Intermittent Thoughts on Building Muscle: IGF-1 and its Splice Variants MGF, IGF-IEa & Co - Master Regulators or a Bunch of Cogs in the Wheel of Muscle Hypertrophy?
|Image 1: With regard to IGF-1 and its splice-variants like MGF, there is probably 10x-100x more bro- than pro-scientific data out there - this does not help us, though, since you never know which of the bro-reports is bogus and which is not.
IGF-1: Insulin, growth hormone, or what?
To be able to answer these and related question we will first have to understand what exactly this "insulin-like growth factor 1" actually is. From a (bio-)chemical perspective it is nothing but a bond of 70 amino acids which are entangled into a specific peptide structure that is characteristic for somatomedin C, as IGF-1 is also called. Both the "growth" in IGF-1, as well as the "somato" in its old-fashioned appellation already suggest that what we are dealing with, here, is a "growth hormone related" polypeptide. And in fact, the synthesis of IFG-1, which, in the case of the systemically available fraction, takes place primarily in the liver, and is triggered by systemic growth hormone (somatotropin) levels.
|Figure 1: Changes in systemic IGF-1 levels after 5-weeks on either a "normal" (=55:15:30 carbs:protein:fats) or a low carb "high protein" (=20:30:50) diet in 8 men with untreated type II diabetes (data adapted from Nuttal. 2006)
|Figure 2: Serum IGF-1 levels in response to whey vs. maltodextrin supplementation and subsequent lower body resistance training (data adapted from Cooke. 2011)
On a side note: The insulin-mediated induction of Akt, which subsequently triggers the phosphorylation of the mammalian target of rapamycin (mTOR) and thusly does its bit to elevate protein synthesis, has no direct relation to IGF-1, which - I cannot emphasize that enough - has a structure resemblance to insulin, nothing more, nothing less. And what's more, the insulin response in the aforementioned study by Cooke et al. was identical in the whey vs. maltodextrin arm of the study.
Systemic vs. local IGF-1 expression: A crucial distinction
If you have been following the daily research updates here at the SuppVersity over the last months, you may now be wondering why I am even caring about those growth hormones (after all you should, after reading the first paragraph, realize that IGF-1 is something like the active incarnation of somatotropin), when Stuart Phillips lab has quite conclusively shown that even the exercise induced elevation of testosterone does not correlate with subsequent increases in muscle protein synthesis. Certainly a good question, but nevertheless not difficult to answer:
- The previous installments of the Hypertrophy 101 (Part 1, Part 2) should have made it quite clear that protein synthesis alone is not sufficient to grow. Without intra-muscular restructuring / reorganization and the recruitement of new myonuclei from satellite cells, you would sooner or later grow beyond the maximally allowed myonuclear domain sizes (assuming that by whatever means you block the healthy upregulation of mystatin that will prevent that) and end up as an over-muscled but completely dysfunctional wrack.
- In a very recently published study, the results of which I have actually been holding back, because I thought I would get to them much earlier in this series, the very same Stuart Phillips whose studies are "responsible" (in fact it is the way they are discussed by the lay-press and abused by the supp-companies that is actually "responsible") for the current over-emphasis on acute increases in the protein synthetic response to exercise and/or supplements, reports that there actually was a statistically significant correlation between exercise induced growth hormone release and increases in mean type I fiber (p<0.06) and type II (p<0.04) cross-sectional area (CSA) in 56 healthy previously non-resistance trained healthy young men in response to a 12-week, 5-day per week resistance training regimen (West & Phillips. 2011).
- While we have hitherto been talking about systemic IGF-1, it has become evident in the course of the last decade that the hepatic IGF-1 output, which is the main determinant of circulating IGF-1 levels, has little to no impact on the IGF-1 induced increases in skeletal muscle mass and remodeling of muscle tissue that has been previously studies in Petri dishes. In fact, recent research suggests that, just like the liver produces IGF-1 for "the whole body", muscles produce their own IGF-1, or I should say, their own IGFs-1, whenever they are challenged to grow and/or repair (Velloso. 2010), and that the decline of muscle mass with age is at least in parts attributable to a defect / reduction in the expression of local IGF-1 splice variants (for an explanation of what this is, see red box below).
