title: Tumour necrosis factor-mediated cell death pathways do not contribute to muscle fibre death in dystrophinopathies.
abstract: 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.
authors.affiliation: Edinger-Institute, Johann Wolfgang Goethe University-Hospital, Deutschordenstrasse 46, 60528, Frankfurt/M, Germany. dominique-suzanne.tews@kgu.de
authors.forename: Dominique S
authors.initials: DS
authors.lastname: Tews
mesh_terms: D000293:Adolescent; D000328:Adult; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western / Q000379:methods; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology*; D009136:Muscular Dystrophies / Q000145:classification / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D053221:TNF-Related Apoptosis-Inducing Ligand; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases