Browse
Submit Data
Databases
API
Help

Dataset Information

9 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Ryanodine receptor remodeling in cardiomyopathy and muscular dystrophy caused by lamin A/C gene mutation.

ABSTRACT: Mutations in the lamin A/C gene (LMNA), which encodes A-type lamins, cause several diseases called laminopathies, the most common of which is dilated cardiomyopathy with muscular dystrophy. The role of Ca2+ regulation in these diseases remain poorly understood. We now show biochemical remodeling of the ryanodine receptor (RyR)/intracellular Ca2+ release channel in heart samples from human subjects with LMNA mutations, including protein kinase A-catalyzed phosphorylation, oxidation and depletion of the stabilizing subunit calstabin. In the LmnaH222P/H222P murine model of Emery-Dreifuss muscular dystrophy caused by LMNA mutation, we demonstrate an age-dependent biochemical remodeling of RyR2 in the heart and RyR1 in skeletal muscle. This RyR remodeling is associated with heart and skeletal muscle dysfunction. Defective heart and muscle function are ameliorated by treatment with a novel Rycal small molecule drug (S107) that fixes 'leaky' RyRs. SMAD3 phosphorylation is increased in hearts and diaphragms of LmnaH222P/H222P mice, which enhances NADPH oxidase binding to RyR channels, contributing to their oxidation. There is also increased generalized protein oxidation, increased calcium/calmodulin-dependent protein kinase II-catalyzed phosphorylation of RyRs and increased protein kinase A activity in these tissues. Our data show that RyR remodeling plays a role in cardiomyopathy and skeletal muscle dysfunction caused by LMNA mutation and identify these Ca2+ channels as a potential therapeutic target.

SUBMITTER: Dridi H

PROVIDER: S-EPMC7906753 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Nanoscale remodeling of ryanodine receptor cluster size underlies cerebral microvascular dysfunction in Duchenne muscular dystrophy.

Project description:Duchenne muscular dystrophy (DMD) results from mutations in the gene encoding dystrophin which lead to impaired function of skeletal and cardiac muscle, but little is known about the effects of the disease on vascular smooth muscle cells (SMCs). Here we used the mdx mouse model to study the effects of mutant dystrophin on the regulation of cerebral artery and arteriole SMC contractility, focusing on an important Ca2+-signaling pathway composed of type 2 ryanodine receptors (RyR2s) on the sarcoplasmic reticulum (SR) and large-conductance Ca2+-activated K+ (BK) channels on the plasma membrane. Nanoscale superresolution image analysis revealed that RyR2 and BK? were organized into discrete clusters, and that the mean size of RyR2 clusters that colocalized with BK? was larger in SMCs from mdx mice (?62 RyR2 monomers) than in controls (?40 RyR2 monomers). We further found that the frequency and signal mass of spontaneous, transient Ca2+-release events through SR RyR2s ("Ca2+ sparks") were greater in SMCs from mdx mice. Patch-clamp electrophysiological recordings indicated a corresponding increase in Ca2+-dependent BK channel activity. Using pressure myography, we found that cerebral pial arteries and parenchymal arterioles from mdx mice failed to develop appreciable spontaneous myogenic tone. Inhibition of RyRs with tetracaine and blocking of BK channels with paxilline restored myogenic tone to control levels, demonstrating that enhanced RyR and BK channel activity is responsible for the diminished pressure-induced constriction of arteries and arterioles from mdx mice. We conclude that increased size of RyR2 protein clusters in SMCs from mdx mice increases Ca2+ spark and BK channel activity, resulting in cerebral microvascular dysfunction.

| S-EPMC6187127 | biostudies-literature

Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation.

Project description:Mutations in the lamin A/C gene (LMNA), which encodes A-type lamins, cause a diverse range of diseases collectively called laminopathies, the most common of which is dilated cardiomyopathy. Emerging evidence suggests that LMNA mutations cause disease by altering cell signaling pathways, but the specific mechanisms are poorly understood. We show that the AKT-mammalian target of rapamycin pathway is hyperactivated in hearts of mice with cardiomyopathy caused by Lmna mutation and that in vivo administration of the rapamycin analog temsirolimus prevents deterioration of cardiac function. We also show defective autophagy in hearts of these mice and demonstrate that improvement in heart function induced by pharmacological interventions is correlated with enhanced autophagy. These findings provide a rationale for treatment of LMNA cardiomyopathy with rapalogs and implicate defective autophagy as a pathogenic mechanism of cardiomyopathy arising from LMNA mutation.

| S-EPMC3700376 | biostudies-other

Dual specificity phosphatase 4 mediates cardiomyopathy caused by lamin A/C (LMNA) gene mutation.

