IPSC-derived cardiomyocytes and engineered heart tissues reveal suppressed JAK2/STAT3 signaling in LMNA-related emery-dreifuss muscular dystrophy.

ABSTRACT: LMNA mutation related Emery-Dreifuss muscular dystrophy (LMNA-related EDMD), is a rare genetic disorder often involving life-threatening cardiac complications. However, the molecular links between LMNA mutations and their related EDMD cardiac phenotypes have remained unclear. Here, using EDMD patient-specific and genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we link the LMNA L204P mutation with the pathogenic phenotypes of arrhythmia and contractile dysfunction. Using multi-omics analysis, we then show that LMNA L204P results in decreased chromatin accessibility, leading to the downregulation of JAK2 in EDMD iPSC-CMs. Mechanistically, JAK2/STAT3 signaling pathway suppression in EDMD iPSC-CMs is shown to cause mitochondrial dysfunction and oxidative stress,

SUBMITTER: Fan H 

PROVIDER: S-EPMC12059692 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature