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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 \u03b3H2AX 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-AMPK\u03b1 interaction and AMPK\u03b1 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 AMPK\u03b1 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2309200120","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T14:08:42Z","timestamp":1700057322000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":14,"title":["Impaired end joining induces cardiac atrophy in a Hutchinson\u2013Gilford progeria mouse model"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9661-3914","authenticated-orcid":false,"given":"Yu","family":"Chen","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and 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