Intermittent Thoughts on Building Muscle: IGF-1, TNF-α, IL-15 & Co and the Emerging Role of an Auto-/Endocrine-Immune Axis in Skeletal Muscle Hypertrophy

Image 1: The word "inflammation" triggers associations which hinder a appropriate understanding of the complexities of the "inflammatory" immune response that is vitally important for (re-)building muscle tissue.

Just to make sure that I do not get off another tangent, again, I will start right off, where I left you in the last installment of the Intermittent Thoughts and that was with the promise to have a closer look at the intricate relationship of (exercise-induced) inflammation and the increases in muscle-specific insulin-like growth factor 1 (IGF-1) and its splice variants, above all the muscle (re-)building mechano-growth factor 1 (MGF-1). Before we are looking how one influences the other, we will yet have to establish a consistent understanding of "inflammation", which, despite being in on everyone's lips these days is commonly (mis-)understood and / or confused with "oxidation", as in the oxidation of "inflammable" substances, you have encountered innumerable times in the form of fire or rust.

What is inflammation? And is it good or bad?

If we simply rely on our everyday understanding of inflammation, we are totally missing the boat on the true significance of a very complex net of biological processes some scientists quite blunderingly labeled "inflammation", which is not the "fire", i.e. the damaging (in many, but by no means all cases oxidative) process, itself, but the appropriate, or, as in the case of auto-immune reactions, inappropriate physiological reaction to it. Whether this misleadingly termed reaction of your immune cells is "appropriate" and thusly healthy or "inappropriate" and thusly detrimental, depends on a whole host of factors, among which the distinction between subclinical chronic inflammation and acute inflammatory responses probably is the most important one.

Illustration 1: The theoretical relationship between the biphasic hormetic curve and exercise salience (Nunn. 2010. Fig. 1)

While scientists believe that a chronic low, yet elevated level of inflammation is the root cause of almost all modern disease, the acute inflammatory response to real threads is the driving force behind those hormetic adaptation processes about which Alistair V. Nunn and his colleagues from Imperial College in London write that their "decline [...] in our daily life may be leading to increased systemic sub-clinical inflammatory tone, decreased metabolic flexibility and suppression of exercise salience" and thusly set the stage for "obesity, the metabolic syndrome, diabetes, vascular disease and even cancer" (Nunn. 2010). It is thusly only consistent of the researchers to demand:

Whether we like it or not, a long and healthy life needs to include regular exposure to occasional doses of environmental stressors, including fasting, natural temperature changes, polyphenols and exercise. Although human intelligence has enabled us to remove most stressors from the environment, common sense may be required to re-introduce some of them.

And while I could unquestionable go into much more detail on the concept of hormesis and its fundamental importance to our health, I am determined not to lose sight of the real intention of this installment of the Intermittent Thoughts, which is to elucidate the intricate relationship between the local inflammatory response to exercise, the intramuscular expression of IGF-1 and its splice variants and the exercise-induced increases in skeletal muscle mass and strength.

The IGF-1 response to acute inflammation

Contrary to what you may have gathered from a cursory read of the literature on the "dangers" of the "growth promoting" and thusly potentially carcinogenic insulin-like growth factor, neither the mature 70 amino acid polypeptide IGF-1 nor any of its splice variants are in and out of themselves carcinogenic. It is the (not even indiscriminate, cf. red box) growth promoting effect they exert on target tissues via interactions with the respective IGF-1 receptors which will promote the growth and proliferation of all sorts of cells, including cancer cells that is responsible for their bad reputation.

