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The Metabolic Effects of β-hydroxybutyrate on Working Skeletal Muscle

Primary Purpose

Aging, Metabolism Disorder, Ketonemia

Status
Recruiting
Phase
Not Applicable
Locations
Denmark
Study Type
Interventional
Intervention
D-β-hydroxybutyrate/D 1,3 butanediol monoester
Sponsored by
University of Aarhus
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Aging

Eligibility Criteria

20 Years - 85 Years (Adult, Older Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria: Male 20-25 years old (n = 12) OR male 65-85 years old (n = 12) BMI range: 19 to 27 Stable weight (< 5% change over last 6 months) Less than 3 x 60 min of structured exercise per week. Exclusion Criteria: Medication that affect energy metabolism. Non-MR-compatible metals or electric devices in the body. Anaemia or bleeding disorders. Heart, lung or other disease that affects the subjects ability to exercise. Smoking. Drug abuse. Lack of compliance. Known allergy towards local anaesthetics. Any condition that the principal investigator considers unsuitable for the subject's ability to complete the study.

Sites / Locations

  • Steno Diabetes Center AarhusRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

First Ketone, then placebo

First placebo, then ketone

Arm Description

Ingestion of ketone monoester D-β-hydroxybutyrate / D 1,3 butanediol monoester on first experimental day and ingestion of a fat placebo drink on the second experimental day.

Ingestion of a fat placebo drink on the first experimental day followed by ingestion of ketone monoester D-β-hydroxybutyrate / D 1,3 butanediol monoester on the second experimental day.

Outcomes

Primary Outcome Measures

Work efficiency
External work performed by the ankle during dorsiflexion per ATP consumed. ATP consumption is assessed by 31P-MRS while external force is measured by the dynamometer.

Secondary Outcome Measures

Oxidative capacity
Assessed by 31P-MRS as phosphocreatine resynthesis.
Glucose oxidation rates (only young group)
Assessed by measuring tracer dilution from blood samples obtained during 3H-glucose infusion while cycling at a fixed intensity.
Palmitate flux (only young group)
Assessed by measuring tracer dilution from blood samples obtained during 3H-palmitate infusion while cycling at a fixed intensity.
ATP generation
ATP generated from different pathways (glycolytic, oxidative, phosphocreatine) assessed by 31P-MRS.
Mitochondrial function
Assessed by high-resolution respirometry on muscle biopsies
Intramuscular pH
Measurements at rest rest and during work assessed by 31P-MRS
Blood 3-OHB
Blood concentration measured by blood sampling
Blood glucose
Blood concentration measured by blood sampling
Blood free fatty acids
Blood concentration measured by blood sampling
Cycle performance
Assessed by a performance test on a bike ergometer with incremental load. The test continues until failure. The test outcome is the power generated at time of failure.
Rating of perceived exertion (only young group)
Subjective measure of exertion during cycling evaluated by reporting on a number assessment scale (Borg scale (6-20)).
Tibialis anterior fatigue
Tibialis anterior fatigue assessed by the dynamometer during 3 minutes of dorsiflexion at a fixed resistance.
Blood growth hormone
Blood concentration measured by blood sampling
Blood insulin
Blood concentration measured by blood sampling
AMPK phosphorylation (only young group)
From muscle biopsies
Blood glucagon
Blood concentration measured by blood sampling
Blood pH
Assessed from arterial blood samples
Blood catecholamines
Blood concentration measured by blood sampling
Blood cortisol
Blood concentration measured by blood sampling
Intramuscular lipid content
Concentration measured in muscle biopsies
Intramuscular glycogen content
Concentration measured in muscle biopsies

Full Information

First Posted
January 17, 2023
Last Updated
October 23, 2023
Sponsor
University of Aarhus
Collaborators
Danish Diabetes Academy, AP Moeller Foundation, Aarhus University Hospital, Novo Nordisk A/S
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1. Study Identification

Unique Protocol Identification Number
NCT05732909
Brief Title
The Metabolic Effects of β-hydroxybutyrate on Working Skeletal Muscle
Official Title
The Metabolic Effects of β-hydroxybutyrate on Working Skeletal Muscle
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 22, 2022 (Actual)
Primary Completion Date
January 10, 2024 (Anticipated)
Study Completion Date
March 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Aarhus
Collaborators
Danish Diabetes Academy, AP Moeller Foundation, Aarhus University Hospital, Novo Nordisk A/S

