. Results: Dystrophin protein level was decreased in hearts from 12-week-old MHC-Cre + mice compared to MHC-Cre -. Reduction of dystrophin was more pronounced with age. No significant difference was observed between 8-week-old MHC-Cre + mice and MHC-Cre -. Immunostainings performed on cardiac sections showed reduced dystrophin signal at the lateral membrane of MHC-Cre + cardiomyocytes. Quantitative RT-PCR showed decreased mRNA levels of Dmd gene encoding dystrophin. Finally, patch-clamp experiments showed a significant decrease in calcium current (I CaL ) in adult MHC-Cre + cardiomyocytes compared to MHC-Cre -. Neither dystrophin nor I CaL was reduced in adult TNT-Cre + mouse hearts compared to TNT-Cre -. Conclusion:In contrary to TNT-Cre + mice, the sole expression of Cre recombinase can alter the cardiac phenotype of MHC-Cre + mice. Thus, researchers should include the "Cre-only" condition as control condition when designing experiments with Cre mouse strains.

show abstract

“…Dystrophin is a large 427-kDa protein product encoded by the Duchenne muscular dystrophy gene. In addition to the full-length dystrophin Dp427, a short isoform Dp71 is also expressed in mouse cardiomyocytes (141). Dystrophin is present at cardiac t-tubules from the time tubules develop.…”

Section: Costamere Complex and T-tubule Membraneassociated Scaffoldsmentioning

confidence: 99%

Cardiac T-Tubule Microanatomy and Function

Hong

Shaw

2017

Physiological Reviews

145

120

View full text Add to dashboard Cite

Unique to striated muscle cells, transverse tubules (t-tubules) are membrane organelles that consist of sarcolemma penetrating into the myocyte interior, forming a highly branched and interconnected network. Mature t-tubule networks are found in mammalian ventricular cardiomyocytes, with the transverse components of t-tubules occurring near sarcomeric z-discs. Cardiac t-tubules contain membrane microdomains enriched with ion channels and signaling molecules. The microdomains serve as key signaling hubs in regulation of cardiomyocyte function. Dyad microdomains formed at the junctional contact between t-tubule membrane and neighboring sarcoplasmic reticulum are critical in calcium signaling and excitation-contraction coupling necessary for beat-to-beat heart contraction. In this review, we provide an overview of the current knowledge in gross morphology and structure, membrane and protein composition, and function of the cardiac t-tubule network. We also review in detail current knowledge on the formation of functional membrane subdomains within t-tubules, with a particular focus on the cardiac dyad microdomain. Lastly, we discuss the dynamic nature of t-tubules including membrane turnover, trafficking of transmembrane proteins, and the life cycles of membrane subdomains such as the cardiac BIN1-microdomain, as well as t-tubule remodeling and alteration in diseased hearts. Understanding cardiac t-tubule biology in normal and failing hearts is providing novel diagnostic and therapeutic opportunities to better treat patients with failing hearts.

show abstract

Subcellular Localization of Dystrophin Isoforms in Cardiomyocytes and Phenotypic Analysis of Dystrophin-deficient Mice Reveal Cardiac Myopathy is Predominantly Caused by a Deficiency in Full-length Dystrophin

Cited by 18 publications

References 18 publications

Absence of full-length dystrophin impairs normal maturation and contraction of cardiomyocytes derived from human-induced pluripotent stem cells

Absence of full-length dystrophin impairs normal maturation and contraction of cardiomyocytes derived from human-induced pluripotent stem cells

Dystrophin and calcium current are decreased in cardiomyocytes expressing Cre enzyme driven by αMHC but not TNT promoter

Cardiac T-Tubule Microanatomy and Function

Contact Info

Product

Resources

About