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

The mTORC1 inhibitor DDiT4L prevents the increase in heart size caused by stress. 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. Physiological cardiac hypertrophy, in response to stimuli such as exercise, is considered adaptive and beneficial. In contrast, pathological cardiac hypertrophy that arises in response to pathological stimuli such as unrestrained high blood pressure and oxidative or metabolic stress is maladaptive and may precede heart failure. We found that the transcript encoding DNA damage–inducible transcript 4-like (DDiT4L) was expressed in murine models of pathological cardiac hypertrophy but not in those of physiological cardiac hypertrophy. In cardiomyocytes, DDiT4L localized to early endosomes and promoted stress-induced autophagy through a process involving mechanistic target of rapamycin complex 1 (mTORC1). Exposing cardiomyocytes to various types of pathological stress increased the abundance of DDiT4L, which inhibited mTORC1 but activated mTORC2 signaling. Mice with conditional cardiac-specific overexpression of DDiT4L had mild systolic dysfunction, increased baseline autophagy, reduced mTORC1 activity, and increased mTORC2 activity, all of which were reversed by suppression of transgene expression. Genetic suppression of autophagy also reversed cardiac dysfunction in these mice. Our data showed that DDiT4L may be an important transducer of pathological stress to autophagy through mTOR signaling in the heart and that DDiT4L could be therapeutically targeted in cardiovascular diseases in which autophagy and mTOR signaling play a major role.