Ask Dr. Andro: The Pharmacokinetics of Creatine (Part II/II) - How Is Creatine Transported into the Muscle?

Illustration 1: There is a bunch of things that could potentially go wrong with creatine uptake: The creatine from dietary sources could be mal-absorbed (1) in the small intestine, (2) not make it into the cell, or (3) be excreted too readily either before or immediately after it was transported into the muscle.

Question from Learner (via comments): Do Creatine Transporters behave the same as glucose transporters? (I.e., serum insulin binds to cellular insulin receptors, which causes Transporters to migrate from inside the cell to the plasma membrane - and the Transporters then pull in the external glucose.)

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:

1. How does creatine get into the blood? (cf. Part I)
   
2. How does creatine get into the muscle?
3. What can influence these processes?
   

Those of you who have already read part I of this installment of "Ask Dr. Andro", will know that, in view of the fact that this is quite an extensive topic, I decided to tackle it in a two part series, where in part 1 (yesterday) I focused on the issue of creatine absorption into the bloodstream, from where I will now go on to explain how the creatine eventually gets stored in the cells of your muscle or cleared by your kidneys (steps 2 and 3 in illustration 1).

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!

Did you know that the longstanding myth that caffeine would counter the beneficial effects of creatine on exercise performance and lean mass gains is bunk despite the fact that caffeine does in fact increase urinary creatine clearance? In a recently published paper on the effect of co-adminsistration of caffeine + creatine to rats (Franco. 2011), the scientists observed statistically significant increases in urinary creatine clearance (+38% after the loading phase with 0.43g/kg creatine and +29% in week 6 of the maintenance phase) over creatine alone when the latter (0.143 g/kg creatine) was administered with 15mg/kg caffeine (human equivalent 2.4mg/kg; ~200mg or 2 small cups of coffee for an 80kg human). When it comes to the real-world results you are looking for, this is yet not likely to be significant.

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.

While researchers initially believed that renal creatine clearance would be equivalent to the glomerular filtration rate (GFR) of roughly 7.0L/h, Poortmans et al. found that, under unsupplemented conditions, creatine clearance is 0.3-0.8L/h, which clearly supports a previously forumlated hypothesis that creatine is reabsorbed and thus "recycled" by the kidneys. Evidence from supplementation studies, where the renal clearance rate increased to 9-22L/h supports the idea that (McCall. 2008)

[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)

This is taken into account with the standard dosing regime, which - after an initial loading phase - uses smaller doses over time. McCall and Persky, explain this as follows:

[...] 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.

One of the best-known and most-studied group of these transporters is the solute carrier family 6, which play an important role in neurotransmitter regulation in the brain. In the early and late 1990s the gamma-aminobutryic acid (GABA) and norepinephrine transporters were among the first of these Na+/Cl- dependent neurotransmitter transporters to be discovered. It is due to their dependence on the electrical potential between negative Cl- and positive Na+ molecules that they have also become known as neurotransmitter:sodium symporters (NSS, Saier. 1999). They are functionally identical to the likewise Na+-dependent amino acid carriers for taurine, betaine and creatine.

Image 2: β-Guanidinopropionate
competes with creatine for transpor-
tation across the cell membrane

Contrary to many other carriers, the creatine transporter (CT) is yet highly specific for creatine. Among the few exceptions which compete with creatine transport across the cell membrane is β-Guanidinopropionate. Those of you who follow my advice and scrutinize the nutritional information on the labels of their supplements, may be rubbing their eyes in disbelief, now, because Guanidino Propionic Acid or β-GPA is one of the standard ingredients in many pre-workout products (cf. Supplement Shootout, NO-Xplode). The reason for that probably (I would have to ask the producers, though ;-) is its hypoglycemic effect (Meglasson. 1993), which will probably remind you of Athletic Edge's Russian tarragon (see above) or of a 2009 study Rocic et al. which found remarkably similar effects for creatine, itself (Rocic. 2009).

