Role of exogenous and endogenous trophic factors in the regulation of extraocular muscle strength during development.

Abstract

Weak eye muscles can cause ophthalmic disorders, and in particular, strabismus. Exogenous trophic factors such as cardiotrophin (CT)-1 and insulin-like growth factor (IGF) have been shown to increase the contractile force of adult heart and skeletal muscles, respectively. In the current study, the effects of endogenous and exogenous trophic factors on extraocular muscle strength and mass were examined in the developing chicken. Superior rectus and superior oblique muscles of hatchling chicks were treated in vivo either to increase levels of trophic factors CT-1, IGF-I, glial cell line-derived neurotrophic factor (GDNF), or brain-derived neurotrophic factor (BDNF), or to decrease their levels with neutralizing antibodies and binding proteins. Forty-eight hours after factors were injected into the orbit, the contractile force of dissected muscles was measured in vitro and the morphology of muscle fibers was compared between control and treated muscles. Treatment with CT-1 or IGF-I significantly increased the mean single-twitch force generation and these trophic factors increased muscle fiber diameters when compared to control muscles. A cocktail of antibodies and binding proteins, directed against endogenous IGF-I, GDNF, and CT-1, significantly decreased mean single-twitch force. This cocktail slightly, but significantly, reduced muscle fiber diameters within treated extraocular muscles. Endogenous trophic factors regulate and/or maintain extraocular muscle force through a rapid mechanism that appears to involve changes in muscle mass and specifically enlargement of muscle fiber diameters. CT-1 and IGF-I may be considered promising candidate trophic factors for therapeutic strengthening of eye muscles in the developing extraocular muscle system.