Creatine and the Insulin-like Growth Factors

June 2006

Contents:

1- Featured Article: Creatine and the Insulin-like Growth Factors


In recent years, there has been much discussion surrounding the possibility that creatine supplementation might provide a direct anabolic effect. That is, that creatine might directly evoke the production of our major anabolic hormones, namely testosterone, growth hormone and the insulin-like growth factors.

Such an effect would need to be distinguished from an indirect release of these same anabolic hormones due to the higher exercise output afforded by creatine supplementation, an accepted stimulus for anabolic hormone release. In truth, this is not a one, or the other, type of argument, as it is quite likely that both scenarios hold true in individuals supplementing with creatine monohydrate. Nevertheless, the cellular mechanisms whereby creatine supplementation might lead to the direct release of an anabolic hormone remain largely unresolved.

In this issue of the Creatine Newsletter, I’ll discuss a recent scientific study demonstrating that creatine supplementation activates the expression of the insulin-like growth factors directly within muscle and independently of an exercise stimulus. It is becoming increasingly clear that creatine supplementation possesses anabolic attributes not requiring exercise to be unveiled. The combination of direct and indirect anabolic consequences of creatine supplementation will increase the potential for muscle development in athletes undergoing training.

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This Month’s Featured Article:

Creatine and the Insulin-like Growth Factors

by Alfredo Franco, PhD

Anabolism simply refers to the growth of a tissue or organism, usually under the influence of our anabolic hormones. By far, our most important anabolic hormone is growth hormone. Growth hormone is released by the anterior pituitary, a small, but extremely important gland at the base of our brains, in response to blood born “releasing factors” that are themselves released by “environmental influences”. Not surprisingly, the production of growth hormone is greatest during our growth spurt at adolescence. Growth hormone is also released during moments of deep sleep. That is, muscle is built in bed. Exercise in another potent liberator of growth hormone.

Growth hormone promotes general anabolism of our bones and muscles by instigating their genetically-based developmental programs as well as stimulating the transport of amino acids into the cell that supports the synthesis of new proteins that are necessary for growth. Therefore, the growth hormone that is released by exercise promotes muscle development following its termination.

Unfortunately, nothing good lasts forever. Our growth hormone levels commence to decline at around 30 years of age until plummeting to only 1/20 of their youthful values by the time we are in our 80s. In addition, a male’s serum testosterone levels also decrease with age, but this will be addressed in another issue of the Creatine Newsletter. Nevertheless, in later life, this hormonal nadir is largely responsible for the loss of bone and muscle mass that is so prevalent in the elderly.

Growth hormone also stimulates fat cells (adipocytes) to release triglycerides into the blood stream for use by the body as an energy source as well as suppresses the ability of adipocytes to take up circulating lipids for subsequent storage. In this special respect, growth hormone is not anabolic (growth promoting) but catabolic (growth inhibiting) since it causes our fat reserves to dwindle. In fact, the “pot-belly” that appears in most males during their 30′s reflects this age-related decline in growth hormone levels – an anti-catabolic effect. Therefore, fat accumulation accompanied by muscle and bone lose is characteristic of aging, resulting from a steady decline in anabolic hormone levels.

The majority of growth hormone’s anabolic effects are not direct, however, but are mediated by another class of growth stimulator known as the Insulin-Like Growth Factors, or IGFs. Of these, insulin-like growth factor 1 (IGF-1), or somatomedin, as it is classically referred to, is the more integral to muscle growth in adults. The traditional explanation given to account for the presence of IGF-1 was that the liver produces it when stimulated by growth hormone that was, in turn, released by the anterior pituitary in response to exercise, sleep, etc. IGF-1 then enters the systemic circulation to provoke the growth of bones and muscles by initiating the reading of genes (transcription) intimately involved in muscle and bone protein synthesis. This is known as the somatomedin model of growth hormone function. We will soon see that this classic model of linking growth hormone and IGFs may need to be revised somewhat to coincide with more recent scientific findings.


