The Metabolic Effects of β-hydroxybutyrate on Working Skeletal Muscle
Study Details
Study Description
Brief Summary
The goal of this clinical trial is to test ketone bodies in healthy old 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:
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Special magnetic imaging techniques
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Intravenous infusion of tracer-marked nutrients
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Performance tests on a ergometer bike and in a dynamometer
Researchers will compare the outcomes between the young and the old group to see if age has an effect on the outcome.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
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 3-OHB on skeletal muscle function and metabolism during muscle work in young and old individuals.
DESIGN Healthy young (20-25 years) and old (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-β-hydroxybutyrate/D 1,3 butanediol monoester), one day with ingestion of a volume and calorie matched placebo. Substrate levels will be maintained through a sipping protocol. During both conditions a low glucose dose will be continuously infused to block 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 (50% of VO2 max) while lipid fluxes and glucose oxidation rates are measured by palmitate- and glucose tracer infusions and carbamide-corrected indirect calorimetry. Lastly on the study days, participants will perform a VO2-max test as a measure of performance. Muscle biopsies are obtained before and just following fixed intensity cycle work. Adipose tissue biopsies are collected at the beginning of the experimental day before ketone/placebo ingestion and after the constant load cycle work. 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. Food intake will be reported by food questionnaire three days up to the study days.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: First Ketone, then placebo 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. |
Dietary Supplement: D-β-hydroxybutyrate/D 1,3 butanediol monoester
Ketone monoester
|
| Experimental: First placebo, then ketone 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. |
Dietary Supplement: D-β-hydroxybutyrate/D 1,3 butanediol monoester
Ketone monoester
|
Outcome Measures
Primary Outcome Measures
- Work efficiency [Over 60 minutes on each of the two experimental days.]
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 [Over 20 minutes at each of the two experimental days.]
Assessed by 31P-MRS as phosphocreatine resynthesis.
- Glucose oxidation rates [At 10 minute intervals over the last 30 min of the 90 min fixed intensity cycling on each experimental day.]
Assessed by measuring tracer dilution from blood samples obtained during 3H-glucose infusion while cycling at a fixed intensity.
- Palmitate flux [At 10 minute intervals over the last 30 min of the 90 min fixed intensity cycling on each experimental day.]
Assessed by measuring tracer dilution from blood samples obtained during 3H-palmitate infusion while cycling at a fixed intensity.
- ATP generation [Over 30 minutes at each of the two experimental days.]
ATP generated from different pathways (glycolytic, oxidative, phosphocreatine) assessed by 31P-MRS.
- Mitochondrial function [Just before and immediately after the constant load cycling at each of the two experimental days.]
Assessed by high-resolution respirometry on muscle biopsies
- Intramuscular pH [Over 60 minutes at each of the two experimental days.]
Measurements at rest rest and during work assessed by 31P-MRS
- Blood 3-OHB [During each of the two experimental days]
Blood concentration measured by blood sampling
- Blood glucose [During each of the two experimental days]
Blood concentration measured by blood sampling
- Blood free fatty acids [During each of the two experimental days]
Blood concentration measured by blood sampling
- Cycle performance [5-8 minutes during each of the two experimental days]
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 [After 30, 60 and 90 minutes of fixed intensity cycling and just after the incremental performance test.]
Subjective measure of exertion during cycling evaluated by reporting on a number assessment scale (Borg scale (6-20)).
- Tibialis anterior fatigue [Over 3 minutes on each of the two experimental days.]
Tibialis anterior fatigue assessed by the dynamometer during 3 minutes of dorsiflexion at a fixed resistance.
- Blood growth hormone [During experimental days]
Blood concentration measured by blood sampling
- Blood insulin [During each of the two experimental days]
Blood concentration measured by blood sampling
- AMPK phosphorylation [Just before and immediately after the constant load cycling at each of the two experimental days.]
From muscle biopsies
- Blood glucagon [During each of the two experimental days]
Blood concentration measured by blood sampling
- Blood pH [During each of the two experimental days]
Assessed from arterial blood samples
- Blood catecholamines [During each of the two experimental days]
Blood concentration measured by blood sampling
- Blood cortisol [During each of the two experimental days]
Blood concentration measured by blood sampling
- Intramuscular lipid content [At the beginning and at the end of each of the two experimental days]
Concentration measured in muscle biopsies
- Intramuscular glycogen content [Just before and immediately after the constant load cycling at each of the two experimental days.]
Concentration measured in muscle biopsies
Other Outcome Measures
- Blood haemoglobin [Measured at the beginning and the end of each experimental day]
Blood concentration measured by blood sampling
- Blood Sodium [Measured at the beginning and the end of each experimental day]
Blood concentration measured by blood sampling
- Blood potassium [Measured at the beginning and the end of each experimental day]
Blood concentration measured by blood sampling
- Blood creatinine [During each of the two experimental days]
Blood concentration measured by blood sampling
Eligibility Criteria
Criteria
Inclusion Criteria:
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Male 20-25 years old (n = 12) OR male 65-85 years old (n = 12)
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BMI range: 19 to 27
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Stable weight (< 5% change over last 6 months)
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Less than 3 x 60 min of structured exercise per week.
Exclusion Criteria:
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Medication that affect energy metabolism.
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Non-MR-compatible metals or electric devices in the body.
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Anaemia or bleeding disorders.
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Heart, lung or other disease that affects the subjects ability to exercise.
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Smoking.
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Drug abuse.
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Lack of compliance.
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Known allergy towards local anaesthetics.
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Any condition that the principal investigator considers unsuitable for the subject's ability to complete the study.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Steno Diabetes Center Aarhus | Aarhus | Aarhus N | Denmark | 8200 |
Sponsors and Collaborators
- University of Aarhus
- Danish Diabetes Academy
- AP Moeller Foundation
- Aarhus University Hospital
- Novo Nordisk A/S
Investigators
- Study Director: Niels Jessen, Professor, Aarhus University Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ketomr