31 12 2012
The role of muscle damage in hypertrophy
I’ve often spoken on how my love for science evolved from my love for sports and fitness. My inability to get clear and truthful answers from the industry at large sought me to take refuge in scientific literature, which sparked a love affair that supersedes even my passion for the sport. It has helped cut a clear path through the myths and bullshit every beginning trainer is buried in. One particular statement that has withstood the test of time, but never quite sat right with me in terms of what we know, is the statement that there is a direct quantitative correlation between muscle damage and muscle hypertrophy. In other words, it always seemed hard to believe that the amount of muscle damage sustained determined the propensity for muscle gain. After all, if that were true, any type of muscle injury or trauma of a certain severity, including tears and sprains, would induce greater gains in muscle mass than exercise. In truth with injury you will be lucky to come out at the end of recovery with the same amount of muscle mass, and in most cases there is a drastic reduction due to atrophy (reduction in muscle size) and apoptosis (loss of muscle fiber). A lot of literature also seemed to question the causal relationship and even the requirement for muscle damage in muscle growth, but it is typically unwise to question conventional wisdom without some form of conclusive proof.
The muscle damage resulting from resistance exercise is minimal
Although there was quite some evidence, much of it I hope to present here today, proving a dose-response relationship between damage and growth was unlikely, it wasn’t until I got my hands on a study by Paulsen et al. (1) that I was able to tie it all together to a coherent hypothesis. There are a number of problems with regards to previous studies on muscle damage. The two main ones are extrapolation to resistance exercise in humans, and the second was the accurate measure of actual muscle damage. In the first case it has to be noted that a lot of data that is often used as proof in the industry at large today stems from research in rats that have either been purposely injured, or rats performing typical aerobic exercise (the difference between resistance exercise and endurance exercise in many animal studies only seems to be the intensity of the wheel running). The Paulsen study is the first to quantify skeletal muscle damage with more accurate and objective markers, and it does so in great detail. However the takeaway message from their lengthy study, for me, was that they quantified muscle damage as being greatest in (traumatic) injury, more than endurance exercise, and in endurance exercise more than resistance exercise. This may come as a shock to many who haven’t read much of the available data on the biochemistry of muscle damage, but as I hope to demonstrate in this article, this conclusion actually makes a great deal of sense in the bigger picture. Especially for me this conclusion was the missing piece of the puzzle in regards to what I knew to be true about how muscle regeneration and hypertrophy work.
By itself it already questions the dose-response curve between damage and growth because we also know the inverse proportion to hold true with regards to muscle size. Endurance trained muscle is smaller than resistance trained muscle, and endurance trained muscle is typical still larger than injured muscle. Of course that latter proportion, unlike the current study failed to hold up as proof because injury is typically associated with inactivity.
Many of the factors typically associated with growth are actually more abundant in endurance trained and injured muscle, and show a better dose-response relationship with muscle damage
This is where things get interesting, because more than debunking the myth that muscle damage and muscle growth share a dose-response relationship, it calls into question the relevance and dose-response relationship with many factors typically associated with hypertrophy. I’m not just talking about calcium and calcium-related transcription, which has already been extensively shown to lead to more fast-to-slow fiber type shifting, I’m actually talking about the involvement of factors like IGF-1 and satellite cells, previously believed to not only be linked to and essential for hypertrophy, that do in fact share a close relationship with muscle damage, likewise not sharing a dose-response relationship with growth. Yes, you hear me right, I’m saying more IGF-1 and more satellite cell involvement don’t equate to more muscle growth.
