CREATINE & THE SCIENCE

The $400,000,000 supplement. Creatine, not to be confused with Korean Teen, is one of the world's most widely researched and consumed supplements. It's a non-ubiquitous (not present everywhere in the body) amino acid that is synthesized in the liver, kidneys, and pancreas through a simple two-step process using the amino acids arginine (non-essential), glycine (non-essential), and methionine (essential) [1,2,4]. Interestingly, the two tissues that have the highest amount of creatine (skeletal and cardiac muscle) have essentially no ability to synthesize it. We get dietary creatine from animal products such as muscle meats and dairy. It's a simple chemical structure, and looks like this:​

HOW DOES IT WORK?

When we consume creatine, 100% of it is absorbed in the small intestine. 95% of creatine is stored in skeletal muscle—70% in the form of Phosphocreatine (PCr) while the other 30% is stored as free creatine (Free Cr) [7]. The average 70kg person has ~120mmol/kg of total creatine (~120g) (PCr + Free Cr) stored at any point in time. The body has the capacity to store up to ~160mmol/kg (~160g) of creatine [7,8,9].

Figure 1. The biosynthesis of creatine [2]

Energy Production

That chart will be tricky to follow at first but once you understand creatine a bit more it will make sense. There's thought to be two main types of metabolism of creatine. But we really only care about the one that yields energy in the muscle since that's the one that helps us lift more weight or sprint for longer. The first exists in high-energy, fast twitch muscle fibers. This system of metabolism is the cleaving of the phosphate on PCr to provide it to ADP during periods of high energy demand.

​​

​PCr + ADP —> Cr + ATP

The second is what's referred to in literature as the creatine transport hypothesis where high energy phosphates are transported to sites of ATP production by creatine kinase isoenzymes [3]. But thats for more boring muscles like the heart. We just want to increase our ability to rep 225 on bench. But in all seriousness, creatine is good for your heart.

Myostatin

Okay, moving on to Myostatin. Have you ever seen those really ripped cows and mice? If not here's a picture:

No, believe it or not, AI did not generate the picture of that bull. That's real. Terrifying right? These animals are what's referred to as Myostatin Knockout (Myo-KO). This is a mutation that rids the animal of the gene responsible for regulating the production of Myostatin. Myostatin is a myokine (hormone secreted from muscle) that regulates muscle mass. It's sole function is to inhibit muscle growth, without it, muscle fibers just keep growing. An emerging body of research has shown that creatine prevents/reverses myostatin-induced muscle atrophy (shrinking) and increases the expression of myostatin-negative regulatory genes. So basically, while it doesn't knockout the gene, it acts like a dimmer switch and turns it down. The mechanism, though it needs further elucidation, seems to be the reducing of mRNA levels [11,12,13]. Pretty sweet.

SO, DO I NEED TO SUPPLEMENT?

Yes. Though we can produce 1-2g of creatine/day in the liver, and we consume it in our diet if we eat meat and/or dairy—this is only enough to keep a saturation level of 60-80% (~120mmol/kg) [1,2]. Supplementing allows us to get the remaining 20%, so if you want to be operating at 100% you'll have to supplement it. For those who steer clear of animal products, it's even more important that you supplement creatine. Countless studies have found that diets abstaining from animal products have much lower levels of creatine concentration in muscle tissue with saturation levels around 40% [1,2,4,7,8,9,16,17,18]. 

Figure 2. Muscle creatine stores in different types of supplementation and eating patterns [16]

Interestingly enough, creatine has been shown to have close ties to GLUT transporters, specifically GLUT4. Carbohydrate intake in tandem with creatine has shown greater rates of absorption and in turn saturation. Working out stimulates translocation of GLUT4 to the surface of cells which in turn leads to even better absorption [5,17,18].

Benefits of supplementing

But what if I don't care to increase my 1RM on bench, what's it matter what my creatine stores are at? Well, creatine is still just the thing for you if any of these positive health attributes sound good to you:

1. Lower cholesterol and triglyceride levels 
2. Reduced fat accumulation in the liver 
3. Reduced homocysteine levels 
4. Enhanced glycemic control 
5. Slowed tumor growth 
6. Minimized bone loss
7. Improved functional capacity if suffering from osteoarthritis 
8. Maintain healthy cognitive function
9. Reduced states of depression 

[24,25,26,27,28,29,30,31,32,33]

So, in addition to increasing strength and muscle mass, creatine provides a host of benefits that most rational people would agree would make for a better state of health. See, creatine isn't just for gym bros.

