scholarly journals Mechanisms of TTNtv-Related Dilated Cardiomyopathy: Insights from Zebrafish Models

2021 ◽  
Vol 8 (2) ◽  
pp. 10
Author(s):  
Celine F. Santiago ◽  
Inken G. Huttner ◽  
Diane Fatkin
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Development ◽  
Heart Function ◽  
Genetic Disorders ◽  
Zebrafish Model ◽  
Sarcomeric Protein ◽  
Treatment And Prevention ◽  
Muscle Disorder ◽  
Genetic And Environmental Factors ◽  
Sarcomere Assembly

Dilated cardiomyopathy (DCM) is a common heart muscle disorder characterized by ventricular dilation and contractile dysfunction that is associated with significant morbidity and mortality. New insights into disease mechanisms and strategies for treatment and prevention are urgently needed. Truncating variants in the TTN gene, which encodes the giant sarcomeric protein titin (TTNtv), are the most common genetic cause of DCM, but exactly how TTNtv promote cardiomyocyte dysfunction is not known. Although rodent models have been widely used to investigate titin biology, they have had limited utility for TTNtv-related DCM. In recent years, zebrafish (Danio rerio) have emerged as a powerful alternative model system for studying titin function in the healthy and diseased heart. Optically transparent embryonic zebrafish models have demonstrated key roles of titin in sarcomere assembly and cardiac development. The increasing availability of sophisticated imaging tools for assessment of heart function in adult zebrafish has revolutionized the field and opened new opportunities for modelling human genetic disorders. Genetically modified zebrafish that carry a human A-band TTNtv have now been generated and shown to spontaneously develop DCM with age. This zebrafish model will be a valuable resource for elucidating the phenotype modifying effects of genetic and environmental factors, and for exploring new drug therapies.

scholarly journals CFTR deficiency causes cardiac dysplasia during zebrafish embryogenesis and is associated with dilated cardiomyopathy

2020 ◽  
Author(s):  
Yanyan Liu ◽  
Ziyuan Lin ◽  
Mingfeng Liu ◽  
Huijuan Liao ◽  
Yan Chen ◽  
...  
Keyword(s):  
Heart Disease ◽  
Dilated Cardiomyopathy ◽  
Heart Development ◽  
Cardiac Development ◽  
Myocardial Dysfunction ◽  
Primary Defect ◽  
Zebrafish Model ◽  
Human Heart Failure ◽  
Stage Of Development

Abstract Background: Mutations in the CFTR gene cause cystic fibrosis (CF) with myocardial dysfunction. However, it remains unknown whether CF-related heart disease is a secondary effect of pulmonary disease, or an intrinsic primary defect in the CF heart. Results: Here, we used a zebrafish model, which lacks lung tissue, to investigate the role of CFTR in cardiogenesis during embryonic development. Our findings demonstrate that a loss of CFTR impairs cardiac development from the cardiac progenitor stage of heart development, resulting in cardiac looping defects, a dilated atrium, pericardial edema, and a decrease in heart rate. Furthermore, we found that cardiac development is perturbed in wild type embryos treated with a gating specific Cftr channel inhibitor, CFTRinh-172, at the blastula stage of development, but not with treatment at later stages. Gene expression analysis of blastulas indicated that transcript levels, including mRNAs associated with cardiovascular diseases, were significantly altered in embryos derived from cftr mutants relative to controls. To evaluate the role of CFTR in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found that CFTR containing I556V mutation, which causes a channel defect, is associated with the disease. Similar to well-studied channel-defective CFTR mutants, CFTR I556V mRNA failed to restore cardiac dysplasia in mutant embryos. Conclusions: The present study reveals an important role for the CFTR ion channel in regulating cardiac development during early embryogenesis, supporting the hypothesis that CF-related heart disease results from an intrinsic primary defect in the CF heart.

scholarly journals Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart

2019 ◽  
Author(s):  
Courtney E. Petersen ◽  
Matthew J. Wolf ◽  
Jeremy T. Smyth
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Development ◽  
Heart Function ◽  
Animal Health ◽  
Normal Heart ◽  
Animal Cells ◽  
Functional Roles ◽  
Store Operated Calcium Entry ◽  
Heart Physiology ◽  
Fractional Shortening

