IL-6 Regulation of Energy Stores During Recovery From an Acute Exercise Bout

Study Overview
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Brief Summary
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The aim of the study is to investigate the role of exercise-induced IL-6 in regulating energy stores and energy metabolism during recovery after an acute exercise bout. To achieve this, 30 men will be randomized to infusion placebo or tocilizumab (IL-6 receptor antibody) combined with a 2-hour exercise bout. Stable isotope tracers will be infused to determine substrate kinetics. Indirect calorimetry will be applied to determine substrate oxidation, and muscle biopsies will be taken to determine substrate uptake and storage.

Official Title
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Role of IL-6 in Regulating Energy Stores During Recovery From an Acute Exercise Bout

Conditions
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Glycogen Depletion

Intervention / Treatment
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* Drug: Tocilizumab/Actemra® (Roche)
* Drug: Saline 9%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Physically active (defined as meeting the ACSM's guidelines of 2.5h per week of moderate to vigorous physical activity per week), young, healthy males will be included. Participants may be included in the study if they meet all the following criteria: Age ≥ 18 years and ≤ 40 years BMI < 18 and > 25 kg/m2 Healthy (based on screening) Stable body weight for 6 months ≥ 2.5h/week moderate to vigorous physical activity Exclusion Criteria: • Cardiovascular disease Rheumatologic disease Metabolic disease Elite sports or high aerobic training status (VO2max > 60 mL O2/min/kg) Frequent/chronic use of medications affecting physical performance or inflammation (NSAIDS, DMARDS, corticosteroids) Aspirin use >100 mg/d Thyroid disease Current infection Aspartate amino transferase (AST) or alanine amino transferase (ALT) >2x upper normal range History of carcinoma History of tuberculosis Ketogenic diet Smoking Anemia (hematocrit <33%) Neutrophil count <0,5x 109/l Thrombocytes <50x 109/l or bleeding disorders

