Muscle Mania Part IV: Macro Mechanisms of Hypertrophy
Exploring Dr. Brad Schoenfeld's Mechanisms of Hypertrophy
So, we’ve covered muscular anatomy and physiology 101, along with hypertrophy cell biology 101, but we’ve yet to touch on the tangible protocols – the reps, the sets, the macronutrients, etc. – surrounding hypertrophy. Moving forward in the Muscle Mania Series(I, II, III) we will transition from the zoomed-in, molecular-biology-centric view of building muscle to the zoomed-out and more practical view, starting with what I will refer to as the macro mechanisms of hypertrophy – the cellular pathways we discussed last time being what I call the micro mechanisms. You know the deal, check out the recap for a refresher and we’ll dive in down below.
Due to email length restrictions, I could not fit my reference list on this post, but you can find it here.
Recap
Muscles are ultimately composed of contractile proteins, called myofilaments, which are organized into structural units, called sarcomeres.
Muscular hypertrophy, or muscular growth, involves building and incorporating myofilaments into sarcomeres to grow the overlying muscle.
Muscle hypertrophy and atrophy are the results of an interplay between muscle protein synthesis (MPS) and muscle protein breakdown (MPB); interestingly, both processes are essential for building muscle.
Protein synthesis involves a macro-level signal (like lifting weights or eating protein) inducing a cellular signal at the micro-level, which provokes transcription of specific parts of the cell’s DNA (i.e. specific genes) into mRNA, the translation of that mRNA by ribosomes, and the construction of the correlating proteins. During muscle protein synthesis, those genes code for specific muscle proteins that will be incorporated into sarcomeres.
Our muscle cells utilize 3 pivotal processes to initiate and propagate hypertrophy: ramping up muscle protein gene expression by activating transcription factors, increasing nuclear capacity via satellite cell addition, and expanding translational capacity through ribogenesis.
Key molecules involved in hypertrophy-related cell-signaling include mTORC1, Akt/PI3K, Myostatin, MAPKs, and intracellular calcium; additionally, key hypertrophy transcription factors include MEF2, SMAD2/3, SRF, UBF, and Pax7.
What are we actually looking for when it comes to exercising for hypertrophy? I think most of us can distinguish between exercise modalities that are primarily directed towards muscle growth and those that are not, such as weight lifting and long distance rowing respectively; after all, you don’t find many Ronnie Coleman types cruising down the Charles River. To be clear, this doesn’t mean that endurance training nor steady-state cardio are harmful to health or fitness – the contrary is true; rather, my point is that resistance training and endurance training leverage different stimuli to achieve different physiological adaptations. Now, we recognize these differences, but we don’t often consider what breeds them. What does lifting weights offer to our muscles to induce MPS (muscle protein synthesis) directed towards hypertrophy where zone 2 cardio would induce the synthesis of mitochondrial proteins? Answering these types of questions – what are we trying to accomplish at the squat rack and cable machine? – allows us to develop targeted training strategies to build up our biceps, quads, glutes, shoulders, and calves alike.
In 2010, Brad Schoenfeld – PhD in Health and Wellness, Associate Professor of exercise science at Lehman College, sports nutritionist for the New Jersey Devils, and world-renowned expert on muscle hypertrophy – made a giant leap towards answering these questions with his publication, The mechanisms of muscle hypertrophy and their application to resistance training (I), where he suggested mechanical tension, metabolic stress, and muscle damage as potential mechanisms for inducing hypertrophy. Since then, Schoenfeld further developed this framework in 2019 as a part of Wackerhage Et al.’s review, Stimuli and sensors that initiate skeletal muscle hypertrophy following resistance exercise (II), and in 2021 with the second edition of his textbook, Science and Development of Muscle Hypertrophy (III). Below, we’ll explore Schoenfeld’s mechanisms of hypertrophy through the past decades’ evolving research and how this all applies to resistance training protocols.
