Why is it easy to believe that metabolic stress triggers hypertrophy (even when it does not)?

If you enjoy this article, you will like my second book (see on Amazon).

Ten years ago, many researchers believed that hypertrophy was caused by three mechanisms (mechanical tension, metabolic stress, and muscle damage). Recently, support for this position has faltered, owing to some very well-designed studies. Indeed, some prominent groups of researchers have now reanalyzed the available evidence that muscle damage contributes to muscle growth, and have subsequently dropped it, leaving only mechanical tension and metabolic stress.

I predict that in another ten years, hypertrophy researchers will have also reanalyzed the evidence that metabolic stress contributes to muscle growth, and will subsequently reject the hypothesis that metabolite accumulation has anything to do with muscle growth.

They will realize that local muscular fatigue (and not metabolic stress) is the trigger for high-threshold motor units to be recruited during light load strength training to failure, while muscle fiber shortening velocities are simultaneously reduced, and that this combination allows greater mechanical tension to be produced (and therefore experienced) by the muscle fibers of those motor units, because of the force-velocity relationship. What happens to the muscle fibers of low-threshold motor units is irrelevant, since they have been trained to their maximum size already by the activities of daily life.

In an earlier article on this blog, I did an historical analysis looking at the key phases in the development of the hypothesis, showing where we made wrong turnings. This article takes a different approach, and walks through the many reasons why you might still be tempted to see metabolic stress as a contributor to muscle growth, and why that would be a mistake.

If you like this article, you will also enjoy my book.

#1. Fatigue and motor unit recruitment

It has been proposed that metabolites increase motor unit recruitment, and that this thereby allows a greater number of muscle fibers to be exposed to mechanical tension.

This is not a very accurate description of what is going on.

Motor unit recruitment increases when we increase effort levels. Effort levels can be voluntarily increased if we discover that we can no longer lift a weight with our previous levels of effort. This situation occurs when fatigue develops during strength training. As fatigue arises, we find that the muscle fibers of our low-threshold motor units can no longer exert sufficient force to continue doing the task that we want to perform. We therefore increase our effort levels and push harder, and this recruits additional motor units to compensate for the muscle fibers that are fatigued.

Fatigue occurs inside muscle fibers due to three mechanisms, which are: (1) reductions in the release of calcium ions from the sarcoplasmic reticulum (disruptions to the excitation-contraction coupling process), (2) reductions in the sensitivity of myofibrils to calcium ions (this is essentially cutting the line of communication between the excitation-contraction coupling process and the crossbridge cycle), and (3) reductions in the ability of actin-myosin crossbridges to produce force (disruptions to the crossbridge cycle).

Metabolites can cause fatigue (and thereby require us to increase effort and thereby increase motor unit recruitment) through all of these mechanisms. Yet, they are not necessary. Eccentric contractions can cause fatigue and require us to increase motor unit recruitment by reducing the release of calcium ions from the sarcoplasmic reticulum without any metabolite accumulation. Muscle damage can also increase motor unit recruitment at a given level of force during the recovery period from exercise, without the presence of metabolites. Ultimately, the only thing that is necessary for motor unit recruitment to increase is for a fatiguing mechanism to occur and reduce the force-producing ability of some of the muscle fibers in a muscle.

In other words, we increase motor unit recruitment by increasing effort levels, and effort levels need to be increased whenever the muscle fibers of our low-threshold motor units become fatigued and can no longer produce enough force to continue lifting the weight on the bar. Fatigue can be mediated by metabolite accumulation, but fatigue can also occur without the presence of metabolites. Therefore, to claim that metabolite accumulation *causes* an increase in motor unit recruitment is misleading, since it is neither the direct cause nor necessary.

N.B. the force-velocity relationship

It is worth noting that the force-velocity relationship is rarely discussed in the context of hypertrophy, despite the fact that is the main regulator of muscle fiber force production, and therefore of the mechanical tension that each muscle fiber experiences during a contraction.

Motor unit recruitment is increased by effort. Therefore, if we exert maximal effort on a rep, then recruitment will be maximal. This can happen regardless of the weight on the bar. Indeed, light-load ballistic movements like throwing a ball or jumping involve high levels of motor unit recruitment, even though they involve very low levels of force production. This is because the level of motor unit recruitment only determines the number of muscle fibers that are activated. It does not determine the force that each fiber produces.

Indeed, light-load ballistic or high-velocity exercises do not trigger very much (if any) hypertrophy precisely because the force exerted and experienced by each fiber is too low. We know it is not “time under tension” that causes the effect, because of studies that have controlled this variable. The reason that each fiber exerts such low forces in fast contractions is because of the fast muscle fiber shortening velocities. Consequently, there are fewer actin-myosin crossbridges formed at any one time, and the number of bound actin-myosin crossbridges is the primary determinant of muscle fiber force (and therefore also of mechanical tension).

Importantly, fatigue causes a reduction in muscle fiber shortening velocity that follows a very similar profile, regardless of the weight on the bar. Therefore, fatigue also allows the muscle fibers of the high-threshold motor units to exert very high forces as they are recruited towards the end of a set. In this way, the effect of fatigue differs from that of effort, because effort is only linked to the level of motor unit recruitment, and not also to the level of mechanical tension being experienced by individual muscle fibers.

#2. Fiber type-specific hypertrophy

It has been suggested the existence of fiber-type specific hypertrophy justifies considering metabolic stress as a mechanism that can cause muscle growth, since metabolic stress is usually greater when using lighter weights. Indeed, a recent study found that high-frequency training with lighter loads with blood flow restriction (BFR) caused more type I muscle fiber growth than normal strength training with heavier loads.

However, this suggestion ignores another key study that has also reported preferential type I muscle fiber growth. If we look at these studies together, it is immediately very clear what is causing the phenomenon (and it is definitely not metabolic stress).

The other study reported that when the eccentric phase of normal dynamic strength training with moderate loads is performed very slowly (to increase the time under tension in that contraction mode), there is preferential type I (slow twitch) fiber hypertrophy. Critically, such slow eccentric phases involve lower metabolic stress than strength training with faster eccentric phases. This study therefore demonstrates that type I fiber type-specific hypertrophy can also occur with lower (and not higher) levels of metabolic stress.

So why might type I fiber type-specific hypertrophy occur in each case?

• Slow eccentric phases — in eccentric contractions, it is harder to activate a muscle voluntarily, and central nervous system (CNS) fatigue is greater. What is more, during the lowering phase of normal strength training, the level of effort is low (even when using a slow tempo). Therefore, motor unit recruitment is low, and the highest threshold motor units that control type II muscle fibers are likely not subjected to any loading during such contractions. This means that slow lowering phases during normal strength training likely involve high levels of mechanical loading (and for long periods of time) on the low-threshold and lowest high-threshold motor units, all of which control type I muscle fibers. While the type I muscle fibers of the low-threshold motor units do not grow, the type I muscle fibers controlled by the high-threshold motor units do, and this causes preferential type I hypertrophy.
• High frequency strength training with light loads and BFR — the study that found greater type I muscle fiber growth after training with light loads and BFR used a fairly high frequency. In high frequency strength training, CNS fatigue is often greater, because there is insufficient time to recover from one workout before doing the next one. Also, CNS fatigue is slightly greater when using lighter loads, than when using heavier loads. CNS fatigue causes a reduction in the level of motor unit recruitment.

Consequently, we can see that in both studies that have found preferential type I muscle fiber growth, there is good reason to believe that a lack of motor unit recruitment is the main contributing factor, not metabolic stress. When motor unit recruitment is reduced, the very last high-threshold motor units that control the only type II muscle fibers in the muscle are not recruited.

#3. Reactive oxygen species (oxidative stress)

Researchers have suggested that the production of reactive oxygen species (ROS) is a mechanism by which metabolic stress could cause hypertrophy because taking antioxidants seems to reduce levels of anabolic signaling after workouts and muscle growth after strength training.

To address these observations, it helps to understand them in the context of what we currently know about (i) the role played by ROS in fatigue during exercise (and how antioxidants affect this), and (ii) the effects of ROS on muscle damage after a workout (and how antioxidants affect this).

#i. Role played by ROS in fatigue during exercise

ROS are produced during fatiguing exercise, likely in response to the influx of calcium ions. ROS can be created through a number of mechanisms during exercise (the mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, phospholipase A2 (PLA2), and xanthine oxidase), but the main source during fatiguing contractions is unclear. If you are interested, most literature reviews cover this issue in quite a lot of detail.

There are three ways in which peripheral fatigue can occur during exercise: (1) reductions in the release of calcium ions from the sarcoplasmic reticulum (disruptions to the excitation-contraction coupling process), (2) reductions in the sensitivity of myofibrils to calcium ions (this is essentially cutting the line of communication between the excitation-contraction coupling process and the crossbridge cycle), and (3) reductions in the ability of actin-myosin crossbridges to produce force (disruptions to the crossbridge cycle).

Traditionally, it has been accepted that the main mechanism by which ROS increase fatigue during exercise is by reducing the sensitivity of myofibrils to calcium ions. However, it has also been noted that ROS can cause a reduction in the release of calcium ions from the sarcoplasmic reticulum. Thus, ROS seem to cause reductions in strength during exercise through at least two of the three mechanisms of peripheral fatigue. Even so, the fatiguing effects of ROS are very complicated. It seems likely that ROS sometimes cause an increase in myofibrillar calcium sensitivity and sometimes cause a decrease. Indeed, the external application of ROS during in vitro studies very often causes increases in myofibrillar sensitivity to calcium. When this happens, it is likely that a greater proportion of peripheral fatigue results from impaired release of calcium ions from the sarcoplasmic reticulum.

Antioxidant supplements have been found to reduce fatigue in submaximal but not maximal exercise, in animal models and also in exercising humans. Recent investigations have suggested that they may negate the (occasionally) positive effects of ROS on myofibrillar sensitivity to calcium ions, and negate the (usually) negative effects of ROS on the release of calcium ions from the sarcoplasmic reticulum. In this way, they shift the fatiguing effects of ROS away from an impaired release of calcium ions from the sarcoplasmic reticulum and towards impaired myofibrillar sensitivity to calcium ions. This is important, because impaired release of calcium ions is caused by damage to the sarcoplasmic reticulum calcium ion release channels, and this is a trigger for endurance-related adaptations, including mitochondrial biogenesis.

Therefore, we can explain the negative effects of antioxidants on endurance exercise adaptations by the observation that they reduce the damage to the sarcoplasmic reticulum calcium ion release channels that is caused by ROS produced during exercise.

Why is this important?

Well, muscle fiber growth is closely tied to an increase in capillarization regardless of the load used during training, because more capillaries are needed to match the larger oxygen requirements of bigger muscle fibers. Indeed, high responders to strength training may have higher levels of capillarization before starting a training program. Conversely, impairing increases in capillarization may lead to impaired hypertrophy. Thus, antioxidants may exert their negative effects on hypertrophy by the same mechanism, since impairing a certain level of endurance-related adaptations would be expected to stop muscle fiber growth from happening.

#ii. Effects of ROS on muscle damage after a workout

ROS appear when calcium ions accumulate inside the cytoplasm, after the mitochondria are overloaded and cannot take up any more. The presence of calcium ions also leads to the production of phospholipases, which degrade the inside of the muscle fiber membrane, thereby allowing more calcium ions to flow in. The high concentration of calcium ions that results then causes muscle damage, through the release of phospholipases and calpains, which are proteases. Therefore, ROS are a good indicator that muscle damage has occurred inside muscle fibers.

Additionally, ROS contribute directly to the muscle damaging processes themselves, likely through peroxidation of phospholipids in the muscle cell membrane. While causing damage directly, this also allows more calcium ions to flow into the muscle fiber, and exert their damaging effects. It is therefore unsurprising that a variety of different antioxidant supplements have been found to reduce the amount of muscle damage that occurs after exercise.

Antioxidants have been found to reduce the anabolic signaling processes that occur after a workout. Such anabolic signaling processes are often assumed to relate solely to muscle fiber hypertrophy. However, it is well-established that anabolic signaling processes (such as the mTOR pathway) are directed towards muscle damage repair and hypertrophy. Thus, we might expect that any treatment that reduces the muscle damage caused by a workout will simultaneously reduce levels of anabolic signaling. Indeed, it is worth noting that in the one study that has measured the effects of antioxidant supplements on post-workout anabolic signaling and long-term muscle growth, anabolic signaling was reduced but hypertrophy was not.

