Creatine and Creatinine Metabolism

Abstract

The goal of this review is to present a comprehensive survey of the many intriguing facets of creatine (Cr) and creatinine metabolism, encompassing the pathways and regulation of Cr biosynthesis and degradation, species and tissue distribution of the enzymes and metabolites involved, and of the inherent implications for physiology and human pathology. Very recently, a series of new discoveries have been made that are bound to have distinguished implications for bioenergetics, physiology, human pathology, and clinical diagnosis and that suggest that deregulation of the creatine kinase (CK) system is associated with a variety of diseases. Disturbances of the CK system have been observed in muscle, brain, cardiac, and renal diseases as well as in cancer. On the other hand, Cr and Cr analogs such as cyclocreatine were found to have antitumor, antiviral, and antidiabetic effects and to protect tissues from hypoxic, ischemic, neurodegenerative, or muscle damage. Oral Cr ingestion is used in sports as an ergogenic aid, and some data suggest that Cr and creatinine may be precursors of food mutagens and uremic toxins. These findings are discussed in depth, the interrelationships are outlined, and all is put into a broader context to provide a more detailed understanding of the biological functions of Cr and of the CK system.

Creatinine inhibits bacterial replication

“…It is widely accepted that CRN is a pharmacologically inactive waste product of muscle metabolism devoid of biological activity. 10,16 Thus, our discovery that this common nitrogenous waste molecule has antibacterial antibiotic properties is, to the best of our knowledge, unique and potentially of great interest. When tested at physiological levels (50-200 mM) on agar or in broth culture, CRN-HCl did not suppress bacterial growth relative to control cultures (data not shown) but when used between 10-100 mM, suppression of growth and killing of all bacterial species were observed including not only drug-resistant strains, such as methicillin-resistant Staphylococcus aureus, but also uncharacterized environmental bacterial strains as well.…”

Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics

“…67 However, this ratio may be elevated or normal in heterozygous CRTR females. Individuals with myopathy and/or low muscle mass may also have increased urinary creatine levels, 27,68 while inconsistent findings have been reported for patients with various kidney disorders. 27 Urinary creatine levels can also be significantly elevated in postprandial samples, particularly after consumption of meat or fish.…”

“…Individuals with myopathy and/or low muscle mass may also have increased urinary creatine levels, 27,68 while inconsistent findings have been reported for patients with various kidney disorders. 27 Urinary creatine levels can also be significantly elevated in postprandial samples, particularly after consumption of meat or fish. Creatine is also a popular and readily available dietary supplement, although this consideration is obviously more important in older patients.…”

“…25,26 While the majority of creatine is stored in skeletal muscle, CRTR is also found in the plasma membrane of kidney, brain, heart, colon, testis, and prostate cells. 27 CRTR deficiency is the most prevalent 30 GAMT deficiency often shows a more complex phenotype (intractable seizures, extrapyramidal movement abnormalities, and dysfunction of the basal ganglia), which may be attributed to the specific toxicity of accumulating guanidinoacetate. 5,24 Females heterozygous for SLC6A8 pathogenic variants may be asymptomatic or present with signs and symptoms of variable severity, ranging from learning disabilities to seizures.…”

Hypoxia decreases creatine uptake in cardiomyocytes, while creatine supplementation enhances HIF activation

“…CrT is a symporter that uses the energy accumulated in the sodium gradient across the membrane to drive the “uphill” transport of Cr into the cell. During the transport cycle, a Cl − ion is also translocated into the cell with a stoichiometry of 2Na + :1Cl − :1Cr (Wyss and Kaddurah‐Daouk 2000). Homeostasis of intracellular Cr content is therefore controlled by modulation of Cr transport capacity.…”