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 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.
Highlights
Disrupted organ growth leads to disease development
Several studies identified mammalian TOR as a key regulator of cardiac hypertrophy; for example, the mTOR inhibitor rapamycin prevents heart-weight gain in an overload model of hypertrophy[5] and blocks cardiomyocyte size increases induced by AngII6 and phenylephrine[7], likely by inhibiting protein synthesis7. mTOR is a conserved serine/threonine kinase with a key regulatory function in cardiovascular physiology and pathology8. mTOR integrates signals from growth factors, nutrients and stresses to regulate multiple processes, including translation, cell cycle progression, autophagy and cell survival9. mTOR function is regulated by the formation of two multi-protein complexes: mTOR complex 1 and mTOR complex 2. mTORC1 is composed of the mTOR catalytic subunit and five associated proteins: Raptor, PRAS40, mLST8/GbL, DEPTOR and Tti1/Tel[2]
We found that cardiac activation of mTORC1 and mTOR complex 2 (mTORC2) was impaired in p38g/d À / À, p38g À / À and p38d À / À mice, as assessed by the phosphorylation of the mTOR targets p70S6K, S6 and FOXO1/3a and by mTOR autophosphorylation on Ser 2481 (Fig. 3a, Supplementary Fig. 3b,c); in contrast, no changes were detected in the a
Summary
(b) Heart-weight-to-tibia-length ratio. (c) Cardiomyocyte cross-sectional area quantified in wheatgerm agglutinin (WGA)-stained hearts. To assess whether mTOR signalling is altered in mice lacking p38g and p38d (Supplementary Fig. 3a), we analysed heart protein extracts by immunoblot. Immunoblot analysis of translation initiation/elongation factors in the hearts of p38g/d À / À mice revealed weak phosphorylation of EIF4E, EIF4G and EIF4B and strong phosphorylation of EF2 (Fig. 3b), indicating that cardiac protein synthesis is impaired in these mice. To confirm this finding, we injected puromycin into WT and p38g/d À / À mice 30 min before heart extraction and measured its incorporation into newly synthesized proteins. P-EF2 EF2 P-EIF4E EIF4E P-EIF4G P-EIF4B EIF4B Vinculin p-ElF4E/t-ElF4E p-EF2/t-EF2 p-S6 (S235-S236)/t-S6 p-MTOR/t-MTOR
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