PodcastCardiovascular Biology

Science Signaling Podcast for 28 February 2017: Balancing autophagy in the stressed heart

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Science Signaling  28 Feb 2017:
Vol. 10, Issue 468, eaam9536
DOI: 10.1126/scisignal.aam9536


This Podcast features an interview with Saumya Das, senior author of a Research Article that appears in the 28 February 2017 issue of Science Signaling, about a protein that inhibits pathological cardiac hypertrophy in mice. Temporary increases in cardiac workload, such as those caused by exercise or pregnancy, induce physiological cardiac hypertrophy, a beneficial type of heart enlargement that is adaptive. However, a sustained increase in workload due to metabolic stress or uncontrolled high blood pressure induces pathological cardiac hypertrophy, which can contribute to heart failure. Simonson et al. found that expression of DNA-damage-inducible transcript 4-like (DDiT4L) increased during pathological hypertrophy, but not during physiological hypertrophy, in mice. DDiT4L promoted stress-induced autophagy in cardiomyocytes by inhibiting signaling through the mechanistic target of rapamycin complex 1 (mTORC1) and stimulating signaling through mTORC2. These findings suggest that targeting autophagy, which is important for cellular homeostasis but can be detrimental in excess, may be useful for treating some cardiovascular diseases.

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Host – Annalisa VanHookWelcome to the Science Signaling Podcast for February 28th, 2017. I’m Annalisa VanHook, and today I'm talking with Saumya Das about a protein that inhibits pathological cardiac hypertrophy (1).

When the heart is subjected to mechanical stress, it enlarges, a phenomenon called cardiac hypertrophy. When we exercise, the increased workload on the heart is temporary, and this induces hypertrophy that’s beneficial. This is called physiological or adaptive hypertrophy. But when the heart is put under sustained mechanical stress, as in the case of uncontrolled high blood pressure or metabolic stress, the resulting cardiac hypertrophy is not beneficial. This is called pathological hypertrophy, and it can contribute to heart failure. One of the cellular processes that’s been implicated in cardiac hypertrophy is autophagy, the process by which proteins and other cellular components are degraded. Autophagy is important for cellular homeostasis and for the ability of cells to adapt to stress, but too much autophagy can be detrimental. A team led by Saumya Das at the Harvard Medical School has identified a protein that promotes autophagy and inhibits pathological hypertrophy in mice, but it doesn’t appear to play a role in physiological hypertrophy. Das spoke to me from Massachusetts General Hospital to explain how this protein called DDiT4L balances autophagy in heart cells.

Interviewer – Annalisa VanHookHello, Dr. Das. Welcome to the Science Signaling Podcast.

Interviewee – Saumya DasHello, I'm happy to be here. Thanks for inviting me.

Interviewer – Annalisa VanHookThere are two types of cardiac hypertrophy—there's physiological hypertrophy and pathological hypertrophy. Physiological hypertrophy is induced by exercise, and it's beneficial. On the other hand, pathological hypertrophy is induced by things like high blood pressure and metabolic stress, and it's not beneficial. How do these two types of hypertrophy differ?

Interviewee – Saumya DasSo, one of the things we have learned over the past decade is that these types of hypertrophy are very different, even early on when they have onset of hypertrophy. The molecular signaling pathways are distinct for physiological hypertrophy but, as you mentioned, can be induced by exercise or pregnancy. And both the transcription factors and other signaling pathways for this type of hypertrophy significantly differ from those induced by pathological stressors like high blood pressure or oxidative stress or metabolic stress. The way these hypertrophy progress are fairly different, as well. Pathological hypertrophy can progress on to fibrosis, overt changes in the structure of the heart, so the heart may dilate and have worse physiological function. And this may eventually lead to both arrhythmias and overt heart failure. On the other hand, physiological hypertrophy does not progress down these pathways and, in fact, can sometimes regress, as seen with pregnancy.

Interviewer – Annalisa VanHookIn terms of anatomy, do these two different types of hypertrophy cause different morphological changes in the heart? I mean, can you look at a heart and say,”Oh that's pathological hypertrophy,” or “That's physiological hypertrophy?”

