Medico! Hyporheses (1998) 51.333-336 0 Harcourt Brace & Co Ltd 1998 ReferPnce #!J The therapeutic potential of oral creatine supplementation in muscle disease M. WYSS, S. FELBER”, D. SKLADAL+, A. KOLLER*, C. KREMSER”, W. SPERL’ Departments of Transplant Surgery, *Magnetic Resonance Imaging, ‘Pediatrics and *Sports Medicine, University of Innsbruck, Innsbruck, Austria;* Children’s Hospital, LKA Salzburg, Austria. Correspondence to: M. Wyss PhD, F. Hoffmann-La Roche Ltd, Vitamins and Fine Chemicals Division, Biotechnology Section, 5ldg 93/456, CH-4070 Base/, Switzerland (Phone: +41 67 688 2972; Fax: +47 67 688 7645; e-mail: markus.wyss@roche.com) Abstract -The decrease in intracellular creatine concentration observed in a number of muscle diseases may deplete energy homeostasis and may, therefore, be one of the factors determining and/or aggravating muscle weakness and degeneration. Two hypotheses are put forward in the present communication to explain: (i) the mechanisms leading to the disturbances in creatine metabolism found in various muscle diseases; and (ii) the potential of oral creatine supplementation in alleviating the clinical symptoms. Introduction Creatine kinase (CK, EC 2.7.3.2), phosphorylcreatine (PCr) and creatine (Cr) are involved in the energy metabolism of cells and tissues with high and fluctu- ating energy demands like skeletal and cardiac muscle, brain, retina and spermatozoa (for reviews see refs 1,2). CK isoenzymes catalyze the reversible transfer of the y-phosphate group of adenosine S-tri (ATP) to the guanidino group of Cr to yield PCr and adenosine S-diphosphate (ADP). Since, in skeletal muscle, PCr and Cr are present in much higher con- centration and are smaller and less negatively charged molecules than ATP and ADP, they serve both as a ‘reservoir’ for ‘high-energy phosphates’ during short periods of intense work and as a ‘transport device’ allowing for a higher flux of high-energy phosphates within the cells during endurance exercise. Several lines of experimental evidence indicate that derangements in the proper function of the CW Recewed 25 June 1997 Accepted 9 September 1997 PCr/Cr system - either on the enzyme or on the substrate level - are associated with impaired muscle function. Transgenic mice lacking the cytosolic CK isoenzyme in muscle are unable to perform burst acti- vity, i.e. they have lost the ability to sustain maximal muscle output during short periods of high-resistance work (3,4). Furthermore, the rate constant for tension recovery after stretching of the muscle fibers is greatly decreased in these transgenic animals (5). Injection of the CK inhibitor 2,4-dinitrofluorobenzene into the aorta of rats causes a metabolic myopathy charac- terized by spontaneous contractures in the hindlimbs, involving mainly the soleus muscle, and by selective type I muscle fiber degeneration (6). Finally, the intra- cellular Cr pools can be depleted by feeding of rats or mice with the Cr analogue 3-guanidinopropionic acid (3-GPA), which competes with Cr for uptake into muscle cells. 3-GPA feeding results in various pathological muscle changes (for a review see ref 7) and aggravates thyrotoxic myopathy in mice (8). 333