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, placebo-controlled, double-blind
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab<br>Participants will receive one 30 min intravenous infusion of tocilizumab/Actemra® (Roche). The dose will be 8 mg/kg bodyweight or a maximum of 800mg. Tocilizumab is dissolved in 100 mL 0.9% saline. | Drug: Tocilizumab/Actemra® (Roche)<br>* The infusion of tocilizumab will antagonize IL-6 signaling for the duration of the study, allowing us to determine the role of IL-6 in regulating energy stores following acute exercise<br>|
| Placebo Comparator: Saline<br>As placebo, participants will receive one 30 min intravenous infusion of 100 mL 0.9% saline. | Drug: Saline 9%<br>* The infusion of saline will serve as placebo for tocilizumab, allowing us to determine the role of IL-6 in regulating energy stores following acute exercise<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in muscle glycogen content (mmol/kg/h) | Comparing change in muscle glycogen in the two groups from before exercise to immediately after exercise, and after 1 hour and 4 hours of recovery | Measured at 0, 120, 180 and 360 minutes | 
| Change in muscle triglycerides content | Comparing change in muscle triglycerides in the two groups from before exercise to immediately after exercise, and after 1 hour and 4 hours of recovery | Measured at 0, 120, 180 and 360 minutes | 
| Change in muscle expression of glucose transporter type 4 (GLUT4) | Comparing muscle expression of GLUT4 before and immediately after exercise and 4 hours after recovery in the two groups | Measured at 0, 120 and 360 min | 
| Change in muscle expression of fatty acid translocase (FAT/CD36) | Comparing muscle expression of FAT/CD36 before and immediately after exercise and 4 hours after recovery in the two groups | Measured at 0, 120 and 360 min | 
| Change in muscle expression of muscle fatty acid binding protein (FABPm) | Comparing muscle expression of FABPm before and immediately after exercise and 4 hours after recovery in the two groups | Measured at 0, 120 and 360 min | 
| Change in muscle expression of fatty acid transporter 4 (FATP4) | Comparing muscle expression of FATP4 before and immediately after exercise and 4 hours after recovery in the two groups | Measured at 0, 120 and 360 min | 
| Change in muscle expression of glycerol transporters | Comparing muscle expression of glycerol transporters before and immediately after exercise and 4 hours after recovery in the two groups | Measured at 0, 120 and 360 min | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in glucose rate of appearance | Comparing glucose rate of appearance during exercise and recovery in the two groups | Measured at -150, -60, -45, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in glucose rate of disappearance | Comparing glucose rate of disappearance during exercise and recovery in the two groups | Measured at -150, -60, -45, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in glucose concentration | Comparing glucose concentration during exercise and recovery in the two groups | Measured at -150, -60, -45, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in glucose enrichment in intramuscular glycogen | Comparing glucose enrichment in intramuscular glycogen during rest, exercise and recovery in the two groups | Measured at 0, 120, 180 and 360 minutes | 
| Change in intramuscular glucose concentration | Comparing intramuscular glucose concentration during rest, exercise and recovery in the two groups | Measured at 0, 120, 180 and 360 minutes | 
| Change in glycogen fractional synthesis rate | Comparing intramuscular glycogen fractional synthesis rate during rest, exercise and recovery in the two groups | Measured at 0, 120, 180 and 360 minutes | 
| Change in gylcerol rate of appearance | Comparing gylcerol rate of appearance during rest, exercise and recovery in the two groups | Measured at -150, -60, -45, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in gylcerol rate of disappearance | Comparing gylcerol rate of disappearance during rest, exercise and recovery in the two groups | Measured at -150, -60, -45, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in gylcerol concentration | Comparing gylcerol concentration during rest, exercise and recovery in the two groups | Measured at -150, -60, -45, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in palmitate rate of appearance | Comparing palmitate rate of appearance during rest, exercise and recovery in the two groups | Measured at -150, -60, -45, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in palmitate rate of disappearance | Comparing palmitate rate of disappearance during rest, exercise and recovery in the two groups | Measured at -150, -60, -45, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in palmitate concentration | Comparing palmitate kinetics during rest, exercise and recovery in the two groups | Measured at -150, -60, -45, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in palmitate oxidation | Comparing palmitate oxidation during rest, exercise and recovery in the two groups | Measured at -150, -60, -45, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in intramuscular palmitate content | Comparing intramuscular palmitate content during rest, exercise and recovery in the two groups | Measured at 0, 120, 180 and 360 minutes | 
| Change in palmitate enrichment in intramuscular triglycerides | Comparing palmitate enrichment in intramuscular triglycerides during rest, exercise and recovery in the two groups | Measured at 0, 120, 180 and 360 minutes | 
| Change in intramuscular triglycerides fractional synthesis rate | Comparing intramuscular triglycerides fractional synthesis rate during rest, exercise and recovery in the two groups | Measured at 0, 120, 180 and 360 minutes | 
| Change in haemoglobin | Comparing haemoglobin during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in haematocrit | Comparing haematocrit during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in differential blood count | Comparing differential blood count during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in plasma IL-6 concentration | Comparing plasma IL-6 concentration during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in plasma TNF-alpha concentration | Comparing plasma TNF-alpha concentration during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in plasma IL-8 concentration | Comparing plasma IL-8 concentration during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in plasma IL-10 concentration | Comparing plasma IL-10 concentration during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in plasma IL-1beta concentration | Comparing plasma IL-1beta concentration during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in plasma IL-1Ra concentration | Comparing plasma IL-1Ra concentration during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in plasma IL-4 concentration | Comparing plasma IL-4 concentration during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in plasma sIL-6R concentration | Comparing plasma sIL-6R concentration during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in insulin | Comparing insulin during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in c-peptide | Comparing c-peptide during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in glucagon | Comparing glucagon during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in growth hormone (GH) | Comparing GH during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in adrenaline | Comparing adrenaline during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in noradrenaline | Comparing noradrenaline during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in cortisol | Comparing cortisol during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in total glucagon-like peptide-1 (GLP-1) | Comparing total GLP-1 during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in active GLP-1 | Comparing active GLP-1 during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in gastric inhibitory peptide (GIP) | Comparing GIP during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in peptide YY (PYY) | Comparing PYY during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in leptin | Comparing leptin during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes | 
| Change in triglycerides | Comparing triglycerides during rest, exercise and recovery in the two groups | Measured at -150, -30, 10, 30, 60, 90, 120, 130, 150, 180, 210, 240, 300 and 360 minutes |