Understanding Muscle Hypertrophy - Study Sheds More Light on Process of Satellite Cell Recruitement: SRF, IL-6, STAT3, COX2, IL4 + More Funky Acronyms With Important Roles in the Structural Component of Muscle Growth.
As you may remember from the Intermittent Thoughts on Building Muscle Series there is more to skeletal muscle hypertrophy than the simple messages such as "increases protein synthesis by X%" that are printed in shiny letters on the boxes of hundreds of the currently available "natural muscle builders" on the real and digital shelves of the supplement vendors. One of these "mores" is the recruitement of satellite cells, muscle stem cells that are incorporated into the musculature to replace damaged myonuclei or increase the myonuclear density to allow for greater protein accretion (learn more).
Decreasing domain sizes = better function + higher growth propensity
"Hold on those are rodents and rodent studies are not relevant!" While it is a good thing to critically assess whether the results of a certain study can be species specific. The contemporary practice to question all rodent studies which are not part of your own cherry picked arsenal is getting onto my nerves. So, please check out the pretty analogues (short term unfortunately) human study by McCay from 2009 (McCay. 2009), before you stop reading after spotting the word "rat" in this article.It is this process of satellite cell activation and incorporation of which Gwenaelle Begue and her colleagues from the University of Montpelier have now confirmed that it depends on the activation of the IL-6/STAT1/STAT3 signaling pathway in a prolonged 10 weeks resistance training scenario. In the course of the latter, 36 male Wistar rats were randomly assigned to one out of the following six groups:
- CTL2, CTL4, CTL10 (CTL = non-training controls, n = 6 in each group) and
- TR2, TR4 and TR10, which were rats trained for 2, 4 and 10 weeks.
Where is the rodent squat machine?
|No rodent squat in the study at hand, but the "stair climbing" is a better full-body workout, anyways.|
"Healthy" muscle growth does therefore require both, protein synthesis (increase in volume), as well as structural adaptations, so that the domain size does remain constant - at least!
"10 weeks of resistance training did not affect the myonuclear domain"
Against that background the last subheading, which is in fact a direct citation from the full text of the Begue paper is - contrary to what a non-SuppVersity reader could believe - good news. Very good news, to be precise:
|Figure 1: Changes in fiber type ratios (left), cross sectional diameter according to fiber type (middle) and fiber area per myonucleus (right; Begue. 2013)|
Satellite cell recruitment, necessary of optional if you want to get big?
In this context, Begue et al. speficially point out that the "recruitment of additional nuclei derived from SC incorporated into muscle fibers" occurs parallel to the better known "resistance training induced enhancement of protein synthesis" that occurs "after the training session and last[s] up to 24–48 h in humans" (Bengue.2013).
"Indeed, several works in humans have evidenced an increase in the number of myonuclei per fiber when fiber size increases approximately more than 25% (Kadi. 2004; Petrella. 2008). Thus, the myonuclear domain (i.e. the theoretical amount of cytoplasm supported by a single myonucleus in a muscle fiber) remained constant although a large increase in fiber CSA via the addition of SC-derived nuclei occurs." (Begue. 2013)
|Since estrogen plays an important role in the regeneration of the satellite cell pool, it's pretty likely that you can literally "SERM your growth potential away" (learn more)|
With +40% increased domain sizes, after only two weeks, it would have been interested to see how things would have developed in the subsequent weeks. I bet(!), the normal mice would have kept growing while their satellite cell depleted peers would have hit a plateau, where their own body woul have pulled the emergency brake aka myostatin (in this context, it's also interesting to remark that myostatin stops the proliferation of satellite cells and does thus indirectly divert the existing ones towards differentiation and incorporation into the muscle, cf. figure 2)
Bottom line: The study at hand delivers further evidence for the intimate connection between "inflammation" or rather the expression of the still demonized inflammatory cytokine interleukin-6 and the incorporation of "fresh" satellite cells into the muscle. With the latter being a necessary prerequisite to keep the domain sizes within functionally optimal limits while the cross section of the fibers is expanding (the muscle is growing), it is likely an (I want to emphasis that!) not yet disproven that continuous muscle growth requires satellite cell recruitment.
Basically you can think of it like the Army. While it is (or at least has historically been) relatively easy to find any recruits (=increase protein synthesis), people who are qualified to become officers and coordinate the actions of the rank and file are hard to find and without an adequate number of them you will end up with a chaotic mess instead of a powerful army. That's actually pretty much what happens to the myostatin negative mice, who may be able to recruit officers,... ah, I mean to recruit satellite cells, but simply outgrow the maximal pace of satellite cell incorporation.
What I can tell you in advance, though, is that strength and size gains of IL-6(-) mice are compromised (Serrano. 2008). So even if I would have to qualify my previous statement that satellite cells are necessary for continuous growth - one thing is sure: Their activation by IL-6 is necessary for optimal growth.
- Begue G, Douillard A, Galbes O, Rossano B, Vernus B, Candau R, Py G. Early Activation of Rat Skeletal Muscle IL-6/STAT1/STAT3 Dependent Gene Expression in Resistance Exercise Linked to Hypertrophy. PLoS One. 2013;8(2):e57141.
- Guerci A, Lahoute C, Hébrard S, Collard L, Graindorge D, Favier M, Cagnard N, Batonnet-Pichon S, Précigout G, Garcia L, Tuil D, Daegelen D, Sotiropoulos A. Srf-dependent paracrine signals produced by myofibers control satellite cell-mediated skeletal muscle hypertrophy. Cell Metab. 2012 Jan 4;15(1):25-37.
- Kadi F, Schjerling P, Andersen LL, Charifi N, Madsen JL. The effects of heavy resistance training and detraining on satellite cells in human skeletal muscles. J Physiol. 2004; 558: 1005–1012.
- McCarthy JJ, Mula J, Miyazaki M, Erfani R, Garrison K. Effective fiber hypertrophy in satellite cell-depleted skeletal muscle. Development. 2011; 138: 3657–3666
- McKay BR, De Lisio M, Johnston AP, O'Reilly CE, Phillips SM, Tarnopolsky MA, Parise G. Association of interleukin-6 signalling with the muscle stem cell response following muscle-lengthening contractions in humans. PLoS One. 2009 Jun 24;4(6):e6027. doi: 10.1371/journal.pone.0006027.
- Petrella JK, Kim JS, Mayhew DL, Cross JM, Bamman MM. Potent myofiber hypertrophy during resistance training in humans is associated with satellite cell-mediated myonuclear addition: a cluster analysis. J Appl Physiol. 2008. 104: 1736–1742
- Serrano AL, Baeza-Raja B, Perdiguero E, Jardí M, Muñoz-Cánoves P. Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell Metab. 2008 Jan;7(1):33-44.