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Growth factors in extraocular muscles: effects on contractile properties
Advisorvon Bartheld, Christopher S.
Biochemistry and Molecular Biology
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Extraocular muscles are a unique group of skeletal muscles, with distinct biological properties, including specialized myofiber types, a unique transverse and longitudinal organization of myofibers, continued muscle plasticity and the retention of activated progenitor cells in adult normal muscles. Those biological features of contractile physiology enable them to meet the specialized functional demands of extraocular muscles: rapid eye movements (the fastest movement in the human body) and precise eye positioning. When contractile properties of extraocular muscles are imbalanced, this causes strabismus, which is an urgent situation in infancy because it disrupts the development of normal neurovisual circuits and binocular vision. In this dissertation, I examined the effects of three growth factors, IGF1 (Insulin-like Growth Factor 1), CT1 (Cardiotrophin 1), and GDNF (Glial-cell line derived neurotrophic factor), on contractile properties of extraocular muscles, and I provide evidence that these growth factors regulate development and plasticity of extraocular muscles. In the first project, I tested the hypothesis that IGF1 and CT1 strengthen superior oblique muscles of juvenile chickens. Using orbital injection of exogenous IGF1 and CT1, I measured the contractile force (twitch tension and tetanic tension) and muscle mass with an in-situ protocol. Both IGF1 and CT1 treatment increased the contractile force of superior oblique muscles to a similar degree, and CT1 also increased muscle mass. My morphological results supported the physiological findings. Both growth factors increased the myofiber area in transverse sections of proximal muscle segments. Furthermore, the number of proliferating cells labeled by BrdU also increased significantly in proximal and middle segments. Based on these data, I concluded that IGF1 and CT1 strengthen superior oblique muscles through increased cross-sectional myofiber area caused by the proliferation of progenitor cells. My second project tested the hypothesis that the growth factors IGF1, CT1, and GDNF contribute to the fast contractile kinetics of extraocular muscles that complete one single twitch contraction in much shorter time than limb skeletal muscles do. Using an in situ protocol, I recorded the contractile kinetics (contraction time and half relaxation time) of superior oblique muscle treated with exogenous growth factors or function-blocking proteins. I found that exogenous CT1 and GDNF shortened contraction time, while exogenous IGF1 and CT1 shortened half relaxation time. Blocking the function of endogenous IGFs prolonged both contraction time and half relaxation time, while neutralizing antibodies against GDNF prolonged contraction time. By quantifying and comparing levels of gene expression of growth factors regulating the fast kinetics of extraocular muscles, I found that the mRNA expression of three growth factors and their receptors were higher in extraocular muscles than those in limb skeletal muscles, implying that contractile kinetics are regulated by the examined growth factors. In conclusion, three growth factors, IGF1, CT1, and GDNF, regulate the contractile properties of extraocular muscles. This new information may aid in the design of a pharmacological therapy for strabismus and other extraocular muscle disorders.