Skeletal Muscle Mitochondria in Ageing

Official title

Exercise as a Countermeasure Against the Effects of Ageing on Muscle Mitochondria, Diffusive Oxygen Transport and Muscle Volume

Overview

Healthy ageing is associated with the loss of muscle mass and physical function. As a result, older people are limited in their independence. The aging of muscles typically begins around the age of 30. From this age onward, muscle strength, muscle mass, and the maximum oxygen uptake of muscles decrease. The reasons for this are not entirely clear, but it seems to be partly related to how oxygen moves from our blood vessels to the muscles and how muscles burn energy. The precise role of age and physical fitness, as well as whether exercise can counteract the effects of ageing, is still unknown. Therefore, in this study, we aim to investigate the muscle function of both physically active and inactive young and middle-aged individuals. We hypothesise that endurance training can mitigate some of the effects of ageing.

Detailed description

Healthy ageing is associated with a loss of muscle mass and physical function. This loss of physical function is underpinned by reductions in characteristics such as muscle strength, power, and maximal oxygen uptake (V̇O2max; reflecting exercise capacity). However, the causal contributors to these age-associated impairments, and the role of exercise training status in mitigating them, remain poorly defined. Skeletal muscle mitochondrial function has been proposed to be a key contributor to age-associated effects on physical function, however many conflicting results are present in the extant human literature. Moreover, diffusion of oxygen from capillaries to mitochondria is a key determinant of V̇O2max, however, whether the skeletal muscle diffusive capacity for oxygen (DmO2) declines with age is unknown. A new technique utilizing near-infrared spectroscopy (NIRS) will enable the non-invasive assessment of skeletal muscle diffusive capacity in young and elderly subjects for the first time to resolve this issue. The primary aims of this study are therefore to 1) compare DmO2 derived via NIRS between young sedentary, young endurance-trained, older sedentary, and older endurance-trained subjects; 2) to compare non-invasive (i.e. with NIRS and 31phosphorous magnetic resonance spectroscopy \[31P-MRS\]) and invasive (i.e. measures of mitochondrial morphology and respiration obtained by skeletal muscle biopsy) markers of mitochondrial function between the same groups, and 3) to assess the relationships between DmO2, mitochondrial measures and assessments of capillarization with functional measurements of muscle strength, power, and V̇O2max.

Interventions

• Other Maximal exercise test
  Participants will undertake an incremental ramp test on a cycle ergometer to determine maximal oxygen uptake (V̇O2max) and the gas exchange threshold (GET). Throughout the exercise test, muscle oxygenation and deoxygenation will be monitored by NIRS.
• Other 3D Ultrasound
  Muscle volume and morphological characteristics will be assessed via 3D ultrasound imaging.
• Other Dynamometry
  To determine the contractile properties of the knee extensors, participants will perform maximal isometric and isoinertial contractions of the knee extensors on a dynamometer.
• Other Exercise test and occlusions
  Participants will perform a series of moderate-intensity constant power output exercise bouts on a cycle ergometer following which the recovery rates of muscle V̇O2 will be determined via a series of intermittent arterial occlusions. Throughout all tests, pulmonary gas exchange and ventilation will be determined and muscle oxygenation and deoxygenation will be monitored by NIRS.
• Other Exercise test in MRI
  Exercise will be performed on a custom-built magnetic resonance-compatible cycle ergometer in supine position for determination of muscle phosphocreatine recovery kinetics using 31phosphorous magnetic resonance spectroscopy \[31P-MRS\].
• Procedure Muscle biopsy
  A muscle biopsy will be obtained from the vastus lateralis using a modified Bergström needle technique with suction.

Primary outcome measures

• Maximal oxygen uptake (V̇O2max) [Time frame: Baseline (visit 1)]
• Muscle volume [Time frame: Baseline (visit 1)]
• Muscle strength [Time frame: Baseline (visit 1)]
• Muscle power [Time frame: Baseline (visit 1)]
• Muscle diffusing capacity for oxygen (DmO2) [Time frame: Baseline (visit 1) and visit 2-4. In total 4 weeks.]
• Muscle mitochondrial fragmentation index (A.U.) [Time frame: Visit 6 muscle biopsy (+/- after 4 weeks).]

Secondary outcome measures (12)

• Gas exchange and ventilatory variables (gas exchange threshold, respiratory compensation point, maximal ventilation) [Time frame: Baseline (visit 1)]
• (Peak) power output [Time frame: Baseline (visit 1)]
• Mean response time of the V̇O2 slope during ramp exercise [Time frame: Baseline (visit 1)]
• (Maximum) heart rate (HR) [Time frame: Baseline (visit 1) and during visit 2-4 (max 4 weeks in total)]
• Maximal O2 pulse [Time frame: Baseline (visit 1)]
• Slope of ventilation (VE) versus carbon dioxide (VCO2) output during ramp exercise (i.e. ventilatory efficiency) [Time frame: Baseline (visit 1)]
• V̇O2/HR slope during ramp exercise [Time frame: Baseline (visit 1)]
• Maximal respiratory exchange ratio (RER) [Time frame: Baseline (visit 1)]
• Maximal ventilatory equivalents [Time frame: Baseline (visit 1)]
• Maximal end-tidal pressures for oxygen (O2) and carbon dioxide (CO2) [Time frame: Baseline (visit 1)]
• Capillary lactate concentration [Time frame: Baseline (visit 1)]
• Maximal respiratory frequency [Time frame: Baseline (visit 1)]

Eligibility criteria

Inclusion criteria

In order to be eligible to participate in this study, young sedentary participants must meet all of the following criteria:

• Aged between 18-30 years
• Male or female
• Not currently engaging in any formal exercise training or competitive sports
• No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise

In order to be eligible to participate in this study, young trained participants must meet all of the following criteria:

• Aged between 18-30 years
• Male or female
• Currently engaging in formal training (at least 3 times per week) in competitive endurance sports
• No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise

In order to be eligible to participate in this study, older sedentary participants must meet all of the following criteria:

• Aged between 50-65 years
• Male or female
• Not currently engaging in any formal exercise training or competitive sports
• No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise

In order to be eligible to participate in this study, older trained participants must meet all of the following criteria:

• Aged between 50-65 years
• Male or female
• Currently engaging in formal training (at least 3 times per week) in competitive endurance sports
• No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise

Exclusion criteria

• Age that falls outside of 18-30 years (young groups) or 50-65 years (middle-aged groups)
• Inability to provide informed consent
• History of claustrophobia
• Ineligibility to perform the exercise test described in this study protocol or follow instructions
• Taking any medications known to interfere with the physiological responses to exercise, e.g. e.g. systemic corticosteroids, statins, SGLT2 inhibitors, GLP1 receptor agonists
• Contraindication for MRI (e.g. pacemaker, claustrophobia)
• Being under investigation for non-diagnosed disease at the time of investigation
• Body Mass Index (BMI) >30 due to adiposity, since this is known to cause difficulties in obtaining muscle biopsies and NIRS measurements
• Pregnancy
• Are current smokers or have been a regular smoker within the last 12 months

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Case-control

Study locations

Netherlands · 1 center

• Vrije Universiteit Amsterdam — Amsterdam

Identifiers

NCT: NCT06539078 · 2023.0746

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