How to approach muscle hypertrophy according to science

May 14 / David Leith

How to approach muscle hypertrophy according to science

Key takeaway points:
In summary, for someone wanting to optimise their hypertrophic training regime, the most effective programme should aim to…

• Induce significant metabolic stress with a moderate degree of muscle tension 
• Employ a repetition range of 6-12 per set
• Execute repetitions at a concentric/eccentric speed of 2 seconds / 3-4 seconds
• Repeat exercises for 3-5 sets in a split-training structure
• Allow for 60-90 second rest intervals between sets
• Include compound multi-joint and single-joint isolative exercises that are executed in varying planes and angles to ensure broad and maximal stimulation of muscle fibers
• Structure training into specific phases (periodise), with select sets being performed to concentric muscle failure, perhaps alternating microcycles of sets to failure with sets not to failure. 
• Incorporate low-load, high volume sets to failure into specific blocks of training to promote broader fiber-specific hypertrophy. 
• End off periodised cycles with brief periods of high-volume over-reaching, followed by an appropriate taper to allow for recovery and super-compensation.
Muscular fitness is an integral part of any person’s life: from an elite athlete needing to exert high levels of force during competition, to a recreational strength-training individual seeking aesthetic improvements, to an elderly person seeking to maintain independence and functionality into old age and for any member of the general public to maintain cardio-metabolic health (e.g. glucose control and its various sequelae). Increased muscle cross-sectional area and muscular strength are in fact associated with reduced risk of chronic disease, including cancer, cardiovascular disease, diabetes and disability. In this light, optimising strategies to maintain or increase muscle size (hypertrophy) and strength are both relevant and important to athletic individuals and the public in general. 

Resistance training (RT) is the most effective method of enhancing muscular size and strength, with marked improvements seen irrespective of age or gender (assuming sufficient dietary protein intake).1 In untrained persons, muscle hypertrophy is initially minimal, since the majority of strength improvements result from neural adaptations.1 After a couple of months of consistent training, hypertrophy becomes the dominant factor. The extent of hypertrophy is mediated by a number of factors including age, gender, genetic makeup, programme design (intensity, volume, exercise selection) and recovery methods (e.g. sleep, nutrition etc).1 Programme design, being a modifiable factor, has been the subject of much deliberation amongst researchers and practitioners over the years, with few conclusive findings. This is due to conflicting findings between research groups, different methodologies, and different research participants being employed. Indeed, such research is highly vulnerable to confounding since humans are so variable in their behaviours, attitudes, genetic make-up and response to even identical stimuli. Therefore, the following outlines the most relevant findings and reviews within strength and conditioning research but is by no means set in stone and will likely change as further research is conducted. 

Before diving into these findings, let’s recap the structure of a muscle fiber, and establish what muscular hypertrophy is and how it occurs. A skeletal muscle is made up of hundreds, even thousands, of muscle fibers (cells) bound together in connective tissue.2 These muscle fibers are compartmentalised into bundles called fasciculus with these being surrounded by a cytoplasm called the sarcoplasm. Each fiber is individually made up of many myofibrils that run the length of the muscle fiber and attach at either end to the outer membrane (sarcolemma) of the muscle fiber. The myofibrils are then made up of the smallest contractile ‘unit’ of muscle tissue, namely the sarcomere. Sarcomeres are comprised thick (myosin) and thin (actin) protein filaments that are responsible for performing muscular contractions in response to specific signal transduction cascades upstream. Specifically, the binding of ATP (energy) to these filaments initiates the active ‘sliding’ of one filament past the other to shorten the muscle and subsequent return to their initial state when ATP has been used.2

Effectively, muscle hypertrophy, or a growth in muscle size, involves the contractile elements (actin and myosin filaments) increasing in size and the extracellular matrix (e.g. collagens) expanding to support this growth.1 The majority of training-induced hypertrophy results from an increase of muscle sarcomeres and myofibrils being added in parallel. Specifically, when skeletal muscle is overloaded, a series of ‘myogenic’ (promoting muscle growth) events are stimulated that lead to an increase in the size and amount of contractile proteins (actin and myosin) and the number of sarcomeres in parallel. This increases the diameter of individual myofilaments, muscle fibers and hence the cross-sectional area of a muscle as a whole.2

