Ribosome Biogenesis Influences Whether High Volumes Cause More Growth

Higher volumes tend to lead to more muscle growth and larger strength gains, but not everyone responds to higher volumes in the same way. A recent study found that people who respond better to higher volumes may do so due to an increase in ribosomal content of their muscle fibers.
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This article is a review and breakdown of a recent study. The study reviewed is Benefits of Higher Resistance-Training Volume are Related to Ribosome Biogenesis by Hammarström et al. (2019)

Key Points

  1. Using a within-subject unilateral design, subjects trained three times per week, performing 6 weekly sets for quads with one leg, and 18 sets with the other leg.
  2. Muscle growth and strength gains were larger in the leg performing more sets, on average.
  3. On an individual level, subjects who experienced more quad growth or larger strength gains with higher volumes also experienced larger increases in ribosome content, while people who had smaller increases in ribosome content tended to respond similarly with both legs to both the high and low volume protocols.

If you think back to 10th grade biology, you probably remember learning that the mitochondria are the powerhouses of the cell, and not much else (assuming you didn’t have to take more biology classes in college). If you wrack your memory a bit more, you may remember the ribosomes, another class of tiny cellular organelles that are responsible for constructing proteins. Due to their function, it may be natural to wonder whether ribosomes affect the way people respond to training.

In the present study, 34 subjects underwent 12 weeks of training. They served as their own controls, with one leg doing 6 sets of quad training per week, and the other leg doing 18 sets of quad training per week. The higher volume condition led to larger strength gains and more muscle growth, on average, but it only resulted in meaningfully more growth or meaningfully larger strength gains in ~30-40% of the subjects. Analysis of cellular data indicated that the subjects who saw better results from higher volumes also experienced larger increases in muscle ribosomal content, whereas subjects who saw similar results from both higher and lower volumes had smaller increases in muscle ribosomal content.

Purpose and Hypotheses

Purpose

The main purpose of this study was to investigate the effects of single- versus multi-set resistance training on strength and hypertrophy. A secondary purpose was to compare the effects of single- and multi-joint training on various markers and signaling pathways associated with hypertrophy.

Hypotheses

No hypotheses were stated.

Subjects and Methods

Subjects

34 subjects completed the study, including 16 males and 18 females. All were healthy but untrained.

Experimental Design

A basic overview of the study can be seen in Figure 1. Briefly, the study started with a body composition and quadriceps muscle size assessment using DEXA and MRI. This was followed by two pre-training strength testing sessions and a vastus lateralis biopsy (to assess all of the various molecular variables the researchers were interested in) obtained in a rested state. After the pre-training testing was completed, subjects trained for 12 weeks. Strength was re-assessed during the study during weeks 3, 5, and 9, with a post-test occurring after week 12. Additional biopsies were performed before and one hour after the fifth training session, and after the completion of the training intervention. Finally, the study ended with post-training DEXA and MRI scans to assess changes in body composition and quad size.

The training intervention consisted of 12 weeks of full-body training. However, the upper body training (consisting of bench press, pull-downs, shoulder press, and seated rows) was the same for all subjects. For lower body training, the subjects performed unilateral leg press, unilateral leg curls, and unilateral knee extensions. One leg performed one set per exercise, while the other leg performed three sets per exercise. Thus, each subject served as their own control. Subjects trained three times per week, with loads progressing from 10RM loads to 7RM loads. One day per week, training loads were reduced by 10% while maintaining the same rep target (so the subjects wouldn’t burn themselves out by doing multiple sets to failure for multiple exercises three days per week).

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Findings

The multi-set condition led to larger strength gains (~22% vs. ~29%) and more hypertrophy (3.59 vs. 5.21% increase in quad CSA). Ratings of perceived exertion (effort-based not reps-in-reserve based) were greater for the multi-set condition, but the difference actually wasn’t particularly large (7.09 ± 1.95 vs. 6.22 ± 1.82). The multi-set condition also led to a greater interconversion of type IIX to type IIA fibers.