IGF-2 is a second insulin-like growth factor that seems to be less dependent on growth hormone for its expression and is somewhat less potent than IGF-1 in stimulating cell growth. IGF-2 also appears to play its predominant role during prenatal development. Nevertheless, despite their differences, interactions between the two IGFs are apparent in the animal postnatally; IGF-2 can stimulate the production of IGF-1.

Again, the majority of growth hormone’s benefits rely on its ability to stimulate the production of the insulin-like growth factors, particularly by the liver. The insulin-like growth factors, on the other hand, do not solely depend on a signal from growth hormone to be expressed. Several insulin-like growth factor-mediated anabolic events are known to arise independently of growth hormone, at least, on the immediate timeframe. The existence of these “brain-independent” effects has been nicely demonstrated in scientific studies whereby the anterior pituitary gland had been removed from the experimental scenario. Firstly, surgically removing the anterior pituitary from laboratory animals does not prevent the exercise-induced rise in serum IGF-1 levels. Secondly, the production of IGF in response to creatine treatment can be observed in isolated muscle cells maintained outside the animal in tissue culture (Ref. 1) and hence, outside of the hormonal influences of the anterior pituitary, or any endocrine gland, for that matter. The source of these IGFs is skeletal muscle itself. In response to certain stimuli, muscle cells produce their own source of IGFs that then stimulate their neighbors to join in communal growth. In fact, creatine appears to be one of these stimulating agents…

Poodle Size and Insulin-Like Growth Factor 1 Levels

Oddly, the dramatic, and specific, effect that IGF-1 levels exert over body size is best illustrated in poodles. A “toy” poodle possesses only one sixth the serum IGF-1 levels of a “standard-sized” poodle, despite possessing normal levels of growth hormone.

Creatine Supplementation Directly Stimulates the Production of the Insulin-Like Growth Factors!

The study we will discuss today originated from one of the leading creatine-research groups in the world: that of Professor Marc Francaux of the Catholic University of Louvain in Brussels, Belgium (Ref. 2). This group is consistently on the forefront of groundbreaking creatine research. The aim of this study was to follow the expression of the insulin-like growth factors, namely IGF-1 and IGF-2 as well as the activation status of two downstream modulators of protein synthesis, p70(s6k) and 4E-BP1.

For the study, three experimental subjects consumed 21 grams of creatine daily, whereas another three individuals took placebo for the same number of days (5). The placebo group thus acted as controls-a baseline value from which to measure the effects of creatine. On the morning of the sixth day, IGF and activated translational factor levels were measures before and after (3 and 24 hours) a specifically designed exercise routine (see below). A washout period of one month was next implemented whereby subjects abstained from ingesting any creatine containing supplements. After washing out, experimental and control groups switched supplement conditions (experimentals became controls and visa versa) and the experiment was repeated. In this manner, all 6 subjects served as their own controls.

It would have been nice to have a larger sample size, since it would have added greater statistical relevance to the findings of the study, but these experiments are expensive and difficult to coordinate with involved governmental agencies as well as experimental subjects.

After warming up, 10 sets of 10 leg-press repetitions were performed at 70% of each individual’s single-repetition maximum. The sets were interspersed with two minutes of rest and five seconds of rest were allowed between individual repetitions. Anyone who has trained will be quick to notice that this is quite a strenuous exercise routine.

Study Results

As expected, intramuscular creatine levels rose because of creatine supplementation. Somewhat less expected, however, was the result that IGF-1 levels were elevated in supplementing subjects at rest. More specifically, just supplementing with creatine, without any exercise stimulus, increased the number of genetic transcript of the gene coding for IGF-1. On the other hand, IGF-2 levels were not so elevated under resting conditions. This result indicates that creatine supplementation promotes muscle growth independently of exercise.

Also expectedly, heavy exercise increased IGF production in all cases, an effect that was still apparent 24 hours after exercise had terminated. Surprisingly, however, creatine supplementation did not increase the exercise induced rise in IGF transcripts either at 3 or 24 hours post-exercise, only before.

Protein indicators of cell anabolism (activated forms of p70(s6k) and 4E-BP1) also rose dramatically in response to exercise, which is in agreement with the previously noted rise in IGFs. These proteins are found in their activated form when the cell is actively synthesizing proteins. Not surprisingly, their appearance signifies anabolism. Importantly, activated 4E-BP1 (gamma form) was still elevated by creatine supplementation 24 hours following exercise!

