Answer Dr. Andro: As you may have noticed, I took the freedom to set Learner's question into a broader context. A context I broached in my dissertations on Athletic Edge Nutrition's new creatine product Creatine RT on Tuesday, Aug 16, 2011. Thus, the questions I will be trying to answer (unfortunately, I have to rely on existing studies and do not have my own lab, here ;-) are the following ones:
- How does creatine get into the blood? (cf. Part I)
- How does creatine get into the muscle?
- What can influence these processes?
How does creatine get into the muscle?
Now that the creatine molecules have successfully passed your digestive tract they are floating largely unbound (binding affinity of creatine to plasma proteins is less than 10%) in your bloodstream. Whatever happens from now on, is called "clearance" in pharmacological terms - this is counterintuitive at first, but it stands in line with what I have already stressed in my blogpost on Creatine RT, Athletic Edge's creatine monohydrate + Russian tarragon formula. You may remember that Jäger et al. assumed that the smaller increase in plasma creatine they observed upon co-administration of Russian tarragon indicated greater "creatine clearance", which would equal greater muscular creatine uptake. Now, it is true that upon supplementation, the main pathway by which your body "disposes" of the increasing level of serum creatinine is skeletal muscle, but firstly, the tarragon extract could have interfered with the absorption of creatine, for example by modifiying gastric pH levels or intestinal permeability (this is not completely unlikely, since this herb has traditionally been used to cure upset stomachs, cf. Tarragon Central), and secondly, muscular creatine uptake is obviously one way the creatine could have been "cleared" from the bloodstream, the kidneys are yet another.
|Image 1: Caffeine + Creatine = Increased renal clearance? Yes! Increased renal clearance = lower performance? No!|
While the increase in urinary loss may increase the time it will take until your muscle creatine stores are saturated, a study by Lee et al. which compared the effects of creatine alone and creatine + caffeine at a much higher dose equivalent to 480mg or 5 cups of coffee found that "caffeine ingestion after creatine supplements augmented intermittent high-intensity sprint performance" (Lee. 2011) - any fears that drinking coffee or even taking stims could completely negate the beneficial effects of creatine are thus unwarranted.
[a]s blood concentrations increase and more creatine is filtered, less reabsorption occurs and a greater percent age of creatine will be lost in the urine [...] as skeletal muscle approaches its capacity to store creatine, the kidney and possibly other tissues are responsible for the removal of creatine from the blood.If we follow Mc Call's line of thought and assume that renal creatine clearance is essentially determined by the filling level of muscular creatine stores, it becomes obvious that supplementation with agents that increase creatine transport into the cell would be most beneficial in the "loading phase" (max. 7), when there is actually enough "room" for the creatine to be "stored" within the cell.
Creatine storage - how does that work after all?
A pros pos storage, it's actually quite telling that we know much more about what happens to the creatine molecules within the cell, than about how they actually get there. If you are interested in how scientists initially believed that phosphocreatine (PCr) "would represent the long sought-for 'immediate' source of energy for muscle contraction" I suggest you read Chapter one of the aforementioned compendium Creatine and Creatine Kinase in Health and Disease (ed. Salomons. 2008). For our purposes here it is most important to know that the capacity of our organs (skeletal muscle, kidney and possibly other tissues) is limited and creatine clearance (remember, this includes both the uptake by muscle tissue, as well the urinary clearance by the kidneys) decreases when muscular creatine stores increase (cf. figure 1).
|Figure 1: Serum creatine levels (in µM) upon administration of identical doses of creatine at the beginning (first dose) and in the course (steady state) of creatine supplementation (based on McCall. 2008)|
[...] during early doses (i.e., doses within the first one to three days) when clearance is high, doses of 10 to 15 g per day will give blood concentrations greater than the Km [this is the creatine level in the blood, where creatine transport into the cell maxes out] for the creatine transporter. As the muscle becomes saturated and clearance decreases, it may be necessary to ingest 3 to 5 g of creatine a day to maintain similar blood concentrations.The higher serum creatine levels upon steady state supplementation you can see in the data in figure 1 clearly substantiate this assumption. Together with the previously mentioned inverse relation of serum creatine to urinary creatine loss, it should also be obvious that taking "loading doses" of more than 10g per day for an extended period of time will at best fill the muscular creatine stores of the rats and cockroaches in the sewer (in case they happen live right next to your sewer pipe ;-)
What controls the muscular creatine transporter?