Image 2: IGF-1 per se is not fattening,
if anything it is "IGF-resistance"

Did you know that a 2008 study by a group of scientists from the University of Leipzig, in Germany, found that the "growth promoting" effect of IGF-1 on adipocytes is negligable, the effect of the latter on systemic IGF-1 expression via negative feedback, on the other hand pretty profound (Klöting. 2008)? As it turned out, not IGF-1, but its absence, or I should say, its inability to activate the receptor in the IGF-R knock-out mice that were used in the study were the underlying cause of both statistically significant increases in body, fat and organ weight, as well as ~20% elevated serum IGF-1 levels. Similar to the fattening effects of insulin, its structural cousin (cf. insulin vs. insulin-like growth factor discussion in the previous installment), it is thusly not the physiological expression of IGF-1, but its inability to trigger necessary cellular signaling cascades and negative feedback that could be at the heart of the metabolic derrangements that oftentimes go hand in hand with elevated levels of circulating IGF-1.

In this context an important result of a meta-study by Claudio Franceschi and his colleagueson genes involved in the etiology of longevity, comes to mind (Franceschi. 2005):

In a longitudinal survey it has recently been shown that older women having low serum levels of IGF-I and high serum levels of IL-6 have the highest risk of disability and mortality, in comparison with women who have low levels of IL-6 and high levels of IGF-1 (Cappola et al., 2003). Such a beneficial effect of high IGF-1 serum level in the elderly is in apparent contrast with the above reported data showing that reduced IGF-I plasma levels are associated with longevity (Bonafè et al., 2003b). In order to reconcile this apparent discrepancy, it can be hypothesised that the decrease in plasma IGF-1 observed in nonagenarians and centenarians might minimise the risk of cancer in these subjects by decreasing a generalised mitogenic stimulation. The price to pay is frailty and massive reduction of muscle strength, two characteristics of such very old people.

With this connection between overexpression of the inflammatory cytokine interleukine 6 (IL-6) and the low, or as we will see insufficient IGF-1 expression in elderly people, we have come full-circle and back to our initial question: How do "inflammation" and IGF-1 expression go together?

Image 3: Unlike Hermes, the Greek messenger of the Gods, cytokines have no intrinsically mischievous side and their vilification is unjust.

Although it was certainly not a good idea to summarize such a complex phenomenon as the release of signaling molecules and the consequent reponse of the immune system under the term "inflammation", the name "cytokine" is actually quite fitting, because the combination of the Greek words -cyto, for "cell", and -kinos, for "movement", denote the exact consequences the release of respective signaling molecules has: it induces the movement of cells, which, in the case of "inflammatory cytokines", obviously are immune cells. The contemporary vilification of all "inflammatory" cytokines in the lay-press is however unwarranted - or would you hold the guy who takes the calls on the emergency line responsible for either the outbreak of the fire (=immune reaction necessary) or another nuisance alarm (unwanted auto-immune reaction)?

A very important clue that points us into the right direction comes from a 2007 study by Pelosi et al. (Pelosi. 2007), who analyzed the regenerative process skeletal muscle tissue undergoes subsequent to injuries. The scientists analyzed the differential expression of the two major inflammatory cytokines TNF-alpha and IL-1-beta, which in turn triggers the release of the aforementioned (and much better known) IL-6 in skeletal muscle (Luo. 2003), in response to cartiotoxin (CTX) injection in normal (wild-type) mice and mice who were genetically engineered to over-express mIGF-1 specifically in differentiated myofibres (MLC/mIGF-1).

Figure 1: Differential expression (relative to maximum) of TNF-alpha and IL-1b in CTX-injected muscle of wild-type and MLC/IGF-1 mice during the 10 days of recovery (data adapted from Pelosi. 2007)

As the data in figure 1 goes to show, the higher mIGF-1 expression (the "m-" indicates autocrine production, i.e. IGF-1 that is produced right at the target tissue, in this case skeletal muscle) in the genetically engineered mice led to a statistically significant amelioration in the expression of pro-inflammatory cytokines, which are involved in the recruitment of monocytes and macrophages.

An "anomaly" you will probably have noticed is the sudden increase of both inflammatory marker on day 5 post injury. I don't know if you are familiar with the term "deep onset muscle soreness", but the "onset" increase in inflammation certainly reminds me of the feeling I tend to have whenever I have gone overboard on squatting. Do you know what I am talking about? This awkward feeling of cramping pain in the quads that tends to appear right then, when you thought that the soreness was abating? Interestingly enough, this sudden onset of inflammation, which is completely absent in the MLC/mIGF1 mice, goes hand in hand with a the peak of  another, less well-known cytokine that goes by the (telling) name of macrophage migration inhibition factor, or MIF. This stands in contrast to the MIF response in the MLC/mIGF-1 mice, where

the significant down-regulation of MIF at 5 days post-CTX injection in MLC/mIGF-1 injured muscle may facilitate the emigration of infiltrating cell pools, leading to a rapid resolution of the inflammatory response.

These facilitatory, or rather dis-inhibiting effects IGF-1 seems to exert with respect to the MIF-driven "lockout" of the macrophages, allows for a "rapid restoration of injured mIGF-1 transgenic muscle", of which Pelosi et al found that it...

was also associated with connective tissue remodeling and a rapid recovery of functional properties.

Show that autocrine mIGF1 via its modulating effect on the inflammatory response and its (related) ability to reduce the formation of fibrotic muscle tissue "creates a qualitatively different environment for sustaining more efficient muscle regeneration and repair" (Pelosi. 2007).

Image 4: The local administration of platelet (and growth factor) rich plasma is about to become a recognized treatment strategy for muscular injuries and chronic degenerative joint diseases such as tendinopathy.

Did you know that a 2006 study from the University of Melbourne showed that both, IGF-1 gene transfer to the injured muscle (which would be comparable to the autocrine mIGF-1 expression discussed in the previous paragraph), as well as systemic IGF-1 administration via mini-osmotic pump at 1.5 mg/kg/day "hastened functional recovery" in artificially injured tibialis anterior muscles of mice? The injection of platelet rich plasma, which contains various growth factors, into injured muscle tissue is already practiced by many physicians working with competitive athletes (Creany. 2007) and appears to be a promising treatment strategy for other (non-muscular) pathologies such as chronic degenerative tendinopathy, as well (Vos. 2010).

If we set these results into a somewhat broader context, it becoms clear that the inflammatory cytokines that are released as a result of muscular damage, summon macrophages and other immune cells to the injured tissue. The concomitant production of local mIGF-1 facilitates their migration into the muscle where they increase the proliferation of satellite cells (Merly. 1999) and help (re-)building (new) muscle tissue (Chazaud. 2003). The "ameliorative" effect of IGF-1 on inflammation is thusly by no means comparable to the "ameliorative" effect firefighters exert on a fire. IGF-1 does not work against the inflammatory response (remember: in 99% of all cases the latter is a completely healthy and beneficial physiological reaction to an external assault on your body!), it works hand in hand with the driving forces of "inflammation", the monocytes, by "opening the door to the muscle" and rejuvenating the satellite cell pool from which, in turn, relies on the immune cells during the incorporation of these progenitor cells into the existing muscle tissue.

The emerging importance of an endocrine-immune-axis in skeletal muscle hypertrophy

Image 5: Control (A) and IL-15 treated (B) myotubes; nuclei are stained yellow; note the wide myotubes in the IL-15 treated muscle (img. from Quinn. 2002)

This intricate interplay of the endocrine (IGF) and the immune (monocytes) system, which is so characteristic for our emerging understand of the true complexity of the mammalian physiology, reminds me of the question Trevor's Facebook question from last week. Trevor, who has obviously done his homework on the "IGF-1 / cytokine connection" wanted to know my thoughts on interleukin-15, one of the less-researched "inflammatory" cytokines, which appears to play a central role in the accrual of myosin heavy chain (MHC) motor proteins (if you have not done so, already you can read more about the role of the motor proteins in Part II of the Hypertrophy 101). Back in 1995, already, a group of scientists from the American Lake VA Medical Center published a ground-breaking (yet hitherto unfortunately largely overlooked) paper on the role of interleukin-15 in skeletal muscle myogenesis (Quinn. 1995). Quinn et al. were for the first time able to show that

IL-15 used at concentrations of 10 or 100 ng/ml increased MHC accumulation five-fold in C2 myoblast cultures and 2.5-fold in primary bovine myogenic cultures. Moreover, C2 myotubes formed in the presence of IL-15 appeared larger than controls.

