Metabolic myopathy produced by acute inhibition of glyceraldehyde-3-phosphate dehydrogenase with ortho-iodosobenzoic acid.

A previously developed model of exercise-induced muscle contracture using iodoacetate to inhibit glyceraldehyde-3-phosphate dehydrogenase in rat hindlimb muscles produced selective type II myofiber damage. Utilizing a modification of the same model system, rats were given intra-aortic ortho-iodosobenzoic acid (700 nmol/kg body weight), which cleaves tryptophanyl peptides from glyceraldehyde-3-phosphate dehydrogenase. Within 2-4 h, spontaneous electrically-silent contracture developed in the injected musculature resulting in a plantar-flexed position of the hindlimb. After 24 h, the extensor digitorum longus and tibialis anterior muscles appeared grossly swollen (edematous) and discolored. Microscopically, the extensor digitorum longus (composed predominantly of type II myofibers) contained many randomly scattered, damaged myofibers, reduced glycogen content, absent glyceraldehyde-3-phosphate dehydrogenase activity, interstitial edema and focal collections of mononuclear phagocytes. Damaged fibers showed degenerative changes and contained stainable intracellular calcium. On modified trichrome-stained sections, an outer red staining rim of material was identifiable in many fibers. The fibers of the soleus muscle (composed predominantly of type I myofibers) were not damaged, indicating a preferential ortho-iodosobenzoic acid effect on type II myofibers.

Metabolic myopathy produced by dinitrofluorobenzene inhibition of creatine phosphokinase.

A previously developed animal model of exercise-induced muscle contractures, which utilized intra-aortic injection of iodoacetate (IOA) to inhibit the second stage glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, showed histological evidence of selective type II muscle fiber involvement with sparing of the type I muscle fibers. A new model has been developed using dinitrofluorobenzene (DNFB) as a selective inhibitor of creatine phosphokinase in a similar, but slightly modified distal aortic injection protocol. Two hours after the injection of a dinitrofluorobenzene solution of 2.22 mg/kg body weight, spontaneous electrically-silent contracture developed in the injected lower extremity, involving principally the soleus muscle. Histologically, selective damage was apparent in the type I muscle fibers, with sparing of the type II muscle fibers. The contrast in findings associated with iodoacetate inhibition of glycolysis or with DNFB inhibition of the phosphocreatine shuttle suggests that type I and type II fibers have markedly different usable pools of readily available ATP: type II fibers must rely on the minute-by-minute replenishment of the usable pool of ATP from glycolysis, while type I fibers must regenerate the usable pool of ATP from phosphocreatine through a creatine phosphokinase-mediated process.