{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:33:01Z","timestamp":1791221581684,"version":"4.1.0"},"reference-count":52,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2016,10,18]],"date-time":"2016-10-18T00:00:00Z","timestamp":1476748800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Ministero dell'Universit\u00e0 e della Ricerca Scientifica e Tecnologica"},{"name":"University of Genoa (Cofinanziamento di Ateneo)"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2017,2]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Inflammation in skeletal muscle is implicated in the pathogenesis of insulin resistance and cachexia but why uremia up\u2010regulates pro\u2010inflammatory cytokines is unknown. Toll\u2010like receptors (TLRs) regulate locally the innate immune responses, but it is unknown whether in chronic kidney disease (CKD) TLR4 muscle signalling is altered. The aim of the study is to investigate whether in CKD muscle, TLRs had abnormal function and may be involved in transcription of pro\u2010inflammatory cytokine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>TLR4, phospho\u2010p65, phospho\u2010ikB\u03b1, tumour necrosis factor (TNF)\u2010\u03b1, phospho p38, Murf 1, and atrogin were studied in skeletal muscle from nondiabetic CKD stage 5 patients (<jats:italic>n<\/jats:italic>\u2009=\u200929) and controls (<jats:italic>n<\/jats:italic>\u2009=\u200914) by immunohistochemistry, western blot, and RT\u2013PCR. Muscle cell cultures (C2C12) exposed to uremic serum were employed to study TLR4 expression (western blot and RT\u2013PCR) and TLR\u2010driven signalling. TLR4 signalling was abrogated by a small molecule chemical inhibitor or TLR4 siRNA. Phospho AKT and phospho p38 were evaluated by western blot.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CKD subjects had elevated TLR4 gene and protein expression. Also expression of NFkB, p38 MAPK and the NFkB\u2010regulated gene TNF\u2010\u03b1 was increased. At multivariate analysis, TLR4 protein content was predicted by eGFR and Subjective Global Assessment, suggesting that the progressive decline in renal function and wasting mediate TLR4 activation. In C2C12, uremic serum increased TLR4 as well as TNF\u2010\u03b1 and down\u2010regulated pAkt. These effects were prevented by blockade of TLR4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>CKD promotes muscle inflammation through an up\u2010regulation of TLR4, which may activate downward inflammatory signals such as TNF\u2010\u03b1 and NFkB\u2010regulated genes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12129","type":"journal-article","created":{"date-parts":[[2016,10,19]],"date-time":"2016-10-19T03:42:40Z","timestamp":1476848560000},"page":"131-144","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":83,"title":["Toll\u2010like receptor 4 signalling mediates inflammation in skeletal muscle of patients with chronic kidney disease"],"prefix":"10.1002","volume":"8","author":[{"given":"Daniela","family":"Verzola","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Nephrology Division and First Clinic of Internal Medicine University of Genova and IRCCS AOU San Martino\u2010IST, and Ospedale Santa Chiara<sup>I<\/sup> Trento Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Bonanni","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Nephrology Division and First Clinic of Internal Medicine University of Genova and IRCCS AOU San Martino\u2010IST, and Ospedale Santa Chiara<sup>I<\/sup> Trento Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Sofia","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Nephrology Division and First Clinic of Internal Medicine University of Genova and IRCCS AOU San Martino\u2010IST, and Ospedale Santa Chiara<sup>I<\/sup> Trento Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Montecucco","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Nephrology Division and First Clinic of Internal Medicine University of 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Internal Medicine University of Genova and IRCCS AOU San Martino\u2010IST, and Ospedale Santa Chiara<sup>I<\/sup> Trento Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Viazzi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Nephrology Division and First Clinic of Internal Medicine University of Genova and IRCCS AOU San Martino\u2010IST, and Ospedale Santa Chiara<sup>I<\/sup> Trento Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Venturelli","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Nephrology Division and First Clinic of Internal Medicine University of Genova and IRCCS AOU San Martino\u2010IST, and Ospedale Santa Chiara<sup>I<\/sup> Trento Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliano","family":"Brunori","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Nephrology 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