Research ArticleCardiovascular Biology

DDiT4L promotes autophagy and inhibits pathological cardiac hypertrophy in response to stress

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Sci. Signal.  28 Feb 2017:
Vol. 10, Issue 468, eaaf5967
DOI: 10.1126/scisignal.aaf5967

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Protecting the heart from bad stress

An increase in workload causes the heart to enlarge. When this occurs in response to good stress (exercise or pregnancy), this is beneficial or adaptive hypertrophy; when this occurs in response to bad stress (high blood pressure or poor heart function), this process is pathological and contributes to heart failure. The kinase mTOR functions in two complexes: mTORC1, which promotes cell growth, and mTORC2, which promotes cytoskeletal rearrangements. Simonson et al. found that, in mice, pathological stress, but not physiological stress, increased the abundance of the mTORC1 inhibitor DDiT4L. In cardiomyocytes, DDiT4L inhibited mTORC1 signaling, which induced autophagy, and stimulated mTORC2 signaling. Mice that overexpressed DDiT4L in the heart developed mild heart dysfunction, which was reversed by turning off the DDiT4L transgene and which was partially reversed by deletion of an autophagy-encoding gene. These results suggest that DDiT4L regulates stress-induced autophagy, a process that is likely beneficial under stress but may exacerbate some heart conditions. Thus, increasing or inhibiting DDiT4L may be useful in various cardiomyopathies.