Clinical trial NCT06539078: 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
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Aging
Keywords: Exercise
Mitochondria
Skeletal muscle
Lead sponsor: VU University of Amsterdam
Sponsor class: OTHER
First posted: 2024-08-06
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 15 sedentary and 15 endurance-trained young and middle-aged individuals will be recruited per age group (i.e. a total of 60 individuals spanning 4 groups). An equal balance of the sexes will be aimed for in each group. All participants will be recruited from specific social media groups, through personal networks of friends, family and colleagues, flyers and posters at local sports clubs and on the VU Campus. All testing will be conducted at the VU or in the Department of Radiology and Nuclear Medicine at Amsterdam UMC location AMC. Therefore, participants should be currently residing in or willing to travel to Amsterdam.

Brief summary: 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.

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

Primary outcomes:
measure: Maximal oxygen uptake (V̇O2max)
timeFrame: Baseline (visit 1)
measure: Muscle volume
timeFrame: Baseline (visit 1)
measure: Muscle strength
timeFrame: Baseline (visit 1)
measure: Muscle power
timeFrame: Baseline (visit 1)
measure: Muscle diffusing capacity for oxygen (DmO2)
timeFrame: Baseline (visit 1) and visit 2-4. In total 4 weeks.
measure: Muscle mitochondrial fragmentation index (A.U.)
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks).
Secondary outcomes:
measure: Gas exchange and ventilatory variables (gas exchange threshold, respiratory compensation point, maximal ventilation)
timeFrame: Baseline (visit 1)
measure: (Peak) power output
timeFrame: Baseline (visit 1)
measure: Mean response time of the V̇O2 slope during ramp exercise
timeFrame: Baseline (visit 1)
measure: (Maximum) heart rate (HR)
timeFrame: Baseline (visit 1) and during visit 2-4 (max 4 weeks in total)
measure: Maximal O2 pulse
timeFrame: Baseline (visit 1)
measure: Slope of ventilation (VE) versus carbon dioxide (VCO2) output during ramp exercise (i.e. ventilatory efficiency)
timeFrame: Baseline (visit 1)
measure: V̇O2/HR slope during ramp exercise
timeFrame: Baseline (visit 1)
measure: Maximal respiratory exchange ratio (RER)
timeFrame: Baseline (visit 1)
measure: Maximal ventilatory equivalents
timeFrame: Baseline (visit 1)
measure: Maximal end-tidal pressures for oxygen (O2) and carbon dioxide (CO2)
timeFrame: Baseline (visit 1)
measure: Capillary lactate concentration
timeFrame: Baseline (visit 1)
measure: Maximal respiratory frequency
timeFrame: Baseline (visit 1)
measure: Pulmonary oxygen uptake - baseline and steady state V̇O2
timeFrame: Baseline (visit 1) and visit 2-4 (max 4 weeks in total)
measure: Pulmonary oxygen uptake kinetics - Phase II V̇O2 time constant and time delay
timeFrame: Visit 2-4 (max 4 weeks in total)
measure: Pulmonary oxygen uptake kinetics - Phase II V̇O2 amplitude
timeFrame: Visit 2-4 (max 4 weeks in total)
measure: Concentrations of NIRS derived muscle oxy- and deoxygenated [haemoglobin + myoglobin] (HbO2, Hbb) and tissue saturation index (TSI).
timeFrame: Baseline (visit 1) and visit 2-4 (max 4 weeks in total)
measure: NIRS derived muscle oxy- and deoxygenated [haemoglobin + myoglobin] (HbO2, Hbb) and tissue saturation index (TSI) versus relative and absolute work rate.
timeFrame: Baseline (visit 1)
measure: Initial and secondary slope of increase during incremental exercise will be reported for NIRS derived muscle oxy- and deoxygenated [haemoglobin + myoglobin] (HbO2, Hbb) and tissue saturation index (TSI) versus relative work rate.
timeFrame: Baseline (visit 1)
measure: Initial and secondary slope during incremental exercise will be reported for NIRS derived muscle oxy- and deoxygenated [haemoglobin + myoglobin] (HbO2, Hbb) and tissue saturation index (TSI) versus absolute work rate.
timeFrame: Baseline (visit 1)
measure: Muscle (de)oxygenation breakpoint during incremental exercise
timeFrame: Baseline (visit 1)
measure: Rate constant of mV̇O2 recovery kinetics under conditions of high, medium and low O2 availability
timeFrame: Baseline (visit 1)
measure: Muscle morphology - Fascicle length
timeFrame: Baseline (visit 1)
measure: Muscle morphology - pennation angle
timeFrame: Baseline (visit 1)
measure: Muscle morphology - (effective) physiological cross-sectional area (PCSA)