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The goal of this clinical trial is to test ketone bodies in healthy elderly and young individuals. The main question it aims to answer are: • Do ketone bodies improve skeletal muscle function? Participants will ingest a ketone monoester and skeletal muscle function will then be evaluated by: Special magnetic imaging techniques Intravenous infusion of tracer-marked nutrients Performance tests on a ergometer bike and in a dynamometer Researchers will compare the outcomes between within the young and elderly groups and between the young and the elderly group to investigate if age has an effect on the outcomes.
Detailed Description
BACKGROUND With ageing, skeletal muscles metabolism changes and muscle function declines. This may lead to muscle weakness and increased risk of developing metabolic diseases. Ketone bodies, namely 3-hydroxybutyrate (3-OHB), is an energy substrate that may change the metabolism and improve efficiency of skeletal muscles in a setting of ageing. OBJECTIVE The study aims to investigate the effects of beta-hydroxybutyrate ingested as a monoester on skeletal muscle function and metabolism during muscle work in young and elderly individuals. DESIGN Healthy young (20-25 years) and elderly (65-85 years) untrained males will be paired based on age corrected VO2-max. Participants will be evaluated in a double blinded cross-over design on two study days: One day with ketone ester ingestion (D-beta-hydroxybutyrate/D-1,3-butanediol; KetoneAid Pro KE4), one day with ingestion of a volume and calorie and taste matched placebo (lipid emulsion). Blood ketone levels will be kept elevated through a sipping protocol. During both conditions a low glucose dose will be continuously infused to block physiological ketogenesis. The order of the study days will be randomized and interspaced by at least 4 weeks. On experimental days, participants meet fasted to perform voluntary contractions with tibialis anterior muscles in a MR compatible dynamometer while oxidative capacity, ATP generation, intramuscular pH, fatiguability and work efficiency is evaluated through 31P-MR spectroscopy. After, participants will bike at a fixed intensity (~45% of Wmax) while lipid fluxes and glucose oxidation rates are measured by palmitate- and glucose tracer infusions and carbamide-corrected indirect calorimetry over 60 min. This was initially intended for both young and elderly individuals, but only involves the young group, as the elderly group had difficulties completing 60 min cycling. Lastly on the study days, participants will perform a cycling test as a measure of performance starting at 70 % of Wmax for 5 min thereafter increasing by 10 % of Wmax every 1 min until exhaustion. Muscle biopsies are obtained before (both groups) and just following fixed intensity cycle work (only young group). Adipose tissue biopsies are collected at the beginning of the experimental day (both groups) before ketone/placebo ingestion and after the constant load cycle work (only young group). Blood samples are performed throughout the day to assess substrate levels, hormones and for proteomics analysis. Before each study day, participant's activity level is measured for 7 days by accelerometry (ActiGraph). Participants will log their diet 3 days prior to each experimental day. Participants are asked to ingest a similar diet 2 days before both experimental days and to withstand from strenuous exercise 2 days prior to both experimental days. Participants are asked not to make any significant changes to their lifestyle while taking part in the study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aging, Metabolism Disorder, Ketonemia, Muscle Disorder