Even so, some research has found that antioxidants reduce muscle growth and strength gains in humans when taken during long-term strength training, although not all investigations have found this effect. This has been explained by attributing ROS with the ability to signal hypertrophy by elevating mTOR signaling, mediated by elevations in calcium ions. In my view, the only way that mTOR signaling would be elevated by an increase in calcium ions is in consequence to their damaging effects on the muscle cell. Indeed, anabolic signaling is identical when mechanical tension is equated but muscle fibers are active (with calcium ions present) or passive (with calcium ions absent). Moreover, the presence of calcium ions without mechanical tension is insufficient to trigger anabolic signaling or developmental muscle growth. It seems far more likely that ROS mediate endurance-related adaptations, and that interfering with these is what blunts hypertrophy, since a certain level of capillarization is necessary to sustain muscle fiber growth.

Summary

ROS increase fatigue during exercise by disrupting the release of calcium ions from the sarcoplasmic reticulum. Through this mechanism (and also by their damaging effects on the muscle cell membrane), they cause muscle damage after a workout. Thus, antioxidants reduce fatigue during exercise and muscle damage (and associated anabolic signaling) after a workout. ROS also trigger endurance-related adaptations by disrupting the release of calcium ions from the sarcoplasmic reticulum. Since antioxidants interfere with this process, such supplements can suppress endurance-related adaptations to exercise. While antioxidants have also been found to interfere with hypertrophy after exercise, the current mechanism for explaining this by implicating ROS in anabolic signaling processes is not satisfactory. It seems more likely that the effects of ROS on endurance-related adaptations and their supporting effects on muscle fiber growth are the real reason for the disruptive effects of antioxidants on muscle growth.

#4. Lactate (and other hormones)

Recently, there has been interest in lactate as an anabolic signaling agent, and it has been suggested this signaling could be a key mechanism by which metabolic stress could trigger muscle growth.

Indeed, some in vitro research in myoblasts has found that lactate increases satellite cell activation. Similar in vitro research in myotubes has found that lactate has anabolic signaling effects. While satellite cell activation could be a general response to exercise (especially when the physical activity model used is endurance training), the anabolic signaling effects are harder to explain away. Also, some in vivo research using rodent muscle has found that lactate can act as an anabolic signaling molecule and trigger muscle growth. Yet, since lactate triggers the production of reactive oxygen species (ROS), and since ROS is very likely a cause of muscle fiber damage, it may be that the presence of lactate stimulates muscle damage repair signaling in such studies, which might easily be conflated with hypertrophy signaling.

Whatever the exact reason for the signaling effects of lactate in these studies, it is highly unlikely that lactate has any stimulating effect on muscle fiber growth, because of where it goes once it has been created. When lactate is produced during glycolysis, it is immediately shuttled out of lactate-producing cells and into lactate-consuming cells. Lactate-consuming cells include other muscle fibers of the same muscle, other muscle fibers of other muscles in the body, and organs, including the brain, liver, and kidneys. In being shuttled to such organs through the bloodstream (especially the brain), lactate does have signaling effects, thereby acting like a hormone.

Therefore, if lactate (or any other hormone for that matter) were to have a signaling effect on muscle fibers to increase in size, then it would increase muscle size indiscriminately around the body. In fact, the muscles that would increase in size most would be those that contain lactate-consuming cells, and not the lactate-producing cells themselves. This would contradict everything we see when taking measurements of muscle size after strength training, which is that increases in muscle fiber size are very localized to the muscles (and even the regions of muscles) that produce force during a workout.

#5. Muscle cell swelling

During strength training, muscles often swell due to increased water content. This swelling lasts for approximately one hour after a workout when lifters are habituated to the exercise, but it lasts for longer in untrained individuals, because of the greater muscle damage. It is frequently associated with those types of strength training that involve greater local muscular fatigue, such as light loads, short rest periods, and advanced techniques such as drop sets.

The exact nature of this muscle swelling is uncertain, although it probably involves an increase in the volume of individual muscle fibers. If it does involve an increase in muscle fiber volume (rather than an increase in the fluid content of the interstitial spaces), then it will necessarily cause outward deformation of the fiber, and this change could be detected in the same way as mechanical tension by receptors near to the surface of the muscle cell.

Importantly, however, swelling of individual muscle fibers would not involve the exact same deformations as muscular contractions. Muscular contractions cause each working muscle fiber to bulge outwards at the M line, at the point where the actin and myosin filaments are overlap to a greater extent, because of a reduction in the size of the H zone. However, an increase in volume of the muscle fiber would cause a much more uniform increase in the diameter of the muscle fiber, which may not have the same stimulating effect.

#6. Sensations

We often naturally assume that when the sensations that we perceive from our body are stronger, the resulting effects likely to be greater. While few researchers mention this, it is likely a key reason why many people firmly believe that strength training with light loads to failure has different effects from heavy load strength training.

We can perceive a number of different sensations during strength training, including (1) effort, (2) fatiguing sensations, (3) pain, (4) whole muscle force, (5) stretch, and (6) where our limbs are in space (proprioception).

Effort is particularly important, because the level of effort is directly related to the level of neural drive, and therefore the degree of motor unit recruitment. Corollary discharge, which is a copy of the central motor command, increases as central motor command increases. Corollary discharge activates sensory areas inside the brain that produce the sensation of effort. Even so, effort is unrelated to mechanical tension experienced by single muscle fibers, because if the weight is light and we are unfatigued, the bar speed produced at high levels of effort will be very fast, and therefore mechanical tension will be low.

Fatiguing sensations are also worth commenting upon. While it was originally assumed that fatiguing sensations were caused by lactate or acidosis, we now know that the effect is caused by the presence of multiple metabolites inside the muscle at the same time (hydrogen ions, lactate, and ATP) and triggering signaling along group III/IV afferent neurons. While fatiguing sensations are therefore a good indicator of metabolite accumulation, they are not a good indicator of fatigue, since this can occur without metabolites. Even so, since metabolite accumulation increases with increasing repetition maximum during strength training, there is a clear difference in the sensations that we perceive when training in different rep ranges.

Importantly, we are unable to perceive the mechanical tension experienced by single muscle fibers when they are working. If you move your limbs very slowly for a short time against no resistance through a small range of motion, you experience few of the above sensations. The working muscle fibers are few in number, so the level of effort is minimal. And the duration of exercise is short, so fatiguing sensations and pain are also not present. The range of motion is small, so there is no stretch. However, the mechanical tension that is experienced by the muscle fibers of the recruited motor units is incredibly high, because of the slow speed and the force-velocity relationship. In fact, the muscle fiber that you are using are producing extremely high forces (but they do not get damaged, because they are so oxidative, which means that they can easily deal with the high level of calcium ion influx).

When we lift a heavy weight, we experience high levels of effort and a high level of whole muscle force. When we lift moderate and light loads to failure, we experience high levels of effort and fatiguing sensations, and perhaps also pain. Consequently, the experience that we have is different between the types of strength training, which leads us to assume that the effects are different. In fact, they are the same, because the real mechanism that is causing muscle growth (mechanical tension on individual muscle fibers) we cannot detect at all. This means that what we feel during a workout is largely unrelated to its effectiveness for muscle growth.

What is the takeaway?

Metabolic stress (the accumulation of metabolites, such as lactate, phosphate, hydrogen ions, and reactive oxygen species) put on a very good show of appearing to cause muscle growth. However, it is only mechanical tension that really triggers hypertrophy. Fatigue can affect the mechanical tension that the muscle fibers of high-threshold motor units experience, but fatigue is not the same thing as metabolite accumulation, as it can occur in its absence.

During normal strength training, muscle fibers only experience mechanical tension after they have been activated by motor unit recruitment. Fatigue can require us to exert more effort and therefore increase motor unit recruitment by reducing the force that low-threshold motor units produce, which necessitates the recruitment of high-threshold motor units to compensate. Fatigue can also increase the mechanical tension that each activated muscle fiber exerts, by slowing down the overall contraction velocity of the muscle. Even so, in both cases, fatigue is merely the indirect method by which a muscle fiber is exposed to increased mechanical tension. Mechanical tension is still the only direct mechanism that triggers muscle fiber growth.

If you enjoyed this article, you will like my second book (see on Amazon).