Dual inhibition of Mst1 and Mst2 exacerbates cardiac dysfunction during pressure overload stress in mice.

Heart failure remains a leading cause of morbidity and mortality worldwide. The evolutionarily conserved Hippo-Yap signaling pathway regulates cardiac responses to stress and progression to heart failure. Mst1 and Mst2 are the core Hippo pathway kinases, yet their role within chronically stressed cardiomyocytes remains largely unknown. Genetic mouse models revealed that the extent of Mst1/2 inhibition elicits opposing effects on stress-induced cardiac dysfunction. Yap-TEAD1 activation, cell cycling, and hallmarks of cardiomyocyte dedifferentiation, which can impair contractile function during sustained stress, were enhanced in Mst1/2 double knockout hearts. These findings implicate a physiological function of Mst1/2 to promote cardiomyocyte maturity in the adult heart.