ABSTRACTStore-operated Ca2+ entry (SOCE) is an essential Ca2+ signaling and homeostatic mechanism present in nearly all animal cells. SOCE refers to influx of Ca2+ into cells that is activated by depletion of endoplasmic or sarcoplasmic reticulum stores (ER/SR) Ca2+ stores. In the SOCE pathway, STIM proteins function as Ca2+ sensors in the ER, and upon ER Ca2+ store depletion STIM rearranges to ER-plasma membrane junctions where it activates Orai Ca2+ influx channels. Multiple studies have implicated STIM and Orai mediated SOCE in the pathogenesis of cardiac hypertrophy. Importantly however, the functional roles of SOCE in normal heart physiology have not been well defined. We have addressed this in Drosophila melanogaster, a powerful animal model of cardiac development and physiology. We show that heart specific suppression of Drosophila Stim and Orai resulted in reduced contractility consistent with dilated cardiomyopathy, characterized by increased end diastolic and end systolic dimensions and decreased fractional shortening. Reduced contractility was apparent in larval hearts and became more pronounced in adults. Myofibers were disorganized and more widely spaced in larval and adult hearts with Stim and Orai RNAi as compared to controls, possibly reflecting decompensation or upregulated stress response signaling due to altered Ca2+ homeostasis. Lastly, we show that reduced heart function significantly affected animal health and viability, as animals with heart specific Stim and Orai suppression exhibited significant delays in post-embryonic development and adults died significantly earlier than controls. Collectively, our results demonstrate that SOCE is essential for normal heart physiology and establish Drosophila as an important model for delineation of functional SOCE roles in cardiomyocytes.

scholarly journals Cardiac Med1 deletion promotes early lethality, cardiac remodeling, and transcriptional reprogramming

2017 ◽  
Vol 312 (4) ◽  
pp. H768-H780 ◽  
Author(s):  
Kathryn M. Spitler ◽  
Jessica M. Ponce ◽  
Gavin Y. Oudit ◽  
Duane D. Hall ◽  
Chad E. Grueter
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cardiac Function ◽  
Dilated Cardiomyopathy ◽  
Cardiac Development ◽  
Heart Function ◽  
Expression Patterns ◽  
Left Ventricular ◽  
Sequencing Analysis ◽  
Early Lethality

The mediator complex, a multisubunit nuclear complex, plays an integral role in regulating gene expression by acting as a bridge between transcription factors and RNA polymerase II. Genetic deletion of mediator subunit 1 (Med1) results in embryonic lethality, due in large part to impaired cardiac development. We first established that Med1 is dynamically expressed in cardiac development and disease, with marked upregulation of Med1 in both human and murine failing hearts. To determine if Med1 deficiency protects against cardiac stress, we generated two cardiac-specific Med1 knockout mouse models in which Med1 is conditionally deleted (Med1cKO mice) or inducibly deleted in adult mice (Med1cKO-MCM mice). In both models, cardiac deletion of Med1 resulted in early lethality accompanied by pronounced changes in cardiac function, including left ventricular dilation, decreased ejection fraction, and pathological structural remodeling. We next defined how Med1 deficiency alters the cardiac transcriptional profile using RNA-sequencing analysis. Med1cKO mice demonstrated significant dysregulation of genes related to cardiac metabolism, in particular genes that are coordinated by the transcription factors Pgc1α, Pparα, and Errα. Consistent with the roles of these transcription factors in regulation of mitochondrial genes, we observed significant alterations in mitochondrial size, mitochondrial gene expression, complex activity, and electron transport chain expression under Med1 deficiency. Taken together, these data identify Med1 as an important regulator of vital cardiac gene expression and maintenance of normal heart function. NEW & NOTEWORTHY Disruption of transcriptional gene expression is a hallmark of dilated cardiomyopathy; however, its etiology is not well understood. Cardiac-specific deletion of the transcriptional coactivator mediator subunit 1 (Med1) results in dilated cardiomyopathy, decreased cardiac function, and lethality. Med1 deletion disrupted cardiac mitochondrial and metabolic gene expression patterns.

scholarly journals CFTR deficiency causes cardiac dysplasia during zebrafish embryogenesis and is associated with dilated cardiomyopathy

2019 ◽  
Author(s):  
Yanyan Liu ◽  
Ziyuan Lin ◽  
Mingfeng Liu ◽  
Huijuan Liao ◽  
Yan Chen ◽  
...  
Keyword(s):  
Heart Disease ◽  
Dilated Cardiomyopathy ◽  
Heart Development ◽  
Cardiac Development ◽  
Myocardial Dysfunction ◽  
Primary Defect ◽  
Zebrafish Model ◽  
Human Heart Failure ◽  
Stage Of Development