timeFrame: Baseline (visit 1)
measure: Muscle morphology - vastus lateralis specific force
timeFrame: Baseline (visit 1)
measure: Muscle morphology - estimated muscle fiber number
timeFrame: Baseline (visit 1)
measure: Adipose tissue thickness at the site of NIRS measurement
timeFrame: Baseline (visit 1)
measure: Mitochondrial respiratory function (background, LEAK, N-linked respiration, OXPHOS, ETS, succinate (S) + rotenone (ROT)-linked uncoupled respiration, )
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks).
measure: Respiratory control ratios
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks).
measure: Intrinsic mitochondrial respiration (each respiratory state outlined below will be normalised to mitochondrial volume density)
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks).
measure: 31P-MRS-derived mitochondrial bioenergetic function - resting and steady-state exercising concentrations and amplitude of exercise-induced changes of skeletal muscle Phosphocreatine [PCr], [inorganic phosphate] and pH
timeFrame: Visit 5 MRI
measure: 31P-MRS-derived mitochondrial bioenergetic function rate constant of PCr
timeFrame: Visit 5 MRI
measure: 31P-MRS-derived mitochondrial bioenergetic function - maximal rate of oxidative ATP synthesis
timeFrame: Visit 5 MRI
measure: Muscle fiber type distribution
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.
measure: (mean) fiber cross-sectional area, also fiber type specific
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.
measure: Weighted fiber cross-sectional area
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.
measure: Mean and fiber type specific succinate dehydrogenase activity
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.
measure: Integrated fiber succinate dehydrogenase activity
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.
measure: Mean and fiber type specific myoglobin concentrations
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.
measure: Muscle capillarization - capillary density
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.
measure: Muscle capillarization - capillary-to-fiber ratio
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.
measure: Muscle capillarization - mean number of capillaries surrounding a fiber (CAF)
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.
measure: Muscle capillarization - mean number of capillaries surrounding a fiber in relation to fiber area (CAFA)
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.
measure: Muscle capillarization - capillary-to fiber-perimeter exchange index (CFPE)
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.
measure: Muscle capillarization - length of capillaries relative to fiber perimeter (LC/PF)
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.
measure: Muscle capillarization - sarcomere length
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.
measure: Mitochondrial dynamics proteins (Mfn1, Mfn2, OPA1, Drp1, Parkin, PINK1, Fis1, MTFP1, NRF1&2, PGC1a, TFAM, OXPHOS protein content (complexes I-V and total protein content)
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - western blot within time window of 2 years.
measure: Physical activity status - pedometer
timeFrame: Baseline 7 days
measure: Mitochondrial area density
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - electron microscopy (EM) within time window of 2 years.
measure: Mitochondrial volume density
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.
measure: Mitochondrial number
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.
measure: Mitochondrial area
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.
measure: Mitochondrial height, width, perimeter and maximal+minimal Feret's diameter
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.
measure: Mitochondrial surface area-to-volume ratio
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.
measure: Mitochondrial circularity
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.
measure: Mitochondrial roundness
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.
measure: Mitochondrial aspect ratio
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.
measure: Mitochondrial cristae area density
timeFrame: Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Vrije Universiteit Amsterdam
state: Noord-Holland
Study officials:
affiliation: VU University of Amsterdam
name: Richie Goulding, PhD
role: PRINCIPAL_INVESTIGATOR
References: