| First Author | Chen Y | Year | 2023 |
| Journal | Proc Natl Acad Sci U S A | Volume | 120 |
| Issue | 47 | Pages | e2309200120 |
| PubMed ID | 37967221 | Mgi Jnum | J:353368 |
| Mgi Id | MGI:7641277 | Doi | 10.1073/pnas.2309200120 |
| Citation | Chen Y, et al. (2023) Impaired end joining induces cardiac atrophy in a Hutchinson-Gilford progeria mouse model. Proc Natl Acad Sci U S A 120(47):e2309200120 |
| abstractText | 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 Lmna(G609G/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 gammaH2AX 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-AMPKalpha interaction and AMPKalpha 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 AMPKalpha 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. |