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 the context of insulin sensitivity, it is interesting to note that Willot also tested the hypothesis that insulin would increase creatine uptake into the cell and found that "insulin had no effect on 14C-labeled creatine uptake at concentrations and under conditions in which effects are seen on glucose uptake glycogen synthesis and glycolysis." This finding does not essentialy contradict previous (Green. 1996), as well as very recent findings (Pittas. 2010), which support the idea of increased creatine retention upon coadministration of insulinogenic nutrients such as carbohydrates and/or protein , because "those may be owing to the expression of the creatine transporter, as opposed to acute effects on the transporter" (Willot. 1999). While it should be mentioned that a previous study by Oodom et al. found a 2x increase in creatine accumulation (again, not uptake! Oodom. 1996) after incubation with 3nM/ml insulin for 48h. The latter lacks real world significance, since even after high-carb meals blood insulin levels do hardly get up to 0.3-0.4pM/ml!.

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.

A 2003 study by Brault et al. confirms Willot's findings on the effect of guanidino propionic acid on creatine influx and retention into skeletal muscle. In the course of seven weeks on a β-GPA-enriched chow the muscular creatine levels of Brault's laboratory animals dropped by -85% (Brault. 2003). Notwithstanding, the flip side of this apparently undesirable effect of β-GPA are increased insulin sensitivity and, more importantly, at least in this context, profoundly augmented creatine uptake.

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).

Yet while the β-GPA induced creatine depletion increased creatine uptake in the subsequent supplementation phase (week 7+) by +24% and +33% in the soleus and the red gastrocnemius, respectively, creatine uptake in the glycolytic white muscle fibers of the gastrocnemius stayed constant. On the other hand, the white fibers of the gastrocnemius showed the expected decrease (-45%) in creatine uptake, when creatine was supplemented for 7 weeks at 0.85g/kg/day (~11g for 80kg human being) without prior β-GPA-induced creatine depletion (Brault. 2003a).

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.

These observation go challenge the previously formulated hypothesis that muscular creatine uptake via creatine transporter would always be linearly dependent on intra-muscular creatine stores. While this seems to be the case for the red, oxidative muscle fibers (violet regression in figure 3), the fast-twitch white glycolytic fibers appear to react assimilate creatine at a constant rate (green regression in figure 3) up to a certain threshold (in Brault's rat study that was ~17µmol/g, which is about +30% more than the maximal creatine content measured in red fibers in the same study), at the creatine uptake suddenly drops (cf. figure 3). What is even more confusing, though is that the insignificant changes in the creatine transporter protein expression measured by the scientists reflect neither the linear decrease nor the constant uptake rates. As Brault et al. point out "it is presently unclear what process may modulate Cr uptake" with high / low intra-muscular creatine levels. Possible mechanisms, according to Brault are...

• 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

In fact, a 2002 study by Wang et al. (Wang. 2002) found an increase in creatine transporter phosphorylation that correlated with a reduction in creatine uptake and Zhao et al. observed a 38% increase in creatine uptake in response to a 30% reduction in serine phosphorylation of the CrT (Zhao. 2002). While it is thus most likely that posttranslational modification, something you probably have encountered in one of my blogpost related to the Akt/mTOR cascade, before is the underlying mechanism that controls how effective our "creatine shuttle" works, the unfortunate truth is that this does not go to tell us how we could possibly influence this process.

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 )

It would yet be unfair to leave you with all those additional gaps in your under understanding of the pharmacokinetics of creatine without a few words on the most important aspect of creatine supplementation, i.e. what works in practice.

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.

A final note on the issue of carbohydrates: In view of what I have stated in the first installment of this series, i.e. the increase in gastric emptying time due to carbohydrate (and other foodstuff), an alternative explanation for the increase in creatine retention (again, not uptake ;-) upon co-administration of carbohydrates or carbohydrates + protein could be the steadier incline in plasma creatine levels. While the 1996 study by Green lacks the respective data, the figures in Pittas (2010) clearly show that creatine clearance in the creatine-only group increases dramatically after the initial spike in serum creatine levels 30min after the administration of 5g creatine. In view of the negative results of Willot's in-vitro studies on the effects of physiological levels of insulin on creatine uptake and the fact that renal creatine clearance increases with serum creatine levels, while the muscular uptake is maxes out at a relatively low threshold (10-100µM) is surpassed, it is at least possible that it is the steady influx of creatine into the bloodstream and not the insulinogenic effects of carbohydrates that facilitates creatine retention (I hope you remember from the first part of this series that the reduction in creatine influx into the blood due to degradation in the stomach is probably negligible, as long as the dose is large enough to reach blood levels beyond the Km value of 10-100µm)

