On Thursday 1 March 2018, Guadalupe Sabio will open the Cardioforo Interactivo 2018 in Badajoz (Spain) with the talk La ciencia básica al servicio de la salud cardiovascular.
Bárbara González-Terán, Juan Antonio López, Elena Rodríguez, Luis Leiva, Sara Martínez-Martínez, Juan Antonio Bernal, Luis Jesús Jiménez-Borreguero, Juan Miguel Redondo, Jesús Vazquez & Guadalupe Sabio.
Disrupted organ growth leads to disease development. Hypertrophy underlies postnatal heart growth and is triggered after stress, but the molecular mechanisms involved in these processes are largely unknown.
Here we show that cardiac activation of p38γ and p38δ increases during postnatal development and by hypertrophy-inducing stimuli. p38γ/δ promote cardiac hypertrophy by phosphorylating the mTORC1 and mTORC2 inhibitor DEPTOR, which leads to its degradation and mTOR activation. Hearts from mice lacking one or both kinases are below normal size, have high levels of DEPTOR, low activity of the mTOR pathway and reduced protein synthesis. The phenotype of p38γ/δ−/− mice is reverted by overactivation of mTOR with amino acids, shRNA-mediated knockdown of Deptor, or cardiomyocyte overexpression of active p38γ and p38δ. Moreover, in WT mice, heart weight is reduced by cardiac overexpression of DEPTOR.
Our results demonstrate that p38γ/δ control heart growth by modulating mTOR pathway through DEPTOR phosphorylation and subsequent degradation.