Santamans, Ayelén MMontalvo-Romeral, ValleMora, AlfonsoLopez, Juan AntonioGonzález-Romero, FranciscoJimenez-Blasco, DanielRodríguez, ElenaPintor-Chocano, AránzazuCasanueva-Benítez, CristinaAcin-Perez, RebecaLeiva-Vega, LuisDuran, JordiGuinovart, Joan JJiménez-Borreguero, JesúsEnriquez, Jose AntonioVilllalba-Orero, MaríaBolaños, Juan PAspichueta, PatriciaVázquez, JesúsGonzález-Terán, BárbaraSabio, Guadalupe2024-03-122024-03-122021-11PLoS Biol. 2021 Nov 10;19(11):e3001447.http://hdl.handle.net/20.500.12105/18918During 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.engVoRhttp://creativecommons.org/licenses/by/4.0/AnimalsAnimals, NewbornCardiomegalyDiet, High-FatEnzyme ActivationFeeding BehaviorFemaleGene DeletionGlucose IntoleranceGlycogenGlycogen SynthaseGlycogen Synthase Kinase 3Insulin ResistanceLipid MetabolismMAP Kinase Signaling SystemMice, Inbred C57BLMitogen-Activated Protein Kinase 12Mitogen-Activated Protein Kinase 13MyocardiumMyocytes, CardiacOrgan SpecificityPhosphorylationMiceAtribución 4.0 Internacional347580181911e300144710.1371/journal.pbio.30014471545-7885PLoS biologyopen access