Metabolic rate of oxygen in the skeletal muscle using [15O]O2-PET

Oxygen consumption in skeletal muscle (draft)

Oxygen transport in skeletal muscle is fast. Oxygen may diffuse between paired and crossing microvessels (Kobayashi & Takizawa, 2002), helping to distribute O2 evenly in the tissue, but also contributing to non-nutritive flow. At least in large mammals and in resting muscle, metabolism is independent of O2 transport (Honig et al., 1971).

During single-leg quadriceps exercise, myoglobin saturation drops to ∼50% when at 50-100% of the maximal of quadriceps O2 consumption (Richardson et al., 1995; Richardson et al., 1998; Molé et al., 1999; Sala et al., 2001). Oxygen extraction fraction (OEF), measured from femoral artery sampling, increases from resting value ∼25% to ∼73% during peak exercise (Bangsbo et al., 2000; Sala et al., 2001). The pO2 in muscle capillaries is ∼13 × higher than the intracellular pO2 (Richardson et al., 1998). During moderate exercise, myoglobin saturation stays at a high level (99.6%); hemoglobin saturation is 98% in arterial blood and 69% in venous blood (Mancini et al., 1994); MacDonald et al., 1999). Although perfusion in the muscle increases linearly as a function of contractile force, the oxygen consumption in inactive motor units may remain near the resting level (Lo et al., 2003). Muscle exercise stimulates and maintains glycolysis, independent on of oxygenation state (Conley et al., 1998).

Hartling et al (1989) have measured forearm oxygen uptake, perfusion, and glucose uptake at rest and during maximal exercise using hand ergometer: O2 uptake increased from 6.3±4.1 to 201±56 µmol;/(min*100mL) (∼32-fold), perfusion from 3.6±2.2 to 43±14 mL/(min*100mL) (∼12-fold), and glucose uptake from 0.44±0.07 to 5.7±8.8 µmol/(min*100mL) (∼13-fold).

Steady-state [15O]O2 studies in skeletal muscle

Kairento et al. (1985) have applied steady-state protocol to study perfusion and oxygen consumption in the muscle and soft tissue tumours of rabbits; MRO2 in the muscle was 4.3 ± 2.1 µmol/(min×dL). At steady state, the ratio of the [15O]O2 and [15O]CO2 images, after correction for the concentration of radiowater, was assumed to represent the oxygen extraction fraction (OEF). Mizuno et al. (2003) applied the steady-state inhalation techniques to measure perfusion and OEF in healthy subjects in rest and after exercise; OEF was ∼60% before exercise, and ∼37% after exercise.

OEF has been measured in rabbit muscle infected with Escherichia coli using steady-state [15O]CO2 and [15O]O2; the authors discuss that the OEF estimate may be underestimated, since the extracted [15O]O2 is not instantly converted to radiowater (Senda et al., 1992).

End-capillary pO2 can be estimated based on OEF measured using [15O]O2 PET, and arterial pO2 and pH (Alpert et al., 1988). In this method, the effect of lactate production on end-capillary pH may need to accounted for, if MRO2 and glucose consumption are not coupled.

Single inhalation [15O]O2 bolus model for skeletal muscle

See references Oikonen et al. 1998, Oikonen 1999, and Nuutila et al. 2000.

PET study

PET study is performed as described in MET5702.

Steps of MRO2 calculation from single inhalation bolus study:

1. Pre-processing of arterial blood curve

Arterial blood data from the on-line sampler needs to be processed before it can be used as input function in the calculation of oxygen consumption. Also metabolite correction is necessary in muscle studies. Blood TACs are corrected for time delay later by the oxygen model fitting software.

Currently, there is no script for this process. It is strongly suggested that you write the commands in a batch/script file to pre-process data from all of your studies. Detailed instructions can be found in the previous links. Below are the commands needed to pre-process an imaginary study us5678, when population averages of whole body oxygen metabolism are used for metabolite correction:

absscal -c=S:\Lab\plasma\bsampler_calibration\pump_cal.dat -i=O us5678.bld us5678blo.kbq
o2metab us5678blo.kbq 1.307e-3 2.034e-3 0 0
tac2svg us5678blo.svg us5678blo_o.kbq us5678blo_w.kbq

After this you would have two data files, us5678blo_o.kbq and us5678blo_w.kbq, which contain the arterial concentrations of [15O]O2 and [15O]H2O, respectively. Both are needed in the analysis.

The corrected blood TAC should always be plotted and controlled visually. It often contains close-to-zero values in the end, which should be removed with a text editor, or left out when determining the fit time. Check also the data units, especially that sample times are in seconds, not minutes. In the example above the graph was written in SVG file.

2. Make regional time-activity curves

Draw the ROIs and compute regional TACs as usual.

Check that data units are the same in regional and blood TACs.

