# Dysferlin stabilizes membrane nanodomains of cardiomyocytes after myocardial infarction

## TL;DR

This study shows that the protein dysferlin helps protect heart cells after a heart attack by stabilizing key membrane structures, which may reduce heart function loss.

## Contribution

The study identifies dysferlin as a novel molecular target for preserving sarcolemmal nanodomains in the heart after myocardial infarction.

## Key findings

- Dysferlin expression increases by 230% in the MI border zone of wild-type mice.
- Dysferlin-knockout mice show larger infarct sizes and reduced heart function after MI.
- Dysferlin stabilizes TAT and ICD nanodomains, as shown by proteomic and imaging analyses.

## Abstract

Despite advances in acute care medicine, myocardial infarction (MI) remains a predominant cause of premature death and heart failure. In the MI border zone, cardiomyocytes are exposed to high biomechanical stress that impairs the integrity of the sarcolemmal membrane. Hence, we hypothesized that the Ca2+-sensitive membrane repair protein dysferlin is crucial for preserving sarcolemmal nanodomains in the MI border zone, like the transverse-axial tubule (TAT) network and the intercalated disc (ICD) membrane folds, and thereby limits the post-MI loss of myocardial function. We employed left anterior descending artery ligation to induce MI in wild-type (WT) versus dysferlin-knockout (KO) mice. While immunohistology identified an upregulated dysferlin expression of 230% in cardiomyocytes of the WT MI border zone, KO mice presented larger infarct sizes and reduced left-ventricular systolic function one week post-MI. To dissect the role of dysferlin in left-ventricular remodelling post-MI, we applied data-independent acquisition mass-spectrometry (DIA-MS) analysing the spatial proteomic profiles in WT versus KO hearts. In total, DIA-MS quantitated 5,700 proteins across all small samples, thereby identifying hundreds of genotype-specific proteomic changes for the left-ventricular infarct, border and remote zones one week post-MI. Complementing with our proteomic results, confocal and super-resolution stimulated emission depletion (STED) microscopy visualized severely degraded TAT membranes and enlarged ICD membrane folds in cardiomyocytes of the MI border zone. Importantly, extensive dysferlin signals clustered in vicinity to residual TAT structures and connexin-43 plaques at the ICD, indicating a stabilizing role of dysferlin in sarcolemmal nanodomain organization. In fact, co-immunoprecipitation-based DIA-MS and complexome profiling decoding the functional cardiac interactome of dysferlin confirmed prominent dysferlin interaction partners at TAT and ICD nanodomains. In conclusion, dysferlin represents a new molecular target that protects the integrity of sarcolemmal nanodomains in cardiomyocytes of the MI border zone, thereby reducing loss of contractility post-MI.

The online version contains supplementary material available at 10.1038/s41598-026-42800-9.