There are a multitude of molecular role-players intertwined in complex signalling pathways, each as important as the other, in facilitating a hypertrophic response to resistance training. However, describing all such processes is beyond the scope of this article (Should you be interested in these finer details, please let me know and I will forward the most relevant articles). In simple terms, it is hypothesised that muscular hypertrophy is stimulated by three primary factors during resistance training: mechanical tension, muscle damage and metabolic stress.1
Mechanical tension refers to the active tension of contractile elements within muscle fibers when undergoing stretch and generating force under load, as well as passive tension generated by extracellular elements e.g. collagen.1 Under tension, the integrity of the muscles is disturbed, which triggers various molecular and cellular responses (e.g. hormonal, growth factor, cytokine etc) and satellite cell activation. The latter reside in a dormant state beneath the sarcolemma and are triggered by a mechanical stimulus to proliferate, attach to the existing fibers and provide precursors needed for repair and muscle growth e.g. nuclei to support synthesis of further contractile proteins. The molecular responses activate ‘myogenic’ signalling pathways (e.g. AKT/mTOR and CamMK pathways) that lead to specific genetic transcription and translation events that favour protein synthesis over degradation and facilitate more contractile apparatus being formed.1 

The degree of mechanical tension generated will be largely influenced by the intensity of the load being lifted and corresponding motor units recruited to perform the lift. In accordance with Henneman’s size principle, 3 motor units are recruited in an orderly fashion, meaning that as force production requirements increase, motor units are recruited according to the magnitude of their force output (small to large). In a given set, lower threshold motor units (Type 1, slow-twitch) are recruited first to lift the load. As these become fatigued, higher threshold (Type 2, fast-twitch) units are recruited.3 Therefore, higher threshold motor units will be recruited and greater mechanical tension generated with loads that are moderate to heavy and are performed at a frequency adequate for the lower threshold units to become fatigued. 

Muscle damage may result from resistance training, particularly when the load experienced by a certain muscle exceeds its capacity and/or the rate at which it is received is excessive.1 This may induce ‘injury’ to various components including the muscle fiber membranes, contractile elements and supportive connective tissues. Damaged fibers attract inflammatory cells that remove debris and signal for satellite cells to proliferate and differentiate, thereby increasing the muscle size. This is particularly evident when heavy eccentric (muscle-lengthening) contractions are performed or even emphasised in the resistance training set.

Lastly, metabolic stress refers to the accumulation of metabolic by-products (e.g. hydrogen ions, lactate, inorganic phosphate) in response to exercise training. This results from the training modality employing high rates of glycolysis (oxygen-independent metabolism) for ATP production, and appears to promote muscular hypertrophy via hormonal changes, free-radical production and the release of growth-oriented transcription factors.1 Resistance training will induce its highest metabolic stress when performed at moderate to high volume and with limited rest periods between sets.

With the above in mind, how should your resistance training programme be structured if your goal is to maximise muscular hypertrophy? The fundamental training principle of specificity prescribes a strategic manipulation of training variables (e.g. load, intensity, repetition scheme, volume, rest etc) to maximise the adaptations sought. In this instance, we are looking for high levels of mechanical tension, metabolic stress and a degree of muscle damage. Probably the most important determinant of achieving these targets is the intensity and corresponding rep scheme used. There are many tables available correlating relative intensity (%1RM) to repetition range. For the purposes of this article we can say > 85% 1RM is prescribed at low (1-5) rep ranges, 65-85% 1RM for moderate (6-12) rep ranges, and < 65% for high rep ranges (> 15). Training within different intensity/rep ranges biases different energy systems, accrues varying levels of mechanical tension and muscle damage and invokes different neuromuscular responses. Generally, research has found that high rep training is inferior for promoting muscle hypertrophy.1 This is because a load of < 65% 1RM is not sufficient to recruit and fatigue high threshold motor units (as described above), despite a high metabolic stress likely being achieved. However, as will be described later, such findings likely resulted from the working sets at these intensities not being taken to failure.3,4

