MON-663 Impact of Triglyceride Chain-Length on Ketogenesis and Muscle Weakness in Critically Ill Mice

Abstract Disclosure: C. Lauwers: None. J. Gunst: None. S. Derde: None. I. Derese: None. S. Vander Perre: None. L. Pauwels: None. S. El Dawy: None. G.H. Van Den Berghe: None. M.P. Casaer: None. L. Langouche: None. Introduction: Ketogenic diets may mitigate age-related declines in muscle function. It remains unclear whether such diets may also attenuate critical illness-induced muscle weakness, and whether medium-chain triglycerides (MCTs) are more effective than long-chain triglycerides (LCTs) at inducing ketogenesis. We studied the impact of MCT- and LCT-rich nutrition as compared to standard feeding preparations on ketosis and muscle weakness in septic mice. Methods: Sepsis was induced in C57Bl/6j mice by caecal ligation and puncture. After 24h fluid resuscitation, mice were randomized to receive 3 types of parenteral nutrition (PN) with different ketogenic potential. The first group received total PN (TPN, composing 49% glucose, 35% LCT and 16% amino acids, n=16), the second an LCT-rich emulsion (LCT, composing 90% LCT and 10% glucose, n=17) and the third group a mixed MCT/LCT emulsion (MCT/LCT, composing 45% MCT, 45% LCT and 10% glucose, n=16). Healthy control mice (HC) were included to provide healthy reference values (n=17). After 5 days of sepsis, ex-vivo muscle force (Aurora Scientific®) was assessed as the primary outcome, and plasma 3-hydroxybutyrate (3HB), plasma lipids (TG, LDL- and HDL-cholesterol) were measured. Hepatic gene expression of ketogenic markers including the peroxisome-proliferator receptor α (PPARα, the transcriptional regulator of ketogenesis) and 3-hydroxymethylglutaryl-CoA synthase-2 (Hmgcs2, the rate-limiting enzyme of ketogenesis) was assessed, and immunoblotting was conducted for Hmgcs2 on liver tissue. Results: After 5 days of sepsis, survival was similar in the three groups (TPN: 84.2%; MCT/LCT: 66.2%; LCT: 85.0%; p=0.6). Muscle force was equally reduced in septic mice as compared with HC (TPN: 68.1%; MCT/LCT: 60.5%; LCT: 74.0% of 144.5 mN/mm²; p>0.05). Plasma 3HB levels were below the detection limit (0.005 mmol/L) in the TPN group. In LCT mice, 3HB levels increased to median 0.11 mmol/L (p<0.001 compared with TPN), while they were lower in MCT/LCT mice (median 0.02 mmol/L; p<0.001 compared with TPN). Plasma TG, glycerol, and HDL- and LDL-cholesterol were suppressed in TPN mice (p<0.03) but equally increased in both lipid-rich groups. Despite differences in plasma 3HB, hepatic gene expression of ketogenic markers was similarly upregulated in the lipid-rich groups compared to the TPN group (p<0.001). Yet, Hmgcs2 protein expression was suppressed in the TPN group as compared to the HC (p=0.009), but increased stepwise in the MCT/LCT and LCT mice (p=0.04 and p<0.001, resp., compared to TPN). Further gene expression and metabolomics analyses in liver and muscle tissue are ongoing. Conclusion: The tested ketogenic diets did not attenuate sepsis-induced muscle weakness. An MCT-rich emulsion was less effective at inducing ketosis than a pure LCT emulsion. Presentation: Monday, July 14, 2025