EXPRESSION OF UTROPHIN (DYSTROPHIN-RELATED PROTEIN) DURING REGENERATION AND MATURATION OF SKELETAL-MUSCLE IN CANINE X-LINKED MUSCULAR-DYSTROPHY

The regulation of utrophin, the autosomal homologue of dystrophin, has been studied in the canine X-linked model of Duchenne muscular dystro phy. Dystrophic muscle has been shown to exhibit abnormal sarcolemmal expression of utrophin, in addition to the normal expression at the ne uromuscular junction, in peripheral nerves, vascular tissues and regen erating fibres. To establish whether this abnormal presence of utrophi n in dystrophic muscle is a consequence of continued expression follow ing regeneration, or is attributable to a disease related up-regulatio n, the expression of utrophin was compared immunocytochemically with t hat of dystrophin, beta-spectrin and neonatal myosin in regenerating n ormal and dystrophic canine muscle, following necrosis induced by the injection of venom from the snake Notechis scutatis. In normal regener ating muscle, sarcolemmal utrophin and dystrophin were detected concom itantly from 2-3 d post-injection, prior to the expression of beta-spe ctrin. Down-regulation of utrophin was apparent in some fibres from 7 d, and it was no longer present on the extra-junctional sarcolemma by 14 d. Neonatal myosin was still present in all fibres at this stage, b ut dystrophin and beta-spectrin had been fully restored. In dystrophic regenerating muscle, downregulation of utrophin occurred from 7 d, al though it persisted on some fibres until 28 d, longer than in normal m uscle. At 42 d, however, utrophin in dystrophic muscle was only detect ed in a population of small fibres thought to represent a second cycle of regeneration, with no immunolabelling of mature fibres. The result s show that most utrophin is down-regulated in regenerating dystrophic fibres, prior to neonatal myosin, thus abnormal sarcolemmal expressio n of utrophin in dystrophic muscle is unlikely to be a continuation of the maturational process. Persistence of both utrophin and neonatal m yosin, however, suggest a delay in the maturation of dystrophic muscle . in addition, a second cycle of degeneration and regeneration in dyst rophic muscle does not occur whilst utrophin is still present, suggest ing it may have a protective role against fibre damage and necrosis.