Creatine synthesis in the skeletal muscle: the times they are a-changin’

A traditional dogma of creatine metabolism claims a spatial separation between the production and utilization of endogenous creatine (1), the main high-energy phosphate-storage molecule in mammals. Creatine (2-[carbamimidoyl(methyl)amino]acetic acid) is formed by the methylation of guanidinoacetic acid, a reaction catalyzed by guanidinoacetate N-methyltransferase (GAMT) expressed mainly in the liver, kidney, pancreas, and testis. Creatine is then released into the circulation and taken up predominantly by the skeletal muscle, the main organ of creatine deposition and usage. The Human Protein Atlas catalogs absent expression of GAMT protein in the muscle tissues [https://www.proteinatlas.org/ENSG00000130005-GAMT], suggesting no creatine biosynthesis inside the myocytes. However, both earlier and contemporary studies document otherwise, with the myocardium and skeletal muscle appear to have their own machinery for creatine synthesis, which perhaps calls for adjusting an old paradigm.

Back in 1985, Dr. Marie Daly from Albert Einstein College of Medicine was arguably the first who demonstrated GAMT activity in the cardiac ventricle and thigh muscle, with low-to-medium GAMT expression found in those tissues calculated to provide up to 4 mM creatine per liter of intracellular water per day (2). Although skeletal muscle GAMT activity was ∼31.5% of the enzyme activity found in the hepatocytes (0.82 vs. 2.6 nmol/mg protein/h), this rate could have the potential to maintain the physiological levels of total creatine needed in this organ. Another interesting study found high GAMT protein expression in different muscles of young postnatal control rats and animal models of Duchenne muscular dystrophy (3), implying an upregulation of creatine synthetic pathway in development/regeneration conditions with impaired cellular bioenergetics. Russell et al. (4) found GAMT protein expression in skeletal muscles of both creatine transporter knockout mice and wild-type mice, with the creatine synthesis rate by the enzyme in the wild-type mice gastrocnemius muscle (1.06 nmol/mg protein/h) slightly higher than reported in a previous trial (2). Finally, a recent study identified muscular expression of GAMT in mice, cattle, and pigs (5), this data give positive evidence for residual GAMT expression.

A limited yet existent GAMT-mediated production of creatine in mammalian muscles could offer a metabolic advantage for conditions characterized by underdeveloped or damaged transport of creatine inside the muscle. De novo creatine synthesis in the myocytes may thus help in maintaining muscle creatine levels and limit cellular energy failure in various neuromuscular disorders (3). Besides, as the skeletal muscle comprises the largest organ in the body, even the lower expression/activity of GAMT could be sufficient enough to provide all creatine needed in this tissue, thus putting forward a decentralization theory of creatine synthesis. This might be particularly highlighted within the group of primates who experience a shift to higher muscular GAMT expression compared with reptiles, birds, and other mammals (5), perhaps illustrated by a rather high GAMT RNA expression (222.2 NX) in the human skeletal muscle [https://www.proteinatlas.org/ENSG00000130005-GAMT]. Further species- and tissue-specific studies are highly warranted to confirm this “decentralization theory” of creatine synthesis while controlling for relevant environmental factors and genetic traits.

DISCLOSURE

No conflicts of interest, financial or otherwise, are declared by the author.

AUTHOR CONTRIBUTIONS

S.O. analyzed data; interpreted results of experiments; drafted manuscript; edited and revised manuscript; and approved final version of manuscript.