The Metabolic Effects of β-hydroxybutyrate on Working Skeletal Muscle

Aging Clinical Trial

Official title:

The Metabolic Effects of β-hydroxybutyrate on Working Skeletal Muscle

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05732909
• Other study ID #: ketomr
• Status: Recruiting
• Phase: N/A
• Start date: December 22, 2022
• Est. completion date: March 1, 2024

Study information

• Verified date: January 2023
• Source: University of Aarhus
• Contact: Ole Emil Andersen, M.D., PhD student
• Phone: 004529934167
• Email: oleemil[@]ph.au.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: March 1, 2024
• Est. primary completion date: January 10, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 20 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Aging
• Ketonemia
• Ketosis
• Metabolic Diseases
• Metabolism Disorder
• Muscle Disorder
• Muscular Diseases

Intervention

Dietary Supplement:
• D-ß-hydroxybutyrate/D 1,3 butanediol monoester
Ketone monoester

Locations

Country	Name	City	State
Denmark	Steno Diabetes Center Aarhus	Aarhus	Aarhus N

Sponsors (5)

Lead Sponsor	Collaborator
University of Aarhus	Aarhus University Hospital, AP Moeller Foundation, Danish Diabetes Academy, Novo Nordisk A/S

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Blood haemoglobin	Blood concentration measured by blood sampling	Measured at the beginning and the end of each experimental day
Other	Blood Sodium	Blood concentration measured by blood sampling	Measured at the beginning and the end of each experimental day
Other	Blood potassium	Blood concentration measured by blood sampling	Measured at the beginning and the end of each experimental day
Other	Blood creatinine	Blood concentration measured by blood sampling	During each of the two experimental days
Primary	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.	Over 60 minutes on each of the two experimental days.
Secondary	Oxidative capacity	Assessed by 31P-MRS as phosphocreatine resynthesis.	Over 20 minutes at each of the two experimental days.
Secondary	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.	At 10 minute intervals over the last 30 min of the 90 min fixed intensity cycling on each experimental day.
Secondary	Palmitate flux (only young group)	Assessed by measuring tracer dilution from blood samples obtained during 3H-palmitate infusion while cycling at a fixed intensity.	At 10 minute intervals over the last 30 min of the 90 min fixed intensity cycling on each experimental day.
Secondary	ATP generation	ATP generated from different pathways (glycolytic, oxidative, phosphocreatine) assessed by 31P-MRS.	Over 30 minutes at each of the two experimental days.
Secondary	Mitochondrial function	Assessed by high-resolution respirometry on muscle biopsies	Just before and immediately after the constant load cycling at each of the two experimental days.
Secondary	Intramuscular pH	Measurements at rest rest and during work assessed by 31P-MRS	Over 60 minutes at each of the two experimental days.
Secondary	Blood 3-OHB	Blood concentration measured by blood sampling	During each of the two experimental days
Secondary	Blood glucose	Blood concentration measured by blood sampling	During each of the two experimental days
Secondary	Blood free fatty acids	Blood concentration measured by blood sampling	During each of the two experimental days
Secondary	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.	5-8 minutes during each of the two experimental days
Secondary	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)).	After 30, 60 and 90 minutes of fixed intensity cycling and just after the incremental performance test.
Secondary	Tibialis anterior fatigue	Tibialis anterior fatigue assessed by the dynamometer during 3 minutes of dorsiflexion at a fixed resistance.	Over 3 minutes on each of the two experimental days.
Secondary	Blood growth hormone	Blood concentration measured by blood sampling	During experimental days
Secondary	Blood insulin	Blood concentration measured by blood sampling	During each of the two experimental days
Secondary	AMPK phosphorylation (only young group)	From muscle biopsies	Just before and immediately after the constant load cycling at each of the two experimental days.
Secondary	Blood glucagon	Blood concentration measured by blood sampling	During each of the two experimental days
Secondary	Blood pH	Assessed from arterial blood samples	During each of the two experimental days
Secondary	Blood catecholamines	Blood concentration measured by blood sampling	During each of the two experimental days
Secondary	Blood cortisol	Blood concentration measured by blood sampling	During each of the two experimental days
Secondary	Intramuscular lipid content	Concentration measured in muscle biopsies	At the beginning and at the end of each of the two experimental days
Secondary	Intramuscular glycogen content	Concentration measured in muscle biopsies	Just before and immediately after the constant load cycling at each of the two experimental days.