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