There has been much debate as to whether low rep or moderate rep training induces greater hypertrophy (e.g. bodybuilders tend to train at a moderate repetition range whilst powerlifters tend to remain at the lower end of the spectrum). Research suggests that moderate rep regimes are more hypertrophic.1,4 This has been attributed to such regimes being able to recruit the high threshold motor units that low rep training does, whilst also inducing a higher metabolic stress (since low rep training relies almost exclusively on the phosphocreatine system and moderate rep training relies heavily on the glycolytic pathway). Moderate rep training also facilitates greater time under tension, which increases the potential for recruiting, fatiguing and causing micro-damage to a spectrum of muscle fibers / motor units.1 

In working at a moderate rep range (6 – 12 reps at 65-85% 1 RM), research suggests that accumulating a higher total volume (i.e. through multi-set programmes) elicits a greater hypertrophic responses.1 This has been reported as both acute anabolic hormone release and longer-term muscle growth, and appears to occur in a dose-response manner, up until a point.1 It is suggested that volume be progressively increased over the periodisation phase to end in a brief period of over-reaching before tapering off to allow for recovery and super-compensation. In a hypertrophic programme, this may start with 3 sets of 6-12 reps in week 1 of training and progress to 4-5 sets by the peak of the phase. Split body routines (focusing on multiple exercises for limited muscle groups per session) appears to help maximise the hypertrophic response to a programme as a whole.1 This could mean, for example, focusing on anterior lower body muscles and upper back muscles on one day, and chest and posterior lower body muscles the following day. It is equally important to avoid overtraining that may result from long periods of overreaching, excessive numbers of sets and/or lengthy sessions that reduce intensity of effort, place unnecessary stress on the body and hamper recovery and the subsequent immune response.

Rest intervals between sets also have the potential to modify the hypertrophic response to training.1 Although short intervals (< 30 seconds) increase metabolic stress, they reduce one’s strength capacity and performance in subsequent sets, thereby decreasing overall mechanical tension. In contrast, long rest periods (2 – 3 minutes) increase the capacity for greater mechanical tension but significantly reduce metabolic stress.1 Therefore, moderate rest intervals (60-90 seconds) provide the balance of maintaining high metabolic stress whilst enabling the athlete to recover strength capacity and sustain high mechanical tension across sets. 

In selecting the most appropriate exercises to stimulate hypertrophy of target muscle tissues, it is suggested to incorporate a combination of multi-joint and single-joint exercises.1 The former are required to recruit large amounts of muscle (including high-threshold motor units), resulting in a large anabolic hormonal response. They also require a significant degree of stabilisation from the rest of the body (e.g. a squat does not only require the quads to work), which allows for muscles that are not specifically targeted to still be stimulated. Single-joint exercises then allow for a specific focus on individual muscles, targeting underdeveloped muscles or regions thereof to promote muscle symmetry and agonist-antagonist balance. Indeed, if the primary aim of training is to maximise muscle size, one should aim to promote uniform growth of muscle tissue by manipulating certain variables of exercises e.g. angles of pull or push, range of motion used etc.1

Muscles may exhibit multiple attachment points, regional differences in muscle fiber type and neuromuscular innervation that can all influence the activity of different muscles in different variations of an exercise. Thus it is suggested to have a multi-angled, multi-planar approach to hypertrophy training, to ensure all fibers within a muscle are stimulated and hypertrophy is maximised. 
An often forgotten metric of exercise performance is tempo or repetition speed. In terms of eliciting an anabolic response, the most important part to consider is the eccentric (muscle-lengthening) component.1 A muscle-tendon unit is able to generate its highest level of force when contracting eccentrically (lengthening under tension) compared to concentrically (shortening under tension). This appears to be related to a number of factors, including a greater contribution of resistance from elastic components and more contractile proteins being ‘engaged’ or active during the eccentric component.1 Furthermore, in contrast to concentric contractions, muscle’s fast-twitch (high force producing) fibers are selectively recruited during eccentric contractions. Thus, it advised to perform eccentric components at a slow speed (3-4 seconds) and the concentric components at a moderate speed (2 seconds) in order to try maximise muscle tension and metabolic demand.

