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Advances in Motion

Manipulating Autophagy in the Heart Inhibits Stress-Induced Pathological Cardiac Hypertrophy

Journal

Originally published on Science Signaling

Key findings

  • DDiT4L gene expression in the heart is activated by pathological stressors, such as high blood pressure, and can be reversed by inhibiting autophagy
  • DDiT4L gene expression is not activated by beneficial stress on the heart, such as that from exercise
  • Overexpression of DDiT4L in the mouse heart induces autophagy
  • The pathophysiology of the cardiac stress phenotype caused by the overexpression of DDiT4L was completely reversed by suppressing the gene and inhibiting autophagy
  • Fully reversible cardiac phenotypes are rare and point to novel pathways to target for new heart disease treatments

Autophagy is a catabolic process that plays a key role in the heart in homeostasis and in responding and adapting to stress. When autophagy is dysregulated, it is implicated in many diseases.

Autophagy is central to both the “good stress” that drives the physiologic hypertrophic cardiac growth response to exercise, and the “bad stress” that underlies the heart’s pathologic hypertrophic response to unchecked high blood pressure and oxidative or metabolic stress.

Enter the DDiT4L gene

Researchers from Massachusetts General Hospital set out to find what drives the “good stress” and “bad stress” responses in the heart. In preliminary in vivo studies, they found that the answer may lie in the gene known as DNA damage-inducible transcript 4-like (DDiT4L).

In a recent investigation published in Science Signaling, the researchers illuminated the roles played by DDiT4L in regulating autophagy in the heart and its regulatory response to stress.

Good stress, bad stress

The study revealed DDiT4L was a top gene candidate that showed increased expression in an animal model of pathological stress and hypertrophy – but not in models of physiological hypertrophy (“good stress”). That same pattern was true in other experimental models of good and bad heart stress. Examination of heart patients in the clinic also found an increased expression of DDiT4L.

Three important implications for human heart health from the study:

  1. DDiT4L activated stress-induced autophagy and differentially regulated the mTORC1 and mTORC2 pathways in heart muscle cells
  2. mTORC1 and mTORC2 have opposite activity based on stressors
  3. Expression of DDiT4L in the heart increased baseline autophagy, which caused mild dysfunction, atrophy and molecular distress signals typical of pathological stress
  4. Turning off DDiT4L expression reversed the symptoms of pathological stress

From stress to autophagy

These results indicate that DDiT4L appears to play an important role in converting pathological stress into autophagy through a well-known regulator of autophagy, mTOR, and its signaling pathway in the heart.

Combined, these insights may lead to a new generation of targeted heart disease therapies where autophagy and mTOR signaling play a role.

10%
 increase was the robust cardiac hypertrophic response produced in models that swam 7 days a week for 4 weeks

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Journal Article Published:

Refer a patient to the Massachusetts General Hospital Corrigan Minehan Heart Center

Listen to a podcast on this topic with senior author Saumya Das, MD

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