Interviewee – Saumya DasI think it depends on what time you look at the heart. So, very early on it will be hard to distinguish the two because there's a phase with pathological hypertrophy where you get thickening of the heart muscle, and you may not have overt fibrosis or you may not have worsening in heart function. And, at that early stage, it might be difficult to tell the difference between physiological hypertrophy and pathological hypertrophy. For example, you look at an athlete's heart, you may notice some of the features that you might see early on in patients with high blood pressure, for example. As time progresses, these differences become much more distinct. And so, with pathological hypertrophy, just by looking at the heart you can see changes, such as an enlargement of the chamber of the heart. If you were to image it, you would see worsening squeeze of the heart, so worsening systolic function. And with more fancy imaging, you can also tell some of these differences perhaps even at an earlier stage, such as using MRI or more sophisticated echocardiographic measurements.

Interviewer – Annalisa VanHookYou identified a gene called DDiT4L that's activated in heart tissue in mice that have pathological hypertrophy, but it's not activated in mice that have this adaptive, physiological type of hypertrophy. What does the protein that's made by that gene do?

Interviewee – Saumya DasSo, we believe that DDiT4L is a stress-related signaling molecule that appears to be an important regulator of autophagy and a negative regulator of hypertrophy acting by its effects on the mTOR pathway. We found it has a very low baseline expression, but it increases in response to various stress signals both in cardiomyocytes—for example, in cell culture—as well as in the animal models that we looked at. These stress signals we examined can affect multiple cellular processes in the heart. For example, if you had glucose deprivation as a form of metabolic stress, cells increase autophagy, a process where they break down their internal components [and] regenerate energy. On the other hand, if you have favorable conditions for growth and have signaling by factors like insulin, the cell can increase protein synthesis in order to grow. For both of these type[s] of processes, mTOR—or the mammalian target of rapamycin—appears to be a key nodal point for integrating these signals, and DDiT appears to regulate aspects of mTOR signaling in response to these kinds of signals.

Interviewer – Annalisa VanHookDo you know how DDiT4L inhibits TORC signaling?

Interviewee – Saumya DasWe know some aspects of it, and others still need to be investigated. We found through both experiments where we had gain of function of DDiT4L—so, increased activity of DDiT4L—versus loss of function where we were able to get rid of DDiT4L function, we found that DDiT4L inhibits mTORC1 signaling by interacting with a protein called Tuberous sclerosis 2 or TSC2, which is upstream of mTORC1. We also found that it can be in the same chamber as mTOR, so it can be associated with mTORC1 under situations of stress. However, the exact details of its other interacting partners and how it inhibits mTORC1 is not completely clear yet.

Interviewer – Annalisa VanHookSo, DDiT4L inhibits signaling through the mTOR complex 1— or mTORC1 — but it doesn't inhibit signaling through mTORC2?

Interviewee – Saumya DasThat's right. There's a complex interaction between mTORC1 and mTORC2. So other investigators, for example, have shown that mTORC1 can inhibit signaling via mTORC2. And what we found is that, by inhibiting mTORC1, DDiT4L can derepress mTORC2, allowing it to get activated. And so the ultimate consequence of DDiT4L activation is that you get inhibition of mTORC1 and activation of mTORC2. It can also inhibit growth in response to stress signals such as phenylephrine, which is a neurohormone we use in cell culture. Conversely, if we get rid of DDiT4L by silencing it, we abolish the response of the cell to increase autophagy in response to metabolic stressors such as glucose deprivation.

Now if we look in mice model, which we created by having a conditional overexpression of DDiT4L in heart cells, these mice show an increased level of autophagy; this is in the absence of any stress, so a baseline increase level of autophagy. They've thinner heart walls, so a somewhat anti-hypertrophic effect, slightly dilated chambers, and a mild decrease in systolic function, as well as smaller length of the individual cardiomyocytes isolated from these hearts. Interestingly, all these effects are completely reversed if we suppress the expression of DDiT4L, at least up to three months of age in these mice.

Interviewer – Annalisa VanHookIs the increased autophagy in pathological hypertrophy a result of the hypertrophy, or is it a cause?

