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(Chest. 1999;116:1434-1441.)
© 1999 American College of Chest Physicians

Nuclear Magnetic Resonance Spectroscopy*

Its Role in Providing Valuable Insight Into Diverse Clinical Problems

Kevin McCully, PhD; Donna Mancini and Sanford Levine, MD, FCCP

* From the Department of Exercise Science (Dr. McCully), Ramsey Student Center, University of Georgia, Athens, GA; the Department of Cardiology (Ms. Mancini), Columbia University, New York NY; and the Divison of Pulmonary Medicine (Mr. Levine), VA Medical Center, Philadelphia PA.

Correspondence to: Kevin McCully, PhD, Department of Exercise Science, Ramsey Student Center, University of Georgia, Athens, GA 30602-3654; e-mail: mccully{at}ibm.net

Abstract

Skeletal muscle plays an important role in respiratory and cardiovascular physiology. The ability to measure metabolic changes in skeletal muscle has been enhanced with the advent of magnetic resonance spectroscopy (MRS). MRS measurements have been used to understand the metabolic control of respiration and to evaluate metabolic changes in the muscle in patients with respiratory and cardiac diseases. The key to the respiratory control measurements is the ability to measure intracellular pH with MRS. Muscle oxidative metabolism has been measured in two ways: during steady-state exercise and using recovery kinetics. The similarities in the metabolic findings for pulmonary and coronary disease suggest the potential for some interesting common pathways.

Key Words: humans • magnetic resonance spectroscopy • metabolism • muscle • respiratory disease

Skeletal muscle plays an important role in respiratory and cardiovascular physiology. During increased activity (exercise), skeletal muscle is the primary consumer of oxygen and generator of CO2 and pH changes. Thus, skeletal muscle is an important part of the stimulus for respiratory drive. In addition, impairments in gas exchange due to environmental conditions or disease will have a direct effect on the function of skeletal muscle. Profound changes in skeletal muscle function and physiology have been reported in patients with both pulmonary1 and cardiovascular2 disease. The ability to measure metabolic changes in skeletal muscle has undergone a tremendous transformation with the advent of magnetic resonance spectroscopy (MRS). MRS, which uses technologies similar to the now more common MRI, can provide a wealth of useful metabolic information in a minimally invasive manner. This is in contrast with traditional methods that require muscle biopsies and venous and arterial cannulas. The noninvasive nature of MRS justifies the expansion of respiratory and muscle studies to a wider range of subjects, including those who are frail or require multiple measurements. This review will present a brief background on the MRS technique, will review how the method has been used to increase our understanding of respiratory and cardiovascular physiology, and will point out some future directions for research.

How MRS Works

This article will focus on the practical aspects of MRS. More detailed presentations of the biophysical principals3 4 as well as extensive reviews of the use of MRS to study muscle metabolism are available.5

MRS is able to obtain signals that are proportional to the free concentrations of particular chemical compounds with the use of radiofrequency bursts and strong magnetic fields. The energy levels associated with these measurements result in no known harmful effects (as long as power levels are kept low enough to prevent the heating of the tissue).6 The chemical compounds that can be detected depend on the nuclei being studied (eg, 1H, 13C, 23Na, and 31P), the amount of the compound in the tissue (usually it must be at least 1 to 2 mM), and the presence of a unique spectral peak for that compound (somewhat arbitrary).

31P MRS has been the most popular approach to studying muscle metabolism due to the ability to identify phosphocreatine (PCr), inorganic phosphate (Pi), and adenosine triphosphate (ATP) (Fig 1 ). Adenosine diphosphate (ADP) is undetectable because most ADP is bound and the free concentrations are too low (~10 µm at rest). One of the key aspects of 31P MRS is that it is one of the best methods of measuring of intracellular pH.7 pH measurements are based on shifts of the frequency of the Pi peak due to different concentrations of the mono- and diprotonated forms of Pi (pK of 6.75 in muscle). Exchange between the two forms of Pi is very fast, so that only one peak with a weighted average frequency is seen in any given cellular compartment.



