Rhonda: Maybe we can talk a little bit about some of the skeletal muscle adaptations from high intensity interval training, maybe compare and contrast when we can to continuous exercise.

But mitochondria are very, I mean, it's probably one of the most important organelles inside most of our cells, particularly in skeletal muscle cells. And I recall quite a few studies from your lab and others showing that high intensity interval training was a very potent stimulus for mitochondrial biogenesis or the generation of new mitochondria.

So can you talk a little bit about, I mean, how it affects mitochondrial biogenesis, maybe the difference between more continuous exercise, why that's important in mitochondrial biogenesis?

Dr. Gibala: Sure. So you're absolutely right. You know, and I think even if people took high school biology, you tend to think of mitochondria, these sort of bean shaped things in your body.

But we now know mitochondria are this amazing reticular network. So it's a bit like if you can imagine all of your capillaries that go through your skeletal muscle fibers, the best evidence now would suggest that mitochondria sort of work the same way. It's this network of organelle that goes through muscle, and they can change, right?

The size of the organelle, but you can have increases or decreases in mitochondrial capacity surprisingly quickly. So you can increase mitochondrial content very, very rapidly, certainly within a few days or weeks of training. And it seems to go the other direction pretty quick as well. So when you detrain, you can lose mitochondrial capacity quite quickly as well.

You know, so what does exercise do? Any type of exercise, if you can imagine exercise is a stress. And so all of these stress compounds or indices of stress change inside your muscles. So you immediately have this large increase in demand for ATP, calcium levels go up, reactive oxygen species, lactate, hydrogen ions change.

And many of those, you can think of those as fuel gauges, or fuel monitors, right? They're saying, oh my goodness, we have an energy crisis, our ATP is going down, this is going to signal that we need more energy. And so many of those compounds, those acute changes have been linked to cellular, molecular signaling pathways that are associated with the growth of new mitochondria.

And so this is the idea of mitochondrial biogenesis, genesis or growth of new mitochondria. And those pathways are really, really well mapped out now, a lot of it based on animal research and, you know, very sophisticated work. But largely, what's seen in humans is, it sort of seems to work the same way. So an acute bout of exercise causes increase in those signaling compounds.

And as I mentioned, within a few days, or weeks, you can see measurable increases in mitochondria measured with microscopy or Western blotting. There's lots of methods to assess that. Now, how does HIIT and continuous compare? Again, we definitely have studies on this, but all of these require muscle biopsies.

So a needle biopsy, a small sample of muscle needs to be taken often by a physician, or at least a highly trained individual under the supervision of a physician. So they're invasive procedures. And what we get is snapshots in time, we don't have real-time changes of how your mitochondria change over days and weeks, we have these little snapshots.

But certainly, you know, my laboratory, a lot of other laboratories that have compared continuous and interval training, there is some evidence that higher intensity, more vigorous exercise when the total dose is matched, can lead to at least a more rapid or larger increase in mitochondrial content, again, at least over the short term.

So is it just getting you somewhere faster? And if you do enough of it over time, it starts to plateau. We don't really have a great answer for that right now.

Rhonda: If you are generating more mitochondria, then, you know, this kind of goes into the fat oxidation, mitochondria are the primary place where you're oxidizing fat, you're using fat to produce energy.

What do you think of this concept of, you know, you have to be...the substrate you're burning during exercise is...so you have to be burning more fat while you're exercising to have adaptations for better fat, you know, oxidation after you're done with exercise, just, you know, at steady state, at rest. So in other words, like, you know, you have to be more in aerobic type of state to have those adaptations.

Dr. Gibala: So, you know, mitochondria consume lots of fuels, right? The primary ones, of course, carbohydrate and fat. So whatever you feed it, feed the mitochondria, as long as it has the capacity, has a sufficient capacity for that, it will burn either of those fuels. But you're right, you know, mitochondrial content largely limits or determines fat oxidation by an individual muscle or fat oxidation during exercise is largely determined by mitochondrial content.

And in particular, a very specific enzyme inside your mitochondria called carnitine palmitoyltransferase or CPT, that's sort of the gatekeeper that gets fatty acids into the mitochondria. Once they're inside the mitochondria, they can be oxidized. But there's good data to show that that's the critical enzyme.

And so with training, you want to increase CPT levels. And, you know, there's various supplements that are supported, purported to increase CPT activity. You know, one of the reasons why carnitine is a popular supplement is it's purported to increase your oxidation of fatty acids. The data on that's, you know, not great, but we could talk about that as well.

But yeah, you know, lots of debate around what's the best way to increase mitochondrial content because that in turn is going to set the upper limit for fat oxidation capacity. And athletes in particular want to have a very high rate of fatty oxidation, because even in very lean individuals, there's ample fat on board, and carbohydrate tends to be a very precious and limited fuel.

So ideally, we'd like to preserve carbohydrate until we really need it, like when we're racing and we need a very high rate of carbohydrate oxidation as well.

