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PXD054236-1

PXD054236 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleChronic activation of tubulin tyrosination in HCM mice and in human iPSC-engineered heart tissues improves heart function
DescriptionRationale Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder caused by sarcomeric gene variants and is associated with left ventricular hypertrophy and diastolic dysfunction. The role of the microtubule network has recently gained interest with findings that microtubule detyrosination (dTyr-MTs) is markedly elevated in heart failure. Acute reduction of dTyr-MTs by inhibition of the detyrosinase (VASH/SVBP complex) or activation of the tyrosinase (tubulin tyrosine ligase, TTL) markedly improved contractility and reduced stiffness in human failing cardiomyocytes, presenting a new perspective for HCM treatment. Objective In this study, we tested the impact of chronic tubulin tyrosination in a HCM mouse model (Mybpc3-knock-in; KI), in human HCM cardiomyocytes, and in SVBP-deficient human engineered heart tissues (EHTs). Methods and Results AAV9-mediated TTL transfer was applied in neonatal wild-type (WT) rodents, in 3-week-old KI mice, and in HCM human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. We show: i) TTL for 6 weeks dose-dependently reduced dTyr-MTs and improved contractility without affecting cytosolic calcium transients in WT cardiomyocytes. ii) TTL for 12 weeks reduced the abundance of dTyr-MTs in the myocardium, improved diastolic filling, compliance, cardiac output, and stroke volume in KI mice. iii) TTL for 10 days normalized cell area in HCM hiPSC-cardiomyocytes. iv) TTL overexpression activates transcription of several tubulin isoforms, and omics GO analysis revealed enrichment of components of the cytoskeleton, sarcomere Z-disc, mitochondria, and intercalated disc in KI mice. v) SVBP-deficient EHTs exhibited reduced dTyr-MT levels, higher force, and faster relaxation than TTL-deficient and WT EHTs. RNA-seq and mass spectrometry analysis revealed distinct enrichment of cardiomyocyte components and pathways in SVBP-KO vs. TTL-KO EHTs. Conclusion This study provides the first proof-of-concept that chronic activation of tubulin tyrosination in HCM mice and in human EHTs improves heart function and holds promise for targeting the non-sarcomeric cytoskeleton in heart disease.
HostingRepositoryPRIDE
AnnounceDate2024-08-28
AnnouncementXMLSubmission_2024-08-28_01:34:42.598.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterBente Siebels
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationListiodoacetamide derivatized residue
InstrumentOrbitrap Exploris 480
Dataset History
RevisionDatetimeStatusChangeLog Entry
02024-07-25 06:37:33ID requested
12024-08-28 01:34:42announced
22024-10-22 06:56:55announced2024-10-22: Updated project metadata.
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: heart function
hypertrophic cardiomyopathy
engineered heart tissue
hiPSC
microtubules
alpha-tubulin tyrosination and detyrosination.
Contact List
Lucie Carrier
contact affiliationDepartment of Experimental Pharmacology and 35 Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 36 Martinistrasse 52, 20246 Hamburg, Germany
contact emaill.carrier@uke.de
lab head
Bente Siebels
contact affiliationSection for Mass spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf
contact emailb.siebels@uke.de
dataset submitter
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