Interviewee – Saumya DasSo, you know, I think that's a really critical question. If you look at the literature, you can find models where inhibiting autophagy has beneficial effects, and you can see other models where activating autophagy has beneficial effects. So what we are learning really is that it is extremely model- and context-dependent, so that the timing of autophagy is a critical determinant of whether inhibition is good or bad for the outcome of the disease. If you look at a very common model of hypertrophy in heart failure, which is called pressure overload — these mice where you can increase the pressure in the heart by ligating the aorta to some degree — initially have some hypertrophy. And during this early phase, you have an increase in autophagy. And then, later on they actually have a marked suppression of autophagy. And if you can activate autophagy in a lot of these models, you actually prevent the deterioration from hypertrophy to heart failure, suggesting that that increased level of autophagy may actually be an adaptive response.

Similarly, there are models with ischemia-reperfusion or creating an infarct in the mouse heart. And in a lot of those models, if you inhibit autophagy in the chronic remodeling phase, you do much worse, whereas if you activate autophagy say by treating the mice with rapamycin, which is an MTORC1 inhibitor, you can improve some of the outcomes. So it really is context-dependent and model-dependent.

Interviewer – Annalisa VanHookWe know that in a lot of contexts autophagy is beneficial; that it helps cells cope with the stress. But, it also sounds like too much autophagy can be bad for the cells.

Interviewee – Saumya DasRight. It is interesting that these mice that have an increased amount of autophagy have this mild dysfunction. And in fact, there are other models with more significant effects. For example, if you knockout components of the mTORC1 pathway, these mice have a much more drastic—although a similar—phenotype of atrophy—you know, thin walls, dilated heart, and a massive increase in autophagy. So I think what this tells us is that if you increase autophagy indiscriminately in the absence of stress, you might see some worse effects on the heart. However, if you increase autophagy in the context of stress, where the increase in autophagy may be an adaptive response, you might actually beneficially affect these models.

Interviewer – Annalisa VanHookIs autophagy potentially a target for treating heart disease given that autophagy is important in the context of stress and too much or too little is bad?

Interviewee – Saumya DasYes, I think it definitely would be a target in certain forms of heart disease and administered at a certain time. There are, as I mentioned, several animal models where activating autophagy has shown clear beneficial effects in the remodeling phase of heart disease, so the sort of signaling pathways that are activated by hypertrophy that ultimately have maladaptive consequences. So increasing autophagy at those time points appears to be beneficial in several heart disease models. We've also learned that there are different forms of autophagy. There is a form of autophagy called alternative autophagy; there are forms of autophagy that go down selectively different pathways. And so, as we learn more about that and are able to target particular forms of autophagy, we might further sort of tease apart what type of autophagy is good and what type of autophagy is maladaptive.

So I feel we're at the verge of finding out more of these distinct pathways of autophagy and when they're activated. And having that knowledge, might then allow us to kind of tease apart therapies that might beneficially affect heart remodeling compared to those that are indiscriminate and may have worse consequences.

Interviewer – Annalisa VanHookSaumya, thanks for speaking with me.

Interviewee – Saumya DasThank you. It was a pleasure.

Host – Annalisa VanHookThat was Saumya Das discussing a paper published in the February 28th issue of Science Signaling by Simonson and colleagues (1). You can read that paper online at stke.sciencemag.org.


The Science Signaling Podcast is a production of Science Signaling and the American Association for the Advancement of Science—Advancing Science, Serving Society. If you have any comments or questions, you can write to us at sciencesignalingeditors{at}aaas.org. I'm Annalisa VanHook. On behalf of Science Signaling and AAAS, thanks for listening.

Educational Details

Learning Resource Type: Audio

Context: High school upper division 11-12, undergraduate lower division 13-14, undergraduate upper division 15-16, graduate, professional, general public and informal education

Intended Users: Teacher, learner

Intended Educational Use: Learn, teach

Discipline: Cardiology, cell biology, pathology, physiology

Keywords: Science Signaling, autophagy, cardiomyopathy, DDiT4L, DNA-damage-inducible transcript 4-like, heart disease, heart failure, mechanistic target of rapamycin complex, mTORC1, mTORC2, pathological cardiac hypertrophy, stress


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