Calcium signaling in relationship to muscle damage and hypertrophy
Let’s start with the obvious however, and the particular factor that has had me questioning the damage-growth hypothesis pretty much since I was able to interpret scientific studies. Calcium plays a key role in muscle contraction and relating the neural stimulation of a muscle into actual contractile activity. An electrical signal across the sarcoplasmic reticulum leads to release of calcium into the sarcoplasm that incites the myosin-actin activity that results in a muscle contracting. We also know there is a difference in the calcium oscillations between resistance exercise and endurance exercise, where the intense short bursts caused by resistance exercise result in a large spike in calcium that quickly decreases, while with endurance exercise we see a more moderate amplification that is sustained for longer periods of time. That also implies, especially with the typically prolonged duration of endurance exercise that is a primary cause of the fiber-type shift, that calcium is elevated for longer periods of time during endurance exercise. This particular pattern leads to the activation of calmodulin (CaM – calcium modulating protein), the cells calcium sensor. CaM in turn activates a number of proteins, like calcineurin (Cn) and Calmodulin Kinase (CaMK) in response to various amplitudes of calcium signaling. Calcineurin is invariably associated with low-amplitude (endurance type) signaling (2), and while some CaMK isoforms seems to be more prone to higher amplitudes (3), they haven’t been linked to physiologic resistance type exercise, possibly because the elevation is not sustained enough (voluntary contraction is less damaging than electricity induced contraction, and the former increases calcium reuptake, while the latter does not). Previously these factors were ascribed roles based on some studies, however all those studies fit in the pattern we are discussing here today. The first study (4) demonstrated hypertrophy in myoblasts in vitro, but myoblasts are merely mature satellite cells in a petri-dish model, and as we will demonstrate later on satellite cells are tightly linked to muscle damage and repair, but not so much to overall skeletal muscle hypertrophy. Another noticed lack of a hypertrophic effect when calcineurin was inhibited in recovery from disuse atrophy (5) but that particular model is dependent more on overcoming atrophy, which fast twitch fibers are more susceptible to than slow twitch fibers, meaning that the lack of calcineurin failed to save a number of fibers from atrophy by inhibiting fast-to-slow fiber type switching. And yet another noticed a lack of hypertrophy when overexpressing IGF-1 (6), another factor that has no dose-response relationship to muscle growth (unlike previously believed), but is critical to satellite cell activation. Meanwhile a whole host of studies have since corroborated that increased calcineurin has no role in hypertrophy (7,8,9,10). Of late it seems that increased calcineurin and Calmodulin Kinase expression plays a pivotal role in fiber-type switching, or the changing of fast glycolytic fibers that are more responsive to hypertrophy, to slow oxidative fibers that are kept small (11,12) through induction of mitochondrial biogenesis through activation of the AMPK-PGC1α pathway, which we also know to inhibit skeletal muscle hypertrophy (see basic biochemical principles of skeletal muscle hypertrophy).
All of the above is consistent with a dose-response relationship between muscle damage and the amount of calcium released, and that higher calcium, though calmodulin dependent signaling, leads to a shift towards more oxidative, smaller fiber. We can extend this when we look at what happens in the case of greater damage, such as with severe injury. In those cases damage to the sarcoplasmic reticulum causes an even greater, uncontrolled release of calcium, and damage to the cell membrane causes release of calcium into the extracellular fluid of other cells. Such high doses of calcium stimulate calcium-dependent proteases like calpains (µ-calpain and m-calpain), that are involved in breaking down the cytoskeletal proteins that hold the sarcomeres together, like nebulin and titin (13), and caspases that are involved in skeletal muscle atrophy and apoptosis (14). In other words we can sketch a picture of a clear quantitive relationship between muscle damage and calcium signaling, and a similar relationship between the amount of calcium signaling and limiting muscle growth, or even breaking down muscle tissue. The Paulsen study (1) now largely and directly confirms this inverse association between muscle damage and hypertrophy.
Satellite cells in relation to muscle damage and hypertrophy
One of the primary reasons that the belief that increased muscle damage leads to increased growth persists is because a lot of studies link damage to the activation of satellite cells. Because muscle cells are post-mitotic (they can’t divide to renew themselves) they need another way to increase or replace their DNA material. As such muscle cells are one of the rare types of cells that are multinucleated (have more than one nucleus, the source of DNA) and they can increase their amount of nuclei using a small pool of normally quiescent cells under the basal lamina of the muscle(15,16), termed satellite cells. Under signaling from increased damage, satellite cells become active, increase in number, and some of them will mature and migrate to the site of damage where they will fuse with the existing muscle cell to donate their nucleus. This new nucleus forms an additional source of fresh DNA for the gene expression of proteins needed to repair the muscle.