Interestingly, the researchers must have apprehended the existence of the previously discussed intreaction of the endocrine and the immune system and tested whether this effect depended on the presence of IGF-1:

Figure 2: Moysin heavy chain expression (arbitrary units) in in bovine muscle cultures after incubation with IL-15 (dose in ng/ml), IGF-1 (dose in ng/ml) or both (data adapted from Quinn. 1995).

From the data in figure 2 it becomes quite obvious that IL-15 has more than a facilitative effect on the IGF-1 induced accrual of motor proteins. A 2002 follow up study on mice myocytes (Quinn. 2002) and a 2003 study using human skeletal muscle myogenic cultures (Quinn. 2003) confirmed the validity of these initial findings.

Figure 3: Myosin heavy chain expression, protein synthesis and protein degradation in rodent muscle in response to IL-15 treatment at different basal levels of IGF-1 (data adapted from Quinn. 2002)

Interestingly, the synergistic effect of IL-15 and IGF-1 appears to be restricted to the accrual of motor proteins (cf. figure 3) and has only marginal effects on protein synthesis and degradation.

mTOR & Co, IGF-1, inflammation ... what's next?

Image 6: Is the role of naturally achievable testosterone levels in the accrual of lean muscle tissue overrated, or not? What exactly does the principal male androgen do on a tissue level and why did your OTC test booster only increase your libido and not the size of your sleeves?  Come back on 01.01.2012 to learn more ;-)

With protein synthesis and degradation, we have come back to one of the initial discussed cornerstones of skeletal muscle hypertrophy (cf. What is Hypertrophy?), of which you should have learned in the previous installment of this series that is a necessary, yet not sufficient prerequisite of sustainable muscle growth. Without the IGF-1 mediated and, as you have learned in this installment, monocyte-driven (re-)construction (increase in myonuclei + accumulation of motor proteins) of the underlying structure of the muscle, however, neither the repair of damaged, nor the accrual new, functional (cf. Hypertophy 101: Part II) muscle tissue would be possible.

The question we still have to answer before we can eventually integrate all those different pathways into a model which would allow us to develop a "hypertrophy-optimized" training, nutrition and supplementation regimen, we do yet still have to shed some light on the role of the legendary "big T": Testosterone! So stick with me and come back next week, or next year, whatever you like better, to learn more about the actual role of the principal male sex in the complex process of skeletal muscle growth.

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.

In view of the fact that we have not covered much ground with the last installment (we did build a pretty solid foundation, though ;-), I will try my very best to steer a middle course between presenting impressive amounts of facts and explaining the complex and in part not even completely elucidated physiological underpinnings of skeletal muscle hypertrophy, or, as the bros would say, getting big and buffed! A pros pros Bro, you will unquestionably have read on one of the myriads of bodybuilding-related bulletin boards how the injection of X amounts of IGF-1 right into the muscle made BigGuns, or whatever the poster's pseudonym may have been, grow "3 inches in 2 weeks"... ok, his profile picture looks impressive, but is that credible? Does IGF-1 really have such profound effects on muscle growth? And about what type of growth are we talking here? The myostatin-negative "ballooning up" of the muscle, which leaves you with overblown myogenic domains and dysfunctional muscles?

