Intermittent Thoughts on Building Muscle: A Preliminary Conclusion - Exercise, mTOR/AKT/MAPK, IGF-1, Testosterone, Estrogen, DHT, Nutrition, Supps & Sleep

Image 1: Arnold obviously is flabbergast that neither of the factors mentioned in the title of this blogpost was necessary to build the impressive physique of the Arnold statue which now stands in front of the Schwarzenegger Museum.

I don't know if some of you have seen it, but on January 3, 2012, ScienceDaily published a brief news-item titled "How work tells muscles to grow". It relates to a recent study by Guerci et al. who have found that the so-called serum response factor, which basically another "gene switch", is responsible, or I should say required for exercise induced satellite-cell mediated hypertrophy (Guerci. 2012). If you have been following all of the past installments of the Intermittent Thoughts from the early "Hypertrophy 101" (Part 1, Part 2), in which I explained the difference between the increase in myonuclear domain sizes as a consequence of increased protein synthesis, on the one hand and the formation of new myonuclear domains via satellite cell recruitement, on the other hand.

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You will probably also remember that myostatin, the legendary TGF beta protein that acts as an inhibitor of muscle growth, is something like a watchdog, who suppresses further increases in myonuclear domain size, when the latter begins to exceed a presumably fiber-type dependent maximum - with highly oxidative type I (slow twitch fibers) exhibiting less growth potential than their glycolytic (fast twitch) cousins. From analyses of muscle fibers from different athletes, we do yet know that the skeletal muscle of bodybuilders, the epitome of maximal skeletal muscle hypertrophy, are not - as some people argue - characterized by an abundance of ultra-fast highly glycolytic type II fibers (cf. figure 1).

Figure 1: Fiber composition of bodybuilders, recreational lifters, endurance rowers and sedentary control; determined via myosin heavy chain (MHC) isoform content of the triceps brachii muscle (data adapted from Jurimäe. 1997)

As you can see in figure 1, quite the opposite is the case, probably as a result of the high training volume, the additional endurance exercise (in the 1990s, when the study was done, no bodybuilder did HIIT ;-) and the use of performance enhancing "supplements", the dominant fiber type in the skeletal muscle of the bodybuilders in the Jurimäe study from 1997 is the intermediate fast-twitch, but still highly oxidative type IIa fiber.

Protein synthesis + satellite cell recruitment = growth!?

You probably did not realize it, but with the brief reference to the recently published study on the effects of the exercise induced release of serum response factor (Srf), the subsequent reminder of the difference in the increase in myonuclear domain sizes and the increase in their number and the allusion to training (and drug) induced changes in fiber-composition, we have covered the fundamental mechanisms by which the scrawny boy on the left side of image 2 turned into a, if not the, figurehead of physical culture and bodybuilding.

Image 2: The fundamentals of skeletal muscle hypertrophy apply to us all.

Yet, although we do have a broad understanding of what happens when we train, eat, sleep, train, eat, ... the underlying physiological processes are more complex than the ostensibly straightforward interplay of protein synthesis and satellite cell recruitment would suggest. Within the follow-ups on the "Hypertrophy 101", I have thusly done my very best to tackle each of the complex physiological processes (most of which are not even fully elucidated, yet) which allegedly or effectively trigger, sustain, facilitate or drive skeletal muscle hypertrophy in separate installments:

1. IGF-1 and its Splice Variants MGF, IGF-IEa & Co - Are the growths hormones master regulators of muscle growth or just a bunch of cogs in the wheel of skeletal muscle hypertrophy?
   
   
2. IGF-1, TNF-α, IL-15 & Co and the Emerging Role of an Auto-/Endocrine-Immune Axis in Skeletal Muscle Hypertrophy  - How does inflammation factor in, is it beneficial or detrimental?
    
3. Zoning in on "The Big T" - Does testosterone (alone) build muscle?
    
4. Quantifying "The Big T" - Do increases of testosterone, which are well within the physiological range matter?
    
5. Understanding the "Big T" - How does testosterone work? What is its effect on stem cells and how come it makes you leaner?
    
6. Estrogen, Friend or Foe of Skeletal Muscle Hypertrophy? - Which role does estrogen play and why could you SERM away your growth potential, when you (ab-)use tamoxifen or potent aromatase inhibitors?
    
7. Dihydrotestosterone (DHT), The All Things Male Hormone - Will it make you bigger, stronger and faster or just balder, fatter and unhealthier? 

In case you have forgotten about the way the local and not the systemic growth hormone response is responsible for the intricate restructuring process, in the course of which the increase in myonuclei (which must not be confused with an increase in muscle cells, i.e. hyperplasia) and motor proteins keeps the growing muscle strong and functional, about how IGF acts as a door opener for the macrophages (immune cells), which then "install" the satellite cells in the inflamed muscle and about the function of testosterone and its metabolites estrogen and dehydrotestosterone in this complex interplay of intra-, para- and endocrine processes, you can read up on all that in the previous installments of this series (see list above).

A picture is worth a thousand words - tying the knots graphically  For those of you who either remember all that or have just returned from their virtual tour through the archives of the SuppVersity, I have come up with a graphical illustration which is an attempt to sum up "all" the major players and their interactions.

Figure 2: Graphical illustration of what you should have learned by now, if you read the previous installments of the this series; note: while I have used the arrows rather indiscriminately (they do not necessary mean "causes"), the stops at the end of other lines indicate an inhibition, eg. the line from exercise to myostatin indicates that exercise inhibits myostatin, which would inhibit increases in myonuclear domain sizes, if it was not "switched off" by exercise...

I bet there are still a few arrows missing here and there, but the overall message is clear: If there was one unifying factor that impacts all important aspects of (natural) skeletal muscle hypertrophy, it would be exercise. Exercise acts directly on the mTOR/p-AKT and the MAPK pathway and thusly increases muscle protein synthesis (assuming the respective substrates are present) and the accrual of motor proteins. It increases mitochondrial biogenesis via PGC-1a and induces adaptive changes in the fiber type composition of the trained muscle. It inhibits myostatin and thusly allows for further expansion of the myonuclear domain. The latter is possible because it will promote the proliferation and the recruitment of satellite cells in response to the exercise induced expression of inflammatory cytokines and local growth factors.

If you can show me another player in this orchestrate with a similarly or even more important function than physical activity with a focus on skeletal muscle overload, let me know... if not, you better make sure you do not miss your next workout ;-)