Chronic phenytoin administration alters the metabolic profile of superficial gastrocnemius muscle fibers in dystrophic mice.

Phenytoin is known to reduce neural overactivity (pseudomyotonia) affecting the hind limb musculature in C57B1/6J dystrophic (dy2J/dy2J) mice. This study reports a change in the metabolic profile of superficial gastrocnemius muscle fibers from dy2J/dy2J animals after chronic phenytoin treatment. The superficial gastrocnemius muscle region from normal mice is composed of 98% fast-twitch glycolytic muscle fibers. In dystrophic mice these fibers (FG) show increased oxidative capacity without evidence of morphologic degeneration during the first few months ex utero. Many of these fibers also store abnormally large amounts of glycogen as determined by periodic acid-Schiff histochemistry. After 104 days of phenytoin treatment, the dy2J/dy2J FG muscle fibers showed a reduction in abnormally high oxidative capacity as monitored by succinic dehydrogenase activity; there was also a reduction of glycogen storage in a number of dy2J/dy2J fibers. One hypothesis suggests that the increase in oxidative capacity of the dy2J/dy2J superficial gastrocnemius muscle fibers is the expected result of overstimulation by the pseudomyotonia. Our experiments indicated that the abnormal metabolic profile observed in those fibers can be altered simply by a reduction in pseudomyotonia. These results mimic those seen after short-term denervation of the same dy2J/dy2J muscle. After phenytoin treatment the mean dy2J/dy2J superficial gastrocnemius muscle fiber cross-sectional area was significantly increased compared with untreated animals. Cursory examination of the degenerated deep region of this same muscle suggested that similar changes did not occur after drug treatment. This suggests that the pseudomyotonia was partially different from the factor(s) causing early degeneration of the oxidative muscle fibers in the dy2J/dy2J animals.