Does metabolic stress cause muscle growth?

Strength training, which leads to increases in maximum strength and muscle size, involves producing force through repeated muscular contractions.

When muscles contract repeatedly, they fatigue.

Fatigue is a reduction in the ability to produce voluntary force, and it can occur through mechanisms inside the central nervous system (central fatigue) or inside the muscle (peripheral fatigue). These two types of fatigue can be further divided into multiple different processes, which are complex.

Traditionally, it was believed that muscle growth could only be achieved by using heavy loads. This made sense, since laboratory research has identified that muscle fibers detect mechanical tension, and detecting this mechanical tension leads to a sequence of anabolic signaling cascades that trigger increases in the rate of muscle protein synthesis, and subsequently cause increases in muscle fiber volume, which we record as hypertrophy.

However, it has recently become clear that strength training with light loads to failure (which involves a very high level of fatigue) can produce similar muscle growth to strength training with heavy loads. Since light loads do not cause hypertrophy unless performed within a certain proximity of failure, this shows that the fatigue experienced during strength training is a factor that contributes to muscle growth.

Some researchers have suggested that the way in which fatigue contributes to muscle growth is through the accumulation of metabolites that occurs in some types of strength training. The accumulation of metabolites is thought to provide “metabolic stress” to the muscle fiber, and trigger anabolic signaling cascades, in a similar way to mechanical tension.

But is this the best interpretation of the facts?

What is the difference between fatigue and metabolic stress?

Fatigue is a reduction in the ability to produce voluntary force.

Reductions in voluntary force can occur either because of a reduction in the size of the signal sent from the central nervous system (central fatigue) or because of a reduction in the ability of the muscle to produce force (peripheral fatigue).

Central fatigue can occur either because of a reduction in the size of the signal sent from the brain or the spinal cord, or because of an increase in afferent feedback that subsequently reduces motor neuron excitability.

Peripheral fatigue arises due to reductions in the activation of individual muscle fibers (either because of a decrease in the sensitivity of actin-myosin myofilaments to calcium ions, or because of a reduction in the release of calcium ions from the sarcoplasmic reticulum), or through factors affecting the ability of individual muscle fibers to produce force, which involves impairments in the function of actin-myosin crossbridges.

It is commonly believed that the effects of peripheral fatigue are caused in the first instance by the accumulation of lactate that occurs during anaerobic glycolysis, or because of the associated release of hydrogen ions (acidosis). However, research show that these metabolic byproducts are not central to the process of fatigue, and other factors are probably more important.

Very broadly, peripheral fatigue seems to occur partly due to an accumulation of ions that reduce the release of calcium ions (extracellular potassium) or impair the sensitivity of the actin-myosin myofilaments to calcium ions (reactive oxygen species), partly due to the production of metabolic byproducts that interfere with actin-myosin crossbridge function (phosphate ions and adenosine diphosphate), and partly due to a reduction in the availability of substrate in the various energy pathways.

Why do researchers hold the hypothesis that metabolic stress produces hypertrophy?

One of the earliest studies exploring the mechanisms of hypertrophy after strength training did not refer to a potential role for metabolic stress, but instead cautiously identified a role for fatigue more generally.

Not long afterwards, researchers suggested that metabolite accumulation could be a stimulus for hypertrophy, partly because they noted that lengthening (eccentric) contractions produced similar muscle growth to shortening (concentric) contractions despite involving greater forces, and partly because they found that continuous, long-duration static (isometric) contractions produced greater muscle growth than the same volume (and time under tension) of less fatiguing, short-duration static (isometric) contractions with rests between contractions.

Much later, researchers further developed the hypothesis of metabolic stress as a contributor to hypertrophy. They noted that conventional bodybuilding programs, which usually involve many sets of moderate loads with short rest periods, tend to produce more metabolic stress than powerlifting programs, which use fewer sets of heavy loads with longer rest periods. More recent work in this area suggests that the weight used (and therefore the repetition range) is the main determinant of the amount of metabolite accumulation, and rest period duration probably does not have a meaningful effect.

Building on this observation, and on the earlier research, a model was developed in which metabolic stress (during light load strength training to failure) could contribute to the muscle growth that is achieved.

Although we are unaware of any “metabolic stress” sensors like there are mechanoreceptors that detect muscle fiber deformation, it has been suggested that metabolite accumulation could contribute to hypertrophy through (1) increased motor unit recruitment, (2) systemic hormone release, (3) muscle cytokine (myokine) release, (4) reactive oxygen species release, and (5) muscle cell swelling.

Let’s look at each of the milestones in the formation of this hypothesis, and then examine the model.

#1. Eccentric and concentric contractions

Lengthening (eccentric) contractions are far more energy efficient than shortening (concentric) contractions, and therefore involve far less metabolite accumulation. On the basis of their results, the researchers proposed that the greater mechanical tension achieved during the lengthening (eccentric) contractions was counterbalanced by metabolic stress in the shortening (concentric) contractions, and this allowed the two types of strength training to cause similar muscle growth.

