Yan Lin Wang

Myogenic hyperuricemia. A common pathophysiologic feature of glycogenosis types III, V, and VII

To identify the mechanism of hyperuricemia in glycogen storage diseases (glycogenoses) that affect muscle, we studied the effects of exercise and prolonged rest on purine metabolism in two patients with glycogenosis type III (debrancher deficiency), one patient with type V (muscle phosphorylase deficiency), and one patient with type VII (muscle phosphofructokinase deficiency). All had hyperuricemia except for one patient with glycogenosis type III. Plasma concentrations of ammonia, inosine, and hypoxanthine increased markedly in all the patients after mild leg exercise on a bicycle ergometer. The plasma urate concentrations also increased, but with a delayed response. Urinary excretion of inosine, hypoxanthine, and urate increased greatly after exercise, consistently with the increases in plasma levels. Hypoxanthine and urate concentrations were extremely high in the plasma and urine of the patient with glycogenosis type VII. With bed rest, the plasma hypoxanthine level returned to normal within a few hours, and the plasma urate concentration decreased from 18.6 to 10.6 mg per deciliter (1106 to 630 mumol per liter) within 48 hours. Similarly, the urinary excretion of these purine metabolites was reduced by bed rest. These findings indicate that muscular exertion in patients with glycogenosis types III, V, and VII causes excessive increases in blood ammonia, inosine, and hypoxanthine due to accelerated degradation of muscle purine nucleotides. These purine metabolites subsequently serve as substrates for the synthesis of uric acid, leading to hyperuricemia.

Exercise Induced Alteration of Erythrocyte Glycolysis Associated with Myogenic Hyperuricemia

Recently we reported ‘myogenic hyperuricemia’ in muscle glycogenosis types III, V and VII (Kono et al., 1986; Kono et al., 1987; Mineo et al., 1985; Mineo et al., 1987). The mechanism of myogenic hyperuricemia is: when energy production does not fill its requirement for continuing exercise, purine nucleotide degradation is accelerated (Fig. 1). The degradation of purine nucletide occurs even with mild exercise in these diseases. Its degradative metabolites such as inosine, hypoxanthine, and ammonia are released from working muscles into blood stream. Inosine and hypoxanthine are taken up by liver and metabolized to uric acid, causing hyperuricemia. In this study, we report exercise-induced alteration of erythrocyte glycolysis in muscle glycogenoses(Fig. 1), which is another metabolic consequence caused by accelerated purine nucleotide degradation in muscle.

Myogenic Hyperuricemia: A Comparative Study between Type V and Type VII Glycogenosis

Glycolysis subsequent to glycogen breakdown is one of the major energy(ATP)-generating systems necessary for muscle exercise. The metabolic process of glycolysis depends on the functional integrity of many enzymes. Glycogenosis types V and VII are genetic errors resulting in deficiencies of muscle phosphorylase and muscle phosphofructokinase, respectively. Patients with these diseases have common muscle symptoms such as easy fatigability, stiffness and pain during exercise. Hyper-uricemia or gout has been documented in some patients with glycogenosis types V and VII. We recently showed that excess purine degradation in exercising muscles due to impaired glycolysis or glycogen breakdown causes hyperuricemia (myogenic hyperuricemia) in these patients (Kono et al., 1986; Mineo et al., 1987). Interestingly, the incidence of hyperuricemia seems to be far greater in type VII than in type V. At least 9 of 26 patients with glycogenosis type VII have been reported to be hyperuricemic (Agamanolis et al., 1980; Hays et al., 1981; Zanella et al., 1982; Vora et al., 1983; Mineo et al., 1985; Fogelfeld et al., 1985; Kono et al., 1986). However, only a few among more than 100 patients with type V have been reported to be hyperuricemic (Hardiman et al., 1987; Kono et al., 1987). In order to elucidate the metabolic basis for the different incidence of hyperuricemia, we compared purine degradation in exercising muscles between type V and type VII glycogenosis.

