I do have a question about recovery and it's one that I think most people are familiar with themselves, which is soreness. We think of it as a muscle soreness, but I was trained early on in my scientific career to always question the seemingly obvious. So a couple of questions about soreness.

First of all, what does soreness really reflect? Is it really muscle soreness? It feels like it's in the muscles, but what other organ systems and tissues and cell types does it involve? And then I'm particularly interested in this concept or this experience that many of us, including myself, had, which is delayed onset muscle soreness.

Why would it be that when we are less in shape or when we perform a movement that is extremely novel to us, the soreness seems to arrive after a reasonable delay of maybe even a day. You know, we're fine the next day, but then 48 hours later, we are exceedingly sore.

And as we get more fit or more familiar with the movement, the soreness seems to arrive earlier. So I realized I just asked you about three questions or more. First of all, what is muscle soreness at a cellular level, which cells, which organ systems and so forth? What does it mean if we are sore is something I know we'll get into a little bit later.

And then why the delayed onset muscle soreness? It's actually one question. So it's totally fine. You answered all, you asked all three because I'm going to actually answer number three, which will answer number two, which will actually answer number one. I'd love to tell you that I set it up that way intentionally, but I'm just happy to hear that where I was unable to be concise, you are able to be concise.

Thank you. Yeah. We are still learning a lot about this area. It's actually really difficult to perform these studies. Anytime you ask a question about something like pain or soreness, you're immediately talking about perception. And there is obviously a physical component to that, and there's also perception. And so teasing those things out is extraordinarily challenging.

That said, there has been a lot of work in this area. And in fact, probably you may have a show already out on pain or maybe one's coming down the road. We did an episode on pain a while ago, but it's definitely time to revisit that literature. I also have some amazing colleagues at Stanford who work on pain, both from the cellular and molecular side, but also from the psychological side about how our understanding of pain and what we believe about pain shapes the experience of pain and pain relief.

Amazing. That stuff is incredibly important, and I'm glad we flagged that, and maybe we'll just call that good for now. They can come back later for another one of your shows. So that being said, why does it happen 28 to 48 hours after you exercise? Well, that actually should give you some clues into what's happening.

So the traditional dogma of delayed onset muscle soreness is what this is called, is that it is a result of "micro tears" in the muscle. And so you can sort of think, I challenged the muscle, there were some small tears in there and I'm feeling the results of that.

Well, in fact, that certainly does happen, and it can happen. That is not what's explaining your muscle soreness, and in fact, you can be quite sore from exercise and have no measurable amount of muscle damage. And so much like anything else, when we're in this idea of pain, it's not a one-to-one explanation.

There are multiple factors that are probably causing your perception of pain. Muscle damage can be one of them. It is not the only one, and it is probably, in my opinion, though this is yet to be shown definitively, probably not even the leading cause of it. And so what's actually happening?

Well, the reason it's taking you 24 to 48 hours is you can actually find various papers, literature reviews dating back a number of years now, over a decade, that show these wonderful curves of an inflammatory and immune response, and we don't need to necessarily go through the entire physiology right now, but effectively what's happening is those things have a little bit of a time delay.

And so some of those steps happen immediately, like right when the exercise is there, and then some of them are delayed 6 to 24 to 48 hours. If you know a little bit about this physiology, you have a combination of neutrophils and macrophages and a bunch of things happening, and this has a time sequence.

So what happens is by the time we get to this 28 to 48-hour window, now the muscle soreness kicks in, which, wait a minute, if this was a result of my muscles being torn and that happened immediately, wouldn't that pain start immediately? Well, the answer is it would. And so that is your first clue that that's not responsible for it.

When we look at that immune response and we see that that has actually peaked 24 to 48 hours later, and then that's the same time the pain kicked in, that's calling you in at the problem. So we have this immune response happening in inflammation, then all of a sudden we start getting fluid accumulation, and now there are what are called nociceptors, and you're probably very, obviously you're very familiar with these, and these are your pain receptors.

What's actually interesting is we don't necessarily know a lot of information about how many pain receptors are in muscle. They're not really in the belly. In fact, this is why I can perform my muscle biopsies and they don't really hurt. You mean in the belly of the muscle? Correct.

Yeah. We do have pressure sensors though, and so if you change the volume of the tissue, you will respond to that very, very quickly. So by enhancing swelling in the actual muscle, that is immediately putting pressure on those pressure receptors, if you will. That's the signal. So what's probably happening here, and I just hate to give you another bone, but a lot of delayed on some muscle soreness is probably just a neural feedback loop rather than it is actual muscle damage.

Yeah. It makes a lot of sense. There's a lot of interactions between the types of neurons that control touch sensation and pain sensation and itch sensation. In fact, a lot of people kind of collapse itch and pain together. Bingo. Yeah. You know, that something is painful and it itches is a familiar thing for people, mosquito bites and such.

And of course, there's the classic gait theory of pain, which people will be familiar with and then I'll explain why I'm explaining this, which is if something hurts, you bonk your knee or you stub your toe. We tend to grab that body part and try and rub it totally.

And that rubbing is not a coincidental thing. It activates a set of touch sensors that are that respond to kind of broad, dull touch. And that actively inhibits through the release of an inhibitory neurotransmitter, the fibers that control the pain signal. So anytime we rub a, you know, like a Charlie horse, our leg, or we, or we stub our toe and we, you know, we wince and then we grab the toe and we got like squeezing it a little bit, that's actually deactivating or partially inactivating the pain mechanism.

