Creatine and Creatinine Metabolism - Physiological Reviews

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1142 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80 On one hand, manipulations of the CK/PCr/Cr system were shown to induce myopathic changes. 1) Skeletal muscle of transgenic mice lacking MM-CK and/or sarcomeric Mi-CK displayed structural and functional alterations such as impaired burst activity, decreased rate constants for changes in muscle tension, and abnormal Ca 2� handling (see sect. VIID). The facts that these mice survive and reproduce, and that the phenotype is milder than previously suspected, may indicate that other systems (e.g., adenylate kinase) take over in part the function of CK (see sect. VIID). 2) With the caveat that the reagent may not be sufficiently specific, injection of the CK inhibitor 2,4-dinitrofluorobenzene (DNFB) into the aorta of rats caused a metabolic myopathy characterized by spontaneous muscle contractures in the hindlimbs and by selective destruction of type I fibers in both soleus and gastrocnemius muscles (233). 3) When fed to experimental animals, the Cr analog GPA competes with Cr for uptake into muscle and therefore results in considerable depletion of the muscle stores of Cr and PCr. In line with the fact that GPA and its phosphorylated counterpart PGPA represent poor CK substrates, a variety of pathological changes have been observed in skeletal muscles of these animals (see sect. VIIIB) (741, 1125). On the other hand, many (neuro)muscular diseases with different underlying defects are accompanied by a variety of disturbances in Cr metabolism. Examples are Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), facioscapulohumeral dystrophy, limb-girdle muscular dystrophy, myotonic dystrophy, spinal muscle atrophy, amyotrophic lateral sclerosis, myasthenia gravis, poliomyelitis anterior, myositis, or diabetic myopathy, to name just a few (for references, see Refs. 639, 826, 955, 1002, 1123). Common findings are increased Cr concentrations in serum and urine; stimulation of creatinuria by oral supplementation with Gly or Cr; decreased urinary Crn excretion; depressed muscle levels of Cr, PCr, P i, glycogen, and ATP; increased serum CK activities; as well as an increased MB-/MM-CK ratio in skeletal muscle, with the latter suggesting induction of B-CK expression in regenerating muscle fibers. In addition, a 67–86% decrease in Mi-CK activity or mRNA levels was reported for chickens with hereditary muscular dystrophy and rats with diabetic myopathy (585, 955). Depending on the particular muscle disease, these disturbances are more or less pronounced. Unfortunately, no sufficiently detailed studies have been published in recent years, whereas the older investigations were performed mostly with rather nonspecific analytical methods. Therefore, the above-mentioned findings await corroboration and expansion, which will hopefully allow us to unravel potential causal links between individual muscle diseases and disturbances of Cr metabolism. In DMD, increased plasma membrane fragility and subsequent leakage of cytosolic components due to dystrophin deficiency are generally accepted to be the primary defects. The muscle concentrations of Cr, PCr, and ATP, the ATP/ADP, PCr/Cr, and PCr/ATP ratios, as well as the phosphorylation potential are significantly decreased, whereas the calculated ADP concentration and intracellular pH are increased (88, 143, 211, 472). Conversely, serum [Cr] is increased, resulting in creatinuria, in considerably reduced tolerance toward orally administered Cr, and, very likely due to competition of Cr and GAA for reabsorption in the kidney, in elevated urinary excretion of GAA. The total bodily Cr pool is reduced because of both muscle wasting and a reduced Cr concentration in the remaining muscle mass, with the consequence that Crn production and urinary Crn excretion are largely decreased. By use of radioactively labeled Cr, Cr turnover was shown to be increased in DMD patients relative to controls, with half times for the decrease in isotope content of 18.9 � 5.1 and 39.8 � 2.6 days, respectively (245). This latter finding may be due either to impaired Cr uptake into muscle (57) or to an impaired ability of muscle to retain Cr. Most probably due to leakage of the plasma membrane and to continued necrosis of immature muscle fibers, both the total CK activity and the proportion of MB-CK in serum are dramatically increased (79, 190, 222, 755). Finally, disturbances of ion gradients across the plasma membrane were observed in skeletal muscle from DMD patients. The muscle concentration of Na � as well as the free intracellular [Ca 2� ] are increased, whereas the muscle levels of K � and P i are decreased. In serum, on the other hand, [K � ], [Ca 2� ], and [P i] are increased, whereas [Na � ] and [Cl � ] are decreased (see Refs. 143, 199, 755). Disturbances very similar to those seen in DMD were observed in mdx mice that display the same primary defect as DMD patients, namely, dystrophin deficiency, and in other dystrophic animal strains (see Refs. 143, 199, 201–203, 790, 799). Additionally, in skeletal muscles of mdx mice, the resting membrane potential was shown to be “decreased” from �70 to �59 mV (see Ref. 199). Remarkably, all pathological changes, i.e., muscle fiber necrosis as well as the disturbances in membrane permeability, in Cr and high-energy phosphate metabolism, and in serum CK activities, were not evident in mdx mice at birth, but only developed after 2–6 wk of life (202, 799, 982). Consequently, dystrophin deficiency alone does not seem to be sufficient to induce muscle damage, thus calling for other factors that may act in conjunction with dystrophin deficiency to bring about plasma membrane damage and muscle cell necrosis. Two hypotheses may be put forward to explain how disturbances in Cr metabolism may contribute to the progression of DMD and of other muscle diseases (see also Ref. 1123). 1) Loike et al. (571) have shown that increasing concentrations of extracellular Cr downregulate Cr transport activity in rat and human myoblasts and
