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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Quantitative Proteomics and Immunohistochemistry Reveal Insights into Cellular and Molecular Processes in the Infarct Border Zone One Month after Myocardial Infarction

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