Interplay of stress responses underlying the development of LMNA cardiomyopathy

ABSTRACT: Mutations in the LMNA gene encoding nuclear lamins A/C cause a diverse array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the molecular perturbations emanating from LMNA mutations, an integrative understanding of the pathogenesis leading to cardiac dysfunction remains elusive. Using a novel cell-type specific Lmna deletion mouse model capable of translatome profiling, we found that cardiomyocyte-specific Lmna deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Prior to the onset of cardiac dysfunction, lamin A/C-depleted cardiomyocytes displayed nuclear envelope deterioration, disruption of the ER-golgi interface, and ER stress. Translatome profiling identified upregulation of Med25, a transcriptional co-factor involved in unfolded protein responses. Culturing Lmna-deleted cardiomyocytes in stiff hydrogels recapitulated these pathological features, confirming that cardiomyocyte-extrinsic factors contribute to the pathogenesis. Pharmacological activation of autophagy or modulation of ER stress significantly improved the cardiac function. These studies support a unified hypothesis wherein cardiomyopathy develops from autophagic impairment that exacerbates ER stress emanating from nuclear envelope deterioration.

ORGANISM(S): Mus musculus

PROVIDER: GSE185620 | GEO | 2022/10/11

REPOSITORIES: GEO