The mistake here is the belief that a myonuclear increase is required for hypertrophy. One long-standing theory was that of the myonuclear domain (17), or the belief that one nucleus is only capable of governing (read : providing the mRNA) a particular amount of cytoplasm. This stemmed from the continuous observations that increases in fiber size of more than 25% were associated with an increase in myonuclear number (18,19,20). That theory, however, has recently become an indefensible one as a whole host of recent research has shown that muscles can atrophy (21) and hypertrophy (22,23,24) without changing their myonuclear number. The first of these studies (23) was met with some skepticism because the hypertrophy was achieved via genetic deletion of myostatin, and the muscle growth was so drastic, that it simply was not functional. The last (22) of these studies on the other hand was achieved in a model of synergist ablation (surgical removal of synergist muscles to increase load on a single muscle), a model that is not only functional, but also considered to be maximal since even the addition of anabolic androgenic steroids failed to further enhance the hypertrophy (25). As a small aside, that same study (25) also demonstrates that anabolic androgenic steroids, one of the few long-used substances to yield large increases in muscle mass actually reduces muscle damage following exercise.
Indeed, when we now look at satellite cells in the context we’ve established where endurance exercise is more damaging to muscle than resistance exercise, we see that smaller oxidative fibers actually have a two times higher myonuclear density (26). So not only have we thus far established that increases in myonuclear number are not required (although under normal circumstances they do occur), but that it has been known for nearly twenty years that smaller oxidative fibers simply have a higher requirement for additional nuclei. This is known as the fiber type-fiber size paradox, which was reviewed extensively in an excellent study by Van Wessel et al. (27), and forms the basis of the next paragraph.
Muscle protein synthesis is higher in oxidative fiber
The fiber type – size paradox demonstrates that pretty much all of the factors that are typically associated with hypertrophy are more abundant in oxidative fiber, which is smaller than glycolytic fiber and more resistant to hypertrophy. We also know that a prolonged specialization in endurance exercise leads to fiber type shifts from glycolytic to oxidative, resulting in higher mitochondrial biogenesis. Mitochondria are the energy factories of a cell and are needed for the oxidation of fatty acids to yield energy from both local and systemic fat stores, and this is in turn required for long, sustained low amplitude activity (ie endurance performance). We also already know that this shift is, among other things, caused by AMPK and calcineurin, factors highly upregulated by endurance exercise as well as muscle damage. An oxidative fiber, and therein lies the paradox, also simply has a higher capacity for muscle protein synthesis than a glycolytic fiber. But this is the result of a significantly enlarged muscle protein turnover. An oxidative fiber is more prone to proteolysis and has a higher need to replace its proteins, so while the synthesis is greater, so is the breakdown. And the only reason it has higher synthesis is to keep up with the rate of muscle protein breakdown, resulting in a null operation in terms of size, where a glycolytic hypertrophying fiber has a much lower breakdown, resulting in protein accumulation and increases in size. The main reason for the greater turnover is, in fact, greater muscle damage, leading to more damaged protein that needs to be replaced.
Other factors associated with increase muscle damage, but not necessarily growth
The RNA content of Myosin Heavy Chain, one of the two primary contractile proteins, in the total RNA pool is no different between oxidative and glycolytic fiber (28), but since the total RNA content of oxidative fibers is twice as large (27), they actually contain twice as much Myosin heavy chain. Myofibrillar protein synthesis, has on occasion been used as a readout of specific muscle protein synthesis and even hypertrophy. This research suggests that the rate of actual accretion of MyHC would be a better determinant of growth. The Van Wessel study (27) also lists a whole host of factors you would commonly associate with maximal muscle growth that I could cite in detail one by one here, to pad my text and references, but that would be sort of foolish re-iteration, so let me give you a short rundown of things that are also highly increase in oxidative versus glycolytic fibers. You already know protein synthesis is higher, that includes the very hub of protein synthesis and central part in hypertrophy, mTORC1 signaling, especially the growth factor pathway. Oxidative fibers have higher levels of proteins involved in the PI3K/Akt and MAPK pathways stimulated by growth factors, and they have higher levels of IGF-1 and its isoforms. Especially the various downstream targets of MAPK, namely ERK, p38 and JNK are discussed at length in the context of studies showing their contribution to mitochondrial biogenesis and oxidative capacity.