Recent attention has been devoted to the benefits or possible detriment of ‘training to failure’ in seeking hypertrophy gains.3 Muscular failure refers to the point when the muscles being trained can no longer produce the necessary force to concentrically lift a given load. Advocates for this type of training advance that it is necessary to activate the highest number of motor units, especially the high threshold motor units (in accordance with Henneman’s size principle discussed earlier); as well as enhance metabolite build-up and subsequent hormonal release.3 A number of studies have explored this conundrum with equivocal findings. A recent meta-analysis concluded that training to failure and non-failure training produce similar increases in strength and muscle size, independent of body region, exercise selection or study design.3 A sub-group analysis of studies where volume was not equated between failure and non-failure training, reported that muscle strength increased to a greater extent with non-failure training, which was attributed to the higher total volume of training.3 A further sub-group analysis (of only a couple studies) found that only in resistance-trained individuals did training to failure increase hypertrophic gains significantly. This may be due to the novel stimulus of failure training in individuals who may have reached a plateau or neared the ceiling of their genetic potential. More research is needed in this area to confirm these findings. Regardless, training to failure is highly fatiguing and increases the risk of overtraining and burnout in regular gym-goers. Therefore, if employed it should be done so briefly and in a structured, periodised manner to allow for adequate recovery and a super-compensation effect to occur.

A further extension of this concept is the potential of training with very low loads (30% 1RM) to muscle failure in order to achieve hypertrophic goals. As mentioned above, this opposes traditional thought that high loads (> 65% 1RM) are required to activate high-threshold motor units and so elicit meaningful hypertrophic gains.4 However, recent studies found low load training (30%) performed to failure (reached at 25-30 reps) conferred similar hypertrophic improvements to high-load training (75-85%, 8-12 reps).4 The authors hypothesised that the similar improvements came about from differing fiber-type specific changes; namely the low load training activates fatigue-resistant type 1 fibers and so training to failure is necessary at these loads to stimulate the fibers adequately to promote hypertrophy.4 In contrast, high load training elicits more hypertrophic gains from type 2 fibers since these are preferentially activated early into a given set. Importantly, whilst hypertrophic changes were similar, the low-load training group improved in muscular endurance more than the high-load group whilst the latter increased in muscular strength to a far greater extent than the low load group.4 This makes sense in light of the ‘specificity’ principle. Overall, these developments suggest that if hypertrophy is the goal, either high-load or low-load training may be utilised, or even a combination thereof to achieve broad fiber-type gains. However if hypertrophy and muscle strength are sought then high-load (more traditional) training is superior.
References:
1. Schoenfeld, B. (2010). The mechanisms of muscle hypertrophy and their application to resistance training. J Strength Cond Res. 24(10): 2857-2872.

2. Joanisse, S., Lim, C., McKendry,J., Mcleod,J, Stokes, T., Phillips, S. (2020). Recent advances in understanding resistance exercise training-induced skeletal muscle hypertrophy in humans. F1000Research. 9:141.

3. Grgic, J., Schoenfeld, B., Orazem,J., Sabol, F. (2020). Effects of resistance training performed to repetition failure or non-failure on muscular strength and hypertrophy: a systematic review and meta-analysis. Journal of Sport and Health Science. https://doi.org/10.1016/j.jshs.2021.01.007

4. Schoenfeld, B., Petersen, M.,Ogborn, D., Contreras, B.,Sonmez, G. (2015).Effects of low- vs. high-load resistance training on muscle strength and hypertrophy in well-trained men. J Strength Cond Res. 29 (10): 2954-2963.