~ Creatine acts as a backup energy source for muscles and the brain to use in times of stress.
~ Genetic variants in genes related to creatine creation can impact muscle pain, athletic performance, and cognitive ability.
~ Creatine supplements are inexpensive and readily available. Studies show that creatine monohydrate supplementation effectively boosts muscle power and brain creatine levels under certain conditions.
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What is creatine?
Creatine is an amino acid important in energy production in brain tissue and muscles.
A little background: Cells use ATP (adenosine triphosphate) for energy. ATP is created mainly in the mitochondria — you know, the powerhouse of the cell. ATP stores energy in the bond between the phosphates, which can then be broken to release the energy in the cell.
The ‘triphosphate’ part of ATP means it has three phosphates bound together. When it gives up energy, it becomes ADP – adenosinediphosphate – with just two phosphates.
Creatine is used in certain types of cells to recycle ADP back into ATP by donating a phosphate group. It can increase cellular energy when it is lacking.
How does the body make creatine?
While you may be most familiar with creatine supplements as something bodybuilders use, it is actually utilized in all types of muscles and the brain.
Creatine is produced from the amino acids glycine and arginine, along with a methyl group donated by SAMe.
The biosynthesis of creatine is a multi-step process.
First, glycine and arginine, which are common amino acids, combine to form guanidinoacetate.
Next, creatine is formed from guanidinoacetate with the addition of a methyl group. This process occurs mainly in the liver and kidneys. The creatine, then, enters the circulation and can be used throughout the body.[ref]
In cells, creatine can be converted to phosphocreatine with the help of the enzyme creatine kinase.
Phosphocreatine (aka creatine phosphate) stands ready, available for converting ADP to ATP when more energy is needed.
Muscle cells need a lot of ATP for energy, as does the brain. When a lot of energy is required, such as lifting something heavy or sprinting, phosphocreatine is used to resynthesize ATP from ADP rapidly. Otherwise, in normal lower-energy situations, ATP is generated in the mitochondria and the cytosol from glucose or fatty acids.
Creatine is also found in foods containing animal protein (mainly muscle meats). Supplemental creatine, such as bodybuilders commonly use, is also a source of creatine for creating the phosphocreatine used when repairing and building muscles.
Diving deeper into creatine kinase:
I mentioned above that creatine kinase is the enzyme used to convert creatine to phosphocreatine, which can then be used by cells for energy when needed.
There are two types of creatine kinase – mitochondrial and cytosolic, in the muscle and brain. The phosphocreatine created in the reaction acts as an energy buffer, available when muscle cells are stressed and need more ATP.[ref]
Lab tests: When tissues are damaged, such as cardiac muscle, during a heart attack, creatine kinase will leak into the blood. It is why doctors measure creatine kinase levels to see if there has been any tissue damage.[ref]
What else elevates creatine kinase (CK) levels on tests?
In addition to being an indicator of a heart attack, CK levels can be elevated up to 15x the normal level after strenuous exercise. For example, after running a marathon, CK levels peak 24 hours later and stay elevated for a week.[ref]
Additional causes of elevated creatine kinase
- People who are obese also tend to have higher CK levels, as to people of African descent.[ref]
- CK levels increase with brain, heart, or muscle damage.[ref]
- Statins can raise CK levels[ref]
Creatine and brain function:
The brain uses up a ton of energy (ATP) – way more than any other organ in the body when you look at it by size.
Creatine is used in the brain as an energy buffer to provide energy in times of stress.[ref] Genetic mutations which cause creatine deficiency in the brain result in severe developmental disorders and seizures.
Creatine from foods and supplements can cross the blood-brain barrier, but it is typically at levels less than is taken up by skeletal muscles. Therefore, higher levels of creatine may need to be ingested to have an effect on the brain. Alternatively, it could be that creatine is prioritized by the muscles unless there is a reason for it to go to the brain.
As one research study puts it: “It could be that the brain relies primarily on endogenous creatine synthesis until there is some sort of challenge to brain creatine status. These challenges, which could cause a decrease in brain creatine, could be acute (e.g., sleep deprivation, intense exercise) or chronic (e.g., aging, traumatic brain injury, depression, Alzheimer’s disease, creatine synthesis enzyme deficiencies).”[ref]
Creatine and Methylation cycle:
The methylation cycle is the way cells create methyl groups (a carbon + 3 hydrogens) for use in many types of reactions. Folate is one source of methyl groups, and choline can also be used in the methylation cycle.
