The Origin of Urinary Creatine in Progressive Muscular Dystrophy 1

Abstract

In an earlier communication (1) an experiment was described in which the isotopic compositions of urinary creatine and creatinine excreted by a patient with progressive muscular dystrophy were studied after a feeding of glycine-N'5. It was found, that in the first few days urinary creatine was much more enriched with N'5 than was urinary creatinine, and that the isotope concentration in the creatine fell far more rapidly than did that in the creatinine. These results were taken to mean that the creatinuria, in this patient, was not a consequence of leakage of creatine out of skeletal muscle but rather represented newly formed creatine, synthesized in liver, which had failed to gain entry into muscle.The present study represents an extension of these observations on two additional patients. Essentially the same technique as previously described was utilized. In view of the fact that the "sarcosine-nitrogen" of creatine derives from glycine nitrogen in liver, as does the nitrogen of hippuric acid, it was considered of interest to compare the abundance of N15 in simultaneously excreted creatine and hippurate after feeding glycine-N'5. To facilitate hippurate isolation from urine, small amounts of sodium benzoate were administered from time to time to each subject. EXPERIMENTALClinical histories Subject T. K., a 31-year-old white male, has exhibited evidences of muscle dysfunction since the age of 4 and was diagnosed as having progressive muscular dystrophy

The Biosynthesis and Turnover of Oxalate in Normal and Hyperoxaluric Subjects *

“…Benzoate loading probably explains why hippurate glycine was less highly labeled than oxalate in the present studies, whereas in the studies of Crawhall and associates (25) free glycine (and presumably hippurate also) was more highly labeled than was oxalate. Finally, the studies reported herein offer additional evidence for the existence of multiple metabolic pools of glycine in poor equilibrium one with another, as previously suggested by studies of a number of other workers (14,27,28).…”

“…Urinary hippuric acid was isolated according to Quick (13) and purified by treatment with Darco and by repeated recrystallizations from hot water (14). The The cumulative incorporation of C14 into urinary oxalate (Figure 2) ranged from 0.027 to 0.081 per cent (mean, 0.051 per cent) of the administered dose of glycine 1-C14 in five control subjects.…”

The Metabolism of Creatine-1-C14 by Mice With Hereditary Muscular Dystrophy*

“…If this is also true for man, a decrease in the N'5 concentration of urinary creatinine would indicate a dilution of body creatine with unlabeled creatine. However, Roche and Benedict and their associates (18,19) found that the N15 concentration of urinary creatine was much higher than that of urinary creatinine even when the N15 concentration of urinary creatinine was decreasing. These two observations appear to be contradictory, unless it is assumed that the source of urinary creatine is different from the source maintaining tissue concentrations.…”

“…A similar defect in the muscular metabolism of creatine occurs in vitamin E-deficient animals (9,17) which also exhibit muscular weakness and wasting, but the primary change in creatine metabolism in progressive muscular dystrophy in man is thought to be a decreased total uptake of creatine because of the smaller muscle mass (18,19). Since the latter might be interpreted as indicating normal metabolism of creatine by the surviving skeletal muscle, it should be pointed out that some of the observations in patients with progressive muscular dystrophy suggest that the changes in creatine metabolism are similar to the changes found in dystrophic mice.…”

“…By contrast, the N'5 concentration of urinary creatinine from the normal subjects did not change during the observation period. Because of these findings it was suggested that the fraction of muscle creatine converted to-creatinine was increased in progressive muscular dystrophy (19).…”