Skeletal Muscle Mitochondria in Ageing
- Conditions
- Aging
- Interventions
- Other: Maximal exercise testOther: 3D UltrasoundOther: DynamometryOther: Exercise test and occlusionsOther: Exercise test in MRIProcedure: Muscle biopsy
- Registration Number
- NCT06539078
- Lead Sponsor
- VU University of 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 60
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
- 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
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Young, sedentary participants 3D Ultrasound * 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 Young endurance-trained participants Maximal exercise test * Aged between 18-30 years * Male or female * Currently engaging in formal training (at least 3 times per week) in competitive endurance sports (i.e. running, cycling, swimming, triathlon, etc.) * No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise Young endurance-trained participants Muscle biopsy * Aged between 18-30 years * Male or female * Currently engaging in formal training (at least 3 times per week) in competitive endurance sports (i.e. running, cycling, swimming, triathlon, etc.) * No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise Middle-aged, sedentary participants Exercise test in MRI * 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 Middle-aged, sedentary participants Muscle biopsy * 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 Middle-aged endurance-trained participants 3D Ultrasound * Aged between 50-65 years * Male or female * Currently engaging in formal training (at least 3 times per week) in competitive endurance sports (i.e. running, cycling, swimming, triathlon, etc.) * No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise Young, sedentary participants Maximal exercise test * 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 Middle-aged, sedentary participants Maximal exercise test * 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 Middle-aged, sedentary participants Dynamometry * 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 Middle-aged endurance-trained participants Maximal exercise test * Aged between 50-65 years * Male or female * Currently engaging in formal training (at least 3 times per week) in competitive endurance sports (i.e. running, cycling, swimming, triathlon, etc.) * No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise Middle-aged endurance-trained participants Exercise test in MRI * Aged between 50-65 years * Male or female * Currently engaging in formal training (at least 3 times per week) in competitive endurance sports (i.e. running, cycling, swimming, triathlon, etc.) * No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise Young, sedentary participants Exercise test and occlusions * 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 Middle-aged, sedentary participants Exercise test and occlusions * 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 Middle-aged endurance-trained participants Exercise test and occlusions * Aged between 50-65 years * Male or female * Currently engaging in formal training (at least 3 times per week) in competitive endurance sports (i.e. running, cycling, swimming, triathlon, etc.) * No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise Young, sedentary participants Dynamometry * 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 Young endurance-trained participants 3D Ultrasound * Aged between 18-30 years * Male or female * Currently engaging in formal training (at least 3 times per week) in competitive endurance sports (i.e. running, cycling, swimming, triathlon, etc.) * No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise Young endurance-trained participants Exercise test in MRI * Aged between 18-30 years * Male or female * Currently engaging in formal training (at least 3 times per week) in competitive endurance sports (i.e. running, cycling, swimming, triathlon, etc.) * No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise Young, sedentary participants Exercise test in MRI * 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 Young, sedentary participants Muscle biopsy * 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 Young endurance-trained participants Dynamometry * Aged between 18-30 years * Male or female * Currently engaging in formal training (at least 3 times per week) in competitive endurance sports (i.e. running, cycling, swimming, triathlon, etc.) * No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise Young endurance-trained participants Exercise test and occlusions * Aged between 18-30 years * Male or female * Currently engaging in formal training (at least 3 times per week) in competitive endurance sports (i.e. running, cycling, swimming, triathlon, etc.) * No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise Middle-aged, sedentary participants 3D Ultrasound * 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 Middle-aged endurance-trained participants Dynamometry * Aged between 50-65 years * Male or female * Currently engaging in formal training (at least 3 times per week) in competitive endurance sports (i.e. running, cycling, swimming, triathlon, etc.) * No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise Middle-aged endurance-trained participants Muscle biopsy * Aged between 50-65 years * Male or female * Currently engaging in formal training (at least 3 times per week) in competitive endurance sports (i.e. running, cycling, swimming, triathlon, etc.) * No chronic health conditions likely to affect exercise tolerance or the physiological responses to exercise
- Primary Outcome Measures
Name Time Method Muscle strength Baseline (visit 1) Newton-metre (Nm)
Muscle power Baseline (visit 1) Watt (W)
Muscle mitochondrial fragmentation index (A.U.) Visit 6 muscle biopsy (+/- after 4 weeks). Degree of fragmentation of the mitochondrial pool.
