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

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, ultimately resulting in the above phenotypes. Conversely, pharmacological or genetic activation of JAK2/STAT3 signaling effectively rescues both the arrhythmic and contractile dysfunction phenotypes in EDMD iPSC-CMs via improvements in mitochondrial function. In addition, whilst EDMD engineered heart tissues (EHTs) display dysfunctional contractile force generation, this can also be significantly alleviated by STAT3 activation. Taken together, we present chromatin compartment change-mediated JAK2/STAT3 suppression as a novel mechanism underlying cardiac pathogenic phenotypes in LMNA-related EDMD. Our findings indicate that activating the JAK2/STAT3 signaling pathway may hold the potential to serve as a novel therapeutic strategy for this condition.