Another in-depth review of the role of muscle damage in hypertrophy was written by Brad Schoenfeld, a researcher who is actually intricately involved in the fitness industry and also writes articles for various bodybuilding and weightlifting websites, and published in the Journal of Strength and Conditioning Research (29). Although Schoenfeld still operates from the assumption of a key role for muscle damage in hypertrophy, he does an excellent job at providing a detailed rundown of the research on both sides and not being partial in presenting the evidence. The reason I cite this study now is because of certain things he cites in favor of such a relationship that I hadn’t read in other literature and needs addressing as well, in the context of the above. Many of the studies he cites do fall in the category of inaccurate measurements of muscle damage, as discussed in the Paulsen study (1). He also extensively cites the link between damage and growth factors and satellite cell activation, but as we discussed here at length, there is a very real quantitative link between those, but all of them relate to smaller, not larger muscle size. One interesting tidbit however is his mention of Interleukin-15 being higher after muscle damage, because at the time he wrote his review it was still believed IL-15 had a role in skeletal muscle hypertrophy, but since then it has been established that a role in a fast-to-slow fiber type switch in favor of smaller, more oxidative muscle is more likely (30,31). And as such you begin to see a very clear picture where literally everything falls into place, and an increase in the amount of muscle damage is linearly correlated with a smaller muscle size.
None of this is surprising, since the link between these factors and muscle damage is in fact very real. The misconception of a quantitative relationship with muscle growth stems from the fact that many of these factors are involved in the process of hypertrophy. The problem with many researchers, and now I’m not exclusively talking about people in the fitness-industry, but in the scientific community as well, is that they fail to look at things in context. A lot of research is done in a bubble, focusing on a single factor, where over-expression or deletion of that factor either in vitro or in a controlled animal model yields certain results and they assume those can be extrapolated to the mammalian population at large in a real world setting. They not only forget to look at all previous research in regards to the same, they neglect the interaction of controlled variables at large. Several researchers have already objected to this way of thinking, promoting a larger scope in research, looking at complete gene expression profiles of those factors using micro-array technology, rather than isolating those factors and relying solely on fenotypical information in a limited setting. But any shift in that direction in the scientific community at large still seems quite a ways away.
Adding perspective and nuance
No doubt much of the information above was shocking to most of you. After all, a lot of what you have been spoon-fed by the supplement and training industry and believed to be true for years, turns out not to be true. Of course it is important to put things in perspective. Many of the factors above do in fact play a role in the hypertrophy process, there is just no dose-response relationship. So just for the record, no one is saying you don’t need IGF-1 to grow, you absolutely do need it for maximal growth, but an increase in IGF-1 does not translate to an increase in growth in a real world setting, there is more nuance to it, since elevated IGF-1 is typically associated with situations of reduced growth, more than increased growth. Satellite cells, meanwhile, have been extensively proven unnecessary for growth, but we need to acknowledge that under normal circumstances growth is associated with an increase in myo-nuclear number, and we cannot forget that all those studies were using models of continuous stimulation, so we cannot exclude a higher myo-nuclear number is needed to maintain mass during periods of inactivity. And most importantly, what is also critical to stress is the higher turnover in oxidative and damage fiber, and the fact that just like the anabolic factors, all the catabolic factors like TNF-alpha, NFκβ and FOXO are also strongly upregulated in oxidative fiber.
Likewise we must conclude that none of the above excludes muscle damage from having a distinct role in hypertrophy. After all, resistance exercise may provide the least amount of damage overall, it does provide damage. And given the link between damage and many of these factors, which do have roles in hypertrophy, it actually seems very likely damage plays some role. At the same time we need to accept that there is no dose-response relationship between damage and growth, and that the next time someone says you need to destroy your muscle more, you better think twice about whether your goal is growth rather than injury or overtraining. After all those things we know to contribute most of all to growth are usually associated with a reduction in damage. So it is very probable that a limited breakdown of muscle tissue is in fact the rate-limiting factor in accumulating muscle protein, rather than simply increasing protein synthesis. Indeed, a lot of evidence seems to be directly in favor of training and nutrition in regards to muscle growth having a relatively low impact on increasing muscle protein breakdown. Resistance exercise and a high protein intake are known to significantly enhance muscle protein synthesis. If growth does not occur as a result, it is likely something else is increasing your protein turnover, such as not eating enough or training too much.