I mentioned above that one step in creatine biosynthesis includes a methyl group. In fact, 40% of the methyl groups produced in the body go towards creating creatine.[ref]
When methyl groups are low, homocysteine levels often will be elevated. High homocysteine is linked to an elevated risk of heart problems.
A placebo-controlled clinical trial found a reduction in homocysteine levels in resistance-training study participants when taking creatine for 8 weeks. The study used 25 g/d for the first five days, followed by 5 g/day for the rest of the trial.[ref]
Methyl groups are also utilized in some detoxification reactions, including the detoxification of arsenic. A study found that in people who have less than optimal choline or folate intake, supplementing with creatine or folic acid helps in the detox reaction for arsenic.[ref]
What happens if you don’t get creatine in your diet?
Creatine is not considered an essential amino acid, meaning you can make it in your body and don’t always have to get it for food.
However, getting creatine in your diet may prevent problems as you age or in times of physical stress.
A study of people over age 65 found that getting less than 1g of creatine via diet each day resulted in more than double the risk of angina (chest pain) and 2.5x the risk of liver problems.
The authors of the study concluded: “The considerable shortage of dietary creatine is associated with an increased risk of heart and liver conditions, which calls for public measures that foster diets rich in creatine-containing foods, and additional research to investigate the role of creatine in age-related diseases.”[ref]
Another study found that getting over 0.95g of creatine in foods daily was protective against cognitive decline in older adults.[ref]
Clinical trials using creatine supplements:
Creatine supplements have been very well studied, with thousands of clinical trials.
Here are just a few of the clinical trials:
- A double-blind, placebo-controlled safety trial using 0.3g/kg of creatine per day in men found: “creatine monohydrate supplementation is safe for health and no detrimental effects on different organs and physiological systems were observed in our cohort of volunteers.”[ref]
- In healthy older adults (aged 50-71), creatine before resistance training increased lean muscle mass and decreased fat mass. The trial ran for 32 weeks and used 0.1g/kg of creatine, compared to a placebo.[ref]
- Vegetarians have lower creatine levels, on average. A study of supplemental creatine showed vegetarians had even greater increases in bench-press strength, lean tissue, and other biomarkers than did non-vegetarians. (Both groups on creatine had better results from resistance training than the vegetarian and non-vegetarian placebo groups.[ref]
- Creatine supplementation helped both men and women increase peak power in bench presses and back squats.[ref]
- Creatine plus electrolytes increased sprint cycling times in a double-blind, randomized control study.[ref]
- Under hypoxic (low oxygen) conditions, creatine helps with cognitive function. The study included 15 healthy adults who took creatine for seven days before the 90-minute hypoxia session.[ref]
Negative study results are also interesting:
- Creatine supplementation did not significantly improve bone health in menopausal women with osteopenia.[ref]
- In fibromyalgia patients, creatine supplementation increased muscle strength, but it didn’t reduce pain or improve quality of life.[ref]
Creatine in adipose (fat) tissue:
In fat cells (adipose tissue), creatine is important in thermogenic respiration. Loss of creatine can decrease whole-body energy expenditure.[ref]
Brown or beige fat is the type of fat that creates heat in the body – especially in babies. Brown fat is darker in color than white adipose tissue (white fat) because it contains a huge number of mitochondria cranking out heat as a metabolic waste product.
Exposure to cold can trigger brown fat to produce more energy. It is essential in infants who are too young to shiver. The brown fat helps them to maintain their temperature.
In animal studies, creatine has been shown to enhance energy production when ADP is limited. When researchers limit creatine levels, the cells try to compensate by increasing the enzymes to produce more creatine. Animals lacking the creatine kinase enzyme had increased body weight and elevated fasting blood glucose.[ref][ref] The research here is new and evolving, but it looks like creatine plays a role in adaptation to cold, energy expenditure, and metabolic health.
Creatine for post-viral fatigue syndrome:
Post-viral fatigue syndrome is just what it sounds like – overwhelming fatigue that doesn’t end after you’ve gotten over a viral infection. It can refer to long covid or chronic fatigue syndrome (ME/CFS).