Of the molecular variables analyzed, the most important seemed to be total RNA levels in muscle. Total RNA is strongly associated with ribosome levels, since most of the RNA in a cell at any given point in time is ribosomal RNA, so an increase in cellular RNA levels indicates that ribosomal content has increased. The multi-set condition led to larger increases in total RNA per gram of muscle tissue.

13 subjects experienced meaningfully larger increases in quad CSA (larger than the smallest worthwhile change; 2.7% in this study) in their multi-set leg, and 16 subjects experienced meaningfully larger increases in strength (at least 4.5% larger strength gains) in their multi-set leg [9]. Conversely, only three subjects experienced meaningfully larger increases in quad CSA, and only one subject experienced meaningfully larger increases in strength in their single-set leg.

Of the variables analyzed, total RNA content during week two of training (from the biopsies taken before the fifth training session) was the strongest predictor of whether subjects would respond more positively to multi-set training than single-set training. In other words, ribosomal content wasn’t necessarily predictive of whether people would respond well or poorly to training in general; however, the subjects that experienced larger increases in ribosome content when doing multi-set training were more likely to experience disproportionate benefits from multi-set training, whereas the subjects that experienced smaller increases (or decreases) in ribosome content were more likely to experience similar gains from both single-set and multi-set training.

Finally, while there was a large spread in individual strength and hypertrophy responses, the correlations between individual responses to single-set and multi-set training were strong (r = 0.8 for strength and r = 0.75 for hypertrophy). In other words, some people simply responded better or worse to training in general, independent of training volume.

Interpretation

Before discussing the findings, I just want to make one thing clear about the training protocol: the single set condition was still performing six quad-focused sets per week (one set of leg press and one set of knee extensions, three times per week), compared to 18 for the multi-set group. So, this study wasn’t like some other volume studies where the low-volume condition is using a pitifully low volume of only 1-2 sets per week. Six sets probably isn’t enough to optimize growth, but it’s certainly within the range of “reasonable” volume, especially for untrained lifters. Conversely, there’s recently been discussion on the science-based side of the fitness industry about how much volume is “too much,” with speculation that per-session volume may be more important than weekly volume (to a point) when it comes to non-functional overreaching. We recently reviewed a pair of studies that found that just 5-10 sets per week seemed to work best when frequency was low (once per muscle group per week), with diminished returns at 15-20 sets (23, 10). In the present study (1), the higher volume group was doing 18 sets of quad work per week, but it was split over three sessions, allowing per-session volume to remain reasonable, and thus yield larger gains.

I’m not incredibly interested in rehashing the Great Volume War of early 2019, however. Rather, I simply found this study interesting because it’s one of the few studies we have investigating mechanistic reasons why some people – but not all people – respond better to certain training stimuli. If this were a typical study in our field, the big takeaway would just be that higher volumes tend to promote more muscle growth and larger strength gains than lower volumes (45). There’s already plentiful evidence for both of those recommendations (to a point). However, this study takes things a step further: It specifically quantified how many people made meaningfully larger gains with higher volume, and it also examined predictors of responding better to higher volumes.

The first advantage – being able to see how many individuals actually benefited from higher volumes – was only possible due to the within-subject unilateral training design. Such a design (where one arm or leg does one training program, while the other arm or leg does another training program) isn’t ideal for investigating strength gains due to the cross-education effect, but it’s an excellent model for studying hypertrophy. Since each subject serves as their own control or comparator, you virtually eliminate sampling variability, and you automatically gain a considerable amount of statistical power (since you can run analyses like paired t-tests instead of independent t-tests). You can also simply count the individuals who saw meaningfully better results on one program versus the other. In the present study (1), 13 out of 34 subjects experienced meaningfully more hypertrophy when training with higher volumes, while 16 out of 34 experienced meaningfully larger strength gains. Only 6 out of 36 subjects experienced meaningfully more hypertrophy and meaningfully larger strength gains. 23 subjects in total experienced meaningfully more hypertrophy or meaningfully larger strength gains. That leads to an interesting conclusion, which I personally find quite intuitive, but which may be surprising if you don’t coach people and mostly just pay attention to differences in group means when reading research: a decent chunk of the subjects in this study would essentially be wasting their time by trying to train with high volumes. For subjects whose main goal was muscle growth, tripling training volume would only yield a ~2 in 5 chance of meaningfully increasing quad hypertrophy. For subjects whose main goal was strength, tripling training volume would only yield a ~1 in 2 chance of meaningfully increasing strength gains. For subjects with both strength and physique goals, they had a ~2 in 3 chance of higher volumes doing something useful, but only a ~1 in 6 chance of higher volumes boosting both muscle growth and strength gains. Now, I don’t think you should necessarily assume that those ratios will apply to all possible training tweaks in all populations. For example, if you want to increase strength in the short run, and you currently train mostly with 60% 1RM loads, I’d bet there’s a much higher than 1 in 2 chance that increasing your average training intensity to 80% 1RM will increase your rate of strength gains. Or, if instead of comparing 6 sets per muscle group per week to 18 muscle groups per week, if you were increasing your volume from 1 set per week to 8 sets, I’d bet that there’s a much higher than 2 in 5 chance of increasing your rate of muscle growth. It’s also worth noting that, in this study, higher volumes weren’t detrimental for many subjects. There was only a ~1 in 11 chance of growing more with lower volumes, and a 1 in 34 chance of having larger strength gains with lower volumes. However, low odds are still non-zero odds. A level of training volume that’s superior, on average, may prove to be excessive and detrimental for you as an individual. Finally, there was a ~1 in 2 chance that higher and lower volumes would both result in similar hypertrophy and strength gains in the present study. You can interpret that one of two ways, depending on how lofty your goals are. You could say “there’s a ~90-97% chance that increasing volume will produce neutral-to-positive results. Increasing volume seems like a no-brainer.” Or, you could just as reasonably say, “there’s a ~50% chance that increasing volume won’t meaningfully improve my results (for one characteristic; ~33% chance it won’t improve either hypertrophy or strength), and if my results do improve, the improvement likely won’t be commensurate with the additional effort (increasing volume by 200% to boost strength gains by ~30% and muscle growth by ~45%), and that doesn’t sound like a deal worth making, since my life doesn’t revolve around the gym.” Once you enter the realm of probabilities, and then sprinkle in differences in goals and values, it’s not reasonable to expect everyone to respond to these findings the same way.

As mentioned, the second benefit of this study is that it examined mechanisms to predict what style of training people would respond best to. The researchers found that if ribosome biogenesis increased substantially within the first couple weeks of training, subjects were more likely to respond better to higher volumes than lower volumes; conversely, if the subjects experienced a smaller increase in ribosome biogenesis or no increase, they were likely to respond similarly to both high and low volumes. That’s not of much practical use to us yet (unless you got some muscle biopsies around the time you started training), but it may prove valuable down the line. If we find that some characteristics that can be assessed non-invasively predict the ribosomal response to training (i.e. some genetic variants), we could then potentially predict whether you’re someone who would benefit from training with high volumes, or whether lower volumes are more appropriate for you (and perhaps manipulating some other factors like frequency or proximity to failure when trying to increase growth or strength gains). Even though we’re still a few steps away from the ribosome findings in this study being actionable, I’m still pretty excited about them, simply because so little research has looked into factors that influence the style of training someone responds best to. For example, a study by Beaven and colleagues found that acute testosterone-to-cortisol ratios predicted whether people would respond better or worse to four different training programs (6), though I don’t think the acute hormonal responses were necessarily the causative factor driving the different training responses. A study by Jones et al found that a (conveniently) proprietary genetic algorithm could predict whether people could respond best to power-type or strength endurance-type training (7); I’m a little skeptical of that study since some of the researchers who ran the study work for the company that owns the proprietary algorithm, and they didn’t make the algorithm public to let other researchers attempt to replicate their findings. There’s at least one study (8) finding that different variants of the ACE gene predict whether people benefit more from moderate versus low training volumes (similar to the present study). On the resistance training side of things, that’s all we have so far, in addition to the present study’s ribosomal findings. It’s clear that different people do, in fact, respond better or worse to various training styles, but there’s just not much research examining the potential mechanisms. Some people do better with higher or lower volumes, some people do better with higher or lower frequencies, some people do better with higher or lower intensities, and without simply troubleshooting, we just don’t yet have many good ways to predict the style of programming an individual will respond best to. The present study (1) was approximately the fourth step in a sparse line of research leading toward a future where, hopefully, we can better predict the styles of programming that will allow each individual to thrive.

