Non-Cell-Autonomous Cardiomyocyte Regulation Complicates Gene Supplementation Therapy for <i>Lmna</i>-Associated Cardiac Defects in Mice.

ABSTRACT: The truncating mutations of LMNA are the major causes of cardiomyopathy. Here we studied 3 mouse models that carry germline, cardiomyocyte-specific, or genetic mosaic Lmna truncating mutations. Whereas the germline mutant manifested cardiac maturation defects, cardiomyocyte-specific mutation triggered pathological hypertrophy. In genetic mosaic analysis, no morphological defects were observed. Three adeno-associated virus (AAV) vectors were applied to addback lamin-A in a ubiquitous, cardiomyocyte-specific, or cardiomyocyte-excluded manner. Strikingly, only ubiquitous and cardiomyocyte-excluded AAV vectors mitigated the cardiac defects. Therefore, Lmna regulates cardiac morphology and function via a non-cell-autonomous mechanism. Noncardiomyocytes are key targets in AA

SUBMITTER: Sun Y 

PROVIDER: S-EPMC11604484 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature