{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T19:22:43Z","timestamp":1774120963304,"version":"3.50.1"},"reference-count":28,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Regulatory, Integrative and Comparative Physiology"],"published-print":{"date-parts":[[2009,9]]},"abstract":"<jats:p> We previously demonstrated that endotoxin-induced sepsis results in caspase 8-mediated diaphragmatic dysfunction. The upstream signaling pathways modulating diaphragm caspase 8 activation in response to endotoxin administration are, however, unknown. The purpose of the present study was to test the hypothesis that the JNK (Jun N-terminal Kinase) pathway is activated in the diaphragm during sepsis and contributes to sepsis-induced diaphragm caspase 8 activation. Endotoxin was administered to intact animals to model the effects of sepsis. We first assessed the time course of JNK activation after endotoxin (12 mg\/kg ip) administration to mice. We then determined whether JNK inhibitor administration ( 30 \u03bcm\/kg ip SP600125) could prevent caspase 8 activation and diaphragm weakness in endotoxin-treated mice. Experiments were then repeated comparing the effects of endotoxin on control and transgenic JNK knockout mice. We finally determined whether cytomix (LPS, TNF\u03b1, IL1\u03b2, and IFN-\u03b3) exposure activated caspase 8 in C2C12 muscle cells and whether caspase 8 activation was attenuated by either chemical inhibition of JNK (30 \u03bcM SP600125) or transfection with a dominant negative JNK construct. We found that endotoxin activated diaphragm JNK ( P &lt; 0.001) and increased active caspase 8 ( P &lt; 0.01). Inhibition of JNK with SP600125 or by use of JNK-deficient animals prevented diaphragm caspase 8 activation ( P &lt; 0.01) and prevented diaphragm weakness ( P &lt; 0.05). JNK inhibition also prevented caspase 8 activation in cytokine-treated muscle cells ( P &lt; 0.001). These data implicate JNK activation as a major factor mediating inflammation-induced skeletal muscle caspase 8 activation and weakness. <\/jats:p>","DOI":"10.1152\/ajpregu.90849.2008","type":"journal-article","created":{"date-parts":[[2009,7,16]],"date-time":"2009-07-16T02:10:53Z","timestamp":1247710253000},"page":"R825-R834","source":"Crossref","is-referenced-by-count":29,"title":["The JNK MAP kinase pathway contributes to the development of endotoxin-induced diaphragm caspase activation"],"prefix":"10.1152","volume":"297","author":[{"given":"Gerald S.","family":"Supinski","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinying","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leigh Ann","family":"Callahan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.251194298"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.24.2.4075"},{"key":"R3","unstructured":"Cho SG, Choi EJ. Apoptotic signaling pathways: caspases and stress-activated protein kinases. J Biochem Mol Biol 35: 24\u201327, 2002."},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1972.52.1.129"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200307-949OC"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1988.64.1.460"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00010.2004"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.162.6.9912144"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1023\/A:1006916206260"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1985.58.6.2033"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200210-1246OC"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.2206020"},{"key":"R13","doi-asserted-by":"crossref","unstructured":"Li YP, Chen Y, John J, Moylan J, Jin B, Mann DL, Reid MB. TNF-\u03b1 acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1\/MAFbx in skeletal muscle. FASEB J 9: 362\u2013370, 2005.","DOI":"10.1096\/fj.04-2364com"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/138.1.5"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.156.2.9611029"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.2202005"},{"key":"R17","doi-asserted-by":"crossref","unstructured":"Saklatvala J, Dean J, Finch A. Protein kinase cascades in intracellular signalling by interleukin-I and tumour necrosis factor. Biochem Soc Symp 64: 63\u201377, 1999.","DOI":"10.1515\/9781400865048.63"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/145.6.1350"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.43.26690"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01288.2005"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00377.2006"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.90404.2008"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1023\/A:1006859920875"},{"key":"R24","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00085.2007"},{"key":"R25","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00166-7"},{"key":"R26","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.23.10352-10365.2004"},{"key":"R27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M512953200"},{"key":"R28","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-200205000-00016"}],"container-title":["American Journal of Physiology-Regulatory, Integrative and Comparative Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpregu.90849.2008","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,8]],"date-time":"2019-09-08T17:13:28Z","timestamp":1567962808000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpregu.90849.2008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,9]]},"references-count":28,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2009,9]]}},"alternative-id":["10.1152\/ajpregu.90849.2008"],"URL":"https:\/\/doi.org\/10.1152\/ajpregu.90849.2008","relation":{},"ISSN":["0363-6119","1522-1490"],"issn-type":[{"value":"0363-6119","type":"print"},{"value":"1522-1490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,9]]}}}