This study aims to investigate the muscle anabolic potential of adding ketone (3-hydroxybutyrate) to whey protein compared with isocaloric, isonitrogenous whey protein in a human model of inflammatory catabolic disease. Further, this study aims to investigate whether the same amount of whey protein has different effects on muscles in an catabolic inflammatory setting compared with a healthy setting.
Background: Muscle wasting during hospitalization is caused by a combination of immobilization (bed rest), hypocaloric diet and inflammation (e.g. sepsis), and preventive measures are needed. Whey protein is particularly potent in inducing muscle protein synthesis compared with other proteins, at least in healthy populations. Further, the ketone body 3-hydroxybutyrate (3-OHB) effectively preserved muscle in a model of acute inflammatory disease. However, little is known about whether 3-OHB can potentiate the effects of whey protein in a catabolic inflammatory setting. Aim: This study aims to investigate the muscle anabolic potential of adding ketone (3-OHB) to whey protein compared with isocaloric, isonitrogenous whey protein in a human model of catabolic inflammatory disease. Further, this study aims to investigate whether the same amount of whey protein has different effects on muscles in an catabolic inflammatory setting compared with a healthy setting. Hypothesis: 1. 3-OHB potentiates the effect of whey protein in maintaining muscle mass in a catabolic inflammatory setting. 2. The same amount of whey protein will have decreased muscle anabolic effects during catabolic inflammatory conditions compared with healthy conditions Interventions: In a randomized crossover design, eight healthy, lean, young men will undergo either: i) Healthy conditions (overnight fast) + whey protein\^ ii) Catabolic conditions (Inflammation (LPS) + 36-hour fast and bed rest\*) + whey protein\^ iii) Catabolic conditions (Inflammation (LPS) + 36-hour fast and bed rest\*) + 3-OHB/whey protein\^" \*LPS will be administered (1 ng/kg) the day prior to the study together with fast and bed rest. On the study day LPS (0.5 ng/kg) will be injected. \^Beverages will be isonitrogenous and isocaloric (fat will be added) with 45 g whey protein + 20 g maltodextrin. Bolus/sip administration will be applied (1/3 bolus, 1/2 sip) " 50 grams of 3-OHB will be orally administered (1/2 bolus, 1/2 sip) Before each study day: The participants arrive fasting (only tap water allowed) by taxi on the study days. They have been without febrile disease the week prior to investigation, and have not performed exercise for 24 hours.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
8
45 g whey + 20 g maltodextrin
50 g ketone + 45 g whey + 20 g maltodextrin
Medical Research Laboratory, DoH, Aarhus University Hospital
Aarhus, Denmark
Change in forearm muscle kinetics measured by phenylalanine tracer (Netbalance, rate of disappearence and rate of apperance of phenylanine, nmol/100ml muscle/min)
Changes of forearm muscle phenylalanine kinetics from baseline to 3.5 hours after intervention using the forearm model
Time frame: Change from baseline to 3.5 hours after intervention
Change in concentration of total aminoacids
Change in total aminoacids from baseline to the end of the 3.5 hour sipping period
Time frame: Change from baseline to 3.5 hours after intervention
Change in concentration of 3-hydroxybutyrate (mmol/L) )
Change in blood BHB levels from baseline to the end of the 3.5 hour sipping period (iAUC)
Time frame: Measured at baseline and every 30. min throughout the 3.5 hour sipping period
Change in glucose kinetics measured by glucose tracer (rate of apperance and rate of disappearance, mg/kg/min)
Change in glucose kinetics from baseline to to the end of the 3.5 hour sipping period
Time frame: Change from baseline to 3.5 hours after intervention
Change in concentration of plasma insulin
Change in plasma insulin levels from baseline to the end of the 3.5 hour sipping period (iAUC)
Time frame: Measured at baseline and every 30. min throughout the 3.5 hour sipping period
Change in concentration of plasma glucose
Change in glucose levels from baseline and after 3.5 hour sipping period expressed as iAUC.