Rhonda: So if you're doing a high-intensity interval training session, and you're going above 80% max heart rate, you're now going to this lactate threshold where you're basically producing more lactate quicker than you can consume it, potentially you're anaerobic maybe.

I mean, so this idea is like that you're not going to be burning fat during that part of the exercise, but that doesn't necessarily mean that you're not going to be able to burn more fat after, because it does, as you just mentioned, increase mitochondrial biogenesis. So you're actually increasing the capacity to oxidize fat later on.

Dr. Gibala: No, absolutely. So to me, what's important is the increase in mitochondrial content, the overall increase in mitochondria. And I think generally, mitochondria have hundreds, more than a thousand different proteins that are all necessary to build the mitochondria, and they probably generally all sort of increase and decrease in parallel, right?

So there's not necessarily a specific way to really only boost that CPT enzyme that I talked about. So I think that the most important adaptation or a critical adaptation in muscle is increasing mitochondrial content, which then will allow a greater fat oxidation capacity as well as a greater carbohydrate oxidation capacity.

And you don't have to only work at a high rate of fatty acid oxidation in order to get that boost in mitochondria. So there's many different ways to stimulate that, including short, intensive types.

Rhonda: What do you, just as a sort of side note, I was reading about the effect of like epinephrine, norepinephrine, which are increased when you're doing more of a higher intensity type of exercise, correct?

And that also sort of has some fat. I mean, is it lipolysis maybe? It does.

Dr. Gibala: So the catecholamines, norepinephrine, epinephrine, they're involved. And so norepinephrine is an important hormone that will signal adipose tissue to start to break down triglyceride and release those fatty acids into the bloodstream. So, you know, much like we were talking about, we use the analogy of oxygen or we're talking about oxygen, it's delivery of oxygen and it's uptake of oxygen. When it comes to fatty acid use, it's delivery of the fatty acids, and it's the uptake and oxidation of those fatty acids. And you can definitely give people supplements that are going to increase lipolysis.

It's going to make more fatty acids available. It's going to increase the breakdown of triglycerides, but it's not necessarily going to increase oxidation. So I think there's quite good evidence that has established that the limit for fat oxidation resides inside the muscle and it's at that level of the CPT, which is that gatekeeper to get the fatty acids into the mitochondria where they can then be burned or oxidized.

Rhonda: Yeah, that's great. And then mitochondrial biogenesis is increasing that CPT. I mean, if you're looking at least at a per cell, you know, level, right? Because you're more mitochondria within that skeletal muscle cell. Yes. Sort of, we were talking about this a little bit earlier off camera about, you know, the...

So talking about mitochondrial biogenesis, the other sort of important factor with mitochondrial health would be mitophagy, which would be the clearance of actual like sort of old damaged mitochondria. As you know, there's definitely not a lot of evidence... There's animal evidence, but how much that can translate to humans is sort of unclear with respect to exercise and particularly high-intensity exercise doing that.

But what I did want to touch on was autophagy, which I think we have a little bit... It's a little bit... We've got more markers to measure it, and it has been measured, at least in human skeletal muscle with respect to response to exercise. And I'm just curious what your thoughts are because it has been shown that high-intensity exercise is more potent for stimulating autophagy in skeletal muscle than just an overnight fast itself.

And you don't even have to be in a fasted state when you're doing the high-intensity exercise, which to me was like, you know... So what is the significance, do you think, for skeletal muscle health? And do you guys look at that or...

Dr. Gibala: We don't study that in our laboratory. I think the bottom line there is exercise is good for the routine maintenance or turnover of many of these cellular processes, including mitochondria.

So it supports mitochondrial health. It sort of promotes the sort of breakdown and the building of new mitochondria. So it's important to maintain mitochondrial health, if you will, the overall health or capacity of these mitochondria. You know, clearly, I'm a proponent of vigorous-intensity exercise.

There's some other studies out there that have shown that really vigorous exercise can temporarily impair mitochondrial capacity. So if you measure it immediately post-exercise or in the short-term after, you can engage in too vigorous an effort. You basically really hammer your cells, and they sort of have a decline in function before they start to come back.

And so there's some criticism of interval training out there based on those studies, especially very intensive Wingate-style all-out-type exercise that can transiently reduce mitochondrial capacity. We're talking about different things there, you know, autophagy and the various processes. But, you know, I think this is the idea that exercise is a stress.

It temporarily disrupts or damages things. And then it's all about the recovery that makes the cellular process better. And we continually do that. And over time, things get better. But certainly, can we acutely over-train or acutely over-...cause some disruption, or it takes a prolonged period of time before it recovers?

Sure. It's a bit like, you know, concentric and eccentric weightlifting exercise. We know that eccentric weightlifting exercise is more damaging to tissues. You get more sore. And so you tend to take a little bit more time to recover. So not as simple as just high-intensity good, continuous not, or less good.

There's a lot of nuance there depending on the process.