Creatine (CK, CPK)


    • Creatine is an amino acid made naturally in the body, with a small amount coming from food.
    • Creatine is an essential, non-proteinaceous amino acid found in all animals, some plants and naturally in muscle cells in vertebrate tissues and excreted as creatinine in the urine.
    • Creatine is synthesized in the kidney, liver, and pancreas from L-arginine, glycine, and L-methionine.
    • In muscle tissue, creatine generally occurs as phosphocreatine.
    • Creatine (α-methyl guanidine-acetic acid) is a dietary supplement that improves exercise performance and increases fat-free mass.
    • Glycine participates in the biosynthesis of heme, purines, and creatine and is conjugated to bile acids and to the urinary metabolites of many drugs.
      • Arginine serves as the formamidine donor for creatine biosynthesis, participates in polyamine biosynthesis, and provides the nitrogen of nitric oxide (NO).
    • Methylation produces creatine, a compound that both your brain and muscles use as fuel. If you've got muscular aches and pains, feel run-down and fatigued, or cant kick your brain into gear, poor methylation, and low creatine might be the reason.
    • Creatine functions as part of the cell's energy shuttle. The high energy phosphate group of ATP is transferred to creatine to form phosphocreatine in the following reaction: Cr + ATP <-> PCr + ADP. The reaction is catalyzed by creatine kinase, and the result is phosphocreatine (PCr). Phosphocreatine binds with adenosine diphosphate to convert it back to ATP (adenosine triphosphate), an important cellular energy source for short-term ATP needs prior to oxidative phosphorylation. In the human body, creatine is synthesized mainly in the liver by the use of parts from three different amino acids - arginine, glycine, and methionine. 95% of it is later stored in the skeletal muscles, with the rest in the brain, heart, testes.

There are three isoforms of the dimeric protein creatine kinase, and their distribution is as follows:

  • MM - skeletal muscle
  • BB- brain
  • MM and BB- cardiac muscle
  • Any damage or lysis of cells in these tissues releases their respective isoform(s) into the bloodstream. These isoforms, particularly the MB isoform, can be used diagnostically for evaluating patients with strokes and myocardial infarctions. In myocardial infarctions, there is a blockage of blood flow to the heart, resulting in lysis of cardiac cells. Total serum creatine kinase (CK) and the creatine kinase (MB isoform [CK-MB]) rise within 5 hours, even though total CK activity may be within normal range. The elevated CK-MB can remain for up to 24-36 hours following a myocardial infarction and thereafter return to normal in 3-5 days. The various CK isoforms can be resolved by gel electrophoresis. Although an ECG is used to differentiate trivial issues from coronary disease, it might not exclude myocardial infarction because minor ECG changes might not be significant enough to detect. Serum LDH levels are used to check whether a myocardial infarction occurred several days prior to an examination. Also, elevated serum levels of cardiac-specific troponins are most often used for rapid diagnosis of myocardial infarction.


    • Supplementing with creatine increase your muscle phosphocreatine stores. Phosphocreatine (PCr) helps form ATP, the key molecule cells use for energy and basic functions of life. It also fuels muscles during high-intensity exercise and improves performance during those exercises.


    • Cr kinase enzymes regulate ATP homeostasis in subcellular compartments by the transfer of phosphates between creatine and adenine nucleotides. The CrK system is regulated by AMP-activated protein kinase via Pcr/ Cr and ATP/AMP ratios.
    • Creatine regulates the differentiation of mesenchymal stem cells (MSCs) in processes such as osteogenesis and myogenesis.
    • Creatine enhances differentiation of myogenic C2C12 cells by activating both p38 and Akt/PKB pathways.
    • Cr feeding to mice skeletal muscle enhances the nuclear content and DNA binding activity with an increase in GLUT4 gene expression.
    • Catecholamines, insulin-like growth factor 1 (IGF-1), insulin, and exercise can influence the net uptake of Creatine into skeletal muscle.
    • Creatine may also have important modulatory effects on the glutamate and GABA-A receptor systems that raise the threshold for the onset of excitotoxicity in the brain.