3. Get arterial O2 content ([O2]a)

Arterial oxygen concentration ([O2]a) is not measured in PET Centre blood laboratory but in the hospital laboratory. It is reported in units mL O2/L blood (around 180-200 mL/L). Convert it to units mL O2/dL blood (1 dL = 100 mL = 0.1 L; about 18-20 mL/dL).

If necessary, the concentrations of O2 can be converted between volume and molar units with the molar volume of an ideal gas, 22.4 mL/mmol. Thus, [O2]a in molar units should be about 0.9 mmol O2/100 mL blood.

4. Compute regional MRO2 and OEF values

Estimate the regional MRO2 and OEF (oxygen extraction fraction, or ratio, OER) using fit_mo2, version 3.0.0 or later. This program corrects also the input time delay separately for each region, because there is often marked differences in the tracer appearance times between different muscle regions.

Continuing with the previous example, if the measured arterial oxygen concentration for this subject was 19.8 mL/100 mL:

fit_mo2 -co2a=19.8 -svg=us5678fit.svg us5678blo_o.kbq us5678blo_w.kbq us5678.dft 400 us5678mro2.res 

Again, the model fits to regional TACs should always be plotted and controlled visually. In the example above the graph was written in SVG file.

Estimated OEF should be between 0.2 and 0.9. If OEF is too close to 0 or 1, you can try to

In the above example, the units of MRO2 are ml O2 / (min * 100 ml tissue). If MRO2 is required per tissue mass instead of volume, it can be divided by tissue density (specific gravity), 1.04 g/mL (Reference Man).


See also:



References:

MET5702: PET Centre Intranet > Quality Documents > SOPs and METs > 6 kliininen > menetelmäohjeet (met) > tieteelliset pet-tutkimukset > met5702reisilihasten hapenkulutuksen ([15o]o2) pet-tutkimus valtimoverinäyttein.

Depairon M, Depresseux JC, Zicot M. Quantitation of regional muscle blood flow and oxygen uptake rate at rest and after exercise in arteriopathic patients. Clin Hemorheol. 1988; 8(3-4): 385-390. doi: 10.3233/CH-1988-83-415.

Depairon M, De Landsheere C, Merlo P, Del Fiore G, Quaglia L, Peters JM, Lamotte D, Zicot M. Effect of exercise on the leg distribution of C15O2 and 15O2 in normals and in patients with peripheral ischemia: a study using positron tomography. Int Angiol. 1988; 7(3): 254-257.

Depairon M, Depresseux J-C, Petermans J, Zicot M. Assessment of flow and oxygen delivery to the lower extremity in arterial insufficiency: A PET-scan study comparison with other methods. Angiology 1991; 42: 788-795. doi: 10.1177/000331979104201003.

Depairon M, Zicot M. The quantification of blood flow/metabolism coupling at rest and after exercise in peripheral arterial insufficiency, using PET and 15-O labeled tracers. Angiology 1996; 47(10): 991-999. doi: 10.1177/000331979604701008.

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ICRP Publication 23, Reference Man: Anatomical, Physiological, and Metabolic Characteristics, International Commission on Radiological Protection, Pergamon Press, New York (1975).

Jones AM, Krustrup P, Wilkerson DP, Berger NJ, Calbet JA, Bangsbo J. Influence of exercise intensity on skeletal muscle blood flow, O2 extraction and O2 uptake on-kinetics. J Physiol. 2012; 590(17): 4363-4376.

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Kusters YH, Barrett EJ. Muscle microvasculature’s structural and functional specializations facilitate muscle metabolism. Am J Physiol Endocrinol Metab. 2016; 310(6): E379-E387.

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Nuutila P, Peltoniemi P, Oikonen V, Larmola K, Kemppainen J, Takala T, Sipilä H, Oksanen A, Ruotsalainen U, Bolli GB, Yki-Järvinen H. Enhanced stimulation of glucose uptake by insulin increases exercise-stimulated glucose uptake in skeletal muscle in humans: studies using [15O]O2, [15O]H2O, [18F]fluoro-deoxy-glucose, and positron emission tomography. Diabetes 2000; 49:1084-1091.

Oikonen V, Nuutila P, Sipilä H, Tolvanen T, Peltoniemi P, Ruotsalainen U. Quantification of oxygen consumption in skeletal muscle with PET and oxygen-15 bolus. Eur J Nucl Med. 1998; 25: 1151. (poster).

Oikonen V. Modelling of low oxygen consumption. In: J. Knuuti, J. Rinne, P.Tenhonen (eds.), Medical Applications of Cyclotrons VIII. Abstracts of the VIII Symposium on the Medical Applications of Cyclotrons. Annales Universitatis Turkuensis D346:16, 1999.

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Thorn CE, Shore AC. The role of perfusion in the oxygen extraction capability of skin and skeletal muscle. Am J Physiol Heart Circ Physiol. 2016; 310(10): H1277-H1284.

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Created at: 2007-09-20
Updated at: 2018-04-07
Written by: Vesa Oikonen