Related Experiment Video
Updated: Jul 11, 2025
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Impaired end joining induces cardiac atrophy in a Hutchinson-Gilford progeria mouse model
Yu Chen1,2, Shiqi Huang3, Zhen Cui1,2
1Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Insights
Hutchinson-Gilford progeria syndrome (HGPS) causes cardiac atrophy in mice due to DNA repair defects. Inhibiting AMPK or using isoproterenol shows promise in treating HGPS-related cardiomyopathy and extending lifespan.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Aging Research
Background:
- Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease characterized by DNA damage and cardiovascular complications.
- Cardiac dysfunction mechanisms in HGPS remain unclear, limiting treatment options for HGPS-related cardiomyopathy.
Purpose of the Study:
- To investigate cardiac dysfunction and its underlying mechanisms in HGPS.
- To explore potential therapeutic strategies targeting cardiac atrophy in HGPS.
Main Methods:
- Utilized LmnaG609G/G609G mice (HGPS mice) to model HGPS.
- Employed a GFP-based reporter system to assess nonhomologous end joining (NHEJ) efficiency in cardiomyocytes.
- Analyzed protein interactions and signaling pathways including γH2AX, Progerin, CHK2, LKB1, AMPKα, and FOXO3A.
- Investigated the effects of AMPK inhibition and isoproterenol treatment on cardiomyocyte size and lifespan.
Main Results:
- HGPS mice exhibited cardiac atrophy.
- NHEJ efficiency was reduced by 50% in HGPS cardiomyocytes due to impaired γH2AX-Progerin interaction, leading to genomic instability.
- A signaling cascade involving CHK2, LKB1-AMPKα, and FOXO3A activation promoted atrophy-related gene transcription.
- Inhibiting AMPK increased cardiomyocyte size, while isoproterenol treatment reduced phosphorylation of AMPKα and FOXO3A, attenuated cardiac atrophy, and extended HGPS mouse lifespan by ~21%.
Conclusions:
- Cardiac atrophy is a key phenotype in HGPS, driven by DNA repair defects and subsequent signaling pathway activation.
- Targeting cardiac atrophy, specifically by modulating the AMPK/FOXO3A pathway, represents a potential therapeutic strategy for HGPS.
- Isoproterenol demonstrates therapeutic potential for HGPS-related cardiomyopathy, improving cardiac function and survival.
Abstract:
Patients with Hutchinson-Gilford progeria syndrome (HGPS) present with a number of premature aging phenotypes, including DNA damage accumulation, and many of them die of cardiovascular complications. Although vascular pathologies have been reported, whether HGPS patients exhibit cardiac dysfunction and its underlying mechanism is unclear, rendering limited options for treating HGPS-related cardiomyopathy. In this study, we reported a cardiac atrophy phenotype in the LmnaG609G/G609G mice (hereafter, HGPS mice). Using a GFP-based reporter system, we demonstrated that the efficiency of nonhomologous end joining (NHEJ) declined by 50% in HGPS cardiomyocytes in vivo, due to the attenuated interaction between γH2AX and Progerin, the causative factor of HGPS. As a result, genomic instability in cardiomyocytes led to an increase of CHK2 protein level, promoting the LKB1-AMPKα interaction and AMPKα phosphorylation, which further led to the activation of FOXO3A-mediated transcription of atrophy-related genes. Moreover, inhibiting AMPK enlarged cardiomyocyte sizes both in vitro and in vivo. Most importantly, our proof-of-concept study indicated that isoproterenol treatment significantly reduced AMPKα and FOXO3A phosphorylation in the heart, attenuated the atrophy phenotype, and extended the mean lifespan of HGPS mice by ~21%, implying that targeting cardiac atrophy may be an approach to HGPS treatment.
