Today’s post is a guest post from Sol Orwell, a very bright guy who has a big passion for creatine supplementation.

 

If there is any supplement that works, it would be Creatine. I’m such a fan that I would go as far to say that it is almost mineral-like in how helpful it is. And unless you are eating 2-4 lb pounds of meat every day, you will need to supplement.

There has been so much research conducted on Creatine that I thought it would be fun to do a guest post slightly different.

Three Things you Probably Already Knew

1. Creatine is a better glucose

• In regards to the two main energy molecules, fatty acids and carbohydrates, there is a rough correlation that the quicker the molecule is used during a period of stress, the less there is on the body. Carbohydrates are used when a cell requires energy faster than fatty acids can supply it, and have less storage. Creatine and its energy form (Creatine Phosphate) are to glucose like glucose is to fatty acids, supplying energy when the requirement exceeds the capabilities of glucose.
• Due to these reasons, it would probably be best to view creatine not as a supplement nor as a ‘vitamin’; it is an energy supplying macronutrient (except unlikely to contribute to obesity, since the oral doses are so low)

2. Creatine Increases Power Output

• Creatine reliably increases power output, with no effect on persons who do not respond to creatine (if you gain water weight upon ingesting high doses of creatine, you respond to it). The degree of improvement, however, is variable. If my game was marketing, I would honestly just say 78.5% more than placebo because that is a conclusion derived from a meta-analysis; apparently for every 100lbs of strength gained in placebo creatine would gain 178.5lbs. Unfortunately, these numbers are (in my opinion) inflated, as this number was derived from a meta-analysis that concluded 4.2% betterment in placebo with exercise and 7.5% improvement with creatine; these relatively small numbers that are confounded with changes in weight (uncontrolled variable) and newbie gains.
• So creatine does increase power, and when applied to newbies and manipulating the percentages there appears to be validity behind the huge claims of creatine. Applying these percentages and rates of improvement relative to placebo in practical settings with athletes, however, is most likely too promising. Conclusions on creatine in the literature may be like newbie gains in weight lifting, where extrapolation beyond the study parameters results in hilariously bad conclusions.
• I will also say that creatine does increase power output in athletes and weight-trained persons who have achieved a certain level of strength already, but it won’t bring you 250lb bench up to 446lbs in 8 weeks; you might get 290lbs if you’re really lucky.

3. Creatine Increases Lean Mass

• Technically, the increase in water weight itself is an increase in lean mass (as water retained by the body is consdered “lean mass”), but creatine itself increases muscle mass beyond water. Interestingly, it also appears to have the ability to do this somewhat independent of exercise (I mean this in the sense that there are mechanisms that creatine can directly influence protein synthesis, which undermines the hypothesis that “all gains are secondary to lifting more weight” a tad), although its effects are greatly augmented by the presence of exercise and muscle contraction.
• It appears to exert benefits to muscle protein synthesis secondary to inducing and mimicking a state of energy surplus in the cell, as the state of energy surplus(hypercaloric consumption, aka “bulking”) increases anabolic factors in a cell and can increase muscle protein synthesis.

Three Things you Probably Did Not Know

4. Creatine is Anti-Diabetic

• Creatine has a weird relationship with glucose in the blood. Inherently, it does not increase glucose uptake into a cell but augments the exercise-induced increase of glucose into a cell (so any anti-diabetic attempt of creatine must be paired with exercise). However, even at rest it can increase glucose oxidation from within the cell (a mechanism similar to fish oil). This appears to be due to increasing activity of a protein called Adenosine Monophosphate Kinase (AMPK), which is a nutrient sensor that is activated normally during times of nutrient deprivation and acts to create ATP from glucose and fatty acids (by taking them into a cell, then oxidizing them). Oddly, though, the typical rules of AMPK may not apply to creatine since the Creatine-Kinase System and AMPK are so highly interregulated.
• Currently, the evidence stands that glucose oxidation is increased in correlation with the amount of creatine in a cell and that supplementation to animals increases glucose oxidation. Studies in humans noting increased glucose oxidation are also those paired with exercise that also note glucose uptake. The AMPK mechanism appears to be relevant due to one study in diabetics noting a seven-fold increase in the particular subunit creatine acts on; this is sort of an inflated number due to low levels of AMPKa in diabetes, but also what underlies the “anti-diabetic” claim, Creatine may act to normalize dysfunctions in skeletal muscle glucose metabolism associated with Type II Diabetes (preliminary stages of research)

5. Creatine is Neuroprotective

• The same mechanism that is behind the ability of Creatine to boost muscle cell contraction is one that offers neuroprotection; when a brain cell has a higher ATP status, it can survive longer during periods of endogenous or toxin-induced stressors. When an acute stress is applied, the cell uses its ATP stores to preserve the integrity of the cell membranes; being destroyed upon depletion of ATP. Creatine has been implicated in preserving cell integrity via this mechanism, which is admittedly weak when compared to some other brain health agents yet is wide-reaching and not inherently associated with negative effects to the cell.
• Additionally, creatine appears to modulate the main excitatory receptor (NMDA) and may attenuate any toxicity mediated from too much excitation (called excitotoxicity); this appears to not be directly related to creatine being an energy buffer.

6. Creatine Entry into a Cell is Regulated by Nutrient Status

• Creatine entry into a cell is wholly regulated by one transporter, the Creatine Transporter (most common variant is called SLC6A8). The factors that change its Vmax and creatine uptake rates are tied in to common proteins that interact with the diet, with a surplus being associated with uptake and a deficit associated with suppression.
• Uptake appears to be enhanced by activation of the Mammalian Target of Rapamycin, mTOR. This protein is activated by dietary leucine and a caloric surplus in general (the more energy in a cell, the more mTOR activation) and is a central lever point for muscle protein synthesis. Additionally, cellular stress (either through kinases or calcium release) increases mTOR activity, which sets up a very nice notion of “more nutrients and muscle contraction leads to more creatine uptake”, which appears to be in accordance with anecdotes surrounding creatine.
• Inside the cell, the transporter is negatively regulated by AMPK; the aforementioned nutrient sensor that responds to dietary restriction and caloric deprivation. Interestingly, creatine acts on AMPK in a concentration-dependent manner and sets up its own negative feedback loop so the cell doesn’t explode from the hypertonic state of excess creatine (basically, AMPK activation may be why muscle cells don’t explode after excess creatine consumption). This negative regulation is mediated simply by AMPK suppressing mTOR, which indirectly eliminates the upregulation by mTOR.
• In the end, the practical relevance of the above is unknown. The above regulation doesn’t constitute all regulation (some from serum) and may precede some supplements that are catered to non-responders, but based on these it might be slightly better to take creatine with meals and not with intentional AMPK activators that are sometimes in fat burners.

TL;DR?

1. Creatine can be equated as quicker and more efficient energy than carbs or fats
2. Creatine helps you get stronger
3. Creatine helps add lean mass
4. Creatine is anti-diabetic
5. Creatine protects your brain cells
6. Creatine supplementation interacts in both fed and fasted states

Our Creatine page has 450+ citations if you want to learn more.

Sol Orwell and Kurtis Frank are co-founders of Examine.com, a science-based compendium on supplements and nutrition.