Maximal oxygen uptake (V̇O2max) Baseline (visit 1) ml/min/kg
Muscle volume Baseline (visit 1) cm\^3
Muscle diffusing capacity for oxygen (DmO2) Baseline (visit 1) and visit 2-4. In total 4 weeks. Differences in recovery constant k (min-1) obtained under conditions of high, medium or low O2 availability
- Secondary Outcome Measures
Name Time Method (Peak) power output Baseline (visit 1) Watt (W)
Capillary lactate concentration Baseline (visit 1) mmol/L
NIRS derived muscle oxy- and deoxygenated [haemoglobin + myoglobin] (HbO2, Hbb) and tissue saturation index (TSI) versus relative and absolute work rate. Baseline (visit 1) HbO2 and Hbb: % maximal value, TSI (%) = HbO2/(HbO2+Hbb) versus relative (%max) and absolute power output (W) Relative and absolute work rates comparisons will be reported for all variables: resting concentration, baseline cycling concentration, (sub)maximal exercise concentration.
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. Baseline (visit 1) concentration\[Hbb/HbO2/TSI\]%/delta%peak power(W)
Maximal ventilatory equivalents Baseline (visit 1) VE/VCO2 and VE/VO2
Pulmonary oxygen uptake - baseline and steady state V̇O2 Baseline (visit 1) and visit 2-4 (max 4 weeks in total) L/min
Pulmonary oxygen uptake kinetics - Phase II V̇O2 time constant and time delay Visit 2-4 (max 4 weeks in total) sec
Muscle (de)oxygenation breakpoint during incremental exercise Baseline (visit 1) Power output (W) and maximal oxygen uptake (L/min)
Muscle morphology - pennation angle Baseline (visit 1) degrees
Mean and fiber type specific succinate dehydrogenase activity Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years. A660/um/s
Mitochondrial surface area-to-volume ratio Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years. um/um\^2
Mean response time of the V̇O2 slope during ramp exercise Baseline (visit 1) sec
V̇O2/HR slope during ramp exercise Baseline (visit 1) beats/L/min
Maximal respiratory exchange ratio (RER) Baseline (visit 1) RER = VCO2/VO2
Maximal end-tidal pressures for oxygen (O2) and carbon dioxide (CO2) Baseline (visit 1) mmHg
Rate constant of mV̇O2 recovery kinetics under conditions of high, medium and low O2 availability Baseline (visit 1) sec
Respiratory control ratios Visit 6 muscle biopsy (+/- after 4 weeks). OXPHOS/ETS, LEAK/ETS, LEAK/OXPHOS, LEAK/NADH-linked, ROT+S/ETS, (OXPHOS-LEAK)/ETS, (OXPHOS-LEAK)/OXPHOS, (ETS-LEAK)/ETS, (ETS-OXPHOS)/ETS
Intrinsic mitochondrial respiration (each respiratory state outlined below will be normalised to mitochondrial volume density) Visit 6 muscle biopsy (+/- after 4 weeks). (pmol/s/mg)/mitochondrial area density (%) For: background, LEAK, N-linked respiration, OXPHOS, ETS, succinate + rotenone-linked uncoupled respiration
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 Visit 5 MRI mM pH = unitless
31P-MRS-derived mitochondrial bioenergetic function - maximal rate of oxidative ATP synthesis Visit 5 MRI mM/s
(mean) fiber cross-sectional area, also fiber type specific Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years. um
Mean and fiber type specific myoglobin concentrations Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years. mM
Muscle capillarization - capillary density Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years. number of capillaries/mm2
Muscle capillarization - capillary-to-fiber ratio Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years. capillary-to-fiber ratio
Muscle capillarization - length of capillaries relative to fiber perimeter (LC/PF) Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years. percentage (%)
Mitochondrial area density Visit 6 muscle biopsy (+/- after 4 weeks) - electron microscopy (EM) within time window of 2 years. Percentage (%)
Mitochondrial number Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years. number/um2
