Contractile homeostasis is an intrinsic barrier to cardiac regeneration
摘要
Adult mammalian cardiomyocytes acquire powerful contractile function as they mature, yet lose regenerative competence. Whether this functional transition actively imposes regenerative arrest is unknown. Here we show that the postnatally induced transcription factor KLF3 establishes contractile homeostasis as an intrinsic barrier to CM regenerative competence. CM-specific Klf3 deletion enhances Ca2+ cycling and contraction, reactivates CM cell-cycle activity and improves cardiac repair after myocardial infarction. Integrated transcriptomic, CUT&Tag and lipidomic analyses reveal that KLF3 represses contractile and Ca2+-handling genes and limits glycosphingolipid biosynthesis. Disruption of contractile homeostasis, by either Klf3 deficiency or pharmacological contractile stimulation, increases membrane mechanical stress and activates neutral sphingomyelinase (nSMase)-dependent sphingolipid remodeling; conversely, nSMase inhibition abolishes the proliferative response. Lactosylceramide (LacCer), a major sphingolipid metabolite elevated in Klf3-deficient hearts, is sufficient to stimulate CM cell-cycle re-entry and promote post-infarction repair. These findings identify contractile homeostasis as an active maturation-linked brake on mammalian cardiac regeneration and uncover a targetable mechanometabolic pathway for cardiac repair.
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