​How much and when

The final question. All this information, but what do we do with it? When supplementing creatine, there should be a loading phase as discussed earlier. This is a topic debated amongst individuals, but research conclusively shows greater efficacy in creatine supplementation with a loading phase (14, 15, 16, 17, 18). This phase should last for ~5 days and requires 20-30g of creatine each day (~0.3g/kg/day) in 5g doses through the day. To maximize uptake, it's best to consume creatine with glucose and to dissolve the creatine completely in a warm beverage such as tea or coffee.

This method of dosing lead to an increase in creatine concentrations of 20-30% in the form of PCr. This is the form of creatine that allows our muscle cells to cleave the phosphate and yield more energy during exercise. 

​PCr —> P + Cr + ADP —> ATP + Cr —> Energy

Once the loading phase is complete, research has shown that we need only 2-5g of creatine per day (0.03g/kg) to maintain these levels of saturation (80%-100%) [18].

The best time to consume creatine once in the maintenance phase is post exercise with a carbohydrate rich supplement. So post workout should be  40-50g whey isolate, 2-5g creatine, and ~25-30g dextrose or other glucose supplement.

COMMON MYTHS

As with any supplement, there is a plethora of misinformation founded on pure ignorance and laziness. Let's address it briefly:

1. All weight gained during supplementation is due to water retention.

2. Creatine supplementation causes renal distress.

3. Creatine supplementation causes cramping, dehydration, and/or altered electrolyte status.

4. Long-term effects of creatine supplementation are completely unknown.

5. Newer creatine formulations are more beneficial than creatine monohydrate (CM) and cause fewer side effects.

6. It's unethical and/or illegal to use creatine supplements.

Numbers 1, 2, and 3: we'll need to address these together since they all stem from the same root: reduction in urinary volume. Several studies have reports that 5-6 days of ingestion at the rate of 20 g/day will result in a body mass increase of 0.5-1.0 kg [17, 21, 22]. The majority of weight gain seen during the loading and even continued supplementation of creatine is total creatine stores (PCr + Free Cr). Total body water (TBW) increases as a result of increased concentration and saturation of creatine stores in muscle (osmosis happens to maintain concentration). This is measured through urinary excretion. During the loading phase, urinary volume decreases ~0.6L/day [17], however, it's noted in the literature that urinary volume returned to normal levels after this phase of loading is complete and creatine intake goes from 0.3g/kg bw/day to 0.03g/kg bw/day [9, 10]. So with adequate water intake and proper supplementation both in amount and phase, the first three points are mute. 

Number 4: As far as the long-term effects of creatine: we supplement, our stores saturate, we maintain the recommended dosage for continued supplementation. Saturated creatine stores are good, so this is good. We stop taking creatine, now what? No evidence has suggested that muscle creatine levels fall below baseline after cessation of creatine supplementation; therefore, the potential for long-term suppression of endogenous creatine synthesis does not appear to occur [19, 20]. This would really be the only concern of long-term effects since outside of that it's fairly innocuous.

Number 5: The "newer forms" of creatine are undefined. There isn't much merit to this claim, but just know all the research uses creatine monohydrate so with that form and proper dosing you will be maximizing the benefits of your supplementation.

Number 6: Creatine is legal and produced in our body and present in the foods we eat. Might as well maximize its benefit.

SUMMARY

We made it, congratulations. Let's bring it all home. Creatine is a very effective, very useful ergogenic aid and/or general daily supplement. It provides a host of benefits at fairly low doses and an affordable price. We synthesize creatine in liver using three amino acids arginine, glycine, and methionine. 95% of creatine is stored in the muscle. Our stores are on average 60-80% saturated, less if you're a vegan/vegetarian. Supplementing aids in energy production in the muscle, saturates stores, and suppresses genes that regulate levels of myostatin. There's a host of other metabolic and neurological benefits we won't get into here.

When supplementing, it's best to leverage a loading phase of 0.3g/kg (body weight)/day for 5-6 days. This loading phase ensures the saturation of creatine stores in the form of Phosphocreatine (PCr) and free creatine (Free Cr). During the loading phase, you should consume the creatine in 4-5 doses throughout the day. When taking it, let the creatine dissolve in a warm beverage to maximize absorption. After the loading phase creatine supplementation should drop down to 0.03g/kg/day for however long you would like to maintain full saturation which is nothing but beneficial. After the loading phase, creatine should be consumed one time through out the day: post-workout (enhances uptake by 54% because of GLUT4 [16]) with glucose and protein. During the loading phase you will experience a negligible amount of water retention that will cease upon the decrease to the sustained dosage of 0.03g/kg/day.

That's all you need to know about creatine. Here's to consuming more grainy white powder. Until next time.

REFERENCES

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