Barbell Medicine - From Bench to Bedside

By Jordan Feigenbaum MS Anatomy and Physiology, Starting Strength Staff,  HFS, CSCS, USAW Club Coach

In part three of this series, we’re going to discuss the practical application of the previous two concepts we discussed, e.g. training specificity and fatigue, to an outcome hypertrophy. Hypertrophy refers to the increased size of a tissue and in our application of training stress to the human’s musculoskeletal system, we’re referring to hypertrophy of skeletal muscle.

Skeletal muscle is fairly unique as far as tissues go as evidenced by its histology (microscopic anatomy). You see, most tissues in the body are comprised of cells that have a single nucleus that houses the cell’s genetic material. When a tissue is called upon to adapt to a new stress or lack of stress different pathways within the cell are activated, inhibited or modified to result in a change in the cell’s functioning. Let’s use an example to illustrate this point:

GLUT4 is a transport protein that shuttles glucose (sugar) from the blood stream into the tissues it [GLUT4] is found in. The two most abundant tissues where GLUT4 is found are the fat and skeletal muscle tissues. When a person eats a meal insulin, a peptide hormone made/stored/released from the beta cells of the pancreas, is released into the blood stream. Insulin acts on a variety of tissues by coupling with its receptor, which is found on the surface of the cells of the tissue, and then triggers a cascade of chemical changes inside the particular cell that all sum to cause a change in something. As far as what the change is specifically, that depends on the tissue. In skeletal muscle (and fat), insulin couples with its receptor and through a cascade of chemically mediated changes inside the cell, it [insulin] increases the number of GLUT4 receptors present on the surface of the muscle cell. When more of these GLUT4 receptors are present on the muscle cell’s surface, more sugar in the blood can be transported into the muscle. How did insulin, a hormone that is acting on the cell surface cause this to happen? Through the domino-like effect of chemical changes occurring inside the cell, insulin triggered the GLUT4 receptors that were previously stored inside tiny intracellular compartments (vesicles) to be transported to the cell’s surface for function. This is the acute change in GLUT4 receptors that insulin is causing. At the same time, different chemical changes inside the cell end up affecting the cell’s genetic material such that it makes more of the GLUT4 receptors via DNA transcription (DNA to RNA) and protein translation (RNA to Protein).

In this way, we can see the function of the nucleus- it stores the cell’s DNA material and responds to signals acting on the cell (like hormones) by making more, less, or different proteins- depending on the signal. Sometimes these proteins end up being hormones, e.g. when growth hormone is released from the anterior pituitary gland and into the blood stream it travels to the cells of the liver and causes them to make insulin-like growth factor (IGF), which has its own functions. Still, we can see that most tissue’s cells only have a single nucleus for making RNA and subsequently, protein.

Enter the skeletal muscle protein cell. Skeletal muscle, you see, is organized such that a single muscle fiber is made up of many muscle cells. Many muscle fibers make up a muscle fascicle (fasciculus is Latin for bundle of sticks) and many fascicles make up an entire muscle. Each muscle cell- and there are many making up a single fiber- has MULTIPLE nuclei (plural of nucleus). By possessing many of the structures that have the potential to respond to any number of signals that act on the muscle, e.g. mechanical loading, circulating hormones, metabolic waste products, etc., we can see the robust potential that muscles possess for responding to signals affecting them.

Hypertrophy refers to the increased size of a tissue without an increase in cell number and, in contrast, hyperplasia refers to increased number of cells with or without an increase in size. Conversely, atrophy refers to decreased size and cellularity (usually) due to the stress or lack thereof applied to the tissue. When it comes to training, hypertrophy results from a variety of factors, i.e. training stress, diet, hormonal status, etc. that together result in increased size. In order of importance, the top three training factors most closely related to hypertrophy are as follows:

  1. Training volume (reps x sets)
  2. Training frequency
  3. Training load

Make no mistake about it, training volume is the single most predictive factor that is not endocrine or nutrition-related. In general, more reps and more sets equals more gainzZz. So if you were looking at a study that came to the conclusion that:

“In accordance with our previous acute measurements of muscle protein synthetic rates a lower load lifted to failure resulted in similar hypertrophy as a heavy load lifted to failure.”-Mitchell et al. (Study here)

The very first thing you’d have to look at is what was the volume in each group? Only when volume is normalized can you start to compare and contrast actual muscle hypertrophy. In absence of any other data, more volume= more hypertrophy most of the time. So is 3 sets of 10 best for muscle growth? Well, it might be better than 3 sets of 5 reps because it’s double the volume, but is it better than 6 sets of 5 where the volume is equivalent? In which group is the weight greater?

