Exercise-regulated Organ Crosstalk, Influence of IL-6 (EVEX)

Overall the study investigates organ crosstalk during exercise. More specifically, the study investigates the role of IL-6 in regulating glucose, fatty acid, and amino acid kinetics at whole body level and in skeletal muscle, liver, and brain. Furthermore, the study investigates the uptake and release of extracellular vesicles in skeletal muscle, liver, and brain in reponse to exercise.

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy Volunteers Only; Energy Metabolism
• Intervention / Treatment: Other: exercise

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Helga Ellingsgaaard, PhD; Phone Number: +4535457641; Email: helga.ellingsgaard@regionh.dk

Study Locations

• Denmark
  • Capital Region
    • Copenhagen, Capital Region, Denmark, 2100
      • Rigshospitalet
      • Contact: Helga Ellingsgaard, PhD; Phone Number: +4535457544; Email: helga.ellingsgaard@regionh.dk
      • Contact: Peter S Plomgaard, MD PhD; Phone Number: +4535457544; Email: Peter.Plomgaard@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Minimum age: 18 years
• Maximum age: 45 years
• Minimum BMI: 18
• Maximum BMI: 25
• Sex: Male
• Healthy (based on screening)
• Stable body weight for 6 months
• VO2max (mL/kg/min) ≥ 50

Exclusion Criteria:

• Smoking
• Thyroid disease
• Heart disease
• Inflammatory diseases
• Current infection
• Liver disease (transaminases more than 2x upper normal range)
• Kidney disease (creatinine more than1.5 mg/dl)
• Known immunosuppressive disease
• Corticosteroid use
• Regular NSAID or paracetamol usage
• Aspirin use more than 100 mg/d
• History of carcinoma
• History of tuberculosis
• Anemia (hematocrit less than 33%)
• WBC less than 1 x 10^3
• Platelets less than 100 x 10^3
• Bleeding disorders
• Obstructive pulmonary disease
• Femoral hernia
• Vascular prosthesis
• Vascular thrombosis
• Previous nerve damage
• Many previous femoral catheter installations

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Saline infusion	Other: exercise; acute exercise bout
Experimental: Tocilizumab; IL-6 receptor antibody infusion (8 mg/kg body weight, max 800 mg)	Other: exercise; acute exercise bout

