PXD054236-1

PXD054236 is an original dataset announced via ProteomeXchange.

Title	Chronic activation of tubulin tyrosination in HCM mice and in human iPSC-engineered heart tissues improves heart function
Description	Rationale 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.
HostingRepository	PRIDE
AnnounceDate	2024-08-28
AnnouncementXML	Submission_2024-08-28_01:34:42.598.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bente Siebels
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-25 06:37:33	ID requested
⏵ 1	2024-08-28 01:34:42	announced
2	2024-10-22 06:56:55	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: heart function

hypertrophic cardiomyopathy

engineered heart tissue

hiPSC

microtubules

alpha-tubulin tyrosination and detyrosination.

Lucie Carrier
contact affiliation	Department of Experimental Pharmacology and 35 Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 36 Martinistrasse 52, 20246 Hamburg, Germany
contact email	l.carrier@uke.de
lab head
Bente Siebels
contact affiliation	Section for Mass spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf
contact email	b.siebels@uke.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD054236
     1. Label: PRIDE project
     2. Name: Chronic activation of tubulin tyrosination in HCM mice and in human iPSC-engineered heart tissues improves heart function