Project description:BackgroundMutations in LMNA gene cause cardiomyopathy, for which mechanistic insights are lacking.ResultsDusp4 expression is enhanced in hearts with LMNA cardiomyopathy, and its overexpression in mice causes it by activating AKT-mTOR signaling that impairs autophagy.ConclusionsDusp4 causes cardiac dysfunction and may contribute to the development of LMNA cardiomyopathy.SignificanceRevealing pathogenic mechanisms of LMNA cardiomyopathy is essential for the development of mechanism-based therapies. Mutations in the lamin A/C gene (LMNA) cause a diverse spectrum of diseases, the most common of which is dilated cardiomyopathy often with skeletal muscular dystrophy. Lamin A and C are fundamental components of the nuclear lamina, a dynamic meshwork of intermediate filaments lining the nuclear envelope inner membrane. Prevailing evidence suggests that the nuclear envelope functions as a signaling node and that abnormality in the nuclear lamina leads to dysregulated signaling pathways that underlie disease pathogenesis. We previously showed that activated ERK1/2 in hearts of a mouse model of LMNA cardiomyopathy (Lmna(H222P/H222P) mice) contributes to disease, but the complete molecular pathogenesis remains poorly understood. Here we uncover a pathogenic role of dual specificity phosphatase 4 (Dusp4), which is transcriptionally induced by ERK1/2. Dusp4 is highly expressed in the hearts of Lmna(H222P/H222P) mice, and transgenic mice with cardiac-selective overexpression of Dusp4 display heart dysfunction similar to LMNA cardiomyopathy. In both primary tissue and cell culture models, overexpression of Dusp4 positively regulates AKT-mTOR signaling, resulting in impaired autophagy. These findings identify a pathogenic role of Dusp4 in LMNA cardiomyopathy.

| S-EPMC3504766 | biostudies-literature

Autosomal dominant Emery-Dreifuss muscular dystrophy caused by a mutation in the lamin A/C gene identified by exome sequencing: a case report.

Project description:BackgroundEmery-Dreifuss Muscular Dystrophy (EDMD) is an uncommon genetic disease among the group of muscular dystrophies. EDMD is clinically heterogeneous and resembles other muscular dystrophies. Mutation of the lamin A/C (LMNA) gene, which causes EDMD, also causes many other diseases. There is inter and intrafamilial variability in clinical presentations. Precise diagnosis can help in patient surveillance, especially before they present with cardiac problems. Hence, this paper shows how a molecular work-out by next-generation sequencing can help this group of disorders.Case presentationA 2-year-10-month-old Javanese boy presented to our clinic with weakness in lower limbs and difficulty climbing stairs. The clinical features of the boy were Gower's sign, waddling gait and high CK level. His father presented with elbow contractures and heels, toe walking and weakness of limbs, pelvic, and peroneus muscles. Exome sequencing on this patient detected a pathogenic variant in the LMNA gene (NM_170707: c.C1357T: NP_733821: p.Arg453Trp) that has been reported to cause Autosomal Dominant Emery-Dreifuss muscular dystrophy. Further examination showed total atrioventricular block and atrial fibrillation in the father.ConclusionEDMD is a rare disabling muscular disease that poses a diagnostic challenge. Family history work-up and thorough neuromuscular physical examinations are needed. Early diagnosis is essential to recognize orthopaedic and cardiac complications, improving the clinical management and prognosis of the disease. Exome sequencing could successfully determine pathogenic variants to provide a conclusive diagnosis.

| S-EPMC9575219 | biostudies-literature

Prevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathy.

Project description:Aberrant expression of the cardiac gap junction protein connexin-43 (Cx43) has been suggested as playing a role in the development of cardiac disease in the mdx mouse model of Duchenne muscular dystrophy (DMD); however, a mechanistic understanding of this association is lacking. Here, we identified a reduction of phosphorylation of Cx43 serines S325/S328/S330 in human and mouse DMD hearts. We hypothesized that hypophosphorylation of Cx43 serine-triplet triggers pathological Cx43 redistribution to the lateral sides of cardiomyocytes (remodeling). Therefore, we generated knockin mdx mice in which the Cx43 serine-triplet was replaced with either phospho-mimicking glutamic acids (mdxS3E) or nonphosphorylatable alanines (mdxS3A). The mdxS3E, but not mdxS3A, mice were resistant to Cx43 remodeling, with a corresponding reduction of Cx43 hemichannel activity. MdxS3E cardiomyocytes displayed improved intracellular Ca2+ signaling and a reduction of NADPH oxidase 2 (NOX2)/ROS production. Furthermore, mdxS3E mice were protected against inducible arrhythmias, related lethality, and the development of cardiomyopathy. Inhibition of microtubule polymerization by colchicine reduced both NOX2/ROS and oxidized CaMKII, increased S325/S328/S330 phosphorylation, and prevented Cx43 remodeling in mdx hearts. Together, these results demonstrate a mechanism of dystrophic Cx43 remodeling and suggest that targeting Cx43 may be a therapeutic strategy for preventing heart dysfunction and arrhythmias in DMD patients.

| S-EPMC7108916 | biostudies-literature

Abnormal p38? mitogen-activated protein kinase signaling in dilated cardiomyopathy caused by lamin A/C gene mutation.

