Creatine and Glutamine: The Next Step

One aspect that is emerging as absolutely essential to producing better results and dramatic gains in muscle is the understanding of transport mechanisms of supplements like creatine and glutamine.

Understanding how a substrate gets inside a cell leads to more efficient and effective uptake and therefore more consistent, continuous results. We can then dictate what state we want our muscle cells to be in!

Recent studies are confirming earlier reports3,6 (always a good thing in science), that glutamine and creatine are so important to the functioning of every cell that they have their own, individual transport systems, particularly in muscle cells.1,4,5

A transport system (a protein bound to the cell membrane and its enzyme) is extremely specific. It only accepts the substrate it was designed for. The amino acid glutamine is so essential it has its own transport system (system Nm) and it is separate from any other amino acid.4,5 Transport system Nm is shown to act like an exclusive entrance for glutamine4,5 and is the fastest transporter in muscle.7 Other amino acids have to use other slower “doorways” like transporter system A.4,5

Substrates such as glutamine and creatine are driven into cells by the energy dependent “Na+/K+ (sodium/potassium) pump.” It powers all cellular transport systems. Na+ and K+ are “pumped” in opposite directions in and out of the cell via the breakdown of energy (ATP). Na+ outside the cell couples to the highly specific transporter, helping to bind the substrate (in this case glutamine) and force it into the cell.

ATP breakdown is constantly linked to ion transport. Although the process is not fully understood it seems clear that the cell transporter is temporarily “phosphorlyated” by attachment of the phosphate group released from ATP. The phosphorlyation step is Na+ dependant (occurs only when Na+ is present). The subsequent dephosphorylation, removal of the phosphate, is K+ dependant, and, probably allows the transport protein to return to its original conformation. The “Na+/K+ pump” is so critical it utilizes about one-third of the cell’s energy supply. It is continuously working, and while glutamine and creatine transport into the cell is dependant on the “Na+/K+ pump”, a critical piece in the muscle building puzzle is that the glutamine transporter system is unlike any other.4,5 Research demonstrates that this transporter, system Nm, is extremely anabolic and is extremely sensitive to changes in cell volume.4,5

Increasing muscle cell volume – increasing the cells’ water content, is a potent, independent trigger of the anabolic mechanisms that build muscle.2 Water does not simply reside inside a cell, it must be drawn into the cell and held there by highly osmotic substrates (like glutamine and creatine) that themselves have high transport rates. Any imbalances of intra- and extracellular osmolarity is paralleled by respective water movement across cell membranes and this creates a subsequent alteration in cell volume.2 When a cell swells dramatic things happen. Muscle building is “turned on” and muscle breakdown is “turned off.”2 This cell volumizing process could be the important mechanism that links creatine and glutamine to their powerful, muscle building effects.

These reports demonstrate that as glutamine moves into the cell it creates rapid cell swelling, and this in turn stimulates transport system Nm to keep increasing the rate of glutamine transport into the cell.4,5 This important finding by the scientists shows that system Nm does not “down regulate” and return the cell to normal like other transport systems do.4,5 The cell remains in a swollen and permanently anabolic state!

The increases in cell volume we are discussing here are miniscule, nothing like a “balloon effect.” However, even the smallest increases in cell volume caused by glutamine trigger a potent muscle building response.6 Therefore the glutamine transporter system Nm found in muscle cells is unique. It appears to be a direct pathway to producing anabolism with the muscle cell.4,5

Recent reports also demonstrate that creatine also has its own highly specific, high affinity transporter in the muscle cell membrane.1,3 The creatine transporter CRT-1 was recently isolated and cloned from human heart muscle cells and its physiological characteristics were closely monitored in a living animal organism.1 Although these researchers were more concerned with pharmacological molecules that inhibit creatine uptake, some interesting aspects were reported.

Creatine uptake was assessed in watery solutions that mimic a cellular environment. And once again, creatine transport was shown to be very highly dependant on extracellular Na+ Cl- (sodium chloride or table salt) concentrations, but to very different extents.1 The rate of creatine uptake increased hyperbolically with creatine or Cl- concentration. Meaning the greater the concentration of these two, the greater the uptake. This was not seen with Na+. Its uptake graph showed a sigmoidal curve (dose dependant). More and more Na+ did not increase the uptake of creatine.1 This may have something to do with the fact the researchers determined that it takes two Na+ and only one Cl- molecule to transport a creatine molecule. Also, interestingly, solutions that did not contain calcium and magnesium ions dramatically inhibited creatine uptake (up to 47%), suggesting a synergistic role among minerals during the uptake of creatine into the cell.

Molecules with similar structure to creatine were also shown not to be taken up by the cells. And while cell volumizing amino acids like taurine have similar transport mechanisms, high concentrations of taurine did not interfere with creatine uptake one bit.

This report also demonstrated that the creatine transporter is a very complex protein. It has several protein kinase phosphorylation sites (binding sites for specific enzymes) and interference with any one of these sites inhibits creatine transport to varying extents.1 This indicates that creatine uptake is an intricate, precise procedure and why it’s been previously so difficult to assess creatine’s effects on a cellular level.

What do these findings on creatine mean? Possibly a lot, maybe nothing. That old, empty scientific clich? really does apply here, “more research is needed.” However, some important factors have been established. Although creatine and glutamine are both dependant on the ‘Na+/K+ pump for active transport into the cell, they each utilize different transporters. This means they both have different and exclusive ways of getting into muscle cells. These may represent true anabolic pathways that may be independently manipulated to produce a permanent anabolic state within the cell.

The creatine transporter is very complex, and transporting creatine into muscle cells is dependent on many substrates and variables. It is not as simple as previously thought. Presently, I would be inclined to consider the use of both substrates at once and investigate a potent, synergistic “cell volumizing” effect or, alternating cycles of the two supplements to prevent cell receptor down regulation.

As I’ll discuss in future articles, this is important. Cells constantly saturated with creatine down regulate or “lose” their creatine transporters, preventing further uptake of creatine. There are important molecular reasons why this occurs, and to find out how to prevent it, stay tuned!


W.Dai et al. 1999 Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus Oocytes. Arch. Of Biochem Biophys. vol 361.#1Jan. p75-84.

D.Haussinger et al. 1998 Functional significance of cell volume regulatory mechanisms. Phys. Rev.vol78.#1.p247-290

J.D.Loike et al. 1988 Extracellular creatine regulates creatine transport in rat and human cells.Proc.Natl.Acad.Sci.USA.vol.85 p807-811.

S.Y.Low et al. 1997 Signaling elements involved in amino acid transport reponses to altered muscle cell volume. FASEBJ. vol11.p1111-1117.

S.Y.Low et al. 1998 Intergrin and cytoskeletal involvement in signaling cell volume to glutamine changes in cell volume. J.Physiol. vol512 #2 p481-485.

S.Y.Low et al. 1996 Response of glutamine transport in cultured rat skeletal muscle to osmotically induced changes in cell volume. J.Physiol.vol492 #3 p877-885.

M.J.Rennie et al. 1996 Glutamine metabolism and transport in skeletal muscle and heart and their clinical relevance. J.Nutr. vol126 p1142S-1149S.

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