p38γ and p38δ regulate postnatal cardiac metabolism through glycogen synthase 1.

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...

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Detalles Bibliográficos
Autores: Santamans, Ayelén M, Montalvo-Romeral, Valle, Mora, Alfonso, Lopez, Juan Antonio, González-Romero, Francisco, Jimenez-Blasco, Daniel, Rodríguez, Elena, Pintor-Chocano, Aránzazu, Casanueva-Benítez, Cristina, Acin-Perez, Rebeca, Leiva-Vega, Luis, Duran, Jordi, Guinovart, Joan J, Jiménez-Borreguero, Jesús, Enriquez, Jose Antonio, Villlalba-Orero, María, Bolaños, Juan P, Aspichueta, Patricia, Vázquez, Jesús, González-Terán, Bárbara, Sabio, Guadalupe
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/18918
Acceso en línea:http://hdl.handle.net/20.500.12105/18918
Access Level:acceso abierto
Palabra clave:Animals
Animals, Newborn
Cardiomegaly
Diet, High-Fat
Enzyme Activation
Feeding Behavior
Female
Gene Deletion
Glucose Intolerance
Glycogen
Glycogen Synthase
Glycogen Synthase Kinase 3
Insulin Resistance
Lipid Metabolism
MAP Kinase Signaling System
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 12
Mitogen-Activated Protein Kinase 13
Myocardium
Myocytes, Cardiac
Organ Specificity
Phosphorylation
Mice
Descripción
Sumario: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.

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