Is this a valid explanation?

Over the last few years, it has become clear that while eccentric and concentric training produce similar changes in muscle volume, they produce different increases in muscle fiber diameter and length.

Eccentric training mainly increases fascicle length, while concentric training mainly increases muscle cross-sectional area. This seems to happen because lengthening (eccentric) contractions require a large proportion of mechanical tension to be provided by passive elements (titin and the extracellular matrix) but shortening (concentric) contractions involve force being produced entirely by the active elements (actin-myosin crossbridges).

When a muscle fiber shortens actively, it bulges outwards in the middle of each sarcomere. This behavior is likely part of the deformation stimulus that is detected and which leads to hypertrophy. In contrast, when a muscle fiber is stretched passively, it elongates without the same outward bulging. Active lengthening (eccentric) contractions involve a combination of both types of deformation. Importantly, these different deformations lead to different anabolic signaling cascades, and these differences are likely the reason for the different types of muscle fiber growth that occur after lengthening (eccentric) and shortening (concentric) contractions.

We cannot assume that just because the force is higher in the lengthening (eccentric) contraction that this will trigger a greater mechanical tension stimulus, since the resulting deformation that leads to increased muscle fiber volume is different in each contraction type. It is possible that the required forces to produce the deformations that lead to a given amount of fiber growth are higher in lengthening (eccentric) contractions.

#2. Long- and short-duration static contractions

Continuous, long-duration static contractions lead to greater fatigue, in tandem with the accumulation of a larger amount of metabolites, than short-duration static contractions with rests between each contraction. On the basis of their results, the researchers proposed that the greater accumulation of metabolites achieved during the continuous, long-duration static contractions was responsible for triggering greater hypertrophy.

Is this a valid explanation?

It is true that several studies have shown that when static contractions are performed for a sustained period of time, the development of fatigue leads to an increase in motor unit recruitment, which is in accordance with the size principle.
Mechanical tension, or deformation of the muscle fiber, stimulates fibers to increase in size. Mechanoreceptors detect changes in the shape of the fiber during contractions and loading, anabolic signaling cascades occur, and this leads to increased muscle protein synthesis, and the accumulation of protein inside the fiber.

According to Newton’s Third Law, the mechanical tension experienced by a muscle fiber during a muscular contraction must be equal and opposite to the tensile force that the fiber exerts on the tendon. In other words, the mechanical tension that triggers a muscle fiber to increase in size is the same as the force that it produces when it attempts to contract.

The main factor that determines how much force that a fiber can produce is the force-velocity relationship. When a fiber is allowed to contract quickly, such as when no resistance is applied, the force it exerts is small. When a fiber is prevented from contracting quickly, such as when a large resistance is applied (or the joint is fixed in place, as in static contractions), the force it exerts is large.

During fatiguing efforts, such as long-duration, continuous static contractions, the muscle fibers of low-threshold motor units become unable to contribute sufficient force to maintain the desired levels. This leads to increased motor unit recruitment, and since the muscle is prevented from shortening, the newly activated muscle fibers of the high-threshold motor units produce high forces, because of the force-velocity relationship. This therefore exposes them to high levels of mechanical tension.

High-threshold motor units govern many times more muscle fibers than low-threshold motor units, and their fibers are more responsive to the strength training stimulus, and display greater anabolic signaling after training. Therefore, when high-threshold motor units are stimulated in a contraction, this leads to much greater muscle growth.

Therefore, it seems valid that continuous, long-duration, static contractions cause increased hypertrophy because of increased motor unit recruitment on account of fatigue, but does this increase in motor unit recruitment happen because of the accumulation of metabolites?

Probably not.

In fact, acidosis is not necessary to produce increased motor unit recruitment, and peripheral fatigue can be produced without any metabolite accumulation (by eccentric contractions with long inter-set rest periods) and yet this state of fatigue still increases neural drive to the muscle.

It seems likely that motor unit recruitment increases in response to a need to produce a greater effort, whether that effort is needed to lift a heavier load, or to lift the same load with weaker (fatigued) muscles, and the exact underlying mechanism that causes the muscle weakness (fatigue) is irrelevant.

Any local mechanism that reduces the force-producing ability of the currently-active muscle fibers in the muscle will probably lead to increased motor unit recruitment, when attempting to produce a given level of force.

#3. Heavy and light loads

Since bodybuilders are focused on attaining greater muscle mass, while powerlifters are focused on increasing maximum strength relative to size, it is logical that bodybuilding training programs include features that are more helpful for increasing muscle size.

Such features include using moderate (6–15RM) instead of heavy (1–5RM) loads, higher volumes, and shorter rests between sets. On the basis of this observation, researchers have proposed that bodybuilders might use moderate loads because this increases muscle growth through increased metabolic stress.

Is this a valid explanation?

When training to failure with the same number of sets, repetition range does not affect the amount of muscle growth that occurs, between 5–30 reps.

In any set to failure, fatigue causes increased motor unit recruitment (which happens because of an increased perception of effort) and progressively decreased bar speed, and therefore reduced muscle shortening velocity. Together, these cause mechanical tension to be experienced by the muscle fibers controlled by the high-threshold motor units.

In practice, it seems likely that each set includes 5 stimulating reps at the end in which motor unit recruitment is high, and bar speed is slow, regardless of the load. However, when rep range is below 5 reps, the muscle growth stimulated by each set is reduced to the number of reps in the set. Essentially, the number of stimulating reps per set is lower.

Bodybuilders might therefore use moderate (rather than heavy) loads because they involve a greater number of stimulating reps, rather than because that rep range involves greater metabolite accumulation. It makes sense to achieve the required number of stimulating reps in as few sets as possible, simply to fit more overall volume into a workout, and volume is a key driver of muscle growth.

Interestingly, most competitive bodybuilders use slightly heavier (7–9RM) loads than most people assume. This gives them the ability to perform the maximum possible number of stimulating reps in each set (which is five) without doing too many additional, unnecessary reps.

#4. The model of metabolic stress

The model of metabolic stress includes five key elements: (1) motor unit recruitment, (2) systemic hormone release, (3) muscle cytokine (myokine) release, (4) reactive oxygen species release, and (5) muscle cell swelling.

As explained above, the accumulation of metabolites (and therefore also the release of reactive oxygen species) is not necessary for an increase in motor unit recruitment. It seems likely that motor unit recruitment increases in response to the perception of increased effort due to fatigue, rather than any peripheral factors inside the muscle.

When we remove the elements of the model that are caused by the perception of effort, and not by the accumulation of metabolites, the model includes the release of systemic hormones and muscle cytokines, and cellular swelling.
The role of post-exercise systemic hormone release in muscle growth is contentious, and at least one leading research group considers it to be completely irrelevant, and the role of muscle cytokines is still unclear.

Cellular swelling involves increased pressure against the cell membrane, and this very likely increases the amount of multi-axial mechanical loading that is experienced by the muscle fiber during each active contraction, which is what leads to the anabolic signaling cascades that produce hypertrophy. This effect could be responsible for the larger increase in muscle size that has been observed in some studies after light load strength training to failure with blood flow restriction, compared to similar training without occlusion.

What does this mean?

Researchers proposed that metabolic stress contributes to muscle growth after making observations about the differences between lengthening (eccentric) and shortening (concentric) contractions, about the differences between long- and short-duration isometric contractions, and about the effects of training with heavy or moderate loads. Subsequently, a model was devised to provide mechanisms to support these observations.

Comparisons between lengthening (eccentric) and shortening (concentric) contractions are hard to make, because they involve different types of muscle cell deformation in response to mechanical loading, and subsequently different changes in muscle fiber length and diameter.

Long-duration isometric contractions produce greater muscle growth than short-duration isometric contractions because they lead to increased motor unit recruitment. This happens because of an increased perception of effort, not because of acidosis or metabolite accumulation.

Bodybuilders probably use moderate loads not because of the greater metabolic stress, but because they definitively allow the maximum number of stimulating reps per set (which is five). This means that more stimulating reps can be performed in any given workout time span. This increases the amount of volume that can be done, which enhances muscle growth.

What is the takeaway?

Peripheral fatigue contributes to muscle growth by increasing motor unit recruitment and decreasing muscle fiber shortening velocity during strength training. These changes increase the mechanical tension experienced by the muscle fibers controlled by high-threshold motor units (which is determined by the force-velocity relationship).

Motor unit recruitment is increased during strength training under fatiguing conditions because this activates extra muscle fibers, and these newly-activated muscle fibers compensate for the lower forces that the weakened, previously-activated muscle fibers are producing. This increase in motor unit recruitment is experienced as an increase in the sensation of effort. The weakened, previously-activated muscle fibers can experience a reduction in force because of various fatigue mechanisms, some of which are associated with metabolite accumulation (metabolic stress), and some of which are not. Therefore, it is probably the reduced force-producing ability of the previously-activated muscle fibers that triggers the increase in motor unit recruitment, and not the specific elements of each fatiguing process.

While other mechanisms involving the release of systemic hormones and muscle cytokines, and cellular swelling have been proposed to explain how the accumulation of metabolites (metabolic stress) might contribute to muscle growth, these are weaker arguments. Even so, to the extent that cellular swelling contributes to hypertrophy, this would also occur by increasing mechanical tension on individual muscle fibers, because of the increased internal pressure inside the muscle.