Hypertrophy - Why Some Make Gains and Others Don't? (Hormones, Genetics, Hyper-responders and Protein Synthesis)

Hypertrophy consists in muscle remodeling and addition of cellular protein structures after a bout of strenuous exercise and muscle damage. As a consequence muscle fibers grow in cross-sectional area and the muscle becomes thicker. Several factors regulate this adaptive response, including hormones, genetics and protein synthesis. 


Hormones as IGF-1, testosterone, and growth hormone play a major role in this response (1,2,3). When these hormone levels are reduced as in elderly populations the hypertrophic response is blunted (4,5). 

However it must be noted that acute short-term rises in these hormones after training have a negligible effect on hypertrophy (6-13). It’s only in the case of supraphysiological levels that these hormones make a difference (9,50,51,52,53).

Skeletal-muscle adaptation is an intrinsic process. McMaster’s University has done much of this work. For example, in one study the same subjects performed both resistance and endurance exercise on each leg and showed different adaptations for each leg. Resistance exercise stimulated both myofibrillar and mitochondrial protein synthesis, while endurance exercise stimulated mitochondrial protein synthesis but not myofibrillar protein synthesis (37).

Exercise programs should not be centered on the manipulation of acute exercise variables and multi-joint exercises seeking to induce a favorable ‘anabolic’ hormonal milieu.

Genetics and hyper-responders

Genetics is a key factor in the variability between individuals (6,14,15,18,43,44), in fact subjects can be stratified as low, moderate and high responders (16,17,18,45). High responders can have 4 to 5 times greater hypertrophic response compared to low responders (18), and interestingly some subjects are in fact non-responders and can even lose muscle mass despite proper training and nutrition.
In one paper the hypertrophic range in cross-sectional area (CSA) for type I and Type 2 fibers was between -22 to 106% and -4 to 67% respectively (6). In another cluster analysis the range for nonresponders was -16 ±99 µm2 for CSA (17). In another study the lowest responders gained about 1 kg while the highest responders gained 5 to 6 kg of LBM, in 12 weeks (18).

In another study results ranged from -2 to +59% (-0.4 to +13.6 cm) in biceps muscle size, with the exercise training program leading to an average of 18.9% gain in biceps CSA size in 12 weeks (14)! 

Even with 3 different programs (volume load equated) there is great variability between trained (>4 years) individuals in hypertrophy ((1.7–13.3%) and strength after 12 weeks (55).

Another study with trained subjects either getting normal or higher protein also show great variability between subjects (54). For the normal protein group (2.3g/kg) and also the higher protein group we can see a mean change in FFM of +1.5kg in 8 weeks, but thankfully we have individual data which is more telling of what can happen:

See those 4 subjects in the NP group above +2kg, and those 2 up there above +4 kg? What about in the HP group those 3 up there around +6kg LBM in 8weeks? Same with the body fat individual data.

Here is another study with creatine and creatine nitrate for only 28 days (56). See those subjects above 4kg LBM and the ones at 7-9 kg LBM? Obviously some of these gains are attributed to water and glycogen via creatine, but...

This variability is related to changes in microRNA androgen expression (6,18,19), satellite cell number for remodeling (20,21,22,23,24,25,26,27,28), intramuscular anabolic signaling protein activation (29), protein synthesis (30,31), and genetic variation (32,41).

In one study investigating the systemic correlates of resistance training-induced hypertrophy (16wk), the change (increase) in androgen receptor protein content and the magnitude of the protein kinase p70S6K phosphorylation (a target of mTOR) after 5h, accounted for 46% of the variance in the hypertrophic response (6). Some of the subjects had a 1.5-2.5 fold increase in AR protein content, suggested to account for about 25% of the variability.

Some subjects show little to no gain, and others show profound changes, increasing size by over 10 cm2 and doubling their strength. There is also variability between men and women; men had only a slight advantage in relative size gains compared with women, whereas women outpaced men considerably in relative gains in strength (46).

Some individuals even lose strength and muscle mass. Another study collected data of untrained healthy men and women (age 19 to 78 years, n = 287 with 72 controls) from ten 2024 weeks RT interventions. Muscle size changed during RT had a range from 11 to 30 % (47).

It is also more difficult to gain muscle mass than strength: 29% of low responders for hypertrophy vs. 7% of low responders for strength gains. Age and sex has little influence (47). The muscle size and strength responses varied extensively between the subjects regardless of subject’s age and sex (47). 

From the total group of 287 training subjects, the response of 35 subjects (12.2 %) were defined as high responders with increased muscle size gains between 10% to above 30% of muscle size (47).

Now if this high-responder gains in the untrained continue over time, if they continue to respond 4-5x better compared to moderate or low responders is unknown from a scientific perspective.

Protein synthesis

The muscle protein synthesis acute response from exercise is a dose-response depending upon exercise intensity and workload. After a latent period after exercise of about 45 minutes to an hour (33), MPS rises sharply (2-3 fold) between 45 and 150 min. 

This increase in MPS may be sustained for up to 4h in the fasted state after exercise (33), and in the presence of increased AA availability up to 24-48h after exercise (34,35) or even 72 (42) before returning to baseline.

Remarkably, even training after fasting (overnight) the rate myofibrillar protein fractional synthetic rate is still elevated over breakdown (36). This means that we are not catabolic in the fasted state. The increased synthesis over breakdown appears to come from non-myofibrillar proteins (i.e. collagen, sarcoplasmic, and/or mitochondrial proteins), because muscle protein breakdown is also elevated after exercise (36). The exercise stimulus is therefore the greatest anabolic signal.

However, acute measures (1-6h post exercise) of MPS following an initial exposure to RE in novices are not correlated with muscle hypertrophy following chronic resistance training (39). There’ also a review on the relationship between acute of muscle protein synthesis response and changes in muscle mass (40). 

Muscle protein breakdown is also important for the regulation of muscle hypertrophy on the long term, and the chronic (positive) balance between MPS and MPB is more important than considering acute rises in MPS.

Keep also in mind that mRNA translation is thought to be the rate-limiting step in protein synthesis (48,49). 

There are many ways and mechanisms of hypertrophy, as summarized by Schoenfeld (38): mechanical tension, muscle damage and metabolic stress. There is no “one-size fits all”, and some will simply respond better or worse than others. Despite all this inter-individual variability, there are some general evidence-based recommendations for hypertrophy, regarding exercise programs.

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