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Whole body substrate kinetics.	Comparing rates of appearances (Ra) and disappearances (Rd) of glucose, glycerol, palmitate, amino acids between placebo and IL-6R ab at rest, during exercise, and recovery.	Comparisons between placebo and IL-6R ab are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
Tissue specific utilization and production of substrates.	Comparing, between placebo and IL-6Rab, by measuring in plasma, the Ra and Rd of substrates in muscle, liver, and brain at rest, during exercise, and recovery using the non-steady-state equations of Steele adapted for stable isotopes.	Comparisons between study arms are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
IL-6 regulation of protein synthesis and degradation.	Comparing differences in protein synthesis and degradation rates between placebo and IL-6Rab at rest, during exercise, and during recovery from exercise.	Comparisons between placebo and IL-6R ab are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
Number of EVs from muscle, liver, and brain.	Comparing the number of EVs deriving from skeletal muscle, liver, and brain.	Comparisons between placebo and IL-6R ab are done before exercise (time points 255 and 270 minutes).
Size of EVs from muscle, liver, and brain.	Comparing EV size deriving from skeletal muscle, liver, and brain.	Comparisons between placebo and IL-6R ab are done before exercise (time points 255 and 270 minutes).
EVs from muscle, liver, and brain.	Comparing the content of EVs deriving from skeletal muscle, liver, and brain.	Comparisons between placebo and IL-6R ab are done before exercise (time points 255 and 270 minutes).
Influence of exercise on EV number.	Comparing the number of EVs deriving from skeletal muscle, liver, and brain in response to exercise.	Comparisons between placebo and IL-6R ab are done throughout a 1-hour exercise bout (time points 285, 300, 315, and 330 minutes).
Influence of exercise on EV size	Comparing EV size deriving from skeletal muscle, liver, and brain in response to exercise.	Comparisons between placebo and IL-6R ab are done throughout a 1-hour exercise bout (time points 285, 300, 315, and 330 minutes).
Influence of exercise on EV content.	Comparing the content of EVs deriving from skeletal muscle, liver, and brain in response to exercise.	Comparisons between placebo and IL-6R ab are done throughout a 1-hour exercise bout (time points 285, 300, 315, and 330 minutes).
Tissue specific proteomic content of EVs.	Comparing differences in proteomic content of EVs from skeletal muscle, liver, and brain in response to exercise.	Comparisons between placebo and IL-6R ab are done at the end of a 1-hour exercise bout (330 minutes).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lactate.	Differences in plasma lactate from skeletal muscle, liver, and brain comparing placebo and IL-6R ab.	Comparisons between placebo and IL-6R ab are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
Pyruvate.	Differences in plasma pyruvate from skeletal muscle, liver, and brain comparing placebo and IL-6R ab.	Comparisons between placebo and IL-6R ab are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
Keto acids.	Differences in plasma keto acids from skeletal muscle, liver, and brain comparing placebo and IL-6R ab.	Comparisons between placebo and IL-6R ab are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
Ketone bodies.	Differences in plasma ketone bodies from skeletal muscle, liver, and brain comparing placebo and IL-6R ab.	Comparisons between placebo and IL-6R ab are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
Influence of IL-6 on fatty acid oxidation rates.	Comparing, between placebo and IL-6R ab, differences in fatty acid, e.g. palmitate oxidation rates, at whole body level and in skeletal muscle, liver, and brain.	Comparisons between placebo and IL-6R ab are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
Influence of IL-6 on insulin.	Comparing differences in plasma insulin concentrations between placebo and IL-6R ab.	Comparisons between placebo and IL-6R ab are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
Influence of IL-6 on glucagon.	Comparing differences plasma glucagon concentrations between placebo and IL-6R ab.	Comparisons between placebo and IL-6R ab are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
Influence of IL-6 on epinephrine.	Comparing differences in plasma epinephrine concentrations between placebo and IL-6R ab.	Comparisons between placebo and IL-6R ab are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
Influence of IL-6 on norepinephrine.	Comparing differences in plasma norepinephrine concentrations between placebo and IL-6R ab.	Comparisons between placebo and IL-6R ab are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
IL-6 levels.	Comparing differences in plasma IL-6 concentrations between placebo and IL-6R ab.	Comparisons between placebo and IL-6R ab are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
Influence of IL-6 on substrate usage.	Differences in respiratory exchange ratio comparing placebo and IL-6R ab.	Comparisons between placebo and IL-6R ab are done at rest (time points 255 and 270 minutes), during exercise (time points 285, 300, 315, and 330 minutes) and during recovery from exercise (time points 345, 360, and 390 minutes).
Influence of IL-6 on perceived exertion.	Differences in rate of perceived exertion during exercise comparing placebo and IL-6R ab.	Comparisons between placebo and IL-6R ab are done during exercise (time points 285, 300, 315, and 330 minutes).

Other Outcome Measures

Outcome Measure	Time Frame
Whole body/liver fractional synthesis rates of both the very low-density lipoproteins fat and protein part (TAG and apolipoprotein B100)	Information will be obtained at rest (time points 255 and 270 min), during exercise (time points 285, 300, 315, and 330 min) and during recovery from exercise (time points 345, 360, and 390 min).
Differences in concentrations as well as fractional synthesis rate of 24 plasma 'fat' proteins (all apolipoprotein, albumin, transthyretin and enzymes related to high density lipoprotein formation comparing IL-6R ab to placebo).	Comparisons between study arms are made at rest (time points 255 and 270 min), during exercise (time points 285, 300, 315, and 330 min) and during recovery from exercise (time points 345, 360, and 390 min).
Detailed information on alanine/glutamate/leucine interactive metabolism and their role in gluconeogenesis at the level of whole body and in skeletal muscle, liver, and brain.	Information will be obtained at rest (time points 255 and 270 min), during exercise (time points 285, 300, 315, and 330 min) and during recovery from exercise (time points 345, 360, and 390 min).
Detailed information on whole body, skeletal muscle, liver, and brain arginine, ornithine, and citrulline metabolism and quantitative total nitric oxide (NO) production rates.	Information will be obtained at rest (time points 255 and 270 min), during exercise (time points 285, 300, 315, and 330 min) and during recovery from exercise (time points 345, 360, and 390 min).

Collaborators and Investigators

• Sponsor: Helga Ellingsgaard
• Investigators: Principal Investigator: Helga Ellingsgaard, PhD, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Estimated): April 9, 2024
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): November 1, 2024

Study Registration Dates

• First Submitted: March 13, 2024
• First Submitted That Met QC Criteria: March 27, 2024
• First Posted (Actual): March 28, 2024

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: exercise; muscle; brain; liver; IL-6; tocilizumab; energy; extracellular vesicles
• Other Study ID Numbers: H-23069670

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No