I was recently asked if I could formulate a usable conclusion from the above. Sadly none of this reveals how muscle does actually grow or provides any useful insight for you, the reader, on how to practically improve your training, it only disproves the long standing notion that the amount of muscle damage is related to the amount of muscle growth. While increased damage does help promote greater muscle protein synthesis, it also facilitates muscle protein breakdown as a means of replacing damaged structures. Liken it to a building in an Earthquake, where the building is your muscle and the earthquake the damage. When a building becomes structurally unsound, it has to be torn down entirely (apoptosis) in order to, in the best case, resurrect a new one. The time course of return to a similar structure, if feasible, is a lengthy one. When the earthquake blows out all your windows (oxidative exercise) you’ll still need to remove the debris of the broken windows (protein loss) before you can place the new ones. Now if the damage was limited to a few cracks and broken pottery (resistance training), you throw a little plaster on, and clean up, but considering there is no insurance involved in these matters, that leaves you with a little money to add some extra security for the next earthquake, while you’ll likely deplete your savings to replace the windows, and may not even be able to afford a new building.
In other words, actual growth depends as much on limiting muscle breakdown, and the muscle damage it is associated with, as it does on increase muscle protein synthesis. That also means if there is a positive correlation between damage and muscle protein synthetic factors, you’ll need to find another way to enhance muscle protein synthesis than through increased damage. The take home message in all this is that it doesn’t even exclude muscle damage altogether from playing a role in hypertrophy. It’s quite possible that a particular type of damage, such as the violent separation of actin-myosin bonds during eccentric contraction, and especially the contraction-sensitive α-actinin in the Z-line, which we know to hold and inactivate key myogenic factors like SRF and PLD1, is a key modulator of initiating hypertrophy, provided it occurs in the absence of increases in structural damage to the cell itself and subsequent massive calcium release (or reduced calcium re-uptake).
“The mere exogenous manipulation of a single factor is unlikely to cause the same results in the real world as it does in a controlled setting.”
That is likely where the key to resistance exercise induced muscle growth lies, in targeted, specific damage, but limited in quantity and location. That is also why resistance exercise leads to an increase in predominantly myofibrillar (contractile) protein, where endurance exercise promotes mostly mitochondrial protein synthesis (ref). Alternatively, or possibly in conjunction, I propose a role for glycogen depletion under transient hypoxia as an equally important factor. This because while we held the belief sacred that minimal load was critical to muscle growth, recent research suggests that not only can low-load high-volume exercise (30-50% of 1RM) cause equal or greater increases in muscle protein synthesis (32), but when performed under venous blood flow restriction (33) can actually produce similar increases in hypertrophy, as long as exercise is conducted to failure. That suggests a major role for glycogen depletion (failure) as a pro-hypertrophic factor, and possibly for venous blood flow restriction as a means to limit protein breakdown. Indeed, one of the principle functions of minimal load is the perceived pump, which is in essence no more than a natural venous blood flow restriction. The question then becomes how does blood flow restriction aid in signaling growth ? Certainly blood pooling, possibly through increased cell swelling, causes independent hypertrophying signals, but that wouldn’t necessarily provide a stimulus for an increase in myofibrillar protein synthesis. It is also possible that restricted afferent blood flow combined with increasing flow of blood into the muscle, especially after the restriction is lifted, results in a greater pooling of amino acids, but we know that amino acid signaling has a ceiling that is probably being reached in most bodybuilders and fitness trainers. One other hypothesis is the transient increase in hypoxia this creates. While prolonged hypoxia is highly catabolic (34), brief, localized hypoxia can indeed have anabolic properties (ref). When you combine transient hypoxia with glycogen depletion you place an energy stress on the muscle it cannot relieve by switching to systemic (endurance) energy, because of the lack of oxygen needed for fatty acid oxidation. This signaling process would no doubt signal the need for greater capacity for glycogen storage, and the only way to achieve that is to achieve a greater storage capacity through tissue growth. It could also possibly be one of the elusive signals in slow-to-fast fiber-type switching in the long haul by making oxidative fibers more glycogen dependent. I stress once again that this is merely a hypothesis that fits in the picture of what we know to be true, and adheres to the principles we employ in proper training for maximal hypertrophy.
Undoubtedly to be continued …
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