Improvements in Aerobic Fitness With Exercise Training: the Role of Myokines

For both healthy adults and patients with cardiovascular disease (CVD), aerobic fitness (V̇O2max) is a stronger predictor of the risk of future chronic disease and premature death than other established risk factors such as hypertension, smoking, or Type 2 diabetes. It is important to improve the understanding of the regulation of V̇O2max to enable optimisation of interventions aimed at increasing V̇O2max in the current predominantly sedentary population. Currently, only exercise training is a viable method for increasing V̇O2max. However, ~10-20% of people who follow fully supervised, standardised training interventions do not demonstrate a measurable increase in V̇O2max. Low response to training is a clinically relevant concern, but the large variability in response to exercise training also provides an opportunity to dissect out the molecular mechanisms responsible for adaptations to V̇O2max by contrasting low vs. high responders to training. It has been previously demonstrated that low responders for VO2max fail to up regulate a number of genes that encode putative 'myokines', while the high responders demonstrated a significant increase in the expression of these genes, suggesting these myokines may play an important mechanistic role in modulating VO2max. The aim of the present study is to examine whether low responders for VO2max have an attenuated increase in the plasma levels of the previously identified myokines.

Study Overview

• Status: Recruiting
• Conditions: General Health
• Intervention / Treatment: Behavioral: Reduced-exertion high-intensity interval training (REHIT)

Detailed Description

For both healthy adults and patients with cardiovascular disease (CVD), aerobic fitness (V̇O2max) is a stronger predictor of the risk of future chronic disease and premature death than other established risk factors such as hypertension, smoking, or Type 2 diabetes. Considering the large medical and economic burden of physical inactivity-related chronic disease it is important to improve the understanding of the regulation of V̇O2max to enable optimisation of interventions aimed at increasing V̇O2max in the current predominantly sedentary population. Furthermore, there is a need to identify novel drug targets to aid pharmacological intervention in those individuals who are unwilling or unable to improve V̇O2max through exercise.

Currently, only exercise training is a viable method for increasing V̇O2max. However, although exercise training on average improves V̇O2max, ~10-20% of people who follow fully supervised, standardised training interventions do not demonstrate a measurable increase in V̇O2max. Low response to training is a clinically relevant concern, but the large variability in response to exercise training also provides an opportunity to dissect out the molecular mechanisms responsible for adaptations to V̇O2max by contrasting low vs. high responders to training.

Using this approach it has previously been shown that in skeletal muscle samples obtained pre- and post- training, 86 genes are differentially regulated in high compared to low responders for V̇O2max. Strikingly, out of these 86 genes, 13 genes encode proteins that have been reported to be released by muscle during or after exercise (i.e., 'messenger proteins' termed myokines). This strongly suggests low responders to exercise training fail to sufficiently upregulate the production and release of these myokines, and that this is (at least partly) the reason why these people do not manage to improve their V̇O2max as much as high responders. However, in order to confirm a mechanistic role of these myokines in increasing V̇O2max, it needs to be demonstrated that beside the change in gene expression, the change in the plasma levels of these myokines is also impaired in low responders for V̇O2max.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Niels Vollaard, PhD; Phone Number: 01786466488; Email: n.vollaard@stir.ac.uk
• Study Contact Backup: Name: Matthew Hutchinson, MSc; Phone Number: 01786466488; Email: matthew.hutchinson@stir.ac.uk

Study Locations

• United Kingdom
  • Stirling, United Kingdom, FK9 4LA
    • Recruiting
    • University of Stirling
    • Contact: Matthew Hurchinson, MSc; Phone Number: 01786466488; Email: matthew.hutchinson@stir.ac.uk
    • Sub-Investigator: Matthew Hutchinson
    • Principal Investigator: Niels Vollaard
    • Sub-Investigator: Jie Zhang

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Male
• Age ≥ 18 y or <40 y
• BMI < 35 kg/m2
• otherwise healthy, untrained individuals

Exclusion Criteria:

• Age <18 y or >40 y
• BMI > 35 kg/m2
• classification of 'highly physically active' according to the International Physical Activity Questionnaire (IPAQ)
• answering 'yes' to one or more questions on a standard Physical Activity Readiness Questionnaire (PAR-Q)
• resting heart rate ≥100bpm, clinically significant hypertension (140/90 mmHg)
• a personal history of metabolic or cardiovascular disease
• Female participants because of unknown effects of the menstrual cycle on the levels of the measured myokines.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Reduced-exertion high-intensity interval training (REHIT); All participants complete 6 weeks (3 sessions/week) of an exercise intervention labelled 'REHIT'. Exercise sessions involve 10 minutes of unloaded cycling interspersed with 2 x 20 sec 'all-out' sprints against a resistance of 7.5% of participant's body weight. Sprints begin at 1:40 min and 5:40 min.	Behavioral: Reduced-exertion high-intensity interval training (REHIT); Description same as Arm description.; Other Names: Sprint interval training (SIT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Training induced changes in VO2max	Maximal aerobic capacity (VO2max) will be measured pre- and post-training to determine the change in VO2max.	Pre-intervention and 3 days post-intervention
Training induced changes in plasma myokines	Plasma myokine levels of 8 myokines will be measured pre- and post-training to determine the change in plasma myokine levels.	Pre-intervention and 3 days post-intervention

Collaborators and Investigators

• Sponsor: University of Stirling
• Investigators: Principal Investigator: Niels Vollaard, PhD, University of Stirling

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2023
• Primary Completion (Estimated): April 30, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: November 13, 2023
• First Submitted That Met QC Criteria: November 18, 2023
• First Posted (Actual): November 21, 2023

Study Record Updates

• Last Update Posted (Actual): November 27, 2023
• Last Update Submitted That Met QC Criteria: November 21, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: VO2max; Cardiorespiratory Fitness; Myokine
• Other Study ID Numbers: UStirling

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