Time frame: Measured at baseline and every 30. min throughout the 3.5 hour sipping period
Change in concentration of free fatty acids (FFA) levels
Change in FFA from baseline to the end of the sipping period
Time frame: Change from baseline to 3.5 hours after intervention
Change in concentration of C-reactive peptide (CRP)
Change in CRP from baseline to the end of the sipping period
Time frame: Change from baseline to 3.5 hours after intervention
Change in concentration of blood leucocytes (x10^9/L)
Change in leucocytes from baseline to the end of the sipping period
Time frame: Change from baseline to 3.5 hours after intervention
Change in concentration of stress hormones (glucagon, cortisol, adrenalin, noradrenalin)
Change in hormones from baseline and after 3.5 hour sipping period
Time frame: Change from baseline to 3.5 hours after intervention
Change in intracellular muscle signalling
Change in muscle signalling in muscle biopsies by western blot from baseline to the sipping period
Time frame: Change from baseline to 3.5 hours after intervention
Difference in muscle forearm kinetics measured by phenylalanine tracer (Netbalance, rate of apperance, rate og disappearance) (healthy vs catabolic)
Phenylalanine forearm kinetics measured by phenylalanine tracer at the end of the 3.5 hour basal period in healthy vs catabolic (pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure)
Time frame: measured at the end of the 3.5 hour basal period
Difference in concentration of total amino acids (healthy vs catabolic)
Total amino acids measured at the end of the 3.5 hour basal period in healthy vs catabolic conditions (pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure)
Time frame: measured at the end of the 3.5 hour basal period
Difference in glucose kinetics measured with glucose tracer (mg/kg/min) (healthy vs catabolic)
Glucose kinetics measured by glucose tracer at the end of the 3.5 hour basal period in healthy vs catabolic conditions (pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure)
Time frame: measured at the end of the 3.5 hour basal period
Difference in concentration of free fatty acids (FFA) (healthy vs catabolic)
FFA measured at the end of the basal period in healthy vs catabolic (pooled mean of the two catabolic days)
Time frame: Measured at the end of the 3.5 hour basal period.
Difference in concentration of C-reactive peptide (CRP) (healthy vs catabolic)
CRP measured at the end of the basal period in healthy vs catabolic (pooled mean of the two catabolic days)
Time frame: Measured at the end of the 3.5 hour basal period.
Difference in concentration of leucocytes (healthy vs catabolic)
Leucocytes measured at the end of the basal period in healthy vs catabolic (pooled mean of the two catabolic days)
Time frame: Measured at the end of the 3.5 hour basal period.
Difference in intracellular muscle signalling (healthy vs catabolic)
Muscle signalling measured in muscle biopsies by western blot during the 3.5 hour basal period in healthy vs catabolic (pooled mean of the two catabolic days)
Time frame: Measured at the end of the 3.5 hour basal period.
Difference in concentration of 3-hydroxybutyrate (mmol/L) (healthy vs catabolic)
3-hydroxybutyrate measured at the end of the basal period in healthy vs catabolic (pooled mean of the two catabolic days)
Time frame: Measured at the end of the 3.5 hour basal period.
Difference in concentration of hormones (insulin, glucagon, cortisol, growth hormone, adrenaline, noradrenalin) (healthy vs catabolic)
Hormones (insulin, glucagon, cortisol, growth hormone, adrenaline, noradrenalin) measured at the end of the basal period in healthy vs catabolic (pooled mean of the two catabolic days)
Time frame: Measured at the end of the 3.5 hour basal period.
Difference in whole body protein metabolism (healthy vs catabolic)
Difference in whole body protein metabolism measured with tyrosine tracers at the end of the basal period in healthy vs catabolic (pooled mean of the two catabolic days)
Time frame: Measured at the end of the 3.5 hour basal period.
Difference in concentration of cytokines (healthy vs catabolic)
Cytokines (TNFalfa, IL-10, IL-6 and IL-1beta) measured between healthy and catabolic conditions (iAUC, a pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure))
Time frame: Measured at baseline and 120 and 240 minutes after LPS administration
Difference in axillary temperature (healthy vs catabolic)
Change in axillary temperature (iAUC). A pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure.
Time frame: Measured at baseline and 1, 2, 3, 4, 5, 6 and 7 hours after LPS administration
Difference in heart rate (healthy vs catabolic)
Change in heart rate (iAUC). A pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure.
Time frame: Measured at baseline and 1, 2, 3, 4, 5, 6 and 7 hours after LPS administration
Difference in mean arterial pressure (MAP) (healthy vs catabolic)
Change in MAP (iAUC). A pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure.
Time frame: Measured at baseline and 1, 2, 3, 4, 5, 6 and 7 hours after LPS administration
Difference in symptom score (healthy vs catabolic)
Change from baseline and throughout the experiment (iAUC). A pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure. Scale 0-5, 0=no symptoms and 5=severe symptoms
Time frame: Measured at baseline and 1, 2, 3, 4, 5, 6 and 7 hours after LPS administration
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