Purine Degradation in Contracting Fast and Slow Muscles of Rats

We previously reported that hyperuricemia found in patients with glycogenosis types III, V, and VII was caused by excess purine degradation due to impaired ATP generation in muscles (myogenic hyperuricemia)(Kono et al., 1986, 1987; Mineo et al., 1987). Even minimal or mild exercise leads to elevated levels of blood inosine and hypoxanthine in patients with metabolic myopathy (Bertorini et al., 1985; Brooke et al., 1983; Hara et al., 1987; Kono et al., 1986; Mineo et al., 1985). Inosine and hypoxanthine serve as precursors of uric acid in the liver. When ATP is utilized during strenuous contraction of skeletal muscle, AMP is deaminated to IMP by AMP deaminase (EC. 3.5.4.6). AMP and IMP are broken down into adenosine and inosine, respectively, by 5′-nucleotidase (EC. 3.1.3.5). It has been reported that regulation of adenine nucleotide degradation is different between fast and slow muscles. Bookman et al. (1983) reported that nucleosides increased in proportion to an increase in lactate in cat slow muscles but not in fast muscles. Meyer et al. (1979) reported that large amount of IMP was produced in fast muscles but there was no significant increase in IMP in slow muscles during ischemic contraction, while Whitlock et al. (1987) showed adenine nucleotide deamination to IMP could occur in slow muscles under specific contraction conditions. However, difference in purine degradation between fast and slow muscles is still controversial. This study was designed to clarify overall purine degradation and its regulation in different types of rat skeletal muscles during ischemic contraction.

Family study of hereditary xanthinuria--decreased duodenal xanthine oxidase activity and increased urinary excretion of xanthine and hypoxanthine in heterozygotes.

Hereditary xanthinuria is caused by a defect of xanthine oxidase (EC. 1.2.3.2) and inherited with an autosomal recessive manner (Auscher et al., 1977; Wilson et al., 1974). It is characterized by decrease of urate and increase of xanthine and hypoxanthine in blood and urine (Holmes et al., 1983).

71 FAMILY STUDY OF HEREDITARY XANTHINURIA -DECREASED DUODENAL XANTHINE OXIDASE ACTIVITY AND INCREASED URINARY EXCRETION OF XANTHINE AND HYPOXANTHINE IN HETEROZYGOTES

We studied two brothers with hereditary xanthinuria (xanthine oxidase deficiency) and their family members. The two brothers had extremely low concentrations of urate but markedly high concentrations of xanthine and hypoxanthine in plasma and urine. Xanthine oxidase activities were virtually absent in the duodenal mucosa. In their parents (presumed obligate heterozygotes), the activities of xanthine oxidase were about half that of normal subjects. Although plasma xanthine and hypoxanthine concentrations of the parents were normal, urinary xanthine and hypoxanthine excretions were significantly higher than those of normal subjects (xanthine, father 17.1 mg/g creatinine and mother 27.4 vs. normal controls 5.7 to 11.0; hypoxanthine, father 14.0 and mother 27.3 vs. controls 4.0 to 8.4). Similar changes in the metabolite concentrations were seen in at least 6 other relatives, suggesting they were heterozygotes. This study indicates that the presumed obligate heterozygotes of xanthine oxidase deficiency retained about half normal enzyme activities causing the partial metabolic blockage in vivo at this enzyme step.

49 PURINE DEGRADATION IN ISCHEMIC AND NON-ISCHEMIC CONTRACTING MUSCLES OF RATS

Degradation of purine nucleotides was evaluated in different types of rat skeletal muscle during ischemic and non-ischemic contraction. Extensor digitorum longus (EDL, fast) and soleus (slow) muscles were stimulated electrically via the sciatic nerve (5 Hz, 10 min). Under non-ischemic condition, the concentrations of IMP, inosine, adenosine, and hypoxanthine increased in EDL muscles but not in soleus muscles during stimulation. Under ischemic condition, these metabolites increased in both EDL and soleus muscles and the changes in concentrations of IMP and inosine were greater in ischemic EDL muscles. The increase in inosine had a strong positive correlation with that in IMP in ischemic EDL and soleus muscles, but the ratio, Δinosine/ΔIMP was smaller in EDL muscles. The increase in adenosine under ischemic condition was not significantly different between the two muscles. These findings suggest that ischemia enhances overall degradation of purine nucleotides in contracting fast and slow muscles, and that although the degradation of adenine nucleotides to IMP is greater in fast muscles than in slow muscles, the relative degradation rate of IMP to inosine with respect to the intramuscular IMP concentration is rather smaller in fast muscles.