The Non-Responders

You are probably not one of these people. They make up less than 15% of those who exercise. These aren’t elite athletes or weekend warriors. They are non-responders.

Key Points

  1. Differences in training response can vary from 5% – 250% in both strength and hypertrophy.
  2. Non-responders often have a genetic profile that reacts like that of inflammation rather than muscle growth.
  3. Non-responders exist, but they still show a physiological response to training.

The idea of a non-responder in the fitness world is paradoxical. Often these people are judged as if they aren’t trying hard enough. Some are even called out for not being dedicated. However, these people do exist and are often frustrated in the gym.

Fear not, there is a physiological explanation. Much like many diseases, some people are at a genetic disadvantage in their response to resistance exercise.

Here’s a hypothetical example: a study finds that a certain exercise protocol causes a 30% increase in muscle mass compared to a different protocol that causes a 15% increase. You would obviously want to use the training regimen that did better between the two. However, what you may not notice is the variation within the groups. Often there are subjects who didn’t respond, or responded very little. This isn’t a new concept. It does make us wonder though – why do some respond when others don’t?

Individual differences in response to training are sometimes beyond statistical error, often thought of as outliers. But they’re still important. These differences may seem like an annoyance to scientists looking for statistical significance, but they reflect the genetic variation that makes people diverse. This diversity is not caused by a specific age, sex, or ethnicity but does play a major role in response to physical activity (3).

Several studies have shown differences in responsiveness to resistance exercise. For example, in one study done by Thalacker-Mercer et al., participants completed 16 weeks of resistance training, 3 days per week. Muscle size was measured across all subjects. This study found that one portion of subjects showed no change (non-responders), one showed moderate change, and one showed an extreme response. Now, this study was heavily monitored for effort and completion, so everyone had the same relative input. What was the difference? The subject’s molecular profile. Specifically, the profile for the extreme responders had enhanced transcriptional regulation, satellite cell function and muscle growth signaling, while the non-responders had a profile with increased inflammatory signaling. This indicates that the muscle of the extreme response group was primed for growth. Furthermore, it tells us that the non-responders may have a metabolic disadvantage to adapt (4).

There is one possible limiting factor with this experiment. It could be that the baseline (pre-exercise) gene expression in muscles is different among responders and non-responders. However, scientists found that baseline gene expression is not related to pre-training size and strength. Thus, this profile clearly reflects the metabolic and functional adaptations of the muscle to resistance exercise (5).

One theory driving these differences is myonuclear addition. This is based on the concept of myonuclear domain, which is the amount of cytoplasm in a muscle fiber that is controlled by a single nucleus. This concept has been confirmed by several studies that show changes in muscle fiber size that are paralleled by changes in the number of myonuclei. They also indicate that the myonuclear domain is controlled by two mechanisms: the gain of myonuclei by fusion of satellite cells during hypertrophy and the loss of myonuclei by apoptosis in atrophying muscle fibers. Importantly, there may be a ceiling on the myonuclear domain (∼2,000 μm2) that is reached before the addition of more nuclei (7). Therefore, it is possible that the genetic profile of non-responders is playing a role by limiting the myonculear domain.

Looking at the big picture is important since you can get bogged down in the molecular details. Therefore, the following study measured more clinically relevant outcomes. A cohort of 585 subjects, age 18-40, participated in a 12 week training study with unilateral resistance exercise in the elbow flexors. Cross sectional area (muscle fiber size) of the arm was measured using MRI. Importantly, subjects who supplemented their diet with additional protein to build muscle were not included. From this large study there is an interesting breakdown of training response. Of all the subjects, 232 (39%) showed an increase in muscle fiber size between 15-25%. However, 36 subjects gained ~5% in muscle size. These subjects were deemed non-responders compared to most of the other subjects, but they still had a physiological response.

Hypertrophy isn’t everything, though. Plenty of people are interested in training for strength and power. In the previous study of 585 subjects, 39% showed an increase in 1RM of 40-60%. This happens to be similar to those who showed the most muscle fiber hypertrophy. Interestingly, these participants were the same ones that responded by increasing muscle size. However, 12 subjects gained less than 5% in 1RM (8). This leads us to believe that there may be a neural component to non-responders since even new weightlifters can have a significant change in 1RM in their first six months.

These results show that there are indeed non-responders to resistance exercise. However, even a non-responder can increase muscle mass or strength by 4-5%. This differential response is most likely due to a genetic difference among individuals. The important thing to remember is that just because you are a non-responder to resistance exercise does not mean that you won’t respond to another type of training. Skeletal muscle is highly adaptable and can respond differently to endurance exercise than resistance exercise.

As I mentioned in the beginning, this is corresponds to only a subset of the population. This is not the reason that you are stuck at a plateau. The main reason I wrote this is for trainers and coaches who may struggle with long-term clients who don’t make (any) progress. I’ll be doing an interview with Strengtheory in the near future to take a deeper look into non-responders and I’ll post the link when it goes live.

  1. Booth, F. W., and M. J. Laye. “The Future: Genes, Physical Activity and Health.” Acta Physiologica 199, no. 4 (August 1, 2010): 549–56. doi:10.1111/j.1748-1716.2010.02117.x.
  2. Bouchard, Claude, Tuomo Rankinen, and James A. Timmons. “Genomics and Genetics in the Biology of Adaptation to Exercise.” Comprehensive Physiology 1, no. 3 (July 2011): 1603–48. doi:10.1002/cphy.c100059.
  3. Bouchard, C., and T. Rankinen. Individual differences in response to regular physical activity. Sci. Sports Exerc., Vol. 33, No. 6, Suppl., 2001, pp. S446–S451.
  4. Thalacker-Mercer, Anna, Michael Stec, Xiangqin Cui, James Cross, Samuel Windham, and Marcas Bamman. “Cluster Analysis Reveals Differential Transcript Profiles Associated with Resistance Training-Induced Human Skeletal Muscle Hypertrophy.” Physiological Genomics 45, no. 12 (June 15, 2013): 499–507. doi:10.1152/physiolgenomics.00167.2012.
  5. Dennis, Richard A., Haiyan Zhu, Patrick M. Kortebein, Heather M. Bush, Jonathan F. Harvey, Dennis H. Sullivan, and Charlotte A. Peterson. “Muscle Expression of Genes Associated with Inflammation, Growth, and Remodeling Is Strongly Correlated in Older Adults with Resistance Training Outcomes.” Physiological Genomics 38, no. 2 (July 2009): 169–75. doi:10.1152/physiolgenomics.00056.2009.
  6. Bamman, Marcas M., John K. Petrella, Jeong-su Kim, David L. Mayhew, and James M. Cross. “Cluster Analysis Tests the Importance of Myogenic Gene Expression during Myofiber Hypertrophy in Humans.” Journal of Applied Physiology 102, no. 6 (June 1, 2007): 2232–39. doi:10.1152/japplphysiol.00024.2007.
  7. Petrella, John K., Jeong-su Kim, James M. Cross, David J. Kosek, and Marcas M. Bamman. “Efficacy of Myonuclear Addition May Explain Differential Myofiber Growth among Resistance-Trained Young and Older Men and Women.” American Journal of Physiology – Endocrinology and Metabolism 291, no. 5 (November 1, 2006): E937–46. doi:10.1152/ajpendo.00190.2006.
  8. “Ovid: Variability in Muscle Size and Strength Gain after Unilateral Resistance Training.”

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