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)

The "insulin" in its name, however, is pretty misleading... or I should say people mislead themselves, by not reading  the name correctly: It's not "insulin-growth factor", but "insulin-like growth factor" and the "like" refers to the structure of the molecule and does not imply that it is released in response to insulin spikes, as you may have read it on one of the aforementioned bulletin boards. If you do take a look at the growth hormone and IGF-1 levels of eight male subjects in a 2006 study on the metabolic of 5-weeks on what the scientists call a "high protein, low carbohydrate diet" (Nuttall. 2006), you will see that an increase in protein and fat from 15% to 30% and 30% to 50%, respectively elicited an 34% increase in serum IGF-1 levels over the treatment period, a finding that is corroborated by the recently published results of Matthew B. Cooke and his colleages from the Department of Health, Human Recreation and Performance at Baylor University.

Figure 2: Serum IGF-1 levels in response to whey vs. maltodextrin supplementation and subsequent lower body resistance training (data adapted from Cooke. 2011)

In their randomized double-blinded cross-over study, Cooke et al. had a group of 10 recreationally active men (2-3 non-resistance training exercise sessions per week) perform a lower body exercise program (leg presses and knee extensions, 4 sets, 8-10 reps at 80% of the individual 1RM) with either 10g of maltodextrose or 10g of whey 30 minutes before the exercise bout (Cooke. 2011). The results of the study (equal IGF-1 response regardless of whey or carbohydrate supplementation) imply that even in the short term, in healthy subjects and in conjunction with exercise the ingestion of carbohydrates is not superior to the provision of fast acting protein sources as a means to either increase or maintain systemic IGF-1 levels.

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:

1. 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.
2. 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).
3. 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).

If we now count 2. and 3. together the result is not 5. but rather that it is the growth hormone mediated, exercised-induced local expression of IGF-1 splice variants, which drives the repair and restructuring process that allows for continuous (healthy) muscle growth.

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).

Of the three primary splice variants that are expressed in skeletal muscle, IGF-IEc, or MGF (Mechano-Growth Factor) has probably received the greatest attention - so much attention that even the aforementioned bros, will probably have grasped the notion that this is somewhat of a local isoform of IGF-1 which is expressed in response to exercise induced muscle damage and could potentially be the magic bullet to grow beyond what we have hitherto believed to be possible... and, guess what, in essence this appears to be correct.

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.

As the data in figure 4 goes to show the effects of the complete polypeptide IGF-1 and its splice variant MGF appear to be mediated, at least partly via distinct receptors. And while recent research suggest that MGF also exerts similar effects on tendon (Olesen. 2006), brain (Dluzniewska. 2005) and nervous tissue (Aperghis. 2004), our primary concern here, is its pivotal role in muscle repair, which involves the activation of satellite cells, their proliferation (Yang. 2002) and migration (Mills. 2007).

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)

If you take a closer look at the data in figure, you will probably notice that there was one subject with an extreme MGF response, the scientists explain by a particularly high type-IIx fiber content of the quadriceps of this individual. If you remember the mouse studies and the analysis of the muscle composition of bodybuilders from the previous installments, you will be aware that the shift from type IIb to type IIx muscle fibers is one of the main characteristics of "getting real big". The extreme MGF response (>10x higher than the mean MGF expression across the other subjects) in this subject thusly suggests the increased growth capacity of type IIx muscle fibers is in part due to their ability to release MGF in response to strenuous exercise and thusly multiply / replenish their satellite cell pool to prepare for future growth.

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)

Interestingly, a 2008 follow up study (this time involving nine healthy young men aged 20–27 years, cf. Hamed. 2008) with a completely different training protocol that consisted of

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 VO2max

illicited 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.

Now, while protein synthesis and increases in domain size are partly mediated via nutrition, the intra-muscular expression of the IGF-IE splice variants appears (at least based on the current research) to depend solely on exercise, or I should say the wear and tear that goes hand in hand with heavy exercise. In that it seems to be less important, whether you are "pumping away" or "cycling like maniac", as long as its "hard" - to put that into perspective, in the 2008 study by Hamed et al. the subjects underwent ~3600 eccentric muscle contractions in only 1 h, their creatine kinase (CK) levels (marker of muscle damage) increased by +183% and all subjects reported profound muscle soreness.

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.