Did you know that the intra-muscular (=autocrine, meaning directly in the tissue where it is supposed to work) "construction process" of the mature 70 amino acid polypeptide IGF-1 gives rise to three different splice variants of insulin-like growth factor (note: the structure of IGF-1 gene does theoretically allow for 6 variants)? And though we are just beginning to understand the physiological roles of IGF-IEa, IGF-IEb and IGF-IEc, also known as MGF (mechano-growth factor), their distinctly timed expression in response to physical overload appears to constitute one of the major driving forces of myocellular hypertophy.In order to fully understand the role "the" insulin-like growth factor 1 plays in the physiology of muscle growth, it is thusly important to realize that the common perception of IGF-1 as a systemic hormone is, at best, incomplete - I would even venture to say that it is totally flawed.
MGF?! Yeah, I have heard of that one!
|Figure 3: Stained myocyte migration (top) and infiltration (bottom) essays for IGF-1 and MGF; more stains = greater effect (taken from Mills. 2007).
In one of the earlier studies on the cellular effect of MGF, Yang et al. were able to show that MGF stops the IGF-1 mediated cell differentiation process (in practice this means that it stops the satellite cells from differentiating = specializing and becoming muscle cells) and increases their proliferation. Or put more simply: While in vitro exposition to IGF would suffice to build muscle, as long as there are enough progenitor cells (satellite cells) available, MGF is necessary to replenishes the satellite cell pool of which you have learned in the previous installments that it is necessary to a) repair damaged muscle tissue and b) increase the number of myonuclei in order to grow beyond the physiological growth limit that arises due to the muscle-type-specific upper limit to the myonuclear domain size (cf. previous installments).
|Figure 4: Cell proliferation data in response to MGF treatment after blocking the IGF-I receptor.
A series of studies by Hammad et al., which was originally intended to investigate the effects of age on the expression of the different IGF splice variants, goes to show that the "muscle (re-)building effects" of MGF are not restricted to the test tube. In their 2002 study (Hamed. 2002), the researchers were able to show profound increases in the MGF expression in the quadriceps muscles of 8 healthy young men (age 29.5 ± 1.5 years, body mass 81.1 ± 2.4 kg, height 179.3 ± 1.8 cm) 2.5h after a single muscle-damaging leg-extension exercise (10 sets of 6 repetitions at 80% 1-RM, 2 min rest between sets):
|Figure 5: MGF (ng mRNA / 10^8 µg RNA) and IGF-IEa ng mRNA / 10^5 µg RNA) expresion in quadriceps muscle of young subjects before and 2.5h after 10 sets of 6 repetitions at 80% 1-RM on a leg-extension machine with 2min rest between sets (data adapted from Hamed. 2002)
|Figure 6: MGF (ng mRNA / 10^8 µg RNA) and IGF-IEa ng mRNA / 10^5 µg RNA) expresion in quadriceps muscle of young subjects after eccentric HIIT exercise on cycle ergometer (data adapted from Hamed. 2008)
60min of opposing the rotation of the pedals down to 60 r.p.m. Subjects performed the following program of six working intervals: six working intervals: 0–6min at 50%, 6–12min at 75%, 12–20min at 100%, 20–25min at 130%, 25–40min at 100% and 40–60min at 75% of the load eliciting concentric VO2maxillicited surprisingly similar results (cf. figure 6). And in both cases, it appears to be the MGF splice variant not the IGF-IEa variety that drives the short term (hours to days) response to strenuous exercise.
HIIT and resistance training a dynamic duo for MGF expression
Assuming that you are following each and every post here at the SuppVersity (you know you should be ;-), this should remind you of a previous blogpost of mine (cf. "HIT Your Satellite Cells to Increase Your Gains!"), in which I explained that one of the many advantages of high intensity training (not even interval) over classic "cardio" training is that it can increase satellite cell proliferation. Now, with this installment of the Intermittent Thoughts you finally understand, why this is the case.
|Image 2: This is not the kind of muscle damage you should be aiming for in the gym.
This controlled amount of muscle damage ties in nicely with the topic of next week's installment which will center around the the intricate relation of the inflammatory response to exercise, the expression of the well-known and less known inflammatory cytokines, TNF-alpha, IL-6 and IL-15 (sorry, Trevor, I have already gone overtime, so your question will have to wait till next week ;-) and the muscle (re-)building effects of IGF-1 and its intra-muscular children.