Abstract Mutations in the CFTR gene cause cystic fibrosis with myocardial dysfunction. However, it remains unknown whether CF-related heart disease is a secondary effect of pulmonary disease, or an intrinsic primary defect in the CF heart. Here, we used a zebrafish model, which lacks lung tissue, to investigate the role of CFTR in cardiogenesis during embryonic development. Our findings demonstrate that a loss of CFTR impairs cardiac development from the cardiac progenitor stage of heart development, resulting in cardiac looping defects, a dilated atrium, pericardial edema, and a decrease in heart rate. Furthermore, we found that cardiac development is perturbed in wild type embryos treated with a gating specific Cftr channel inhibitor, CFTRinh-172, at the blastula stage of development, but not with treatment at later stages. Gene expression analysis of blastulas indicated that transcript levels, including mRNAs associated with cardiovascular diseases, were significantly altered in embryos derived from cftr mutants relative to controls. To evaluate the role of CFTR in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found that CFTR containing I556V mutation, which causes a channel defect, is associated with the disease. Similar to well-studied channel-defective CFTR mutants, CFTR I556V mRNA failed to restore cardiac dysplasia in mutant embryos.The present study reveals an important role for the CFTR ion channel in regulating cardiac development during early embryogenesis, supporting the hypothesis that CF-related heart disease results from an intrinsic primary defect in the CF heart.

OBESITY: CLINICAL AND PATHOGENETIC JUSTIFICATION OF PREVENTION AND TREATMENT

2020 ◽  
pp. 5-10
Author(s):  
O. M. Korzh
Keyword(s):  
Metabolic Syndrome ◽  
Antihypertensive Drugs ◽  
Critical Role ◽  
Cardiovascular Complications ◽  
Excess Body Weight ◽  
Treatment And Prevention ◽  
Prevalence Of Obesity ◽  
Tissue Sensitivity ◽  
Genetic And Environmental Factors ◽  
Weight Correction

Obesity is one of the most common chronic diseases worldwide. Numerous studies in recent years have identified obesity as a key cause of type 2 diabetes, metabolic syndrome, and cardiovascular disease. Comprehensive medical and non−medical treatment of metabolic disorders, obesity and correction of excess body weight are the urgent tasks for both the patient and doctor. When defining the obesity as a chronic psychosomatic disease caused by the interaction of numerous genetic and environmental factors there is emphasized the complexity of the problem, including psychological, medical, social, physical and economic aspects. The widespread prevalence of obesity, which determines its comorbid nature, dictates the need to clarify the principles and options for treatment and prevention. In the process of active study, the multicomponent pathogenesis of obesity with the important role of different parts of the brain determines the relevance of a combination of pharmacotherapy and lifestyle intervention. In pharmacotherapy, the weight correction is an important component and reduces the risk of cardiovascular complications, improves quality of life and prognosis. The basis of weight correction measures is a change in lifestyle, increased physical activity and alteration in diet in order to achieve a balance between energy consumption and expenditure. Weight loss is accompanied with an increased tissue sensitivity to insulin, improved lipid metabolism, elimination of latent inflammation, lowering blood pressure and, accordingly, plays a critical role in prevention of the associated diseases and reducing the risk of complications. The fight against obesity is not only an improvement in the patient general condition, but also a great economic benefit, as the doses of drugs are reduced or the need for hypolipidemic, antidiabetic and antihypertensive drugs disappears. Key words: obesity, metabolic syndrome, diabetes mellitus, cardiometabolic risk, microbiota, insulin resistance, treatment, prevention.

Abstract 194: Characterization of Arrhythmogenic Dilated Cardiomyopathy Caused by Novel Filamin C Splice Variant in a Zebrafish Model

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Rene L Begay ◽  
Teisha J Rowland ◽  
Charles A Tharp ◽  
August Martin ◽  
Sharon L Graw ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Splice Variant ◽  
Systolic Dysfunction ◽  
Family Members ◽  
Muscle Disease ◽  
Heart Tube ◽  
Zebrafish Model ◽  
Cell Stage ◽  
Cardiac Phenotype ◽  
Filamin C

Although dilated cardiomyopathy (DCM) is a serious and frequent genetic cause of heart failure, only 30-40% of cases can be attributed to a known DCM gene mutation. To identify and confirm additional disease genes involved in DCM, we performed whole exome sequencing in two multigenerational families with DCM, both from the same geographic region of Italy, and found a novel splice variant in the gene encoding filamin-C (FLNC). Previously characterized mutations in FLNC had been primarily linked to skeletal muscle disease, although none of the affected family members displayed skeletal myopathy. To confirm and further characterize the arrhythmogenic DCM phenotype observed in family members, we performed embryonic knockdown experiments using morpholino (MO) treatment in zebrafish (Danio rerio) targeting the FLNC ortholog, filamin Cb (flncb). Following MO injection into 1-2 cell stage zebrafish embryos, 63.4% (78 of 123) of viable flncb MO-injected embryos displayed a cardiac phenotype at 72 hours post fertilization (hpf) (vs. 17.0% [30 of 177] of control MO-injected embryos; p≤0.001). Increases in mortality were observed, with 20.8% (54 of 260) of flncb MO-injected embryos surviving at 7 days post fertilization (vs. 65% [162 of 249] of control embryos; p≤0.001). The flncb MO-injected embryos demonstrated pericardial edema, dysmorphic or dilated cardiac chambers, and abnormal looping of the heart tube suggestive of systolic dysfunction. The flncb MO-injected embryos additionally demonstrated a lower mean stroke volume than controls (0.076 vs. 0.181 nl; p=0.015), a reduced mean cardiac output (10.8 vs. 25 nl/min; p=0.02), and an increase in the fraction of retrograde blood flow over the cardiac cycle (0.42 vs. 0.03; p=0.027). Overall, this flncb MO treatment recapitulated a DCM phenotype similar to the state caused by the human splicing variant, supporting haploinsufficiency as the mechanism leading to DCM in these families. Our findings suggest that approaches to augment endogenous filamin C protein levels may represent a viable treatment strategy that warrants exploration in future studies.

