PXD053051-2

PXD053051 is an original dataset announced via ProteomeXchange.

Title	Dysferlin facilitates tubular membrane proliferation promoting hypertrophic remodeling of the heart under pressure overload - left ventricular myocyte data
Description	BACKGROUND: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies, but can result in cardiac failure if left untreated. We hypothesized that the tail-anchored protein Dysferlin with multiple Ca2+-binding C2-domains is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes, and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy. OBJECTIVE: To reveal the impact of the membrane fusion and repair protein Dysferlin on TAT network stabilization and proliferation necessary for the hypertrophic growth of cardiomyocytes. METHODS AND RESULTS: Super-resolution light and electron microscopy of mouse cardiomyocytes identified a specific localization of Dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum (SR), a.k.a. junctional complexes for Ca2+-induced Ca2+ release. Mass spectrometry was used to characterize the cardiac Dysferlin interactome, thereby identifying a novel protein interaction with the membrane-tethering SR protein Juncophilin-2, a known interactor of L-type Ca2+ channels and Ryanodine Receptor Ca2+ release channels in junctional complexes. While the Dysferlin knockout caused a mild progressive phenotype of dilated cardiomyopathy in the mouse heart, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction (TAC), Dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while Dysferlin knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging demonstrated a profound reorganization of the TAT network in wild-type left-ventricular myocytes post-TAC with robust proliferation of axial tubules, which critically depended on the increased expression of Dysferlin within newly-emerging tubule components. CONCLUSIONS: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-SR junctional complexes for regulated excitation-contraction coupling, and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure-overload.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:49:53.529.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christof Lenz
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-12 12:16:31	ID requested
1	2024-07-15 09:07:35	announced
⏵ 2	2024-10-22 06:49:53	announced	2024-10-22: Updated project metadata.

10.1161/CIRCRESAHA.124.324588;

submitter keyword: pressure overload, cardiac remodeling, proteomics,dysferlin

Christof Lenz
contact affiliation	University Medical Center Goettingen, Department of Clinical Chemistry, Core Facility Proteomics
contact email	christof.lenz@med.uni-goettingen.de
lab head
Christof Lenz
contact affiliation	Max Planck Institute for Biophysical Chemistry
contact email	christof.lenz@mpibpc.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD053051
     1. Label: PRIDE project
     2. Name: Dysferlin facilitates tubular membrane proliferation promoting hypertrophic remodeling of the heart under pressure overload - left ventricular myocyte data