Gas exchange and ventilatory variables (gas exchange threshold, respiratory compensation point, maximal ventilation) Baseline (visit 1) L/min
(Maximum) heart rate (HR) Baseline (visit 1) and during visit 2-4 (max 4 weeks in total) beats per minute (bpm)
Pulmonary oxygen uptake kinetics - Phase II V̇O2 amplitude Visit 2-4 (max 4 weeks in total) L/min
Concentrations of NIRS derived muscle oxy- and deoxygenated [haemoglobin + myoglobin] (HbO2, Hbb) and tissue saturation index (TSI). Baseline (visit 1) and visit 2-4 (max 4 weeks in total) HbO2 and Hbb: % maximal value, TSI (%) = HbO2/(HbO2+Hbb) For all variables resting concentration, baseline cycling concentration, (sub)maximal exercise concentration will be reported.
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. Baseline (visit 1) concentration\[Hbb/HbO2/TSI\]%/deltaW
Muscle morphology - (effective) physiological cross-sectional area (PCSA) Baseline (visit 1) cm2
Adipose tissue thickness at the site of NIRS measurement Baseline (visit 1) mm
Maximal O2 pulse Baseline (visit 1) ml/beat
Slope of ventilation (VE) versus carbon dioxide (VCO2) output during ramp exercise (i.e. ventilatory efficiency) Baseline (visit 1) V̇E/V̇CO2 slope
Maximal respiratory frequency Baseline (visit 1) breaths/min
Mitochondrial respiratory function (background, LEAK, N-linked respiration, OXPHOS, ETS, succinate (S) + rotenone (ROT)-linked uncoupled respiration, ) Visit 6 muscle biopsy (+/- after 4 weeks). pmol/s/mg
31P-MRS-derived mitochondrial bioenergetic function rate constant of PCr Visit 5 MRI Rate constant of Phosphocreatine \[PCr\] on- and off-kinetics (sec)
Weighted fiber cross-sectional area Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years. um2
Muscle capillarization - mean number of capillaries surrounding a fiber (CAF) Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years. number of capillaries
Muscle capillarization - mean number of capillaries surrounding a fiber in relation to fiber area (CAFA) Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years. number of capillaries/um2
Muscle capillarization - capillary-to fiber-perimeter exchange index (CFPE) Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years. CFPE (unitless)
Muscle capillarization - sarcomere length Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years. um
Mitochondrial circularity Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years. Circularity (AU)
Mitochondrial cristae area density Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years. Percentage (%)
Muscle morphology - vastus lateralis specific force Baseline (visit 1) N/cm2
Muscle morphology - estimated muscle fiber number Baseline (visit 1) PCSA/muscle fiber cross-sectional area
Muscle fiber type distribution Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years. Type I, IIa, IIx and hybrid fiber-type proportions (%)
Integrated fiber succinate dehydrogenase activity Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years. A660.um/s
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) Visit 6 muscle biopsy (+/- after 4 weeks) - western blot within time window of 2 years. ug/mg loaded sample
Physical activity status - pedometer Baseline 7 days Number of steps per day
Mitochondrial area Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years. um2
Mitochondrial height, width, perimeter and maximal+minimal Feret's diameter Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years. um
Mitochondrial volume density Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years. um3.um3.10\^2
Mitochondrial roundness Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years. Roundness (AU)
Mitochondrial aspect ratio Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years. Aspect ratio (AU)
Muscle morphology - Fascicle length Baseline (visit 1) cm
Trial Locations
- Locations (1)
Vrije Universiteit Amsterdam
🇳🇱Amsterdam, Noord-Holland, Netherlands