Project description:We previously interrogated the transcriptome in heart tissue from Lmna(H222P/H222P) mice, a mouse model of cardiomyopathy caused by lamin A/C gene (LMNA) mutation, and found that the extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase branches of the mitogen-activated protein (MAP) kinase signaling pathway were abnormally hyperactivated prior to the onset of significant cardiac impairment. We have now used an alternative gene expression analysis tool to reanalyze this transcriptome and identify hyperactivation of a third branch of the MAP kinase cascade, p38? signaling. Biochemical analysis of hearts from Lmna(H222P/H222P) mice showed enhanced p38? activation prior to and after the onset of heart disease as well as in hearts from human subjects with cardiomyopathy caused by LMNA mutations. Treatment of Lmna(H222P/H222P) mice with the p38? inhibitor ARRY-371797 prevented left ventricular dilatation and deterioration of fractional shortening compared with placebo-treated mice but did not block the expression of collagen genes involved in cardiac fibrosis. These results demonstrate that three different branches of the MAP kinase signaling pathway with overlapping consequences are involved in the pathogenesis of cardiomyopathy caused by LMNA mutations. They further suggest that pharmacological inhibition of p38? may be useful in the treatment of this disease.

| S-EPMC3441127 | biostudies-literature

A novel de novo mutation in Lamin A/C gene in Emery Dreifuss Muscular Dystrophy patient with atrial paralysis.

Project description:We present a 26 year old female Indonesian patient with full spectrum Emery Dreifuss Muscular Dystrophy (EDMD) characterized with contracture of elbows, heel cord and pelvic muscle wasting and weakness and atrial paralysis, as rare cardiac findings in EDMD . A novel de novo pathogenic heterozygous missense mutation (NM_170707.3: c.122G>T, p.Arg41Leu) in exon 1 was detected. Preventing atrial paralytic patients from systemic embolism is important. Early diagnosis, intervention, targeted management and counseling are necessary for a better health and life quality of individuals with EDMD.

| S-EPMC5673335 | biostudies-literature

Mild and severe muscular dystrophy caused by a single gamma-sarcoglycan mutation.

Project description:Autosomal recessive muscular dystrophy is genetically heterogeneous. One form of this disorder, limb-girdle muscular dystrophy type 2C (LGMD 2C), is prevalent in northern Africa and has been shown to be associated with a single mutation in the gene encoding the dystrophin-associated protein gamma-sarcoglycan. The previous mutation analysis of gamma-sarcoglycan required the availability of muscle biopsies. To establish a mutation assay for genomic DNA, the intron-exon structure of the gamma-sarcoglycan gene was determined, and primers were designed to amplify each of the exons encoding gamma-sarcoglycan. We studied a group of Brazilian muscular dystrophy patients for mutations in the gamma-sarcoglycan gene. These patients were selected on the basis of autosomal inheritance and/or the presence of normal dystrophin and/or deficiency of alpha-sarcoglycan immunostaining. Four of 19 patients surveyed had a single, homozygous mutation in the gamma-sarcoglycan gene. The mutation identified in these patients, all of African-Brazilian descent, is identical to that seen in the North African population, suggesting that even patients of remote African descent may carry this mutation. The phenotype in these patients varied considerably. Of four families with an identical mutation, three have a severe Duchenne-like muscular dystrophy. However, one family has much milder symptoms, suggesting that other loci may be present that modify the severity of the clinical course resulting from gamma-sarcoglycan gene mutations.

| S-EPMC1914841 | biostudies-other

New Duchenne muscular dystrophy mutation

Project description: Not available

| S-BSST237 | biostudies-other

Cardiac dysrhythmias,cardiomyopathy and muscular dystrophy in patients with Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B.

Project description:Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy type 1B (LGMD1B) are characterized by cardiac dysrhythmias, late-onset cardiomyopathy, slowly progressive skeletal myopathy and contractures of the neck, elbows and ankles. The causative mutation is either in the emerin gene (X-linked recessive EDMD) or lamin A/C gene (autosomal dominant EDMD2 or LGMD1B). We report three cases of EDMD, EDMD2 and LGMD1B. A 14-yr-old boy showed limitation of cervical flexion and contractures of both elbows and ankles. Sinus arrest with junctional escape beats was noted. He was diagnosed as X-linked recessive EDMD (MIM 310300). A 28-yr-old female showed severe wasting and weakness of humeroperoneal muscles. Marked limitation of cervical flexion and contractures of both elbows and ankles were noted. Varying degrees of AV block were noted. She was diagnosed as autosomal dominant EDMD2 (MIM 181350). A 41-yr-old female had contractures of both ankles and limb-girdle type muscular dystrophy. ECG revealed atrial tachycardia with high grade AV block. She was diagnosed as autosomal dominant LGMD1B (MIM 159001). Cardiac dysrhythmias in EDMD and LGMD1B include AV block, bradycardia, atrial tachycardia, atrial fibrillation, and atrial standstill, causing sudden death necessitating pacemaker implantation. Cardiologists should know about these unusual genetic diseases with conduction defects, especially in young adults.

| S-EPMC2808607 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data