PROJECT SUMMARY Nearly every stressor reactivates the fetal gene program in cardiac myocytes, but why they make this transition is unclear given fetal metabolic and functional reprogramming is insufficient to sustain adult cardiac performance yet this fate change negatively impacts cardiac regeneration, which is an underlying determinant of heart failure. Thus, understanding fetal to adult myocyte state transitions is has broad therapeutic impact when considering how to boost the heart’s performance and tolerance for pathologic stress. A potent regulator of fetal to adult state transitions and the switch from hyperplastic to hypertrophic growth in the postnatal heart is an RNA binding protein causal for myotonic dystrophy (DM), Muscleblind-like 1 (MBNL1). Mosaic MBNL1 deficiency was newly identified in the myocyte population following 2 weeks of pressure overload. Interestingly, only the MBNL1 deficient myocytes reactivated the fetal gene program, suggesting MBNL1 might regulate this switch during cardiac stress. Indeed experimentally-derived MBNL1 deficiency in nearly every myocyte prevented pressure overload-induced hypertrophic remodeling, but these hearts rapidly decompensated which we ascribe to their inability to divide or hypertrophy. By contrast MBNL1 overexpression in pressure overloaded hearts prevented fetal gene reprogramming and increases hypertrophic growth broadly across the myocyte population. Collectively these data suggest a model whereby MBNL1 appears to regulate the optimal distribution of fetal versus adult myocytes states needed to preserve cardiac performance in response stress and MBNL1-driven deviations in those distributions determine the nature and severity of maladaptive remodeling. Hence this application will test this hypothetical model by [1] examining the contribution of mosaic MBNL1 deficiency to the nature and severity of cardiac remodeling in response to pathologic and physiologic increases in workload, [2] determining the effects of maintaining MBNL1 expression in myocytes on cardiac remodeling, and [3] comparing the effects of human mosaic MBNL1 deficiency from genetic deletion or DM on engineered cardiac tissue growth, maturation, and performance in response to afterload.