As I have already hinted at in part I of this installment of "Ask Dr. Andro", for most of us, it does not really matter whether it takes 3, 5 or 10 days until the creatine stores in our muscles are saturated. Moreover, even high quality creatine monohydrate is so "dirt cheap" that you do not really have to care about potential losses (in the 0.3-0.6mg/day range) due to caffeine supplementation or potentially sub-optimal creatine retention in the absence of large boluses of fattening carbohydrates. Personally, I would just stick to what has been working for generations of trainees, now: plain creatine monohydrate taken at a dose of 10-15g/day for 3-5 days followed by a maintenance dose of 3-5g/day.

Anti-Creatine β-Guanidinopropionic Acid (GPA) Increases AMPK, Decreases Blood Glucose & Insulin, Induces Weight loss Without Dieting, Increases Oxidative Capacity and Can Even Delay the Development of Mammary Cancer! BUT...

While he may be so fast that he is almost out of the focus, when the photographer finally released the shutter, Usain Bolt, the fasted man on earth actually doesn't look as if his fiber type composition was highly type II dominant, does he? 

While the relation may be distant, you will soon see that today's blogpost is somewhat related to Saturday's news item about the ability of high dose nicotinic acid to shift the muscle fiber type composition from a towards the oxidative side of things. After all, there is hardly anything that is more "glycolytic" (I am using the word here in a very broad sense) than the use of the intramuscular phosphocreatine stores to squeeze out another rep or explode out of the starting block and sprint towards the finish line in less than 10 seconds.

Ah, yes those phosphocreatine stores, they are great and creatine is the staple supplement for anyone looking to improve his glycolytic performance. But hey, wait a minute: Shouldn't that actually mean that taking creatine would be a bad thing for an ironman (not the one from the cinema, but the Hawaiian ;-)?

GPA - Supplemental creatine unloading for edurance athletes!?

Well, the answer to the question "Is creatine bad for endurance athletes" is, as long as you stick to reasonable doses "No! It isn't.". It neither helps nor hinders endurance performance and a "real" Ironman could probably even get away with one of those sugar-laden "cell-volumizers" without doing much harm. His body is would just burn through the carbs without any of them ending up as additional ballast on his hips. That said, previous studies by Vanakoski et al. or Chwalbiñska-Moneta clearly show that performance detriments are not an issue and in the latter of the two studies, the creatine supplement did even improve the "endurance (expressed by the individual lactate threshold) and anaerobic performance, independent of the effect of intensive endurance training" so that the highly trained rowers who participated in the study at hand would in fact have had an edge at the end of the race and may - if they would have otherwise been on par with the competition - probably have won the race (Vanakoski. 1998; Chwalbiñska-Moneta. 2003).

Surprise: Anyone of you who has ever taken NO Xplode 2.0 (new or old formula) has already been supplementing with GPA - both the original and the "advanced strength" formula contain an undisclosed amount of GPA. Apropos, if you are interested in the differences between the two, check out my previous article on the matter - I guess I don't give away too much, when I tell you that they are few and far between.

There is however a significant difference between not supplementing with creatine and relying on your own body's ability to produce the "meat amino acid" ("creatine" is derived from the greek word for meat) from L-arginine, glycine, and L-methionine and using a "supplement", or rather, another amino acid that does actually hamper its recycling and thus availability by the creatine kinase enzyme. β-guanidinopropionic acid (bGPA, simply GPA or N-(aminoiminomethyl)-beta-alanine), an amino acid with a similar molecular structure as creatine, is such a molecule. GPA reduces the flux through the CK reaction, by reducing cellular creatine uptake and will thus effectively have similar effect as the genetic ablation of the CK enzyme, which does - probably to your surprise - not just hamper the viability of respective mouse mutants, but will also (and here we are getting back to the effects of nicotinic acid) improved their muscular endurance and lead to a shift from type II to type I fiber predominance (Van Deursen 1993; Ventura-Clapier 2004; Vaarmann, 2008).

