Exercise as a Countermeasure Against the Effects of Ageing on Muscle Mitochondria, Diffusive Oxygen Transport and Muscle Volume
Overview
- Phase
- N/A
- Intervention
- Not specified
- Conditions
- Aging
- Sponsor
- VU University of Amsterdam
- Enrollment
- 60
- Locations
- 1
- Primary Endpoint
- Muscle strength
- Status
- Recruiting
- Last Updated
- last year
Overview
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.
Investigators
Dr Richie Goulding
Principal Investigator
VU University of Amsterdam
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
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
Outcomes
Primary Outcomes
Muscle strength
Time Frame: Baseline (visit 1)
Newton-metre (Nm)
Muscle power
Time Frame: Baseline (visit 1)
Watt (W)
Muscle mitochondrial fragmentation index (A.U.)
Time Frame: Visit 6 muscle biopsy (+/- after 4 weeks).
Degree of fragmentation of the mitochondrial pool.
Maximal oxygen uptake (V̇O2max)
Time Frame: Baseline (visit 1)
ml/min/kg
Muscle volume
Time Frame: Baseline (visit 1)
cm\^3
Muscle diffusing capacity for oxygen (DmO2)
Time Frame: 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 Outcomes
- (Peak) power output(Baseline (visit 1))
- Capillary lactate concentration(Baseline (visit 1))
- NIRS derived muscle oxy- and deoxygenated [haemoglobin + myoglobin] (HbO2, Hbb) and tissue saturation index (TSI) versus relative and absolute work rate.(Baseline (visit 1))
- 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))
- Maximal ventilatory equivalents(Baseline (visit 1))
- Pulmonary oxygen uptake - baseline and steady state V̇O2(Baseline (visit 1) and visit 2-4 (max 4 weeks in total))
- Pulmonary oxygen uptake kinetics - Phase II V̇O2 time constant and time delay(Visit 2-4 (max 4 weeks in total))
- Muscle (de)oxygenation breakpoint during incremental exercise(Baseline (visit 1))
- Muscle morphology - pennation angle(Baseline (visit 1))
- Mean and fiber type specific succinate dehydrogenase activity(Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.)
- Mitochondrial surface area-to-volume ratio(Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.)
- 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)
- 31P-MRS-derived mitochondrial bioenergetic function - maximal rate of oxidative ATP synthesis(Visit 5 MRI)
- Mean response time of the V̇O2 slope during ramp exercise(Baseline (visit 1))
- V̇O2/HR slope during ramp exercise(Baseline (visit 1))
- Maximal respiratory exchange ratio (RER)(Baseline (visit 1))
- Maximal end-tidal pressures for oxygen (O2) and carbon dioxide (CO2)(Baseline (visit 1))
- Rate constant of mV̇O2 recovery kinetics under conditions of high, medium and low O2 availability(Baseline (visit 1))
- Respiratory control ratios(Visit 6 muscle biopsy (+/- after 4 weeks).)
- Intrinsic mitochondrial respiration (each respiratory state outlined below will be normalised to mitochondrial volume density)(Visit 6 muscle biopsy (+/- after 4 weeks).)
- (mean) fiber cross-sectional area, also fiber type specific(Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.)
- Mean and fiber type specific myoglobin concentrations(Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.)
- Muscle capillarization - capillary density(Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.)
- Muscle capillarization - capillary-to-fiber ratio(Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.)
- 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.)
- Mitochondrial area density(Visit 6 muscle biopsy (+/- after 4 weeks) - electron microscopy (EM) within time window of 2 years.)
- Mitochondrial number(Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.)
- Gas exchange and ventilatory variables (gas exchange threshold, respiratory compensation point, maximal ventilation)(Baseline (visit 1))
- (Maximum) heart rate (HR)(Baseline (visit 1) and during visit 2-4 (max 4 weeks in total))
- Pulmonary oxygen uptake kinetics - Phase II V̇O2 amplitude(Visit 2-4 (max 4 weeks in total))
- 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))
- 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))
- Muscle morphology - Fascicle length(Baseline (visit 1))
- Muscle morphology - (effective) physiological cross-sectional area (PCSA)(Baseline (visit 1))
- Adipose tissue thickness at the site of NIRS measurement(Baseline (visit 1))
- Maximal O2 pulse(Baseline (visit 1))
- Slope of ventilation (VE) versus carbon dioxide (VCO2) output during ramp exercise (i.e. ventilatory efficiency)(Baseline (visit 1))
- Maximal respiratory frequency(Baseline (visit 1))
- Mitochondrial respiratory function (background, LEAK, N-linked respiration, OXPHOS, ETS, succinate (S) + rotenone (ROT)-linked uncoupled respiration, )(Visit 6 muscle biopsy (+/- after 4 weeks).)
- 31P-MRS-derived mitochondrial bioenergetic function rate constant of PCr(Visit 5 MRI)
- Weighted fiber cross-sectional area(Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.)
- Muscle capillarization - mean number of capillaries surrounding a fiber (CAF)(Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.)
- 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.)
- Muscle capillarization - capillary-to fiber-perimeter exchange index (CFPE)(Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.)
- Muscle capillarization - sarcomere length(Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.)
- Mitochondrial circularity(Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.)
- Mitochondrial cristae area density(Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.)
- Muscle morphology - vastus lateralis specific force(Baseline (visit 1))
- Muscle morphology - estimated muscle fiber number(Baseline (visit 1))
- Muscle fiber type distribution(Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.)
- Integrated fiber succinate dehydrogenase activity(Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.)
- 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.)
- Physical activity status - pedometer(Baseline 7 days)
- Mitochondrial area(Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.)
- Mitochondrial height, width, perimeter and maximal+minimal Feret's diameter(Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.)
- Mitochondrial volume density(Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.)
- Mitochondrial roundness(Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.)
- Mitochondrial aspect ratio(Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.)