Mechanical Tension
Of the three proposed mechanisms of hypertrophy, mechanical tension is widely viewed as the most important and most well-supported in terms of a causal role in building muscle. Firstly, common sense points to mechanical tension – the force load applied to a muscle when it is activated – as an important factor in stimulating muscle growth, in that you will not achieve hypertrophy without applying some type of load to your muscles; furthermore, research showing that limb immobilization – such as when a person’s arm or leg is put in a cast following a fracture – leads to muscle atrophy (decrease in muscle size) as compared to the mobile limb suggests that muscle loading dictates muscle size. (I, II, IV) Though the mobile limbs also decrease in size in these studies, they do so considerably less than the fully immobilized limbs, supporting the mechanical tension theory two-fold:
1. The decrease in mechanical tension on the mobile limb – presumably due to decreased physical activity during the patient’s recovery – suggests that loading is important for muscle size, as the mobile limb does atrophy slightly.
2. The attenuation of muscle loss in the mobile limb as compared to the immobilized limb suggests that the mechanical tension that the mobile limb does still receive in daily activities reduces muscle loss during this period.
Of particular note, both the mobile and immobilized limb do not receive inputs from metabolic stress nor muscular damage – the other proposed mechanisms for hypertrophy – while the patient is inactive and in recovery, which isolates mechanical tension as the remaining mechanism for inducing the observed differences between limbs.
In addition, research shows that mechanical tension provokes a host of pathways and molecular players associated with muscle hypertrophy – such as phosphatidic acid, Akt/PI3K, mTORC1, intracellular calcium, and MAPKs – through activating mechanotransducers (molecular complexes that sense changes in force), like integrin adhesion complexes, dystrophin glycoprotein complexes, and focal adhesion kinases. (I, II, III, V, VI)
In terms of a functional perspective, mechanical tension translates to exercise through the amount of load on a muscle – how much weight you are lifting – and the duration for which the muscle is under that load – time under tension. Interestingly, research suggests that a broad spectrum of loads, ranging from 30%-90% of 1-rep-max (1RM ; the maximum amount of weight a person can lift one time) are capable of inducing hypertrophy, provided the sets are performed to or near failure – the point at which the lifter cannot complete another rep with good form. (III, VII, VIII, IX) Since lifting to failure with 30% 1RM requires many more reps than doing so with 90% 1RM, this also suggests that a wide spectrum of hypertrophy-inducing intraset volumes – how many repetitions you perform in each set – exists.
Metabolic Stress
Anybody who has exercised with decent effort has experienced the stinging sensation of fatigue, commonly known as the burn or pump. In the world of exercise science, this concept can be generally referred to as metabolic stress and is defined by an accumulation of metabolic byproducts of muscular activity, such as lactate, hydrogen ions, and reactive oxygen species (ROS). In addition to this build up, metabolic stress is characterized by a decreased intracellular pH (increased acidity due to hydrogen ion accumulation), hypoxia (reduced local oxygen availability), and decreased intracellular phosphocreatine (a molecule utilized for rapid energy production). (I, II, III) You can think of metabolic stress through the lens of moving into a new home, where the work required to unravel and configure all of your belongings is equivalent to muscular work, and the accumulation of torn tape, carved boxes, and crumpled sandwich wrappers is equivalent to the metabolite buildup that comes hand and hand with intense and prolonged exercise. Since metabolic stress is seemingly intertwined with many resistance training regimens, such as those implemented by hypertrophy-focused bodybuilders, Schoenfeld and others have posed this physiological process as a possible mechanism of hypertrophy. (I, II, III, XII)
One argument for metabolic stress suggests that cell swelling and muscular fatigue, both of which result from the high-rep and long-duration protocols associated with metabolic stress, are conducive to the mechanotransduction mechanisms mentioned above. Some researchers propose that, by increasing pressure within muscle fibers, cell swelling – resulting from increased intracellular hydration– can activate mechanical sensors and instigate signaling cascades associated with hypertrophy. (I, II, III, X, XII) In addition, some researchers believe that, though they activate less muscle fibers initially, the lower loads used to induce metabolic stress can ultimately maximally activate muscle fibers through the fatigue that occurs as time under tension accrues. (II, III, XII)) This idea builds off of the Henneman Size Principle, which says that the smallest motor neurons of a muscle are activated before that muscle’s larger motor neurons. In other words, you will only activate a muscle’s larger motor neurons and more forceful muscle fibers if you exert a force (i.e. lift a weight) that exceeds the force output of the smaller motor neurons and less forceful muscle fibers. Based on this concept, only lifting heavy loads will stimulate most or all of the muscle fibers in a given muscle; however, some posit that lifting lower loads for higher reps can activate those more forceful muscle fibers by fatiguing the less forceful ones and creating a need for more force production.(III, XII) If true, this could allow lower load, higher rep resistance training to induce a comparable degree of mechanical tension to that of higher load, lower rep resistance training.
