Skeletal Muscle Mitochondria in Ageing
NCT Number: NCT06539078
Acronym: AGAMEMNON
Status: RECRUITING
Study Type: OBSERVATIONAL
Conditions: Aging
Interventions: OTHER: Maximal exercise test|OTHER: 3D Ultrasound|OTHER: Dynamometry|OTHER: Exercise test and occlusions|OTHER: Exercise test in MRI|PROCEDURE: Muscle biopsy
Sponsor: VU University of Amsterdam
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 60
Study Design: Observational Model: |Time Perspective: p
Start Date: 2024-03-25
Completion Date: 2026-12
Locations: Vrije Universiteit Amsterdam, Amsterdam, Noord-Holland, 1081HV, Netherlands

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.

Primary Outcome Measures: Maximal oxygen uptake (V̇O2max), ml/min/kg, Baseline (visit 1)|Muscle volume, cm\^3, Baseline (visit 1)|Muscle strength, Newton-metre (Nm), Baseline (visit 1)|Muscle power, Watt (W), Baseline (visit 1)|Muscle diffusing capacity for oxygen (DmO2), Differences in recovery constant k (min-1) obtained under conditions of high, medium or low O2 availability, Baseline (visit 1) and visit 2-4. In total 4 weeks.|Muscle mitochondrial fragmentation index (A.U.), Degree of fragmentation of the mitochondrial pool., Visit 6 muscle biopsy (+/- after 4 weeks).
Secondary Outcome Measures: Gas exchange and ventilatory variables (gas exchange threshold, respiratory compensation point, maximal ventilation), L/min, Baseline (visit 1)|(Peak) power output, Watt (W), Baseline (visit 1)|Mean response time of the V̇O2 slope during ramp exercise, sec, Baseline (visit 1)|(Maximum) heart rate (HR), beats per minute (bpm), Baseline (visit 1) and during visit 2-4 (max 4 weeks in total)|Maximal O2 pulse, ml/beat, Baseline (visit 1)|Slope of ventilation (VE) versus carbon dioxide (VCO2) output during ramp exercise (i.e. ventilatory efficiency), V̇E/V̇CO2 slope, Baseline (visit 1)|V̇O2/HR slope during ramp exercise, beats/L/min, Baseline (visit 1)|Maximal respiratory exchange ratio (RER), RER = VCO2/VO2, Baseline (visit 1)|Maximal ventilatory equivalents, VE/VCO2 and VE/VO2, Baseline (visit 1)|Maximal end-tidal pressures for oxygen (O2) and carbon dioxide (CO2), mmHg, Baseline (visit 1)|Capillary lactate concentration, mmol/L, Baseline (visit 1)|Maximal respiratory frequency, breaths/min, Baseline (visit 1)|Pulmonary oxygen uptake - baseline and steady state V̇O2, L/min, Baseline (visit 1) and visit 2-4 (max 4 weeks in total)|Pulmonary oxygen uptake kinetics - Phase II V̇O2 time constant and time delay, sec, Visit 2-4 (max 4 weeks in total)|Pulmonary oxygen uptake kinetics - Phase II V̇O2 amplitude, L/min, 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)., HbO2 and Hbb: % maximal value, TSI (%) = HbO2/(HbO2+Hbb) For all variables resting concentration, baseline cycling concentration, (sub)maximal exercise concentration will be reported., Baseline (visit 1) and visit 2-4 (max 4 weeks in total)|NIRS derived muscle oxy- and deoxygenated [haemoglobin + myoglobin] (HbO2, Hbb) and tissue saturation index (TSI) versus relative and absolute work rate., 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., 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., concentration\[Hbb/HbO2/TSI\]%/delta%peak power(W), Baseline (visit 1)|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., concentration\[Hbb/HbO2/TSI\]%/deltaW, Baseline (visit 1)|Muscle (de)oxygenation breakpoint during incremental exercise, Power output (W) and maximal oxygen uptake (L/min), Baseline (visit 1)|Rate constant of mV̇O2 recovery kinetics under conditions of high, medium and low O2 availability, sec, Baseline (visit 1)|Muscle morphology - Fascicle length, cm, Baseline (visit 1)|Muscle morphology - pennation angle, degrees, Baseline (visit 1)|Muscle morphology - (effective) physiological cross-sectional area (PCSA), cm2, Baseline (visit 1)|Muscle morphology - vastus lateralis specific force, N/cm2, Baseline (visit 1)|Muscle morphology - estimated muscle fiber number, PCSA/muscle fiber cross-sectional area, Baseline (visit 1)|Adipose tissue thickness at the site of NIRS measurement, mm, Baseline (visit 1)|Mitochondrial respiratory function (background, LEAK, N-linked respiration, OXPHOS, ETS, succinate (S) + rotenone (ROT)-linked uncoupled respiration, ), pmol/s/mg, Visit 6 muscle biopsy (+/- after 4 weeks).