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Updated: Mar 7, 2026
Activating Autophagy by Aerobic Exercise in Mice
Published on: February 3, 2017
DDiT4L promotes autophagy and inhibits pathological cardiac hypertrophy in response to stress
Bridget Simonson1, Vinita Subramanya2, Mun Chun Chan1
1Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
Insights
DNA damage-inducible transcript 4-like (DDiT4L) protein promotes pathological cardiac hypertrophy by activating autophagy via mTOR signaling. Suppressing DDiT4L or autophagy reversed cardiac dysfunction, suggesting therapeutic potential for heart disease.
Area of Science:
- Cardiovascular Biology
- Cellular Stress Response
- Molecular Cardiology
Background:
- Physiological cardiac hypertrophy is adaptive, while pathological hypertrophy is maladaptive and precedes heart failure.
- Pathological cardiac hypertrophy is linked to stimuli like high blood pressure, oxidative stress, and metabolic stress.
- The role of specific molecular pathways in differentiating these hypertrophy types is crucial.
Purpose of the Study:
- To investigate the role of DNA damage-inducible transcript 4-like (DDiT4L) in pathological cardiac hypertrophy.
- To elucidate the signaling mechanisms, including mTORC1 and mTORC2, by which DDiT4L influences cardiac function and autophagy.
- To explore DDiT4L as a potential therapeutic target for cardiovascular diseases.
Main Methods:
- Utilized murine models of physiological and pathological cardiac hypertrophy.
- Investigated DDiT4L expression and localization in cardiomyocytes under stress.
- Employed cardiac-specific DDiT4L overexpression and genetic suppression of autophagy in mice.
- Assessed cardiac function, autophagy levels, and mTOR signaling pathway activity.
Main Results:
- DDiT4L was expressed in pathological but not physiological cardiac hypertrophy models.
- DDiT4L localized to early endosomes and promoted stress-induced autophagy via mTORC1 inhibition and mTORC2 activation.
- Cardiac-specific DDiT4L overexpression led to systolic dysfunction and altered mTOR signaling, which were reversible.
- Genetic suppression of autophagy also reversed cardiac dysfunction in DDiT4L-overexpressing mice.
Conclusions:
- DDiT4L acts as a key transducer of pathological stress to autophagy through the mTOR signaling pathway in the heart.
- Targeting DDiT4L or modulating autophagy and mTOR signaling presents a potential therapeutic strategy for cardiovascular diseases.
- Understanding DDiT4L's role is critical for developing novel treatments for heart failure.
Abstract:
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.
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