On top of those mechanical pathways, metabolic stress may contribute to hypertrophy through hypoxia. When a muscle contracts, it partially occludes surrounding blood vessels, restricting blood flow to and from the area. This occlusion is less metabolically significant when lifting heavier loads due to the short set duration, as the vessels are not restricted for an extensive period of time. On the other hand, when lifting lighter loads for higher reps, the longer set duration can lead to a large amount of local hypoxia; additionally, this restriction can propagate metabolite buildup within the myofibers by limiting the export of those metabolites through the bloodstream. In theory, the combination of these metabolic stressors – reduced oxygen and elevated intracellular metabolites – could initiate hypertrophy through key chemical signaling pathways, such as mTORC1, MAPKs, myostatin, and nitric oxide – all of which metabolic stress is shown to impact in myofibers.(XI, XII)
In recent decades, research around metabolic stress has come into fruition through blood flow restriction (BFR) protocols that utilize straps to additionally occlude blood flow to target muscles in upper and/or lower limbs – similar to how a phlebotomist uses an elastic to restrict blood flow to your lower arm before drawing blood. Interestingly, some research shows that light loads (as low as 20% 1RM) can induce similar increases in both hypertrophy and strength as higher loads when combined with BFR, but that those same low loads are ineffective in the absence of BFR.(XI, XII) If this reigns true, then BFR – provided it is safe otherwise – could serve as a powerful intervention for safely lifting weights later in life or during recovery from an injury, as you could achieve similar strength and hypertrophy gains while utilizing far lighter weights. In addition, BFR could be valuable for older populations because it leads to significantly less post-training soreness than higher-load resistance training, which may reduce the risk of falling during subsequent days. (XIII)
For a deep dive into BFR and its potential mechanisms for inducing hypertrophy, check out this review by Pearson et. al and Peter Attia’s podcast with Jeremy Loenneke, PhD. Also, check out Loenneke et. al.’s 2011 review of BFR training’s safety profile here.
Though there is some evidence to support the metabolic stress hypothesis, one argument against metabolic stress as a sufficient solo stimulus for inducing hypertrophy – at least optimal hypertrophy – is the lack of significant muscle growth following endurance training protocols – such as interval training – that create high degrees of metabolic stress but little mechanical tension relative to resistance training.(III)
As I’ve alluded to, in terms of exercise protocols, resistance training oriented towards metabolic stress revolves around lighter loads, higher rep ranges, longer set durations, and shorter rest periods between sets. Stay tuned for Part V of the Muscle Mania Series, where we will start breaking down these training variables.
Muscular Damage
The last of Schoenfeld’s three proposed mechanisms of hypertrophy is possibly the most intuitive: muscular damage. If you have ever rolled out of bed following leg day only to find that you and your quads, hamstrings, and glutes seem to be speaking different languages, then you are familiar with the concept of muscular damage resulting from exercise – specifically, this limp-demanding discomfort and stiffness is called delayed onset muscle soreness (DOMS). At first glance, it seems obvious that muscle damage would lead to hypertrophy or better physical performance in general, as muscle damage often appears to exist in a causal line:
Exercise with a high degree of effort → Wake up sore the next morning → Repeat the process → Get stronger, faster, etc. over time
However, when you dive a little deeper below the surface, you are forced to question whether muscle damage is really causing hypertrophy, or if it is just a necessary byproduct that is correlated with the true cause; furthermore, you are left wondering how much muscle damage is really necessary for hypertrophy. In other words, is there a threshold at which you are gaining all that can be gained from muscular damage, or is there a benefit to destroying your myofibers to the point where you are crawling to your toothbrush in the AM?
Prior to investigating the necessity of muscle damage for hypertrophy, let’s return to the Sliding Filament Theory of Muscular Contraction from Part II of this series and identify what creates this muscle damage. As we previously described, during muscular contraction, myosin heads bind to actin filaments, cock their heads in a power stroke motion, and slide the two filaments (both actin and myosin) past each other to shorten the sarcomere. In order for the muscle to relax, lengthen, and return to baseline following contraction, those myosin heads must disconnect from the actin filaments and allow the filaments to slide back into place. Typically, ATP – a molecule used to provide energy for chemical reactions within cells – enables that disconnection to occur (yes, you read correctly: you actually need ATP to relax the muscle, not to contract it); however, when the myofiber is depleted of ATP, such as during strenuous exercise, it is the mechanical force of lengthening the muscle that removes those myosin attachments, dragging them down the sarcomere and causing damage to the structure as a result.(III) In addition, since some myofibers are more forceful and of different lengths than others, there is a non-uniform force distribution through the muscle during contraction that can create further shearing and damage to the muscle fibers.(I, II, III)
So, what does this have to do with hypertrophy? Some argue that this damage evokes a healing and repair process that leads to muscle growth, as muscle damage is associated with satellite cell and immune system activity.(I, II, III, XVI, XVII) On the contrary, some argue that muscular damage is not causing the hypertrophic adaptation; rather, they suggest that it is merely a necessary effect of mechanical tension, which they propose as the true cause of the muscle growth that follows.(III) In support of this idea, some research shows that muscle damage is not ultimately correlated with muscle growth.(III, XV) Regardless of muscle damage’s role in hypertrophy, it is reasonable – as Schoenfeld and others have suggested – to accept a limit to the usefulness of muscle damage, as too much damage-induced soreness would limit the frequency and intensity of follow-on training sessions.(III)
Though muscle damage is associated with resistance training and intense exercise in general, eccentric training – focusing on controlling the muscle-lengthening portion of the movement (in a bicep curl, this is the part where you are lowering the weight downwards) – is especially linked to this mechanism.(II, III, XIV) As we continue in the Muscle Mania Series, we’ll take a look at how repetition tempo – the speed with which you perform an exercise – and additional technique variables impact hypertrophy.
Since his original propositions in 2010, Schoenfeld – along with others in the field of hypertrophy – has highlighted mechanical tension as his prime pick for driving muscle-building adaptations at the cellular level; however, he has described the quagmire of elucidating the relative contributions of each mechanism towards hypertrophy, in that they are difficult to isolate. (III) In other words, it is tough to assess how much each mechanism is impacting changes in muscle size when each mechanism is occurring simultaneously. For example, is the metabolic stress induced by BFR really inducing hypertrophy itself, or is the protocol just another way to induce mechanical tension, and the metabolic stress is a passenger that comes along for the ride? Luckily for us, as long as we can confirm strategies and protocols that effectively increase muscle size, the concrete determination of minute mechanistic nuances is less important on a functional level.
Now that you understand both the micro and macro mechanisms of hypertrophy, we can start talking about the specifics of such strategies and protocols that leverage everything we’ve discussed – from mechanical tension all the way down to muscle protein synthesis. In other words, it’s time for some, “Gym Bro Science.”