Abstract
Purpose :
Previous studies have implicated glial derived neurotrophic factor (GDNF) in the development of strabismus. Microarray studies of extraocular muscles from subjects with strabismus showed decreased GDNF gene expression (Agarwal et al., 2016). A previous study showed that early sustained GDNF treatment of infant non-human primates resulted in the development of a significant strabismus (McLoon et al., 2016). To further investigate the effect of GDNF in extraocular muscles, we analyzed twitch and muscle fiber properties of adult rabbit superior rectus muscles following sustained GDNF treatment.
Methods :
Pellets were implanted under superior rectus muscles of adult rabbits, supplying GDNF at a dose of 1μg/day with a placebo pellet transplanted on the contralateral side. One month after implantation, the GDNF and placebo muscle forces were determined using in vitro physiological methods, and these data were compared to naïve control muscles. Muscles were processed for histology and myofiber cross-sectional areas were determined.
Results :
Analysis of muscle force generation parameters at 10 hertz (hz) showed significant decreases in time to 50% relaxation and time to 100% relaxation for the GDNF treated muscles, on average over 30% longer, compared to naïve controls. There were minimal changes in the placebo treated muscles compared to controls. The maximum rate of relaxation was significantly reduced for the GDNF (36% slower) and placebo (16% slower) treated muscles when compared to naïve controls. No changes were seen in time to peak force, maximum rate of contraction, or in total force generated at 10hz. Myofibers of the GDNF treated muscles were significantly larger than naïve control muscles along the length of the treated muscles, on average 2-fold larger.
Conclusions :
Sustained GDNF treatment of adult rabbit superior rectus muscles caused significant changes to overall time and rate of muscle relaxation after 10hz stimulation. In addition, treated myofibers were significantly larger after 1 month of GDNF treatment. These functional studies, combined with the evidence that muscles from human strabismus subjects had decreased GDNF gene expression and that sustained GDNF treatment of infant monkey muscles induced strabismus, support the hypothesis that altered GDNF signaling between the muscles and their innervating motor neurons may play a role in the etiology of infantile strabismus.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.