In short, when you use 5g of creatine as a means to "load" your PCr stores, the administration of GPA will have an "unloading" effect. This effect has in fact been studies in a number of previous studies. The effects and potential side effects of GPA are yet unclear and that despite the notwithstanding that it is freely available on the market and *surprise* you may well have been taking very small quantities of it in the past (maybe even still are), since NO Xplode 2.0 is by no means the only supplement that contains small (and obviously undisclosed) amounts of GPA in its kitchen sink ... ah, I mean "proprietary blend" (see "Ask Dr. Andro: Are There NO Changes in the New N.O.-Xplode 2.0 Advanced Strength Formula?", read full article). Reason enough for Inge Oudman, Joseph F. Clark and Lizzy M. Brewster from the Academic Medical Center in Amsterdam (Netherlands) and the University of Cincinnati to conduct a systematic review to assess the effect of this substance on the mammalian energy metabolism (Oudman. 2013).

So what did the scientists find? Is GPA the "next creatine" we've been waiting for?  ;-)

The primary outcome of the review was the effect of GPA on energy metabolism, function, and morphology of tissues "with high and fluctuating energy demands" (Oudman. 2013) - this includes the obvious,...

• skeletal muscle, where it reduces creatine, phosphocreatine, total creatine, and ATP by 66.1%, 79.7%, 86.7% , and 38.8%, blunted the total creatine kinase activity (-28.6%), but increased the intra-mitochondrial creatine recycling (CK activity) by 200%, reduced the activity of glycolytic enzymes (phosphorylase -38.8%, lactate dehydrogenase -16.2%), increased AMPK expression by 45% and AMPK mRNA by 20%, promoted GLUT-4 expression (+45% in slow-, +33% in fast twitch fibers) and subsequently doubled muscle glycogen content, while decreasing blood glucose (-5%) and insulin levels (-27% in non-diabetic animals), improved endurance during non-/light weight bearing exercises and hampered it during heavier exercise, doubled mitochondrial DNA (evidence for the shift towards an oxidative muscle type), and decreased total and relative muscle weight by 19% and 10% respectively;
• heart muscle, where similar decreases in creatine, phosphocreatine, total creatine, and ATP occurred and GPA decreased the survival rates after myocardial infarction by ~50%

but also the vascular musculature, where no significant effects were observed, in the central nervous system and the brain, where GPA reduced the creatine concentration (brain), doubled the adenylate kinase and succinate dehydrogenase activity (both are involved in energy reallocation), increased the risk of seizures, but showed potentially protective effects against neurodegenerative diseases.  Furthermore the scientists report that GPA reduced creatine uptake in the kidney, reduced the body temperature and increased the amount of BAT (+3.4%, in rodents!). And last, but certainly not least, GPA delayed the development of mammary gland tumors in a rodent model (cf. Chira. 1995; Metzner. 2009)

To summarize...

It looks like a marathon supplement, but it's not even sure that endurance athletes would benefit from taking GPA. In the off.season it could "intensify" the training, but before a race it appears to be rather counter-indicated (photo trainerjosh.com).

Overall the review confirms the notion that the administration of GPA leads to marked reductions in creatine, phosphocreatine, and ATP concentrations and reduces cytosolic, while increasing mitochondrial CK activity in skeletal muscle. These observations stand in line with a shift from a glycolitic to a mitochondrial oxidative metabolism that is facilitated / goes hand in hand with

• a shift from type II to type I fiber predominance,
• increased glucose tolerance, and
• reduced skeletal muscle and body weight

which do not incidentally remind us of the adaptive responses to endurance exercise. It goes without saying that mainstream science is psyched about the "reduced body weight with unchanged food intake" of which the Oudman et al. argue that it "may be related to the fiber type shift, as an association between type II fiber predominance and body weight was previously reported".

