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S. Bose, K. Rarey, A. Chen, C. Kenney, K. Waymire, D. Wallace; Mitochondrial Changes in Extraocular Muscles of Hyperthyroid C57BL/6 Mice . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5730.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To evaluate histological, ultrastructural and histochemical changes in the extraocular muscles (EOM) of experimentally induced hyperthyroid mice.Thyroid eye disease (TED) is the clinical involvement of the eyes seen in hyperthyroidism and is characterized by an orbital inflammatory process involving EOMs resulting in visual morbidity . Since mitochondria, the major site of oxidative phosphorylation (OXPHOS) in the cell, are considered a likely target for the action of 3,3’,5 Triiodo–L–Thyronine (T3), it is hypothesized that T3–induced hyperthyroidism might result in a reduction of mitochondrial energy and OXPHOS generation with or without structural alteration in the EOMs causing the myopathy seen in TED. Methods: T3 hyperthyroidism was induced in 6–8 weeks old, female wild–type C57BL/6 mice, using daily intraperitoneal injections of 5µg/100g body weight T3 (hyperthyroid group, n=16) for 4 weeks. All animals were monitored for clinical evidence of hyperthyroidism. At 4 weeks, animals were humanely sacrificed and blood was analyzed for T3 and TSH. Orbital dissection for EOM studies including light and electron microscopy, and dual histochemical stains using cytochrome c oxidase (COX, complex IV respiratory chain, encoded by mtDNA) and succinate dehydrogenase (SDH, complex II, encoded by nuclear DNA) were performed. All results were compared with the control group (n=20) that received intraperitoneal injection of the vehicle. Results: T3 and TSH levels in hyperthyroid mice (mean 398±50 ng/dl; <0.01 µIU/ml) vs. control mice (182±45; 0.2±0.01) confirmed clinical hyperthyroidism (p<0.01). In contrast to controls, the EOMs of hyperthyroid mice demonstrated interstitial edema with deposition of protein–like material with no cellular infiltration, COX deficient–SDH positive muscle cell infiltration (representing mitochondrial damage), and elongated abnormal looking mitochondria. EOM mitochondria in the hyperthyroid mice were seen to aggregate near the cell membrane in contrast to their linear alignment by the sarcomere seen in the controls. Conclusions: The presence of COX–deficient EOM cells and abnormal mitochondria in this mouse hyperthyroid model suggest that mitochondria may play a significant role in the pathogenesis of TED.
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