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Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy due to sarcomere disruption and protein aggregate formation

ABSTRACT: Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy due to sarcomere disruption and protein aggregate formation

PROVIDER: PRJNA702141 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13723500_1.fastq.gz	Fastqsanger.gz
	SRR13723500_2.fastq.gz	Fastqsanger.gz
	SRR13723600_1.fastq.gz	Fastqsanger.gz
	SRR13723600_2.fastq.gz	Fastqsanger.gz
	SRR13723501_1.fastq.gz	Fastqsanger.gz

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Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy due to sarcomere disruption and protein aggregate formation

Project description:An amino acid exchange (P209L) in the HSPB8 binding site of the human cochaperone Bcl2-associated athanogene 3 (BAG3) gives rise to severe dominant childhood cardiomyopathy. To phenocopy the human disease in mouse and gain insight into its mechanisms, we have generated humanized transgenic mouse models. Expression of human BAG3P209L-eGFP in mice caused Z-disc disintegration and formation of protein aggregates. This was accompanied by massive fibrosis resulting in a severe, early-onset restrictive cardiomyopathy with increased mortality, as observed in patients. RNA-Seq and proteomic analysis revealed changes in the protein quality control system and increased autophagy in hearts from hBAG3P209L-eGFP overexpressing mice. Also, the mutation renders hBAG3P209L less soluble in vivo and induces protein aggregation, but does not abrogate hBAG3 binding properties. Thus, we have established a mouse model recapitulating mimicing the human disease and found that the disease mechanism is due to accumulation of hBAG3P209L and mouse BAG3, causing sequestering of components of the protein quality control system and the autophagy machinery leading to the reduction of the stability and functional organization of sarcomeres. We have also tested a gene therapy approach utilizing expression of shRNA against hBAG3 in cardiac muscle via AAV and demonstrate that this halted and even partially reversed major phenotypic features of the disease.

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Project description:Restrictive cardiomyopathy (RCM) is a severe cardiac disorder characterized by impaired ventricular filling and diastolic dysfunction, with mutations in sarcomeric proteins representing major causative factors. Mutations of TNNI3 gene (e.g. p.R192H) constitute major genetic causes of RCM, particularly affecting pediatric patients and being associated with poor prognosis. Here, we demonstrate that adenine base editor (ABE) is able effectively correct RCM-causing mutation and alleviate RCM in a murine model. We first developed a novel murine model harboring the Tnni3R193H mutation that recapitulates the hallmark features of human RCM. Importantly, targeted delivery of ABE via adeno-associated virus (AAV) achieved efficient and precise correction of the Tnni3R193H mutation in adult RCM mice, leading to significant improvement of cardiac functions. Our findings establish base editing as a therapeutic strategy for RCM and highlight its broader potential for treating genetic cardiomyopathies in clinical settings.

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Project description:To investigate the physiological characteristics of cardiomyocytes (CM) in restrictive cardiomyopathy (RCM), we established RCM(heterozygous)-iPSC and produced RCM(homozygous)-iPSC and corrected Isogenic-iPSC using CRISPER-CAS9 technology. Then, we used the RNA-seq data obtained from these three iPSCs and three different healthy iPSC-derived CMs for gene expression profiling analysis.

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Project description:End stage heart failure due to ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) have similar characteristics, enlargement of the ventricles, relatively thin-walled ventricle, which leads to a limited contraction force and blood loading. Nevertheless, the response for present therapeutics is very variable and the prognosis is still very bad for ICM and DCM in general. Thus, the ability to differentiate the etiologies of heart failure based structural and physiological changes of the heart would be a step forward to enhance the specificity and the success of given therapy.

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Heart Failure Associated Changes in Alternative Splicing of Sarcomere Genes

Project description:Alternative mRNA splicing is an important mechanism for regulation of gene expression. Changes in gene expression contribute to the pathogenesis of heart failure. However, changes in mRNA splicing have not been systematically examined in heart disease. We hypothesized that mRNA splicing is changed in diseased hearts. We used the Affymetrix exon array, which separately measures expression of each known and computationally predicted exon, to globally evaluate changes in mRNA splicing in left ventricular myocardial RNA from control and ischemic cardiomyopathy (ICM) patients. We found that mRNA splicing is systematically changed in heart failure. RTPCR validated 9 previously unreported alternative splicing events. Furthermore, we demonstrated that the splicing of four key sarcomere genes, cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), myosin heavy chain 7 (MYH7), and filamin C (FLNC), was significantly altered in ICM. Altered splicing of these genes in heart disease was confirmed in independent ICM samples, and in dilated cardiomyopathy and aortic stenosis. The minor variant fraction of these five genes was sufficient to classify samples into control or disease groups with 95% accuracy. Our data indicate that alternative splicing is systematically altered in human heart disease, suggesting that disease-associated perturbation of RNA splicing may contribute to the pathogenesis and development of heart failure. Disease-related changes in splicing of sarcomere genes may directly impact cardiomyocyte function.

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Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle

Project description:Muscle contraction is driven by the molecular machinery of the sarcomere. While the constituent components of the sarcomere are well characterized, it is less clear how the activity and turnover of sarcomeric proteins is regulated. In particular, phosphorylation is critical regulator of muscle function. Thus, identification of regulatory kinases is key to understanding the sarcomere function. Pathogenic variants in alpha kinase 3 (ALPK3) cause cardiomyopathy and musculoskeletal disease, but little is known about this atypical kinase. Here we show that ALPK3 localizes to the M-Band of the sarcomere and define the ALPK3-dependent phosphoproteome. ALPK3 deficiency disrupted sarcomeric organization and calcium kinetics in hPSC-derived cardiomyocytes and reduced force generation in cardiac organoids. Phosphoproteomic profiling identified ALPK3-dependant phospho-peptides that were enriched for sarcomeric components of the M-band and the ubiquitin-binding protein SQSTM1. Analysis of the ALPK3 interactome confirmed binding to M-band proteins including SQSTM1. Importantly, in hPSC-derived cardiomyocytes modeling ALPK3 deficiency and cardiomyopathic ALPK3 mutations, sarcomeric organization and M-band localization of SQSTM1 were abnormal. These data suggest ALPK3 has an integral role in maintaining sarcomere integrity and proteostasis in striated muscle. We propose this mechanism may underly disease pathogenesis in patients with ALPK3 variants.

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Project description:Thick-filament sarcomere mutations are a common cause of hypertrophic cardiomyopathy (HCM), a disorder of heart muscle thickening associated with sudden cardiac death and heart failure, with unclear mechanisms. We engineered four isogenic induced pluripotent stem cell (iPSC) models of β-myosin heavy chain and myosin-binding protein C3 mutations, and studied iPSC-derived cardiomyocytes in cardiac microtissue assays that resemble cardiac architecture and biomechanics. All HCM mutations resulted in hypercontractility with prolonged relaxation kinetics in proportion to mutation pathogenicity, but not changes in calcium handling. RNA sequencing and expression studies of HCM models identified p53 activation, oxidative stress, and cytotoxicity induced by metabolic stress that can be reversed by p53 genetic ablation. Our findings implicate hypercontractility as a direct consequence of thick-filament mutations, irrespective of mutation localization, and the p53 pathway as a molecular marker of contraction stress and candidate therapeutic target for HCM patients.

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