Strength And Exercise Performance:

    • Supplementing with creatine can increase body mass and improve performance in high-intensity, short duration exercises.
    • Supplementing in combination with strength training amplifies the increase in muscle cell nuclei concentration, increasing the growth of adult skeletal muscle in healthy males.
    • Supplementation enhanced free-fat mass, physical performance, and muscle morphology in response to heavy resistance training.
    • Elevated protein myostatin slows or inhibit new muscle growth. Creatine can reduce these levels and increase growth potential in healthy male subjects.
    • Adding creatine to a training program can increase muscle strength by 8%, weightlifting performance by 14% and bench press one-rep max by up to 43%, compared to training alone.
    • High doses (around 100 mg/kg) can increase testosterone levels, which can have a positive effect on exercise.
    • Creatine can aid in improving the rate of recovery of knee extensor muscle function after injury.
    • Supplementation can decrease plasma lipid peroxidation markers and enhances anaerobic performance.
    • 5 g creatine and 900 mg fenugreek extract increased upper body strength and improved body composition.
    • For quick bursts of energy, cardiac and skeletal muscle cells rely on existing ATP and an additional reserve of a high-energy phosphate called creatine phosphate.
    • Creatine is synthesized from glycine and arginine and irreversibly phosphorylated to creatine phosphate by the enzyme creatine kinase (also called creatine phosphokinase [CPK or CK)]. During this period of exercise, the muscle cells excrete large amounts of lactate into the bloodstream from the anaerobic glycolytic pathway, causing the blood pH to drop.
    • Aerobic metabolism begins to generate much more ATP in an effort to supply the energy for carrying out sustained muscle contraction. Creatine-P levels are nearly depleted within 5-10 seconds of hard exercise. In the initial phase of hard exercise, the existing ATP needed to carry out muscle contraction is rapidly used but the overall ATP levels do not significantly drop (from approximately 5 to 4 mM) because ATP is quickly replenished from three sources:
    • Creatine-P + ADP -7 Creatine + ATP
    • 2 ADP f--7 AMP + ATP
    • Anaerobic glycolysis -7 2 ATP

Brain Performance:

    • Oral creatine monohydrate supplementation in vegetarians can have a positive effect on working memory and intelligence.
    • In the elderly creatine can improve cognitive performance.
    • After 36 hours of sleep deprivation and being supplemented with creatine can improve performance on a random number of generation task.
    • Creatine supplements for older adults can improve the quality of life and may reduce the disease burden associated with sarcopenia and cognitive dysfunction.

Parkinson’s Disease:

    • Creatine monohydrate supplementation in patients with Parkinson’s Disease improved upper body strength and could enhance the benefits of resistance training.
    • Combination therapy with Coenzyme Q 10 could delay the decline of cognitive function in PD-MCI (Parkinson’s Disease-Mild Cognitive Impairment) patients and could lower their plasma Phospholipid levels.
    • Creatine has been shown to benefit those with Parkinson’s by preventing 90% of the drop in dopamine levels which characterize Parkinson’s.

Neurological Diseases:

    • Oral supplementation of creatine which is a substrate for creatine kinase, may increase Phosphocreatine (PCr) and buffer against ATP depletion and thereby exert neuroprotective effects.
    • Daily creatine supplementation can decrease depression symptoms in women suffering from Major Depressive Disorder.
    • 8-hydroxy-2-deoxyguanosine, a marker for damaged DNA, was abnormally high in patients with Huntington’s disease, but creatine treatment reduced this marker.
    • Oral creatine supplementation provided improvements in lifespan, muscle strength or motor unit numbers in patients with Amyotrophic lateral sclerosis, a disease that affects brain cells and the spinal cord.
    • Creatine supplements can help treat other diseases like Alzheimer’s’, Ischemic stroke, epilepsy, brain or spinal cord injuries in animal models.


    • A five-day dose of creatine in women may be an effective strategy for delaying the onset of neuromuscular fatigue.
    • Creatine supplementation had reduced ratings of perceived leg fatigue in endurance-trained males who performed exercises in heat.


    • Creatine can lower homocysteine levels. Homocysteine can increase the risk for heart disease, so lowering homocysteine can help with cardiovascular protection. 20g daily can lower cholesterol by 5%, lowering risk for heart attacks or other problems.

Blood Sugar Levels And Diabetes:

    • Creatine can decrease OGTT (Oral glucose tolerance test) area under the curve in healthy male subjects undergoing aerobic training.
    • Creatine supplementation is a possible nutritional therapy adjuvant with lowering blood sugar effects, particularly when used in conjunction with exercise.

The Elderly:

    • Creatine supplementation without associated training in the elderly could potentially delay atrophy of muscle mass, improve endurance and strength, and increase bone strength. Supplementation, when combined with resistance training, increased lean tissue mass and improved leg strength, endurance, and average power in men around 70 years old. Long-term supplementation combined with resistance training improves the ability to perform functional tasks and promotes a greater increase in maximal strength, fat-free mass, and muscle mass in older women.

