An interventional study of Casein and Whey in Muscle Protein Synthesis, Endotoxemia and Nutrition, sponsored by University of Aarhus. Completed at 1 site in Denmark. Open to male participants aged 20 Years to 40 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-04-25.
Sponsored by University of Aarhus · Not applicable, Interventional, and Basic science
This study compares three different protein supplements (casein, whey and leucine-enriched whey) and their effect on post-inflammatory muscle waste in a model of acute disease. Each test person will undergo all three interventions.
It is believed that leucine is the primary driver of muscle protein synthesis and therefore we hypothesize that leucine-enriched whey and whey are superior to casein in combating post-inflammatory muscle waste, because of its higher leucine content (16%, 11% and 9% leucine, respectively).
Background:
Acute illness is accompanied by infection/inflammation, anorexia and immobilization all contributing to muscle loss, making nutritional supplement optimization an obvious target for investigation and eventually clinical intervention. In the clinical setting large heterogenicity among patients complicates investigations of muscle metabolism during acute illness. Therefore we introduce a disease model by combining "Inflammation + 36 hour fast and bedrest". Inflammation/febrile illness will be initiated by using the well-established "human endotoxemia model" with a bolus injection of Escherichia coli lipopolysaccharide (LPS), known to cause inflammation comparable with the initial phase of sepsis. The amino acid leucine has shown to be particularly anabolic in performance sports, but little is known about its potential beneficial effects during acute illness. Leucine is a powerful activator of muscle protein synthesis and it seems that protein supplements with the highest leucine content elicit a greater increase in protein synthesis than those with a smaller fraction of leucine.
The protein supplements used most in hospitals contain casein derived protein, which has a much lower leucine content than the whey protein compounds typically used in performance sports.
This study compares three different protein supplements.The study is an open, randomized crossover trial. Laboratory technicians, test subjects and investigators will be blinded.
Interventions:
I. LPS (1 ng/kg as bolus) + 36 h fasting + 36 h bedrest + Casein (9% leucine) II. LPS (1 ng/kg as bolus) + 36 h fasting + 36 h bedrest + Whey (11% leucine) III. LPS (1 ng/kg as bolus) + 36 h fasting + 36 h bedrest + Leucine-enriched whey (16% leucine)
The test objects will be given 0,6 g protein/kg, 1/3 as a bolus and 2/3 as sipping over a period of 3,5 hour. Muscle metabolism will be investigated by phenylalanine tracer using the forearm model and total protein metabolism using a carbamide tracer. Through muscle biopsies intracellular signalling pathways will be investigated.
Exclusion Criteria:
"LPS + 36 hour fast and bedrest" + Casein (9% leucine) - 0.6 g protein/kg bodyweight, 1/3 as bolus and 2/3 as sipping.
Dietary Supplement: Casein
"LPS + 36 hour fast and bedrest" + Whey (11% leucine) - 0.6 g protein/kg bodyweight, 1/3 as bolus and 2/3 as sipping
Dietary Supplement: Whey
"LPS + 36 hour fast and bedrest" + Leucine-enriched whey (16% leucine) - 0.6 g protein/kg bodyweight, 1/3 as bolus and 2/3 as sipping
Dietary Supplement: Leucine-enriched whey
see experimental description
see experimental description
see experimental description
Change in muscle phenylalanine netbalance over the forearm muscle
Changes of muscle phenylalanine net balance (= arterio(phe conc)-venous(phe conc) x flow) 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 whole body protein metabolism measured by a combination of phenylalanine- and tyrosine tracer
Changes in whole body protein synthesis rates (umol/kg/h), breakdown rates (umol/kg/h), phenylalanine to tyrosine conversion rates (umol/kg/h) and net balance (umol/kg/h)
Time frame: Change from baseline to 3.5 hours after intervention
Blood enrichment of essential amino acids
measures of essential amino acids in the blood
Time frame: At baseline and every 30 minutes during the intervention period (3.5 hours)
Changes in insulin concentrations
Measures of insulin concentration in blood
Time frame: At baseline and every 30 minutes during the intervention period (3.5 hours)
Change in Intracellular signalling in muscle measured by western blotting.
Investigating intracellular activity of muscle metabolism pathways by western blotting.
Time frame: Change from baseline and after 2 hours of intervention
Energy expenditure
Using indirect calorimetry for 15 min
Time frame: At baseline and after 2.5 hours of intervention
Changes in Glucose, fat and protein oxidation rates
Using indirect calorimetry for 15 min for measuring glucose- (mg/kg/min), fat- (mg/kg/min) and protein oxidation (mg/kg/min)
Time frame: At baseline and after 2.5 hours of intervention
Change in muscle breakdown and synthesis rates measured by phenylalanine tracer
changes from baseline to 3.5 hours after intervention in Ra(phe)=breakdown (umol/kg/h) and Rd(phe)=synthesis rate (umol/kg/h)
Time frame: Change from baseline to 3.5 hours after intervention
Changes in Glucagon concentrations
Glucagon concentrations in blood
Time frame: Change from baseline and to 1 hour and 3.5 hour after the intervention
Changes in GIP concentrations
GIP concentrations in blood
Time frame: Change from baseline and to 1 hour and 3.5 hour after the intervention
Changes in GLP-1 concentrations
GLP-1 concentrations in blood
Time frame: Change from baseline and to 1 hour and 3.5 hour after the intervention
Changes in Glucose concentrations
Glucose concentrations in blood
Time frame: At baseline and every 30 minutes during the intervention period (3.5 hours)
Changes in heart rate profile upon repeated LPS exposure
heart rate (beats/min)
Time frame: Measured at baseline and 1,2,3,4,5,6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in temperature profile upon repeated LPS exposure
Axillary temperature (celcius)
Time frame: Measured at baseline and 1,2,3,4,5,6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in blood pressure profile upon repeated LPS exposure
blood pressure (mmHg)
Time frame: Measured at baseline and 1,2,3,4,5,6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in symptom score profile upon repeated LPS exposure
symptom score (from 0-5) for nausea, back pain, muscle pain, headache and chills. 0=no symptoms, 5=severe symptoms.
Time frame: Measured at baseline and 1,2,3,4,5,6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in TNfalfa profile upon repeated LPS exposure
TNfalfa blood concentrations
Time frame: Measured at baseline and 1, 2, 4, 6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in IL-1 profile upon repeated LPS exposure
IL-1 blood concentrations
Time frame: Measured at baseline and 1, 2, 4, 6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in IL-6 profile upon repeated LPS exposure
IL-6 blood concentrations
Time frame: Measured at baseline and 1, 2, 4, 6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Changes in IL-10 profile upon repeated LPS exposure
IL-10 blood concentrations
Time frame: Measured at baseline and 1, 2, 4, 6 and 24 hours after LPS (6-8 weeks between visit 1,2 and 3)
Plan to share: No — We will analyse all data ourselves
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University of Aarhus