p38γ and p38δ regulate postnatal cardiac metabolism through glycogen synthase 1
Ayelén M. Santamans, Valle Montalvo-Romeral, Alfonso Mora, Juan Antonio López, Francisco González‐Romero, Daniel Jiménez-Blasco, Elena M. Rodríguez Rodríguez, Aránzazu Pintor‐Chocano, Cristina Casanueva-Benítez, Rebeca Acín‐Pérez, Luis Leiva‐Vega, Jordi Durán, Joan J. Guinovart, Jesús Jiménez-Borreguero, José Antonio Enrı́quez, María Villalba‐Orero, Juan P. Bolaños, Patricia Aspichueta, Jesús Vázquez, Bárbara González‐Terán, Guadalupe Sabio
Abstract
During the first weeks of postnatal heart development, cardiomyocytes undergo a major adaptive metabolic shift from glycolytic energy production to fatty acid oxidation. This metabolic change is contemporaneous to the up-regulation and activation of the p38γ and p38δ stress-activated protein kinases in the heart. We demonstrate that p38γ/δ contribute to the early postnatal cardiac metabolic switch through inhibitory phosphorylation of glycogen synthase 1 (GYS1) and glycogen metabolism inactivation. Premature induction of p38γ/δ activation in cardiomyocytes of newborn mice results in an early GYS1 phosphorylation and inhibition of cardiac glycogen production, triggering an early metabolic shift that induces a deficit in cardiomyocyte fuel supply, leading to whole-body metabolic deregulation and maladaptive cardiac pathogenesis. Notably, the adverse effects of forced premature cardiac p38γ/δ activation in neonate mice are prevented by maternal diet supplementation of fatty acids during pregnancy and lactation. These results suggest that diet interventions have a potential for treating human cardiac genetic diseases that affect heart metabolism.