In order to understand the fundamental biochemical underpinnings of this interplay of dietary, serum and intra-muscular creatine, we do yet still have to identify the pathway by which the creatine molecules eventually get into the muscle. According to the most fundamental (and essentially oversimplified) cell model, a cell is a three-dimensional entity that is surrounded by a protective wall - the cell wall. This wall, of which most of you will have heard that it consists of phospholipids (note the word "lipid" indicates that fats! not proteins are the fundamental building blocks of the cell membrane), has the fascinating characteristic of being selectively permeable. Under physiological conditions transporter proteins function as "gate-keepers" and "taxi-drivers". They select and pick up specific molecules from the bloodstream and carry them across the "border" and into the cell (cf. illustration 2).
|Illustration 2: A transporter like the creatine transporter is an active gatekeeper within the cell membrane.|
|Image 2: β-Guanidinopropionate|
competes with creatine for transpor-
tation across the cell membrane
So after all creatine and β-GPA share the same transporter and artemisia dracunculus (Russian tarragon, RT), creatine and β-GPA share the same beneficial effect on muscular insulin sensitivity. Now, Jäger et al. suggest that by increasing insulin sensitivity their RT extract would increase muscular creatine uptake. While this does seem to make sense, the results of Rocic et al. who found creatine to be equally effective as metformin in reducing blood glucose levels would suggest that creatine administration alone should increase it's own uptake ;-) This formally logical, but not very realistic conclusion is yet undermined by the established effect of guanidino propionic acid, which despite identical effects on insulin sensitivity, decreased creatine uptake by muscle cells by 82% (Willot. 1999) in vitro!
|Image 3: Of sugar and salt, the "worst enemies" of many dieting body builders and figure athletes, salt and not sugar (or insulin) turns out to be creatine's most eager supporter on its way across the cell membrane (img. squidoo.com)|
In view of the fact that a -82% decrease in the Na+ concentration of the incubation medium reduced the creatine uptake by 77%, the addition of sodium to your creatine drink may be of greater importance than the fattening loads of simple carbs, anyway.
|Figure 2: Effect of 7 weeks of β-GPA supplementation followed by 3 weeks of creatine supplementation on creatine and β-GPA content of the white gastrocnemius muscle in rats; data expressed relative to maximal concentrations (40µmol/g) of the two molecules (data calculated based on Brault. 2003).|
|Figure 3: Creatine uptake (y-axis, in nmol/h/g) as a function of intramuscular creatine content (x-axis, in µmol/g) as measured by Brault. 2003.|
- with increasing intracellular creatine levels the Na+ gradient, which is necessary to drive the creatine into the cell, could become insufficient (unlikely)
- with more creatine in the cell the release process that takes place once the creatine transporter enters the cell may slow down, as if the "taxi driver" would not find a parking lot
- the number of creatine transporters in the sarcolemmal membrane could be modulated according to intracellular creatine content in a similar manner as the expression of GLUT-4 is modulated by exercise (Goodyear. 1998)
- high intramuscular creatine levels could lead to posttranslational modification of the creatine transporter, similar to what we see in its "relatives", the GABA/taurine transporters, whose activity
is modified by protein phosphorylation
Conclusion - little do we know about the actual process of creatine uptake
If you look back at what you may or may not have learned from the second part of this write-up, you may notice that I have artistically evaded a direct response to Learner's question whether "creatine transporters behave the same as glucose transporters". Nevertheless, you should have been able to read between the lines that ...
- despite studies showing increased creatine retention (not celullar uptake or creatine transporter protein expression) upon co-administration of insulinogenic nutrients (carbohydrates in Green. 1996 and carbohydrates + protein in Pittas. 2010), in-vitro studies have shown that insulin has no direct effect on muscular creatine uptake (Willot. 1999) - unless supraphysiological doses are used
- at least in red oxidative muscle fibers, there is an inverse linear relationship between intra-muscular creatine levels and creatine uptake (Brault. 2003)
- increases and decreases in creatine uptake are not mediated by respective increases in creatine transporter protein expression (Brault. 2003)
- the most likely hypothesis explaining how intra-cellular creatine levels control the "effectivity" of the creatine transporter is via posttranslational modification, of which we do not yet know for sure how to influence it (the fact that tarragon and other insulin-sensitizers appear to increase creatine uptake could as well be related to changes in the phosphorylation of the creatine transporter as their insulin-sensitizing effects could be related to dephosphorylation of )
|Image 4: If its not the insulin, then|
maybe a steadier influx of creatine
into the blood which can explain the
increased creatine retention upon co-
administration of carbohydrates.