Yuefang Zhou1, Henry J Kaminski2, Bendi Gong3, Georgiana Cheng4, Jason M Feuerman5, Linda Kusner2. 1. Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, Missouri, United States. 2. Departments of Neurology, Pharmacology, and Physiology, George Washington University, Washington, DC, United States. 3. Department of Pediatrics, Washington University, St. Louis, Missouri, United States. 4. Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, United States. 5. Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States.
Abstract
PURPOSE: Myasthenia gravis demonstrates a distinct predilection for involvement of the extraocular muscles (EOM), and we have hypothesized that this may be due to a unique immunological environment. To assess this hypothesis, we took an unbiased approach to analyze RNA expression profiles in EOM, diaphragm, and extensor digitorum longus (EDL) in rats with experimentally acquired myasthenia gravis (EAMG). METHODS: Experimentally acquired myasthenia gravis was induced in rats by intraperitoneal injection of antibody directed against the acetylcholine receptor (AChR), whereas control rats received antibody known to bind the AChR but not induce disease. After 48 hours, animals were killed and muscles analyzed by RNA expression profiling. Profiling results were validated using qPCR and immunohistochemical analysis. RESULTS: Sixty-two genes common among all muscle groups were increased in expression. These fell into four major categories: 12.8% stress response, 10.5% immune response, 10.5% metabolism, and 9.0% transcription factors. EOM expressed 212 genes at higher levels, not shared by the other two muscles, and a preponderance of EOM gene changes fell into the immune response category. EOM had the most uniquely reduced genes (126) compared with diaphragm (26) and EDL (50). Only 18 downregulated genes were shared by the three muscles. Histological evaluation and disease load index (sum of fold changes for all genes) demonstrated that EOM had the greatest degree of pathology. CONCLUSIONS: Our studies demonstrated that consistent with human myasthenia gravis, EOM demonstrates a distinct RNA expression signature from EDL and diaphragm, which is based on differences in the degree of muscle injury and inflammatory response. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
PURPOSE:Myasthenia gravis demonstrates a distinct predilection for involvement of the extraocular muscles (EOM), and we have hypothesized that this may be due to a unique immunological environment. To assess this hypothesis, we took an unbiased approach to analyze RNA expression profiles in EOM, diaphragm, and extensor digitorum longus (EDL) in rats with experimentally acquired myasthenia gravis (EAMG). METHODS: Experimentally acquired myasthenia gravis was induced in rats by intraperitoneal injection of antibody directed against the acetylcholine receptor (AChR), whereas control rats received antibody known to bind the AChR but not induce disease. After 48 hours, animals were killed and muscles analyzed by RNA expression profiling. Profiling results were validated using qPCR and immunohistochemical analysis. RESULTS: Sixty-two genes common among all muscle groups were increased in expression. These fell into four major categories: 12.8% stress response, 10.5% immune response, 10.5% metabolism, and 9.0% transcription factors. EOM expressed 212 genes at higher levels, not shared by the other two muscles, and a preponderance of EOM gene changes fell into the immune response category. EOM had the most uniquely reduced genes (126) compared with diaphragm (26) and EDL (50). Only 18 downregulated genes were shared by the three muscles. Histological evaluation and disease load index (sum of fold changes for all genes) demonstrated that EOM had the greatest degree of pathology. CONCLUSIONS: Our studies demonstrated that consistent with humanmyasthenia gravis, EOM demonstrates a distinct RNA expression signature from EDL and diaphragm, which is based on differences in the degree of muscle injury and inflammatory response. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
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