Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Duchenne muscular dystrophy is an X-linked recessive disorder, primarily characterized by progressive muscle weakness and wasting. The disease results from the absence of dystrophin, however the precise molecular mechanisms leading to muscle pathology are poorly understood. Dystrophic muscles undergo increased oxidative stress and altered calcium homeostasis, which may contribute to myofiber loss by triggering both necrosis and apoptosis. Recent studies have identified ARC (apoptosis repressor with caspase recruitment domain) as an abundant protein in human muscle that can inhibit both hypoxia and caspase-8-induced apoptosis as well as protect cells from oxidative stress. To explore a potential role for ARC in protecting muscle fibers from dystrophic breakdown, we have cloned and characterized murine ARC and studied its expression in normal and dystrophic mouse muscle. ARC is expressed at high levels in striated muscle and displays fiber-type restricted expression patterns. ARC expression levels are normal in dystrophic mdx mice, although the intracellular localization pattern of ARC is slightly altered compared with normal muscles. Overexpression of ARC in transgenic mdx mice failed to alleviate the dystrophic pathology in skeletal muscles, suggesting that misregulation of the molecular pathways regulated by ARC does not significantly contribute to myofiber death.
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PMID:Characterization of ARC, apoptosis repressor interacting with CARD, in normal and dystrophin-deficient skeletal muscle. 1464 4

There is evidence that apoptotic cell death mechanisms contribute to muscle fibre loss in dystrophinopathies, but little knowledge about the activators of the final degrading caspase cascade in muscle fibre apoptosis. As mitochondria-related activation of this caspase cascade, through e.g. APAF-1, could not be proven in dystrophin-deficient muscle, this study searches for other prospective candidates that may directly trigger apoptotic cell degradation by mitochondria-independent pathways involving the interaction of tumour necrosis factor-alpha (TNF-alpha) and TRAIL with death receptors and subsequent activation of caspase-8. The expression of TNF-alpha, TNF-R1, TRAIL, NF-(kappa)B and caspase-8 were studied in muscle biopsy specimens from 14 patients with a dystrophinopathy [10 Duchenne muscular dystrophies (DMD), 2 Becker MD, and 2 DMD carriers] by immunohistochemistry and Western blotting. In all types of dystrophinopathies, necrotic muscle fibres undergoing myophagocytosis displayed strong expression of TNF-alpha, TNF-R1, and TRAIL, which, however, was attributed to phagocytosing cells and not to the muscle fibres themselves. There was no up-regulation in normal-shaped or atrophic non-necrotic muscle fibres, or in intact muscle fibre segments adjacent to segmental necrosis and myophagocytosis. The expression profiles of caspase-8 and NF-(kappa)B resembled that of normal control muscle. There were likewise no significant differences in the Western blot analyses between normal control and dystrophin-deficient muscle. Based on these findings, a contribution of TNF-alpha or TRAIL-mediated cell death pathways to muscle fibre apoptosis or necrosis in dystrophinopathies could not be confirmed.
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PMID:Tumour necrosis factor-mediated cell death pathways do not contribute to muscle fibre death in dystrophinopathies. 1579 80

Pressure ulcer is a complex and significant health problem. Although the factors including pressure, shear, and ischemia have been identified in the etiology of pressure ulcer, the cellular and molecular mechanisms that contribute to the development of pressure ulcer are unclear. This study tested the hypothesis that the early-onset molecular regulation of pressure ulcer involves apoptosis in muscle tissue. Adult Sprague-Dawley rats were subjected to an in vivo protocol to mimic pressure-induced deep tissue injury. Static pressure was applied to the tibialis region of the right limb of the rats for 6 h each day on two consecutive days. The compression force was continuously monitored by a three-axial force transducer equipped in the compression indentor. The contralateral uncompressed limb served as intra-animal control. Tissues underneath the compressed region were collected for histological analysis, terminal dUTP nick-end labeling (TUNEL), cell death ELISA, immunocytochemical staining, and real-time RT-PCR gene expression analysis. The compressed muscle tissue generally demonstrated degenerative characteristics. TUNEL/dystrophin labeling showed a significant increase in the apoptotic muscle-related nuclei, and cell death ELISA demonstrated a threefold elevation of apoptotic DNA fragmentation in the compressed muscle tissue relative to control. Positive immunoreactivities of cleaved caspase-3, Bax, and Bcl-2 were evident in compressed muscle. The mRNA contents of Bax, caspase-3, caspase-8, and caspase-9 were found to be higher in the compressed muscle tissue than control. These results demonstrated that apoptosis is activated in muscle tissue following prolonged moderate compression. The data are consistent with the hypothesis that muscle apoptosis is involved in the underlying mechanism of pressure-induced deep tissue injury.
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PMID:Muscle apoptosis is induced in pressure-induced deep tissue injury. 1964 27