Sustained Release of Bone Morphogenetic Protein-4 in Adult Rabbit Extraocular Muscle Results in Decreased Force and Muscle Size: Potential for Strabismus Treatment

Abstract

Purpose. To assess the effect of a sustained-release preparation of bone morphogenetic protein-4 (BMP-4) on EOM force generation and muscle size. Methods. Sustained-release pellets, releasing 500 nanograms/day of BMP-4 for a maximum of 3 months, were implanted beneath the superior rectus muscle (SR) belly in anesthetized adult rabbits. The contralateral side received a placebo pellet as a control. After 1, 3, and 6 months, SRs were removed, and force generation at twitch and tetanic frequencies as well as fatigue resistance were determined in vitro. Myofiber size, myosin heavy chain isoform expression, and satellite cell density were assessed histologically. Results. SR force generation was significantly decreased by BMP-4 compared with the contralateral controls. Force generation was decreased by 25-30% by 1 month, 31-50% by 3 months, and at 6 months, after 3 BMP-4-free months, force was still decreased by 20-31%. No change in fatigue was seen. Significant decreases in muscle size were seen, greatest at 3 months. At all time points Pax7- and MyoD-positive satellite cell densities were significantly decreased. Conclusions. The decreased force generation and muscle size caused by sustained release of BMP-4 suggests that myogenic signaling factors may provide a more biological method of decreasing muscle strength in vivo than exogenously administered toxins. Treating antagonist-agonist pairs of EOM with titratable, naturally occurring myogenic signaling and growth factors may provide safe, efficacious, nonsurgical treatment options for patients with strabismus.