p38 gamma and delta promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation

Abstract

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 p38 gamma and p38 delta increases during postnatal development and by hypertrophy-inducing stimuli. p38 gamma/delta 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 p38 gamma/delta(-/-) mice is reverted by overactivation of mTOR with amino acids, shRNA-mediated knockdown of Deptor, or cardiomyocyte overexpression of active p38 gamma and p38 delta. Moreover, in WT mice, heart weight is reduced by cardiac overexpression of DEPTOR. Our results demonstrate that p38 gamma/delta control heart growth by modulating mTOR pathway through DEPTOR phosphorylation and subsequent degradation.