Next Steps

There’s already a decent body of research looking for genes that predict how well people will respond to training in general, but we’re generally lacking studies examining whether genes can predict what style of training an individual will respond best to (except for the Jones study with the proprietary algorithm). If we found that gene testing could be useful for this application, that would be a big improvement over measuring changes in ribosome content – which requires multiple muscle biopsies – since you can sequence a genome from just a cheek swab or blood draw.

Application and Takeaways

  1. Overall, higher volumes still tend to promote more muscle growth and larger strength gains.
  2. Not everyone benefits from higher training volumes. Some percentage of people respond similarly well to both lower volumes (to a point) and higher (to a point). A small minority of people actually respond better to low volumes.
  3. Whether or not you’re able to pump out a bunch of new ribosomes may predict whether ramping up training volume will help you build more muscle and strength.

Free PDF: Concise breakdowns of 10 recent studies

This article was first published in MASS Research Review. You can get a free PDF issue of MASS containing 9 more pieces of content just like this one. Just enter your email address below, and you'll get instant access.

References

  1. Hammarström D, Øfsteng S, Koll L, Hanestadhaugen M, Hollan I, Apro W, Whist JE, Blomstrand E, Rønnestad BR, Ellefsen S. Benefits of higher resistance-training volume are related to ribosome biogenesis. J Physiol. 2019 Dec 8.
  2. Barbalho M, Coswig VS, Steele J, Fisher JP, Giessing J, Gentil P. Evidence of a Ceiling Effect for Training Volume in Muscle Hypertrophy and Strength in Trained Men – Less is More? Int J Sports Physiol Perform. 2019 Jun 12:1-23.
  3. Barbalho M, Coswig VS, Steele J, Fisher JP, Paoli A, Gentil P. Evidence for an Upper Threshold for Resistance Training Volume in Trained Women. Med Sci Sports Exerc. 2019 Mar;51(3):515-522.
  4. Schoenfeld BJ, Ogborn D, Krieger JW. Dose-response relationship between weekly resistance training volume and increases in muscle mass: A systematic review and meta-analysis. J Sports Sci. 2017 Jun;35(11):1073-1082.
  5. Ralston GW, Kilgore L, Wyatt FB, Baker JS. The Effect of Weekly Set Volume on Strength Gain: A Meta-Analysis. Sports Med. 2017 Dec;47(12):2585-2601.
  6. Beaven CM, Cook CJ, Gill ND. Significant strength gains observed in rugby players after specific resistance exercise protocols based on individual salivary testosterone responses. J Strength Cond Res. 2008 Mar;22(2):419-25.
  7. Jones N, Kiely J, Suraci B, Collins DJ, de Lorenzo D, Pickering C, Grimaldi KA. A genetic-based algorithm for personalized resistance training. Biol Sport. 2016 Jun;33(2):117-26.
  8. Colakoglu M, Cam FS, Kayitken B, Cetinoz F, Colakoglu S, Turkmen M, Sayin M. ACE genotype may have an effect on single versus multiple set preferences in strength training. Eur J Appl Physiol. 2005 Sep;95(1):20-6.
  9. “Smallest worthwhile change” may sound like a value judgement, but it’s essentially just an increase of 20% of the group’s pre-training standard deviation for a particular measure. It’s essentially the cut off between a “trivial” and “small” Cohen’s D effect size, applied to an individual instead of a population. In other words, if the standard deviation for bench press strength in a group is 10kg, the smallest worthwhile change in bench press strength for a subject in that group would be 2kg.
  10. Notice:  The studies by Barbalho et al cited in this article have come under scrutiny due to improbable data patterns. Keep that in mind when reading this article. We will provide further updates if there are further developments. You can read more about the improbable data patterns here, and here.
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