Bone Health:

    • Bone growth factors work with creatine to increase osteoblast formation, which helps increase bone formation and bone repair.
    • Daily doses of creatine can reduce pain and symptoms of osteoarthritis in older women.


    • Creatine during pregnancy may benefit the fetus in cases of fetal growth restriction, premature birth, or when childbirth is delayed or complicated by oxygen deprivation of the newborn.
    • Creatine loading before birth significantly protects the diaphragm from hypoxia-induced damage at birth. Increasing maternal dietary creatine consumption could be a useful treatment for preventing a lack of oxygen in newborns.

Non-Alcoholic Fatty Liver Disease:

    • Creatine can reduce fat accumulation, resulting in beneficial effects in fatty liver and non-alcoholic liver disease.
    • Creatine prevents liver steatosis and lipid peroxidation with a high-fat diet. There was also a reduction in the accumulation of lipids in the liver cells.
    • Creatine is made in the liver, and an unhealthy liver that is not working properly will not be able to make the normal amount of creatine. For chronic liver disease, there can be a 50 percent reduction in the production of creatine. This means that there will be lower levels of creatinine in the blood, which can be checked with a simple blood test called a serum creatinine test.


    • Creatine is a nutrient that enhances endurance, strength building, and brain function. Although it is not necessary to obtain creatine from dietary sources, there are studies that show that creatine supplements can provide health benefits.
    • Vegetarians are more responsive to creatine supplementation in physical performance than non-vegetarians. Vegetarians who take creatine can see a greater increase in lean muscle tissue and total work performance compared to non-vegetarians.
    • About 95% of the body’s creatine is stored in skeletal muscles, in the form of phosphocreatine. The other 5% is stored in the brain, kidney, and liver.
    • It is found in the liver, pancreas, and kidneys.
    • In these foods:
      • Beef
      • Chicken
      • Rabbit
      • Milk

Side Effects:

    • Weight Increase
    • Cramps
    • Digestive Problems


    • Short-term supplementation (e.g. 20 g/day for 5-7 days) increases total content by 10-30% and phosphocreatine stores by 10-40% depending on you and your current levels. A loading protocol is the fastest way to maximize muscle creatine stores. It involves taking a high dose for a few days, and then a lower maintenance dose after that. This usually means 20-25 grams of creatine per day, split into 5-gram doses, for 5-7 days. Then this is followed by a maintenance dose of 3-5 grams per day.



    • Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor.

Argininosuccinate Lyase Deficiency: rs28941472:

    • Deficiency of argininosuccinate lyase (ASL), the enzyme that cleaves argininosuccinic acid to produce arginine and fumarate in the fourth step of the urea cycle, is characterized by a severe neonatal onset form and a late-onset form.
    • There is not enough phosphorus (P) to make creatine phosphate (CP), the amino acid arginine, (which is a main amino acid in the urea cycle), shunts to combine with the amino acid glycine to help make more CP not just for energy but also as a way to rid some of the NH3 through its breakdown into creatinine.
    • Having inadequate arginine for the urea cycle and NH3 becomes elevated as the CP is not as efficient in detoxifying NH3 as the urea cycle.
    • Taking phosphorus can aid in supporting the creatine pathway more effectively and keep some arginine for the urea cycle.

Gene Interactions:

    • COL2A1 Affects co-treatment , Increases abundance
    • GATM Increases chemical synthesis
    • CASP3 Affects co-treatment, Decreases activity
    • CSF3 Affects co-treatment, Decreases abundance
    • SNCA Affects co-treatment, Decreases expression
    • GAMT Increases chemical synthesis
    • PPARGC1A Increases expression
    • HRAS Decreases expression

Disease Inference:

