Sunday, January 1, 2012

Intermittent Thoughts on Building Muscle: Zoning in on "The Big T" - Does Testosterone (Alone) Build Muscle?

Image 1: As a "serious" researcher you better don't use the words "testosterone" and "muscle" without "anti-doping", "hypogonadism" or "sarcopania" in one of your papers, if you don't want to risk your career.
In many of the past installments we have been talking about funky things such as mTOR, myostatin, IGF splice variants and even more exotic stuff. Testosterone, the "big T", the allegedly most important contributor to skeletal muscle hypertrophy has hitherto been "overlooked" - was it the principle of saving the best for last which drove my decision not to address the influence of testosterone on muscle building in the first installment? Was it ignorance? Plain stupidity? Or did I want to start the new Year off with a big Tang... ah pardon "bang"?  The answer is, I was scared. Not because the word "testosterone" has gotten such a bad rep in our metrosexual/feminist society that I was put on the index of "too masculinizing" websites, but rather because I feel very uncomfortable, whenever I have to talk about things I don't fully understand... and if we are honest to ourselves, few other aspects of the physiological underpinnings of skeletal muscle hypertrophy are still so obscure as the role the "big T" plays in-between all those signaling cascades, phosphorylated proteins and newly discovered growth factors.

Testosterone, the big bad T!?

One reason for the our lack of knowledge about how (some researchers may even say "if") testosterone builds muscle certainly is a practical one. Unless you can do your research under the pretext of trying to
  • treat muscle wasting disorders (associated with age, cancer, AIDS, etc.),
  • invent new methods that could be useful in the WADA's antic battle against doping, or
  • help infertile or hypogonodal men to a better life
you, as a researcher, will not only have a hard time to find "sponsors" to fund your obviously very expensive (think of large scale studies with many healthy human participants, think of "potential risks", think of compensations, think of all the expensive lab work) studies, you may even risk to get labeled as "the doping doctor", an appellation which would certainly not be career-enhancing.

Testosterone, the Jerry Bruckheimer of skeletal muscle hypertrophy?

Even if you got enough funds for your research, were not afraid to put your reputation at stake and got the approval of all the ethical committees, you would still be faced with the problem that testosterone, contrary to muscle protein synthesis, mTOR activity in tissue samples, and even the muscle specific splice variants of IGF-1, is a systemic hormone. It is (at least this is what scientists currently believe) not expressed at the tissue level (autocrine), but produced (predominantly) in your testes, from which it then carried through your bloodstream to "dock" (even that is a total inadequate oversimplification) to its receptor and... but I don't want to waste our time by going into the details of a process, of which I would assume that you have read about roughly 143x on other websites. Instead, I want to provide you with another metaphor (you know I love those), of which I hope that it will help you to understand both the complexity of the issue, as well as the current dilemma we are in.

Image 2: The producer of a movie (here Jerry Bruckheimer at the set of PoC4, img screenrant.com) is obviously an important guy, but do you know what he does? He is important, right, but how?
Imagine "Skeletal Muscle Hypertrophy" was the title of the newest blockbuster from tinseltown. It would be pretty easy for you to name the main protagonists, like Mr. L. Leucine, Mrs. A. Mpk, Mr. M. Tor and all the others. You could assign their names to the respective characters and would have at least a preliminary understanding of what their function in the plot of the movie may be. If you take a closer look at the film poster, you recognized another familiar name "a Big T production"... "Yo, cool! Big T that is the guy who has produced all those blockbusters. Man, this guy, must really know what he is doing...", you may be thinking, but tell me: Do you have any clue what guys like Jerry Bruckheimer actually do? No? Well, me neither. We know that without the producer there would not even be a movie, we know that he is of utmost importance and we know... or I guess, we automatically assume that guys like Jerry Bruckheimer (cf. image 2) have a fundamentally important role in the whole production process - I mean, wtf., they are called "producers" ;-)

In essence the situation for scientists (and science geeks like us) looking at the "the big T" is not much different from your's in front of the film poster:
  1. We know that the loss of lean body and interestingly also bone mass is one of the fundamental characteristics of hypogonadism (below "normal" testosterone levels).
     
  2. We know that restoring testosterone levels to normal via hormone replacement therapy (HRT) alone will oftentimes suffice to reverse / repair the muscle loss.
     
  3. We know, or I should rather say, we like to believe that the granite hard muscle of 99% of the IFBB pro bodybuilders are built on supraphysiological levels of testosterone. 
But even if we take all that for granted (and I am not tackling the first two issues here, as they are pretty irrelevant for us). The question for average gymrats and science-geeks like us remains:  

"Does testosterone build muscle?"

Image 3: Granted, Prof. Hubert from Futurama would probably need some exogenous test, anyways. Luckily Bhasin et al. recruited young eugonadal men for their study ;-)
Imagine you were a brainy, not brawny scientist, someone like Professor Hubert from Futurama (cf. image 3). What would be the most obvious way to answer this vexing question? Well, that's easy: You sit down on your chair in the lab, inject some testosterone and just continue your overly intellectual day work. Before each of your weekly testosterone enanthate injections, you briefly hop into the DEXA scanner in the neighbouring medical department, measure your tighs and quads and take a blood sample to the lab. If after about half a year you still did not see any changes in body composition (DEXA), muscle size (tighs and quads), although your blood analysis reveal that your testosterone levels have been persistently elevated into super-physiological ranges, the answer to the question is... NO! If, however, you start noticing more and more muscle on your scrawny body, your little gut has disappeared, and you have to pay attention not to slam the lab-doors too hard, you know: Testosterone builds muscle!

Probably in view of the aforementioned "obstacles", there is only a single well-designed, and above all, extensively documented study in which researchers put our thought-experiment into practice. Obviously, the latter was no N=1 study, but involved a a group of 61 absolutely healthy eugonodal (= totally normal testosterone levels) young men (age 18-35y). Over a time-course of 20 weeks, the subjects received a weekly injection of an GnRH antagonist (to shut down endogenous testosterone production) and 25, 50, 125, 300, or 600 mg of testosterone enanthate (Bhasin. 2001). They did not exercise (in fact they were specifically advised to refrain from "strength training or moderate-to-heavy endurance exercise during the study"), did not increase their protein intake, did not co-administer any other performance enhancing drugs, yet still, they grew - well, to be precise that was the case for 3/5 of the subjects (cf. figure 1):
Figure 1: Changes in body composition measured by under water weighing (UWW) and DEXA after 20 weeks on the given amounts of testosterone enanthate; due to a -5% decrease in the fat-free mass to water ratio in the 125mg group (all other groups draw, not lost water) the highlighted UWW value is unrealiable (data calculated based on Bhasin. 2001)
As you can see in figure 1, only the subjects in the groups which received 125mg, 300mg, and 600mg testosterone enanthate per week were able to increase their lean muscle mass and decrease their body fat levels by literally lying on the couch (+5%, +15% and +37% increase in the free-to-fat mass ratio). The changes in the body composition of the 25mg and 50mg groups, on the other hand, were less favorable, to say the least (+37% and +16% body fat, as measured by DEXA in the 25mg and 50mg groups) - but how come, I mean testosterone does build muscle, right?
Figure 2: Changes in total testosterone (ng/dl) and IGF-1 (ng/ml) levels (left) and testosterone to IGF-1 ratio (right) of young eugonodal men after 20 weeks of GnHR antagonist + different doses of testosterone enanthate  (data calculated based on Bhasin. 2001).
If we take a look at the actual changes in the testosterone levels of the participants, the answer is quite obvious. With the exogenous suppression of the their own natural testosterone production by the Gonadotropin-releasing hormone (GnRH) antagonist, only 25mg or 50mg of testosterone enanthate per week, and corresponding reductions of both total and free testosterone by -57% and -46%, respectively, the poor sobs were essentially hypogonodal.

The complexities emerge: The testosterone-IGF1 connection

If you are the intelligent reader, I suppose you are, you will already suspect that I did included the relatively minor changes of the serum IGF-1 levels for a purpose - a purpose, those of you who have followed the last last installments of this series will probably already anticipate. After all, we do now know that testosterone does build muscle, but in the previous installments we have learned that a myriad of other factors, IGF-1 included, appear to do the same.

In view of the fact that I am still bone weary from New Year's Eve and do not want to compromise the quality of this series (and don't tell me it had no quality ;-), I will take a break here and catch up on this thought... tomorrow - I mean I know that it would be unfair to put you on the racks for a whole week ;-)