Possible Involvement of Fas-Mediated Apoptosis in Eye Muscle Tissue from Patients with Thyroid-Associated Ophthalmopathy

Abstract

In order to investigate the possible involvement of apoptosis in the pathogenesis of thyroid-associated ophthalmopathy (TAO), we studied the expression of Fas, Fas ligand (FasL), and Bcl-2 in extraocular muscle tissues from patients with TAO by immunohistochemistry using monoclonal antibodies against Fas, FasL, and Bcl-2. Apoptosis was detected by in situ end-labeling of fragmented DNA. Apoptosis was detected in extraocular muscle tissues from 17 of 19 patients with TAO and, to a smaller degree in 4 of 7 normal control subjects. The mean percentages of apoptotic nuclei were 12.1% in TAO eye muscle fibers and 16.4% in TAO interstitial cells, compared with 2.2% and 0.4% in normal eye muscle fibers and interstitial cells, respectively. The percentage of apoptotic nuclei in eye muscle fibers correlated with the enlargement of eye muscle tissue (r = 0.47, p < 0.05). Fas was demonstrated on the surfaces of extraocular muscle fibers in 11 of 18 patients with TAO, but not in normal extraocular muscle tissues. Neither TAO nor normal extraocular muscle tissues expressed Bcl-2. FasL was detected in infiltrating mononuclear cells in extraocular muscle tissue from a patient with TAO. These data suggest that Fas-mediated apoptosis may occur in extraocular muscle tissue from patients with TAO and may be involved in the late stage of TAO.

Activated Satellite Cells in Extraocular Muscles of Normal Adult Monkeys and Humans

“…It is also possible that some percentage of these activated satellite cells may apoptose and never integrate into existing myofibers. Our laboratory and others have recently demonstrated that there a certain amount of apoptosis that occurs in normal, uninjured adult rabbit 9 and human 39 EOMs, and this has been corroborated by the presence of apoptotic markers demonstrated by expression profiling. 40 However, the demonstrated occurrence of myonuclear addition into uninjured myofibers of EOMs in both mature rabbits 7 and mice 8 certainly supports the notion that at least some, if not most of these activated satellite cells would follow the same pathway in both human and monkey EOM and fuse into existing myofibers.…”

Deficiency of the Bax gene attenuates denervation-induced apoptosis

“…3,50 Clinical reports have well documented that apoptosis is involved in a variety of muscle Wild-type Bax -/-disorders including spinal muscular myopathies, peripheral neuropathies, amyotrophic lateral sclerosis, muscle dystrophies, metabolic/mitochondrial myopathies, inflammatory myopathies, congenital myopathies, distal myopathies, thyroid-associated ophthalmyopathies, chronic heart failure-associated myopathies, critical ill myopathies, and burn injury-associated muscle wasting. 3,4,7,8,[51][52][53][54][55][56][57][58][59] A recent study clearly demonstrated that inhibition of apoptosis improves the outcome of skeletal muscle wasting pathology in the genetically knockout mice that were deficient of the laminin-α2 gene, an animal model of congenital muscular dystrophy. 60 By adopting genetic intervention by crossbreeding the laminin-α2-deficient mice with pro-apoptotic Bax-deficient mice or with mice carrying the muscle-specific anti-apoptotic Bcl-2 transgene, Girgenrath and colleagues 60 have shown that the extent of muscle pathology is ameliorated by either inactivation of the pro-apoptotic protein Bax or overexpression of the anti-apoptotic protein Bcl-2.…”

Management of Graves' Ophthalmopathy: Reality and Perspectives

“…Antibodies to the other eye muscle antigens might then represent a secondary phenomenon after eye muscle damage and antigen exposure. Recently, evidence of Fas-mediated apoptosis was provided in extraocular muscle tissue from GO patients (75), but this is likely to represent a late event in the course of eye disease, preceding fibrotic changes in eye muscles.…”