Replication Data for: Ketogenic Nutrition in Combination with PPARα Activation Induced Metabolic Failure and Exacerbated Muscle Weakness in Septic Mice

Suppression of the peroxisome proliferator-activated receptor alpha (PPARα) has been related to poor outcome in sepsis and may compromise ketogenesis during critical illness. Infusion of 3-hydroxybutyrate (3HB) was shown to attenuate muscle weakness in septic mice. We hypothesize that endogenous ketogenesis induced by pharmacological PPARα activation, either alone or combined with ketogenic nutrition, is safe and can also mitigate muscle weakness in septic mice. In a fluid-resuscitated, antibiotic-treated mouse model of prolonged sepsis, we first (Study 1) assessed the safety and effectiveness (impact on ketosis and muscle weakness,) of the PPARα agonist pemafibrate (1mg/kg/d, n=16), versus placebo (n=15) combined with standard balanced parenteral nutrition (PN), composed of glucose, amino acids and long-chain triglycerides (LCT) (balanced-TPN). We subsequently (Study 2) evaluated the impact of pemafibrate combined with four types of PN on ketosis and muscle weakness: balanced-TPN (n=18), TPN with extra LCTs (TPN+LCT, n=18), low-dose pure LCT emulsion (Low-LCT, n=16) and high-dose pure LCT emulsion (High-LCT n=18). Carbohydrates and amino acids were omitted in the pure LCT groups. Healthy control mice (HC, n=19) served as reference. Ex vivo 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.