We know that loading tends to have a significant effect on outcomes due to a variety of factors like mechanical stress, substrate utilization, metabolic waste production, muscle mass used, and hormonal changes (Mechano-Growth Factor for example). So in my opinion (and knowing some data on this topic is coming out soon), more weight given the same volume tends to yield more muscle hypertrophy overall than a lighter load provided the cumulative fatigue imparted by the heavier loading does not outstrip the trainee’s ability to recover for too long. In other words, it’s important to have context here. So when I’m making the case that “more weight is better than less weight at a given volume”, I’m saying that with the understanding that the loading is still appropriate in the context of the overall programming.

For example, I would rather a trainee do 4 sets of 6 reps (total volume= 24) with a weight that is challenging but not impossible- say an RPE 8-9 INSTEAD of doing 2 sets of 12 (total volume=24) with the same relative effort (RPE 8-9).

The final consideration is frequency and in my opinion, this is where there is the most room for experimentation. Frequency, i.e. how many times per week/month/time period, you train the “muscle group(s)” is clearly related to volume- just over a longer period of time. As mentioned in previous parts of this series, muscle protein synthesis (MPS) – which occurs due to training (and nutrition/endocrine) induced signaling of the muscles’ nuclei- tends to elevate for a period of time after an “overload event” and then come back down. How long this process lasts is dependent on many factors, but principally the training status of the individual. A person who is more “trained”, i.e. an advanced lifter, has a shorter time course for the elevation of MPS because a single overload event, e.g. one training session, is less stressful to them than one training session is to a novice. Interestingly, the advanced lifter has accumulated MORE muscle nuclei (myonuclei) over the course of their years training. This is an adaptation the muscles make in response to repeated stress so they can make sufficient amounts of protein (from the nucleus’ DNA> RNA>Protein) to maintain the area of the muscle fiber it (the nucleus) is responsible for.

If we put values on these “MPS time frames” with full knowledge that they are highly variable by individual and training status/experience, a novice typically has a 48hr window where MPS gets elevated and then comes back to baseline. An advanced lifter might see this same cycle of MPS rates in 16-24hrs (or less). Moreover, MPS levels tend to be limited in magnitude with any overload event significant enough to be an overload event, i.e. it’s hard enough, challenging enough, and/or cumulatively (with preceding workouts) fatiguing enough to drive a MPS response. So no, Virginia, doing “more” isn’t better. Doing the amount necessary to drive the response and doing that as often as you need- knowing that both variables are going to change as you become more “trained”- is better.

It intuits well that…wait…some hippie started out an infamous quote like that. I can’t go there.  If we have the idea that “I need to get hyoooge, bro”, then we can understand the importance of training frequently enough to generate the most MPS we can and do it as often as possible. For a novice, this might mean training legs 3 times per week. For an advanced lifter, this might mean training “legs” 5 to 7 or even more times per week. For both individuals, doing endless sets isn’t a good idea. Rather, starting at an intelligent (if arbitrary) point like 3 sets of 5 reps for untrained folks and then gradually increasing volume/tonnage/fatigue/frequency over time is the ticket. This should be pretty obvious by now, right?!

We still have a few more parts to this series and in the next one we’ll talk about strength. Later on, we’ll put it together with a progression template to look at how things change over a lifter’s career. However, it should be abundantly clear that if your coach, trainer, Instagram life coach, or “best friend from high school who lifted more than you before he hurt his back” tells you to do some ultra high volume program (GVT and Smolov come to mind) within the first year of training that they’re absolutely not to be trusted with your gainzZz.


About Jordan Feigenbaum

Jordan Feigenbaum, owner of Barbell Medicine, has an academic background including a Bachelor of Science in Biology, Master of Science in Anatomy and Physiology, and Doctor of Medicine. Jordan also holds accreditations from many professional training organizations including the American College of Sports Medicine, National Strength and Conditioning Association, USA Weightlifting, CrossFit, and is a former Starting Strength coach and staff member. He’s been coaching folks from all over the world  for over a decade through Barbell Medicine. As a competitive powerlifter, Jordan has competition best lifts of a 640lb squat, 430lb bench press, 275lb overhead press, and 725lb deadlift as a 198lb raw lifter.

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