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.
Several studies identified mammalian TOR (mTOR) as a key regulator of cardiac hypertrophy; for example, the mTOR inhibitor rapamycin prevents heart-weight gain in an overload model of hypertrophy and blocks cardiomyocyte size increases induced by AngII and phenylephrine, likely by inhibiting protein synthesis.
mTOR is a conserved serine/threonine kinase with a key regulatory function in cardiovascular physiology and pathology. mTOR integrates signals from growth factors, nutrients and stresses to regulate multiple processes, including translation, cell cycle progression, autophagy and cell survival.
mTOR function is regulated by the formation of two multi-protein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is composed of the mTOR catalytic subunit and five associated proteins: Raptor, PRAS40, mLST8/GbL, DEPTOR and Tti1/Tel2. In mTORC2, the mTOR catalytic subunit is associated with six proteins: mLST8/GbL, DEPTOR, Tti1/Tel2 (in common with mTORC1) and Rictor, mSin1 and Protor. The activities of the mTORC1 and mTORC2 pathways are regulated by the common inhibitory component DEPTOR.
Researchers 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.
These results demonstrate that p38γ/δ control heart growth by modulating mTOR pathway through DEPTOR phosphorylation and subsequent degradation.
http://www.nature.com/ncomms/2016/160122/ncomms10477/full/ncomms10477.html
New understanding on cardiac hypertrophy
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