So the idea that a swelling response would then trigger a neural response that then would recruit the pain receptor response here, I'm using broad, broad brush strokes here to explain this makes very good sense to me now. And only now that you've explained how this process works. I can actually even add more to that.

So if you remember how muscles work, so we have to have some sort of signal from the nervous system that has to actually go in and tell the muscle to contract. Well, remember there a few episodes ago, we covered the physiology here of what's called a motor unit. Okay.

Well, what I didn't explain to you are called muscle spindles. And we have talked about proprioception in an episode of before as well, but we never tied this picture together. So let me walk you through that really quickly. And it's going to tie this loop into a nice bow.

So what happens is this motor unit is coming in from what's called an alpha motor unit. And that's going to be innervating your muscle fibers and that's going to tell the muscle fibers to contract. Those are typically spread out throughout the all sides of the muscle in interior, exterior all over.

On the outside though, there is another type of muscle called a muscle spindle. Now these are non-contractile, so they don't have that actin and myosin and they don't produce force. They are responsive, they are proprioceptive. So what that means is they sense stretch. And this is why, for example, if you were to stretch a hamstring, stretch any muscle group, it doesn't really matter, or muscle, its innate response is to fire back to close that distance.

And this is what keeps you from, say, if you're leaning to the right, you can imagine that the example we give is if you're standing on one foot and you start swaying to the right. All right, let's say you're standing on your right foot, and let's make this easier for folks.

And you start swaying to the right, like you're going to fall on your right ear, will hit the ground. The inside of your right calf muscle will start being stretched. The outside will start being compressed, right? So the stretch on the inside of the right calf muscle will sense that stretch and it will respond by contracting.

That pulls you back to the middle and stops you from falling. That's proprioception. And muscle spindles sense stretch and tell you to contract. The way that they work is through gamma motor neurons. And so these are sensory things. So what's happening is, unlike when you tell your muscle to contract, it goes alpha to the muscle, contract.

These muscle spindles work such that it is, "Oh, I've been stretched," sends signal back to some central point, typically in the spinal cord, and we don't actually want to go all the way up to the brain. We've got a time delay. This is why these are subconscious, autonomic, right, versus somatic.

So that gamma is going to go back to the central location and then come back through the alpha motor neurons and tell it to contract. So you have this wonderful mechanism of sensing stretch going back. Well, one theory that's been put forward regarding muscle damage is that the pressure is actually being applied to those nerve endings of the muscle spindles.

And that's actually responsible for the pain signal that's going back and coming up to your brain and you're registering that as pain rather than it is actually in the contractile units, so the muscle fibers. That's a very intriguing idea because it would suggest that stretching muscles in order to alleviate soreness might be the exact incorrect thing to do.

Yeah. Now, I'm not saying that's for certain. I'm just building off the mechanistic logic that we've laid out here. Yeah. Really that you've laid out here. There is a more effective principle based on exactly that, which is this is generally why low level movement is effective at reducing acute soreness.

Because that's low level contraction of the muscles. And you're going to contract and get tissue out and get fluid out. Wow. You're literally pumping it out of the cell. Yes. In our previous episode where we were talking about programming or confusing the we, but let's be fair here, where you were educating us, including me and the audience about different structures for programming, exercise for specific adaptations, et cetera, the month, week, year scales, et cetera.

We had a brief discussion about the fact that if one trains legs very hard with resistance training, some heavy squatting or dead lifting it, and there's some soreness that oftentimes doing some "lighter cardio" or some low impact work the next day or any number of different things that involve not high intensity contractions of the muscles, but that do require contractions of the muscles, that it can alleviate soreness more quickly than if one were to simply lie around and watch Netflix or something.

Yeah, that's exactly right. The, to go back just a little bit as well, if that's really the case, the question is like, where is this inflammatory signal coming from? And while there's much to be learned there, there is a little bit of information right now that suggests it's potentially coming from free radicals released from the mitochondria.

Again that may or may not hold up as more research comes, I'm not sure. But if you remember back to our conversation on endurance, so we talked about the electron transport chain and aerobic metabolism, regardless of whether or not you're getting energy from glycolysis or carbohydrates, remember they have to be finished through aerobic metabolism.

So even if you're lifting weights and you're using carbs for your fuel, you have got to finish that metabolism by running it into the mitochondria and performing oxidative metabolism. As a result of that, that electron transport chain runs. So theoretically, if free radicals, which are hyperreactive oxygen species, basically they're oxygen molecules that are missing an electron so that they react to a lot of things.

They're the opposite of antioxidants by the way, this is oxygen molecules with extra protons so they can balance the charge. If those leak out, that in and of itself is going to be a massive inflammatory signal and that's probably what signals the cause of these neutrophils and macrophages and kicks off this entire cascade.

Again I believe we need more research there. I need to look into it, maybe it's more definitive than I know. But that's probably what's happening, potentially what's happening rather, that causes that cascade in signal. Also what you have is this combination of, well if that's the case, why am I not getting tremendous amount of muscle damage when I do more aerobic based exercise?

Well because you don't have the mechanical tension pulling on the fibers that's actually causing damage to the cell wall that allows these free radicals to escape the mitochondria and the cell wall. It's the best we can postulate at this moment as to why those things are happening. And then why, again, low level exercise tends to enhance, even things like percussion.

So using either instruments that put a low level of vibration into your leg or like pneumatic boots so you can massage, all these things are generally probably helping because they're moving that stuff out, edema most specifically, so pressure comes off of those nerve endings and the muscle spindles and allows you to stop receiving that signal of pain despite the fact that you didn't actually regenerate tissue at all yet.