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Dysferlin and its role in cardiac disease

ABSTRACT: Mouse hearts of five WT vs. Dyferlin KO mice each at an age of 16 and 32 weeks were perfused on a modified Langendorff setup for 2 min with 0.9% NaCl to wash out blood from the myocardium, dissected and immediately snap-frozen. Quantitative data-independent acquisition (DIA) mass spectrometry was performed on left ventricular tissues as described previously.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Christof Lenz

LAB HEAD: Christof Lenz

PROVIDER: PXD043108 | Pride | 2024-07-15

REPOSITORIES: Pride

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Source:

			Action	DRS
	20220425_223350_2022_06_S_Brandenburg_040222_MouseHeart_HybridLibrary.sne	Other
	2022_06_S_Brandenburg_040222_HybridLibrary.xls	Xls
	SDRF.tsv	Tabular
	S_Brandenburg_040222_050422_DDA_R1_F01_GA1_1_2438.d.zip	Other
	S_Brandenburg_040222_050422_DDA_R1_F02_GA2_1_2439.d.zip	Other

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Project description:BACKGROUND: Despite significant advances in acute care medicine, myocardial infarction (MI) remains a predominant cause of premature death and heart failure. In the infarct border zone, cardiomyocytes are exposed to high biomechanical stress that impairs the integrity of the sarcolemmal membrane. Here, we hypothesized that the Ca2+-sensitive membrane repair protein dysferlin is key to preserving sarcolemmal nanodomains like the transverse-axial tubule (TAT) endomembrane network and the intercalated disc (ICD) membrane folds in the infarct border zone. METHODS: We employed permanent left anterior descending artery ligation to induce MI in mice, and used data-independent acquisition mass spectrometry (DIA-MS) to analyze the spatial proteomic profile in wild-type versus dysferlin-knockout hearts post-MI. Stimulated emission depletion (STED) nanoscopy and electron tomography were applied to study membrane nanodomain remodeling and dissect the role of dysferlin in local membrane protection and repair in cardiomyocytes of the infarct border zone. Co-immunoprecipitation-based DIA-MS and complexome profiling were used to further decode the cardiac interactome of dysferlin. RESULTS: DIA-MS quantitatively analyzed 5,700 proteins, segregating the proteomic profiles of the left-ventricular infarct zone, border zone and remote zone in wild-type versus dysferlin-knockout mice one week post-MI. While dysferlin protein expression was significantly upregulated in the MI border and remote zone, dysferlin-knockout mice presented larger infarct sizes and reduced left-ventricular systolic function post-MI. In cardiomyocytes of the WT infarct border zone, STED nanoscopy visualized severely disrupted TAT membranes and enlarged ICD membrane folds. Importantly, extensive dysferlin signals clustered in nanometric proximity to residual TAT structures and connexin-43 plaques at the ICD, stabilizing functional nanodomain organization for preserved excitation-contraction coupling and intercellular communication. Interactomic analyses revealed connexin-43 as a novel dysferlin interaction partner.

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Dysferlin and its role in cardiac disease

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