Creatine and Methylation Capacity

The last few issues of the Creatine Newsletter outlined how creatine supplementation improves cellular methylation status, which, in turn, will translate into heightened anabolic potential, since methylation is a key step in the activation of many of our anabolic agents. In brief, creatine spares our methyl reserves by circumventing the need to synthesize creatine from available amino acids; creatine synthesis is the single largest drain of the body’s methyl reserves. In essence, resorting to creatine synthesis may deprive some tissues (possibly muscle) of much needed methyl groups, which will limit their capacity to grow. Moreover, such an effect would be apparent at rest, without having to recruit the anabolic cascade set into motion by exercise. In other words, an improvement in methylation status would heighten our anabolic potential without having to train, although training would certainly put this metabolic advantage to better use.

Take Home

It is becoming increasingly clear that creatine supplementation heightens one’s anabolic status, independently of, and in addition to, its positive effect on exercise capacity, which, in turn, will also increase one’s ability to build new muscle. First, creatine supplementation heightens methylation status, a biochemical mechanism that supports every other methylation-dependent anabolic process in the body. As discussed in the previous issue of the Creatine Newsletter, the production of the polyamines, biochemical mediators that lay down the foundations for nearly all of the anabolic processes of the body, depends entirely on cellular methylation. Creatine supplementation should then facilitate the production of the polyamines, enhancing anabolism. Secondly, as shown by this study, creatine supplementation increases the muscular expression of the insulin-like growth factors, extremely important growth-promoting agents.

New research is revealing that creatine supplementation is particularly beneficial for senior citizens. Firstly, a drop in systemic IGF levels is largely responsible for the decrease in muscle mass observed in the elderly, a physiological process known as sarcopaenia. The possibility therefore exists that creatine supplementation may retard the loss of muscle mass associated with advanced age. Secondly, the insulin-like growth factors also fortify bone strength. Given that a loss of bone mass is a common consequence of the normal aging process, it is possible that creatine supplementation might also slow the progression of osteoporosis in the elderly. Thirdly, a recent study has shown that creatine supplementation improves glucose tolerance by increasing, and maintaining, the expression of the glucose transporter type 4 (GLUT 4) on the muscle surface (Ref. 3). Increasing GLUT 4 expression on the cell surface is one of the major roles of insulin as well as the insulin-like growth factors. Although the positive effect of creatine supplementation over cellular glucose acquisition was monitored during the physical rehabilitation of a previously immobilized limb, it may have repercussions for the uninjured athlete as well. Moreover, given the alarmingly increasing incidence of diabetes in our steadily aging population, this aspect of creatine supplementation has very important implications for the older athlete.

Author’s Note: How to best poise your body’s metabolism towards anabolism, and away from catabolism, is discussed in Creatine: A practical guide.

In brief, this study showed that creatine supplementation recruits the anabolic effects of the insulin-like growth factors at times beyond that normally induced by exercise: specifically before exercise (at rest) as well as after the typical exercise-induced rise in IGFs would have normally receded. Indeed, creatine supplementation is proving to be anabolic to a degree never before imagined.

For more information about growth hormone please visit the following link.

Author’s Note: Creatine: A practical guide clearly explains how to combine creatine supplementation with safe nutrients for maximal muscle anabolism and improved overall health.

Scientific References

(Ref. 1) Louis, M. et al., (2004) Creatine increases IGF-1 and myogenic regulatory factor mRNA in C2C12 cells. Federation of European Biochemical Societies Letters, Volume 557, pages 243–247.

(Ref. 2) Deldicque, L. et al., (2005) Increased IGF mRNA in human skeletal muscle after creatine supplementation. Medicine & Science in Sports and Exercise, Volume 37 (5), pages 731–736.

(Ref. 3) Derave, W. et al., (2003) Combined creatine and protein supplementation in conjunction with resistance training promotes muscle GLUT-4 content and glucose tolerance in humans. Journal of Applied Physiology, Volume 94, pages 1910–1916

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