1041Early changes in regional heart function in Tgalphaq*44 murine model of dilated cardiomyopathy as assessed by CMR Tagging

2013 ◽  
Vol 14 (suppl_1) ◽  
pp. i18-i18
Author(s):  
A Osiak ◽  
U Tyrankiewicz ◽  
M Jablonska ◽  
K Jasinski ◽  
PT Jochym ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Murine Model ◽  
Heart Function ◽  
Cmr Tagging

scholarly journals An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Jun Zou ◽  
Diana Tran ◽  
Mai Baalbaki ◽  
Ling Fung Tang ◽  
Annie Poon ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Disease Severity ◽  
Protein Product ◽  
Dominant Negative ◽  
Precise Position ◽  
Internal Promoter ◽  
Sarcomeric Protein ◽  
Skeletal Myopathy ◽  
The Difference ◽  
Shed Light

Truncating mutations in the giant sarcomeric protein Titin result in dilated cardiomyopathy and skeletal myopathy. The most severely affected dilated cardiomyopathy patients harbor Titin truncations in the C-terminal two-thirds of the protein, suggesting that mutation position might influence disease mechanism. Using CRISPR/Cas9 technology, we generated six zebrafish lines with Titin truncations in the N-terminal and C-terminal regions. Although all exons were constitutive, C-terminal mutations caused severe myopathy whereas N-terminal mutations demonstrated mild phenotypes. Surprisingly, neither mutation type acted as a dominant negative. Instead, we found a conserved internal promoter at the precise position where divergence in disease severity occurs, with the resulting protein product partially rescuing N-terminal truncations. In addition to its clinical implications, our work may shed light on a long-standing mystery regarding the architecture of the sarcomere.

scholarly journals Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

2017 ◽  
Vol 114 (30) ◽  
pp. E6250-E6259 ◽  
Author(s):  
Ana Maria Manso ◽  
Hideshi Okada ◽  
Francesca M. Sakamoto ◽  
Emily Moreno ◽  
Susan J. Monkley ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Heart Function ◽  
Membrane Integrity ◽  
Heart Muscle Cell ◽  
Functional Changes ◽  
Adhesion Sites ◽  
Improve Heart Function ◽  
Simultaneous Loss ◽  
Protein Reduction ◽  
Sarcolemmal Integrity

Continuous contraction–relaxation cycles of the heart require strong and stable connections of cardiac myocytes (CMs) with the extracellular matrix (ECM) to preserve sarcolemmal integrity. CM attachment to the ECM is mediated by integrin complexes localized at the muscle adhesion sites termed costameres. The ubiquitously expressed cytoskeletal protein talin (Tln) is a component of muscle costameres that links integrins ultimately to the sarcomere. There are two talin genes, Tln1 and Tln2. Here, we tested the function of these two Tln forms in myocardium where Tln2 is the dominant isoform in postnatal CMs. Surprisingly, global deletion of Tln2 in mice caused no structural or functional changes in heart, presumably because CM Tln1 became up-regulated. Tln2 loss increased integrin activation, although levels of the muscle-specific β1D-integrin isoform were reduced by 50%. With this result, we produced mice that had simultaneous loss of both CM Tln1 and Tln2 and found that cardiac dysfunction occurred by 4 wk with 100% mortality by 6 mo. β1D integrin and other costameric proteins were lost from the CMs, and membrane integrity was compromised. Given that integrin protein reduction occurred with Tln loss, rescue of the phenotype was attempted through transgenic integrin overexpression, but this could not restore WT CM integrin levels nor improve heart function. Our results show that CM Tln2 is essential for proper β1D-integrin expression and that Tln1 can substitute for Tln2 in preserving heart function, but that loss of all Tln forms from the heart-muscle cell leads to myocyte instability and a dilated cardiomyopathy.

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