Acceleration by MS-818 of early muscle regeneration and enhanced muscle recovery after surgical transection

Abstract

The synthesized pyrimidine compound MS-818 has neurotrophic effects in several kinds of neuronal cells, but its effect with respect to muscle cells remains unknown. We therefore examined the effects of MS-818 on regeneration for 12 weeks in a wounded area (damaged and gap areas) of cut muscle in adult rats. The right semitendinosus muscles of reated and control groups were severed and sutured at the belly and the left semitendinosus muscles were left intact. MS-818 was administered intraperitoneally to the treated group at a dose of 5 mg/kg once daily. Control rats received an equal volume of physiological saline. A reference group underwent no surgical procedure. MS-818 significantly increased the maximal isometric twitch tension (Tmax) compared to control and reference rats after week 4 (approximately 1.4-fold control value; 0.6-fold reference value). Northern blotting showed that MS-818 enhanced myogenin mRNA expression to about 1.5-fold above the control level at 2, 4, and 7 days after surgery. Immunohistochemical and histochemical studies showed significant enhancement in the treated group since myogenic cells expressed desmin and were positive for neonatal myosin, and the fiber diameters and numbers of premature myofibers and end plates were increased when compared with those in the control group. These results show that MS-818 accelerated the proliferation and differentiation of activated satellite cells and the fusion of myotubes to form immature myofibers. At week 12, Tmax, fiber diameter, and number of end plates in the treatment group recovered 60, 85, and more than 100%, respectively, compared to the reference group. The mechanism of MS-818 effects on the accelerated regeneration of cut muscle is discussed. © 2002 John Wiley & Sons, Inc. Muscle Nerve 25: 218–229, 2002 DOI 10.1002/mus.10028