Other, per se unquestionably more favorable confounding factors are the increased cellular fatty acid transporter protein concentration, fatty acid oxidative capacity and the compensatory increase in AMPK expression that is actually a response to the perceived energy (ATP) deficiency that develops in response to the administration of GPA (click here to learn more about AMPK's role in fatty acid oxidation and glucose metabolism). So, as paradox as it may sound: Despite its negative effects on the use of glucose as a substrate GPA could actually improve, not deteriorate glucose metabolism via an AMPK mediated "metformin-esque" effect on GLUT-4 expression.

---

Way too many trainees tend to forget the true meaning of "supplement". Supplements are something that "supplement" something else. In the case of creatine supplementation the latter supplements your efforts in the gym and won't (and this has recently been confirmed) build muscle on its own.

So what's the verdict then? Now, all that does certainly sound pretty cool, well - at least for a cut - so would it be better to avoid creatine for leaner muscle gains and use GPA, whenever you are cutting? The first of these bottom-line questions is easy to answer: No! Studies have repeatedly shown that creatine supplementation does not only increase the mass gains, it also improves the ratio of lean to fat mass more than resistance training alone (as long as you the baseline diets are identical).

What about GPA as a diet tool, then? While it certainly would appear that taking (hitherto by the way unknown) amounts of GPA could help you lose weight, it is unlikely that this weight loss will make you look the way, you want to look. I mean if you have to lose weight at all costs, because your health depends on it, GPA could provide a viable AMPK promoter that may help you achieve just that.

Especially strength athletes, sprinters and the like, as well as anyone wanting to look / perform like one of these athletes should yet resort to the tried and proven dietary tweaks to get rid of the extra weight. And there is actually no reason not to continue taking a regular maintenance dose of 3g of creatine during the cut,also in view of the fact that the "beneficial" effects of GPA supplementation are actually brought about by blocking one out of two energy sources - much like keto dieting, by the way, but that's a topic for another blogpost ;-)

Related read: "Ask Dr. Andro: The Pharmacokinetics of Creatine"- Part I & Part II

References:

• Chwalbiñska-Moneta J. Effect of creatine supplementation on aerobic performance and anaerobic capacity in elite rowers in the course of endurance training. Int J Sport Nutr Exerc Metab. 2003 Jun;13(2):173-83.
• Metzner L, Dorn M, Markwardt F, Brandsch M. The orally active antihyperglycemic drug beta-guanidinopropionic acid is transported by the human proton-coupled amino acid transporter hPAT1. Mol Pharm. 2009; 6: 1006– 1011.
• Ohira Y, Inoue N. Effects of creatine and beta-guanidinopropionic acid on the growth of Ehrlich ascites tumor cells: i.p. injection and culture study. Biochim Biophys Acta. 1995; 1243:367–372.
• Oudman I, Clark JF, Brewster LM. The Effect of the Creatine Analogue Beta-guanidinopropionic Acid on Energy Metabolism: A Systematic Review. PLoS One. 2013;8(1):e52879.
• Vaarmann A, Fortin D, Veksler V, Momken I, Ventura-Clapier R. Mitochondrial biogenesis in fast skeletal muscle of CK deficient mice. Biochim Biophys Acta. 2008; 1777: 39–47.
• Vanakoski J, Kosunen V, Meririnne E, Seppälä T. Creatine and caffeine in anaerobic and aerobic exercise: effects on physical performance and pharmacokinetic considerations. Int J Clin Pharmacol Ther. 1998 May;36(5):258-62.
• Van Deursen J, Heerschap A, Oerlemans F, Ruitenbeek W, Jap P. Skeletal muscles of mice deficient in muscle creatine kinase lack burst activity. Cell. 1993; 74: 621–631
• Ventura-Clapier R, Kaasik A, Veksler V. Structural and functional adaptations of striated muscles to CK deficiency. Mol Cell Biochem 2004; 256–257: 29–41.