Creatine metabolism and the consequences of creatine depletion in muscle

Abstract

Currently, considerable research activities are focussing on biochemical, physiological and pathological aspects of the creatine kinase (CK) -phosphorylcreatine (PCr) -creatine (Cr) system (for reviews see [1,2]), but only little effort is directed towards a thorough investigation of Cr metabolism as a whole. However, a detailed knowledge of Cr metabolism is essential for a deeper understanding of bioenergetics in general and, for example, of the effects of muscular dystrophies, atrophies, CK deficiencies (e.g. in transgenic animals) or Cr analogues on the energy metabolism of the tissues involved. Therefore, the present article provides a short overview on the reactions and enzymes involved in Cr biosynthesis and degradation, on the organization and regulation of Cr metabolism within the body, as well as on the metabolic consequences of 3-guanidinopropionate (GPA) feeding which is known to induce a Cr deficiency in muscle. In addition, the phenotype of muscles depleted of Cr and PCr by GPA feeding is put into context with recent investigations on the muscle phenotype of 'gene knockout' mice deficient in the cytosolic muscle-type M-CK. (Mol Cell Biochem 133/134: 51-66, 1994).

Creatine: a miserable life without it

“…A lack of creatine, as seen in creatine deficiency syndromes due to either genetic defects of the enzymes involved in endogenous creatine synthesis, AGAT or GAMT (Stockebrand et al 2016;Schulze et al 2016), or genetic defects in the creatine transporter (CrT) (Santacruz and Jacobs 2016;Perna et al 2016), leads to more or less severe neuromuscular and neurological phenotypes, similar to what is seen in CK-deficient (Streijger et al 2005) or creatine-depleted (GPA) animal models (Wyss and Wallimann 1994). Thus, a specific caveat should be announced here for women who consume vegan or vegetarian diets, and thus who have lower levels of total creatine in their body organs, to either switch their diet to allow for fresh meat and fish during pregnancy or to supplement with highly pure creatine in order to support healthy embryonic and neonatal development (see Wallimann et al 2011).…”

Supranormal Myocardial Creatine and Phosphocreatine Concentrations Lead to Cardiac Hypertrophy and Heart Failure

“…Creatine is not synthesized in the heart but is taken up by cardiomyocytes against a large concentration gradient via the Na ϩ -creatine cotransporter (creatine transporter, CrT). 20 Most likely, downregulation of creatine transport is the major mechanism leading to creatine and PCr depletion in the failing heart. 21 We have previously attempted to increase myocardial creatine and PCr levels in normal and failing hearts by feeding rats a diet containing 3% creatine.…”

Exercise restores insulin, but not adiponectin, response in skeletal muscle of high-fat fed rodents

“…To our knowledge, this is one of the first studies to determine metabolic effects of ␤-GPA supplementation of this brief duration, as most studies with chronic supplementation extend between 4 and 10 wk (26,27,38). Prolonged supplementation typically decreases intramuscular PCr and ATP by ϳ90% and 50%, respectively (35), leading to increased phosphorylation of AMPK (34), increased GLUT-4 expression, and mitochondrial biogenesis (23,41). In the current study, 1 wk of ␤-GPA supplementation induced a 46% decrease in intramuscular PCr content, without corresponding changes in ATP, AMPK phosphorylation, or GLUT-4 content.…”

“…Rats were fed a HF diet for 4 wk to induce soleus muscle insulin and Ad resistance. This was followed by 1 or 2 wk of intervention with either treadmill exercise training, or dietary supplementation of ␤-guadinoproprionic acid (␤-GPA), a pharmacological insulinsensitizing agent that decreases intramuscular phosphagen stores and promotes metabolic adaptations in muscle similar to those induced by endurance exercise training (23,27,35). We hypothesized that exercise training or pharmacological inter-vention would restore muscle Ad response, and this would precede or coincide with the recovery of insulin response.…”