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Model Description
Two-day cross-over design.
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
First Ketone, then placebo
Arm Type
Experimental
Arm Description
Ingestion of ketone monoester D-β-hydroxybutyrate / D 1,3 butanediol monoester on first experimental day and ingestion of a fat placebo drink on the second experimental day.
Arm Title
First placebo, then ketone
Arm Type
Experimental
Arm Description
Ingestion of a fat placebo drink on the first experimental day followed by ingestion of ketone monoester D-β-hydroxybutyrate / D 1,3 butanediol monoester on the second experimental day.
Intervention Type
Dietary Supplement
Intervention Name(s)
D-β-hydroxybutyrate/D 1,3 butanediol monoester
Intervention Description
Ketone monoester
Primary Outcome Measure Information:
Title
Work efficiency
Description
External work performed by the ankle during dorsiflexion per ATP consumed. ATP consumption is assessed by 31P-MRS while external force is measured by the dynamometer.
Time Frame
Over 60 minutes on each of the two experimental days.
Secondary Outcome Measure Information:
Title
Oxidative capacity
Description
Assessed by 31P-MRS as phosphocreatine resynthesis.
Time Frame
Over 20 minutes at each of the two experimental days.
Title
Glucose oxidation rates (only young group)
Description
Assessed by measuring tracer dilution from blood samples obtained during 3H-glucose infusion while cycling at a fixed intensity.
Time Frame
At 10 minute intervals over the last 30 min of the 90 min fixed intensity cycling on each experimental day.
Title
Palmitate flux (only young group)
Description
Assessed by measuring tracer dilution from blood samples obtained during 3H-palmitate infusion while cycling at a fixed intensity.
Time Frame
At 10 minute intervals over the last 30 min of the 90 min fixed intensity cycling on each experimental day.
Title
ATP generation
Description
ATP generated from different pathways (glycolytic, oxidative, phosphocreatine) assessed by 31P-MRS.
Time Frame
Over 30 minutes at each of the two experimental days.
Title
Mitochondrial function
Description
Assessed by high-resolution respirometry on muscle biopsies
Time Frame
Just before and immediately after the constant load cycling at each of the two experimental days.
Title
Intramuscular pH
Description
Measurements at rest rest and during work assessed by 31P-MRS
Time Frame
Over 60 minutes at each of the two experimental days.
Title
Blood 3-OHB
Description
Blood concentration measured by blood sampling
Time Frame
During each of the two experimental days
Title
Blood glucose
Description
Blood concentration measured by blood sampling
Time Frame
During each of the two experimental days
Title
Blood free fatty acids
Description
Blood concentration measured by blood sampling
Time Frame
During each of the two experimental days
Title
Cycle performance
Description
Assessed by a performance test on a bike ergometer with incremental load. The test continues until failure. The test outcome is the power generated at time of failure.
Time Frame
5-8 minutes during each of the two experimental days
Title
Rating of perceived exertion (only young group)
Description
Subjective measure of exertion during cycling evaluated by reporting on a number assessment scale (Borg scale (6-20)).
Time Frame
After 30, 60 and 90 minutes of fixed intensity cycling and just after the incremental performance test.
Title
Tibialis anterior fatigue
Description
Tibialis anterior fatigue assessed by the dynamometer during 3 minutes of dorsiflexion at a fixed resistance.
Time Frame
Over 3 minutes on each of the two experimental days.
Title
Blood growth hormone
Description
Blood concentration measured by blood sampling
Time Frame
During experimental days
Title
Blood insulin
Description
Blood concentration measured by blood sampling
Time Frame
During each of the two experimental days
Title
AMPK phosphorylation (only young group)
Description
From muscle biopsies
Time Frame
Just before and immediately after the constant load cycling at each of the two experimental days.
Title
Blood glucagon
Description
Blood concentration measured by blood sampling
Time Frame
During each of the two experimental days
Title
Blood pH
Description
Assessed from arterial blood samples
Time Frame
During each of the two experimental days
Title
Blood catecholamines
Description
Blood concentration measured by blood sampling
Time Frame
During each of the two experimental days
Title
Blood cortisol
Description
Blood concentration measured by blood sampling
Time Frame
During each of the two experimental days
Title
Intramuscular lipid content
Description
Concentration measured in muscle biopsies
Time Frame
At the beginning and at the end of each of the two experimental days
Title
Intramuscular glycogen content
Description
Concentration measured in muscle biopsies
Time Frame
Just before and immediately after the constant load cycling at each of the two experimental days.
Other Pre-specified Outcome Measures:
Title
Blood haemoglobin
Description
Blood concentration measured by blood sampling
Time Frame
Measured at the beginning and the end of each experimental day
Title
Blood Sodium
Description
Blood concentration measured by blood sampling
Time Frame
Measured at the beginning and the end of each experimental day
Title
Blood potassium
Description
Blood concentration measured by blood sampling
Time Frame
Measured at the beginning and the end of each experimental day
Title
Blood creatinine
Description
Blood concentration measured by blood sampling
Time Frame
During each of the two experimental days

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Male 20-25 years old (n = 12) OR male 65-85 years old (n = 12) BMI range: 19 to 27 Stable weight (< 5% change over last 6 months) Less than 3 x 60 min of structured exercise per week. Exclusion Criteria: Medication that affect energy metabolism. Non-MR-compatible metals or electric devices in the body. Anaemia or bleeding disorders. Heart, lung or other disease that affects the subjects ability to exercise. Smoking. Drug abuse. Lack of compliance. Known allergy towards local anaesthetics. Any condition that the principal investigator considers unsuitable for the subject's ability to complete the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ole Emil Andersen, M.D., PhD student
Phone
004529934167
Email
oleemil@ph.au.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Niels Jessen, Professor
Organizational Affiliation
Aarhus University Hospital
Official's Role
Study Director
Facility Information:
Facility Name
Steno Diabetes Center Aarhus
City
Aarhus
State/Province
Aarhus N
ZIP/Postal Code
8200
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ole Emil Andersen, M.D., PhD student
Phone
004529934167
Email
oleemil@ph.au.dk

12. IPD Sharing Statement

Learn more about this trial

The Metabolic Effects of β-hydroxybutyrate on Working Skeletal Muscle

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