A trend I’ve picked up on when it comes to supplements is that people can view them from a lens of “upgrading” or “getting a personal edge”, in the sense that supplements become tools to enhance a person’s performance in whatever metric they feel the need to “get an edge” on, whether it’d be sleep, or mood, or strength, or endurance, or focus, etc. This is particularly common in sports and fitness, where the majority of us do not even need to focus on performance metrics, such as max speed, one rep max, length of time running/sprinting etc., as you would if you were a competitive/professional athlete but regardless, we all find joy in perusing the supplement aisle in the pharmacy or supermarket, looking for those aids that will give us any semblance of an added boost. 

A good example of this is creatine, known as a muscle-enhancing supplement, also happens to be one of the most, if not the most widely researched supplement in the world and I propose that the benefits of this well-established fitness enhancer extend beyond the benefits one would obtain in the gym. For starters, creatine is produced by humans in the liver, kidneys, and pancreas through the metabolism of L-arginine, using the methyl donor SAMe (S-adenosyl-methionine) to methylate the intermediaries of L-arginine into creatine. Creatine is primarily found in tissues that carry a high energy demand, particularly skeletal muscle, which carries approximately 95% of the body’s creatine pool, but the brain, heart, liver, kidney, photoreceptor cells, inner ear cells, enterocytes, and photoreceptor cells, are also sites where creatine metabolism occurs (Bonilla et al, 2021). This elucidates why creatine has benefits that extend beyond muscular strength and endurance. 

The simplified technicality behind creatine’s muscle-enhancing function is that the enzyme creatine kinase can transfer an N-phosphoryl group from phosphorylcreatine, the by-product of creatine metabolism, to adenosine diphosphate, regenerating adenosine triphosphate, the body’s primary energy molecule. This process is actually reversible, meaning that creatine kinase can catalyse the conversion of creatine to phosphorylcreatine and vice versa. Essentially, if creatine supplementation increases intramuscular phosphorylcreatine content, then it also increases energy provision, highlighting its common use by athletes and those who engage in frequent physical activity (Campos-Ferraz et al, 2014). 

Additionally, increased intramuscular creatine stores facilitate the uptake and retention of glycogen, an important substrate metabolised during high-intensity or long-duration endurance exercise, aid in phosphate shuttling, facilitating ATP transport from sites of ATP production to sites of ATP utilisation, which mitigates oxidative stress, a contributor to exercise-induced fatigue, and increases calcium re-uptake into the sarcoplasmic reticulum (site of calcium storage in myocytes), which enhances myofibrillar cross-bridge cycling (muscle contraction) and force development (Forbes et al, 2023). 

If creatine has profound influences on skeletal muscle function, then it would be safe to assume that it may also benefit the heart, a muscle with very high energy demands. It turns out that creatine supplementation can stimulate mitochondrial creatine kinase and scavenge oxidant free radicals, through augmenting phosphocreatine/creatine ratios and stabilising cellular ADP/ATP (adenosine diphosphate/adenosine triphosphate) ratios, which lead to a reduction in hydrogen peroxide (a by-product of mitochondrial metabolism and a reactive oxygen species).

This indicates that creatine has antioxidant capacity and may help prevent heart disease by mitigating oxidative stress, which is a key contributor to cardiovascular disease. Furthermore, the same antioxidant effects of creatine may improve vascular health via improving nitric oxide (a vasodilating and blood-pressure reducing compound) production, as free radicals can oxidize tetrahydrobiopterin (BH4) (a co-factor needed for endothelial nitric oxide production) into dihydrobiopterin (BH2), which leads to a breakdown of the enzyme necessary for NO production, and creatine can mitigate these effects (Clarke et al, 2021). 

Body system	Benefits to by creatine supplementation
Neurological	Creatine can be synthesized in the brain, given that the brain is a metabolically-demanding organ and neurons require constant ATP supply to fuel processes such as synaptic functioning, maintaining ion gradients, and neurotransmitter exocytosis. Creatine supplementation has been shown to raise creatine levels in the brain, especially in those with creatine synthesis disorders, and this is likely because the brain synthesis its own creatine and does not require exogenous creatine. However, in the elderly and vegetarians (comparing to meat eaters), improved measurements of memory were found with creatine supplementation at 20 grams per day for seven days (Forbes et al, 2022). Additionally, in mice/rat studies, creatine supplementation was found to reduce brain damage following a traumatic brain injury but more research is needed in humans as creatine supplementation increases brain creatine I animals at much higher percentages than in humans. However, children with traumatic brain injury showed improvements in cognition metrics (memory, communication, personality, behaviour) and symptoms, such as headaches, dizziness, and fatigue, following creatine supplementation (Roschel et al, 2021).
Reproductive	Spermatozoa can sustain high fluctuating energy requirements, which promotes resiliency and enables them to withstand environmental stress. This is partly due to the presence of creatine kinase enzymes in sperm cells and the creatine-phosphocreatine shuttle supplies ample phosphate groups to meet the energy-intensive demands of these cells (Ostojic et al, 2022).  Oxidative stress and lactate (from glycolysis, which sperm cells use to produce energy) can cause DNA damage, reduce mitochondrial activity, and lower cytoplasmic pH level, which alter mechanisms of sperm motility and viability. Creatine may mitigate these effects in the same fashion as it occurs in muscle cells, where increased contraction and relaxation don’t induce oxidative stress and low intracellular pH. However, this effect has not been directly studied in humans but it has been shown that sperm cells prepared for in vitro fertilization increased fertilizing capacity and motility when creatine was added to the culturing medium (Umehara et al, 2018).

References

Bonilla, D.A., Kreider, R.B., Stout, J.R., Forero, D.A., et al. (2021) Metabolic basis of creatine in health and disease: a bioinformatics-assisted review. Nutrients, 13(4), 1238. https://doi.org/10.3390/nu13041238

Campos-Ferraz, P.L., Andrade, I., Neves, W., Hangai, I., et al. (2014). An overview of amines as nutritional supplements to counteract cancer cachexia. Journal of cachexia, sarcopenia and muscle, 5(2), 105-110. https://doi.org/10.1007%2Fs13539-014-0138-x

Clarke, H., Hickner, R.C., & Ormsbee, M.J. (2021). The potential role of creatine in vascular health. Nutrients, 13(3), 857. https://doi.org/10.3390/nu13030857

Forbes, S.C., Candow, D.G., Neto, J.H.F., Kennedy, M.D., et al. (2023). Creatine supplementation and endurance performance: surges and sprints to win the race. Journal of the international society of sports nutrition, 20(1) https://doi.org/10.1080/15502783.2023.2204071

Forbes, S.C., Cordingley, D.M., Cornish, S.M., Gualano, B., et al. (2022). Effects of creatine supplementation on brain function and health. Nutrients, 14(5), 921. https://doi.org/10.3390/nu14050921

Ostojic, S.M., Stea, T.H., & Engeset, D. (2022). Creatine as a promising component of paternal preconception diet. Nutrients, 14(3), 586. https://doi.org/10.3390/nu14030586

Roschel, H., Gualano, B., Ostojic, S.M., & Rawson, E.S. (2021). Creatine supplementation and brain health. Nutrients, 13(2), 586. https://doi.org/10.3390/nu13020586

Umehara, T., Kawai, T., Goto, M., Richards, J.S., et al. (2018). Creatine enhances the duration of sperm capacitation: a novel factor for improving in vitro fertilization with small numbers of sperm. Human reproduction, 33(6), 1117-1129. https://doi.org/10.1093/humrep/dey081