{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T01:55:57Z","timestamp":1787795757787,"version":"build-2784847793"},"reference-count":45,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,12]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Suppression of the peroxisome proliferator\u2010activated receptor alpha (PPAR\u03b1) has been related to poor outcomes in sepsis and may compromise ketogenesis during critical illness. Infusion of 3\u2010hydroxybutyrate (3HB) was shown to attenuate muscle weakness in septic mice. We hypothesise that endogenous ketogenesis induced by pharmacological PPAR\u03b1 activation, either alone or combined with ketogenic nutrition, is safe and can also mitigate muscle weakness in septic mice.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In a fluid\u2010resuscitated, antibiotic\u2010treated mouse model of prolonged sepsis, we first (Study 1) assessed the safety and effectiveness (impact on ketosis and muscle weakness) of the PPAR\u03b1 agonist pemafibrate (1\u2009mg\/kg\/d,\n n<\/jats:italic>\n \u2009=\u200916), versus placebo (\n n<\/jats:italic>\n \u2009=\u200915) combined with standard balanced parenteral nutrition (PN), composed of glucose, amino acids and long\u2010chain triglycerides (LCT) (balanced\u2010TPN). We subsequently (Study 2) evaluated the impact of pemafibrate combined with four types of PN on ketosis and muscle weakness: balanced\u2010TPN (\n n<\/jats:italic>\n \u2009=\u200918), TPN with extra LCTs (TPN\u2009+\u2009LCT, n\u2009=\u200918), low\u2010dose pure LCT emulsion (Low\u2010LCT,\n n<\/jats:italic>\n \u2009=\u200916) and high\u2010dose pure LCT emulsion (High\u2010LCT\n n<\/jats:italic>\n \u2009=\u200918). Carbohydrates and amino acids were omitted in the pure LCT groups. Healthy control mice (HC,\n n<\/jats:italic>\n \u2009=\u200919) served as controls. Ex\u00a0vivo muscle force was measured as the primary outcome. Metabolic, inflammatory and microstructural parameters were assessed on plasma and in muscle and liver tissue by targeted metabolomics, gene expression analysis, biochemical and metabolite assays and histological assessment.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Pemafibrate treatment with balanced\u2010TPN upregulated hepatic gene expression of PPAR\u03b1 (\n Ppara<\/jats:italic>\n ) and its downstream genes (\n Cd36<\/jats:italic>\n ,\n Cpt1a<\/jats:italic>\n ,\n Atgl<\/jats:italic>\n ,\n Acadl, Hadha, Acox1,<\/jats:italic>\n and\n Hmgcs2<\/jats:italic>\n ) (\n p<\/jats:italic>\n \u2009<\u20090.0001) and was well tolerated. However, pemafibrate treatment with the use of balanced\u2010TPN administration did not induce detectable ketosis or improve muscle weakness. In combination with pemafibrate, TPN\u2009+\u2009LCT also did not induce ketosis, nor did it affect muscle weakness. In contrast, 3\u2010hydroxybutyrate plasma concentrations increased with High\u2010LCT (95\u2010fold) and Low\u2010LCT (10\u2010fold) (\n p<\/jats:italic>\n \u2009<\u20090.0001) in combination with pemafibrate, yet muscle force declined further (High\u2010LCT 25.0%, Low\u2010LCT 10.7% of HC,\n p<\/jats:italic>\n \u2009<\u20090.0001). Blood glucose was lowered with pure High\u2010LCT and Low\u2010LCT (High\u2010LCT 86.9%, Low\u2010LCT 55.1% of TPN,\n p<\/jats:italic>\n \u2009<\u20090.05), while plasma lipids and LC\u2010carnitines were increased (\n p<\/jats:italic>\n \u2009<\u20090.0001). Markers of hepatic protein catabolism were upregulated with High\u2010LCT and Low\u2010LCT (\n p<\/jats:italic>\n \u2009<\u20090.007), while muscle glycolytic intermediates (\n p<\/jats:italic>\n \u2009<\u20090.0001) and ATP levels (\n p<\/jats:italic>\n \u2009<\u20090.0001) were depleted.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n In septic mice, pemafibrate combined with balanced\u2010TPN or lipid\u2010rich TPN induced PPAR\u03b1 activation but did not result in ketosis nor affect muscle weakness. Pemafibrate combined with pure LCTs induced ketosis in sepsis but worsened muscle weakness, possibly explained by muscular bioenergetic failure.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.70156","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T23:09:46Z","timestamp":1765321786000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Ketogenic Nutrition in Combination With PPAR\u03b1 Activation Induced Metabolic Failure and Exacerbated Muscle Weakness in Septic Mice"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7278-2708","authenticated-orcid":false,"given":"Caroline","family":"Lauwers","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Laboratory and Clinical Division of Intensive Care Medicine KU Leuven Leuven 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