July 2000 CREATINE AND CREATININE METABOLISM 1143 myotubes. Similarly, Cr supplementation of the diet downregulates Cr transporter expression in rat skeletal muscle (317). In muscle diseases that are characterized by decreased tissue levels of Cr and PCr, the muscle should respond to this deficit by an increased Cr uptake across the plasma membrane. However, because of the chronically increased serum concentration of Cr that is observed in many muscle diseases, the Cr transport activity may even be depressed, thereby resulting in a further depletion of the muscle stores of Cr and PCr. This progressive Cr depletion would likely compromise the energy metabolism of muscle and would make the muscle cells more vulnerable to (membrane) damage upon further use. 2) Let us assume that the changes in membrane permeability and the concomitant disturbances of ion gradients across the plasma membrane represent early events in pathological muscle fiber degeneration. Because the Cr transporter is driven by the electrochemical gradients of Na � and Cl � across the plasma membrane (see sect. IVB), the consequences would be a diminished rate of Cr uptake into muscle and partial depletion of the intracellular high-energy phosphate stores which, in turn, may further deteriorate ion homeostasis. If either of these purported vicious circles 1 or 2 were in fact operative, oral Cr supplementation may represent a promising strategy to alleviate the clinical symptoms and/or to slow or even halt disease progression. If only hypothesis 2 is correct, continuous supplementation with Cr is indicated. If, however, hypothesis 1 is valid, intermittent short-term supplementation with high doses of Cr is expected to provide superior results. In support of these hypotheses, preincubation of primary mdx muscle cell cultures for 6–12 days with 20 mM Cr prohibited the increase in intracellular Ca 2� concentration induced by either high extracellular [Ca 2� ]or hyposmotic stress (790). Furthermore, Cr enhanced mdx myotube formation and survival. Patients with chronic renal failure commonly present with muscle weakness and display disturbances in muscular Cr metabolism (see Refs. 93, 716). Histochemical studies revealed type II muscle fiber atrophy. In skeletal muscle of uremic patients, [ATP], [PCr], and [ATP]/[P i] are significantly decreased both before and after hemodialysis, whereas [Cr] and [P i] may either be unchanged or increased. Disturbances in ion homeostasis similar to those observed in DMD were also reported for uremic myopathy (99) and may be due, in part, to depressed Na � -K � -ATPase activity (648, 950). Nevertheless, the benefit of oral Cr supplementation for uremic subjects has to be questioned, since the plasma level of Cr most likely is normal, and since an increase in the total body Cr pool would be paralleled by a further increase in the plasma concentration of Crn which, in turn, is a precursor of the potent nephrotoxin methylguanidine (see sect. IXH). In gyrate atrophy of the choroid and retina, the disturbances of Cr metabolism seem to be brought about by a different series of events (Fig. 11). Gyrate atrophy is an autosomal recessive tapetoretinal dystrophy. The clinical phenotype is mainly limited to the eye, beginning at 5–9 yr of age with night blindness, myopia, and progressive constriction of the visual fields. By age 20–40 yr, the patients are practically blind. In addition to the retinal degeneration, type II muscle fiber atrophy, an increase in the proportion of type I muscle fibers with age, as well as the formation of tubular aggregates in affected type II fibers were observed in vastus lateralis muscle of gyrate atrophy patients (900). The underlying primary defect is a deficiency in mitochondrial matrix L-ornithine:2-oxo-acid aminotransferase (OAT; EC 2.6.1.13), the major enzyme catabolizing ornithine (see Refs. 95, 398, 792). Because of this deficiency, ornithine accumulates in the body, with the plasma concentration being raised 10- to 20-fold (450– 1,200 �M vs. �40–60 �M in controls) (897, 899). Ornithine, in turn, inhibits AGAT (K i � 253 �M) (897), the rate-limiting enzyme for Cr biosynthesis, and therefore slows production of both GAA and Cr (899). Accordingly, [GAA] is decreased in plasma and urine by a factor of 5 and 20, respectively. Similarly, [Cr] is reduced in plasma, FIG. 11. Disturbances of Cr metabolism in gyrate atrophy of the choroid and retina. Due to a block of L-ornithine:2oxo-acid aminotransferase, ornithine accumulates, competitively inhibits AGAT, and thereby depresses the rate of GAA and Cr biosynthesis. 1) L-ornithine:2-oxoacid aminotransferase; 2) AGAT; 3) GAMT.
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