Hibernation-like mice obtain improved cardiac regeneration ability through activated purine biosynthesis (PRJCA028453)

Adult cardiomyocytes (CM) lose their regenerative capacity while growing. The decline of CM proliferation is associated with altered temperature and metabolism in adults. In this study, we delve into the intriguing question of whether inducing torpor, a hibernation-like state with reduced body temperature and metabolism, could enhance CM proliferation in adult mice. Our findings reveal that torpid mice had significantly increased CM proliferation in physiological conditions and after myocardial infarction (MI), highlighting the potential of torpor in enhancing cardiac regeneration. Single-nucleus RNA sequencing (snRNA-seq) analysis identified that torpor induced a distinct subpopulation of proliferating CMs. These proliferating CMs had enriched genes in purine metabolism compared to non-proliferated CMs. Specifically, ATIC, a bifunctional enzyme catalyzing the de novo purine synthesis (DNPS), was highly upregulated in proliferating CMs. Atic expression reduced in CMs during growth. Knockdown of Atic decreased the proliferation of neonatal CMs, while overexpression of Atic led to increased CM proliferation. AAV-mediated Atic overexpression in mice showed increased cardiac proliferation and improved cardiac function 6 weeks after MI. Moreover, the knockdown of Atic in torpid mice diminished the torpor-induced cardiac regeneration after MI. Our data suggest that torpor could reprogram the purine metabolism to promote CM proliferation for cardiac regeneration.