In people with post-viral fatigue syndrome (PVFS), muscle fatigue is reached much more rapidly than normal. It is thought that PVFS perturbs energy metabolism in the muscles. Research shows patients with chronic fatigue have reduced levels of hippocampal creatine also. While there is “not enough evidence to unequivocally endorse supplemental creatine for PVFS”, researchers do think it is possibly effective — as well as being low-risk and inexpensive.[ref]
Sarcopenia and creatine
Sarcopenia is the loss of muscle mass causing decreased strength in aging or chronic disease.
It is tempting to think creatine could be used to stop the aging effect on muscles, but research shows it isn’t quite that easy.
Studies in older adults show creatine supplementation alone has little effect on muscle function or mass. But… when creatine supplementation is added to weight training, the results show that it enhances the muscle’s response to training, potentially increasing capacity for higher intensity exercise and improving the muscle’s response post-exercise.[ref]
Thus, one way creatine may be beneficial in older adults is by increasing their capacity for exercising a little longer or lifting a little more weight. Even minor increases in exercise capacity can be important in older adults, and increasing muscle mass or grip strength can help with stability and independence.[ref]
Creatine Synthesis Genotype Report
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Biosynthesis of creatine
GATM gene: encodes the arginine:glycine amidinotransferase enzyme used in the first step of converting glycine and arginine into creatine. Low levels are linked to an increased risk of muscle pain with statin use. Researchers believe this is due to decreased creatine synthesis.[ref] Rare mutations that significantly affect the function of the GATM enzyme cause arginine:glycine amidinotransferase deficiency, which results in mild to moderate intellectual disability, delayed speech, and possibly autistic behaviors.[ref]
Check your genetic data for rs1346268 (23andMe v4, v5; AncestryDNA):
- C/C: reduced risk of muscle pain with statins (good)[ref]; likely higher levels of GATM
- C/T: reduced risk of muscle pain with statins; likely higher levels of GATM
- T/T: typical
Members: Your genotype for rs1346268 is —.
Check your genetic data for rs80338737 (AncestryDNA):
- A/A: rare mutation linked to Arginine:glycine amidinotransferase deficiency[ref]
- A/C: rare mutation linked to Arginine:glycine amidinotransferase deficiency[ref]
- C/C: typical
Members: Your genotype for rs80338737 is —.
Conversion of creatine for energy
The CKM gene encodes the mitochondrial type of creatine kinase specific to muscles. This enzyme converts creatine to phosphocreatine, which can be used to restore ATP levels in times of stress.
The first variant causes decreased creatine kinase levels, which may cause muscle problems. The next two variants increase creatine kinase, which is of benefit to athletes and muscle/joint health.
Check your genetic data for rs11559024 E83G (23andMe v5):
- C/C: significantly decreased creatine kinase levels[ref][ref]
- C/T: decreased creatine kinase levels
- T/T: typical
Members: Your genotype for rs11559024 is —.
Check your genetic data for rs8111989 (23andMe v4, v5):
- C/C: found in higher frequency in elite combat sports athletes[ref]; associated with better physical performance[ref]; possibly more creatine kinase
- C/T: found in higher frequency in elite combat sports athletes; slightly better physical performance; possibly more creatine kinase
- T/T: typical
Members: Your genotype for rs8111989 is —.
Check your genetic data for rs4884 (23andMe v4, v5; AncestryDNA):
- G/G: protective against knee osteoarthritis (good)[ref]
- A/G: protective against knee osteoarthritis
- A/A: typical
Members: Your genotype for rs4884 is —.
Mutations not covered here:
The SLC6A8 gene encodes the creatine transported into muscles and the brain. Rare mutations in this gene cause severe developmental delays. Similarly, rare mutations in the CKB – creatine kinase brain – gene also cause severe developmental problems.
MTHFR and methylation cycle:
The MTHFR gene encodes a key enzyme needed for converting folate from foods (or from folic acid) into methylfolate, which is used in the methylation cycle. Read more about MTHFR here (members will see their MTHFR data in the Lifehacks section below).
The rest of this article is for Genetic Lifehacks members only. Consider joining today to see the rest of this article.
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