    • Retinal Detachment 9.51
    • Hemangiosarcoma 8.01
    • Carcinoma 7.43
    • Carcinoma, Transitional Cell 6.8
    • Guanidinoacetate methyltransferase deficiency 6.54
    • Arginine:Glycine Amidinotransferase Deficiency 6.44
    • Heart failure 6.44
    • Achondrogenesis type 2 6.17
    • Epiphyseal Dysplasia, Multiple, with Myopia and Conductive Deafness 6.17
    • Kniest dysplasia 6.17
    • Legg-Calve-Perthes Disease 6.17
    • Osteoarthritis with Mild Chondrodysplasia 6.17
    • Platyspondylic Lethal Skeletal Dysplasia, Torrance Type 6.17
    • Spondyloepiphyseal dysplasia, congenita 6.17
    • Stickler syndrome, type 1 6.17
    • Stickler Syndrome, Type I, Nonsyndromic Ocular 6.17
    • Strudwick syndrome 6.17
    • Parkinson Disease 1, Autosomal Dominant 6.15
    • Parkinson Disease 4, Autosomal Dominant Lewy Body 6.15
    • Sepsis 6.15
    • Hyaloid Retinal degeneration of Wagner 5.83
    • Mega Epiphyseal dwarfism 5.83
    • Otospondylomegaepiphyseal Dysplasia 5.83
    • Spondylometaphyseal dysplasia, Kozlowski type 5.83
    • Mammary Neoplasms, Animal 5.82
    • Nevus, Sebaceous of Jadassohn 5.71
    • Skin Neoplasms 5.67
    • Chondrosarcoma 5.63
    • Femur Head Necrosis 5.48
    • Muscular Dystrophy, Animal 5.28
    • Mammary Neoplasms, Experimental 5.25
    • Penile Neoplasms 5.25
    • Seminoma 5.25
    • Amino Acid Metabolism, Inborn Errors 5.23
    • Urinary Bladder Neoplasms 5.17
    • Cardiofaciocutaneous syndrome 5.16
    • Costello Syndrome 5.16
    • Splenic Neoplasms 5.16
    • Diabetes Mellitus, Experimental 5.13
    • Autism 5.09
    • Neoplastic Processes 5.08
    • Lameness, Animal 5.05
    • Diabetes Mellitus, Type 2 5.02
    • Gaucher disease 5.0
    • Disease Susceptibility 4.97
    • Melanoma 4.96
    • Bowen's Disease 4.94
    • Soft Tissue Neoplasms 4.89
    • Neoplasms, Second Primary 4.86
    • Noonan Syndrome 4.86
    • Bone Marrow Neoplasms 4.83
    • Lymphoma, AIDS-Related 4.8
    • Ceroid lipofuscinosis, neuronal 1, infantile 4.73
    • Synovitis 4.68
    • Scleroderma, Localized 4.67
    • Myopia 4.66
    • Osteochondrodysplasias 4.64
    • Thyroid cancer, follicular 4.64
    • Infarction 4.63
    • Leiomyosarcoma 4.63
    • Liver Neoplasms 4.61
    • Somatosensory Disorders 4.59
    • Nervous System Diseases 4.57
    • Lewy body dementia 4.55
    • Manganese Poisoning 4.44
    • Tongue Neoplasms 4.41
    • Lymphoma, B-Cell 4.35
    • Nerve Degeneration 4.34
    • Hepatolenticular Degeneration 4.3
    • Uterine Neoplasms 4.27
    • Hepatic Veno-Occlusive Disease 4.26
    • Hyperbilirubinemia 4.26
    • Stomatitis 4.22
    • Head and Neck Neoplasms 4.13
    • Arthritis 4.11
    • Myocardial infarction 4.11
    • Intellectual Disability 4.1
    • Small cell lung carcinoma 4.09
    • Mucositis 4.05
    • Pancytopenia 4.04
    • Hodgkin's lymphoma 4.03
    • Alcohol dependence 4.02
    • Kidney disease 4.02
    • Mycoplasma Infections 4.02
    • Cataract 4.01
    • Arthralgia 4.0
    • Recurrence 3.99
    • Agranulocytosis 3.98
    • Edema 3.95
    • Copper-Overload Cirrhosis 3.93
    • Hearing Loss, Sensorineural 3.93
    • Dilated cardiomyopathy 3.91
    • Adenoma, Liver Cell 3.86
    • Anemia, Aplastic 3.85
    • Neuroblastoma 3.84
    • Hypertrophy 3.81
    • Lung adenocarcinoma 3.81
    • Mouth Neoplasms 3.81
    • Esophageal Neoplasms 3.79
    • Multiple myeloma 3.79
    • Carcinoma, Adenoid Cystic 3.78
    • Lymphoma, Non-Hodgkin 3.78
    • Arthritis, Experimental 3.77
    • Erythema 3.77
    • Papilloma 3.76
    • Neurodegenerative Diseases 3.75
    • Osteoarthritis 3.73
    • Abortion, Spontaneous 3.72
    • Amphetamine-Related Disorders 3.72
    • Pulmonary Fibrosis 3.72
    • Thyroid carcinoma 3.72
    • Breast carcinoma 3.71
    • Muscle Weakness 3.7
    • Leukopenia 3.67
    • Liver Failure, Acute 3.65
    • Carcinoma, Non-Small-Cell Lung 3.64
    • Ventricular Dysfunction, Left 3.63
    • Myocardial Ischemia 3.61
    • Brain Injuries 3.6
    • Parkinsonian Disorders 3.6