|Respiratory control ratios, OXPHOS/ETS, LEAK/ETS, LEAK/OXPHOS, LEAK/NADH-linked, ROT+S/ETS, (OXPHOS-LEAK)/ETS, (OXPHOS-LEAK)/OXPHOS, (ETS-LEAK)/ETS, (ETS-OXPHOS)/ETS, Visit 6 muscle biopsy (+/- after 4 weeks).|Intrinsic mitochondrial respiration (each respiratory state outlined below will be normalised to mitochondrial volume density), (pmol/s/mg)/mitochondrial area density (%) For: background, LEAK, N-linked respiration, OXPHOS, ETS, succinate + rotenone-linked uncoupled respiration, Visit 6 muscle biopsy (+/- after 4 weeks).|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, mM pH = unitless, Visit 5 MRI|31P-MRS-derived mitochondrial bioenergetic function rate constant of PCr, Rate constant of Phosphocreatine \[PCr\] on- and off-kinetics (sec), Visit 5 MRI|31P-MRS-derived mitochondrial bioenergetic function - maximal rate of oxidative ATP synthesis, mM/s, Visit 5 MRI|Muscle fiber type distribution, Type I, IIa, IIx and hybrid fiber-type proportions (%), Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.|(mean) fiber cross-sectional area, also fiber type specific, um, Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.|Weighted fiber cross-sectional area, um2, Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.|Mean and fiber type specific succinate dehydrogenase activity, A660/um/s, Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.|Integrated fiber succinate dehydrogenase activity, A660.um/s, Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.|Mean and fiber type specific myoglobin concentrations, mM, Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.|Muscle capillarization - capillary density, number of capillaries/mm2, Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.|Muscle capillarization - capillary-to-fiber ratio, capillary-to-fiber ratio, Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.|Muscle capillarization - mean number of capillaries surrounding a fiber (CAF), number of capillaries, 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), number of capillaries/um2, Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.|Muscle capillarization - capillary-to fiber-perimeter exchange index (CFPE), CFPE (unitless), 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), percentage (%), Visit 6 muscle biopsy (+/- after 4 weeks) - staining within time window of 2 years.|Muscle capillarization - sarcomere length, um, 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), ug/mg loaded sample, Visit 6 muscle biopsy (+/- after 4 weeks) - western blot within time window of 2 years.|Physical activity status - pedometer, Number of steps per day, Baseline 7 days|Mitochondrial area density, Percentage (%), Visit 6 muscle biopsy (+/- after 4 weeks) - electron microscopy (EM) within time window of 2 years.|Mitochondrial volume density, um3.um3.10\^2, Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.|Mitochondrial number, number/um2, Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.|Mitochondrial area, um2, Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.|Mitochondrial height, width, perimeter and maximal+minimal Feret's diameter, um, Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.|Mitochondrial surface area-to-volume ratio, um/um\^2, Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.|Mitochondrial circularity, Circularity (AU), Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.|Mitochondrial roundness, Roundness (AU), Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.|Mitochondrial aspect ratio, Aspect ratio (AU), Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.|Mitochondrial cristae area density, Percentage (%), Visit 6 muscle biopsy (+/- after 4 weeks) - EM within time window of 2 years.