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  		Figure 1. Examples of 31P MRS data from forearm flexor muscles of a COPD patient. Exercise spectra (bottom tracing) were recorded during isometric handgrip exercise. Note the broad "hump" on which the phosphorus peaks sit and the partial overlap of the PCr and ATP peaks. Both of these conditions can introduce errors when determining peak areas. Figure modified from Kutsuzawa et al.35

 
Clinical MRI machines can be used to perform MRS experiments, but they require optional software and hardware that is not always present. Two basic sizes of magnets have been used in human studies. In addition to the standard whole-body clinical magnets, there are smaller bore magnets (20 to 30 cm in diameter). In order to obtain reasonable MRS signals, the magnetic fields have to be at least 1.5 T. In general, the stronger the magnetic field (currently up to 4.7 T), the narrower the MRS peaks and the better the signal obtained.8

Measurements during rest can be made on almost any muscle. The only limitations are localizing signals from very small muscles and the ability to position the muscle in the center of the magnet (where field homogeneity is good enough to allow MRS data collection). This is why respiratory muscles are difficult to study with MRS. Because most investigators prefer to study muscles during exercise, published studies have been limited to a few muscle groups, as exercise studies require the placement of an ergometer system in the magnet. Muscle groups commonly studied have included wrist and finger flexors,9 plantar flexors and extensors,10 and quadriceps and hamstring muscle groups.11 The insert portion of Figure 2 illustrates the major changes in the spectra that can occur with exercise. During exercise there is an increase in the Pi signal and a decrease in the PCr signal. In addition, there maybe a shift in the Pi peak frequency, indicating a change in muscle pH.



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  		Figure 2. Summary of the major changes that occur with exercise. With exercise, Pi increases and PCr decreases. The Pi peak also may shift: a shift to the right would indicate alkalosis, and to the left, acidosis. The example here shows muscle pH changing from 7.08 to 6.57.

 
Metabolic Measurements

There are two key steps involved in converting MRS spectra into meaningful metabolic measurements. The first is conversion of MRS spectral peaks into physiologic concentrations. While spectra-fitting programs are fairly common, MRS often presents its own problems, including baseline corrections for the broad peaks from bound forms of phosphorus and compensation for overlapping spectral peaks. In addition, the absolute quantification of peaks into concentrations presents difficulties. With 31P MRS, a simple solution is often to assume that ATP concentrations are a certain value for all tests and subjects and to normalize the values of the other peaks to ATP.

The second step in analyzing MRS spectra is to convert concentrations of compounds into meaningful metabolic measurements. The level of sophistication in MRS data presentation varies widely, from peak concentrations and simple ratios of peak concentrations to determination of flux rates of various metabolic pathways in units of millimoles per minute.

Measurements of oxidative metabolism make use of the assumption that the activity level of oxidative metabolism is reflected by levels of ADP (and Pi).12 This assumes that oxidative metabolism is regulated and controlled by levels of a primary substrate (ADP) that builds up when ATP is used, for example, during exercise. In addition, MRS measurements make use of the creatine kinase reaction, in which Pi + Cr <-> PCr buffers the ATP <-> the ADP + Pi reaction.12 From this, changes in Pi and PCr, which are easily measured, can be used to reflect levels of ADP, which can only be calculated indirectly. It should be pointed out that the use of Pi/PCr ratios to approximate ADP levels assumes that there is no change in muscle pH (values of approximately 7.0), as H+ is part of the creatine kinase equation. And, obviously, in skeletal muscle in which blood flow is limited, such as in calf muscles distal to arterial stenosis, oxygen levels will be the major controlling substrate.

Two basic approaches have been used when making measurements of oxidative metabolism, steady-state, and recovery kinetics (Fig 3 ). For steady-state measurements, the metabolic response to a given level of work is obtained. This information can be presented as a simple ratio of metabolites at normalized (to muscle size or strength) work levels, or as a calculated flux rate. The advantage of the steady-state measurements of muscle metabolism is that relatively long time periods of time (3 to 6 min) can be used to collect data at each work level.



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  		Figure 3. Shows the use of steady-state exercise and recovery kinetics to measure oxidative muscle metabolism. Left: the curve shows how steady-state exercise protocols can be used to determine a Vmax. Right: the curve shows changes in PCr during recovery from exercise and the calculation of Vmax with this approach. In both cases, the calculations are sensitive to changes in muscle pH. PCrend = PCr at the end of exercise.

 
A second approach is to determine the rate of recovery of high-energy phosphates. PCr recovery closely reflects oxygen consumption,13 and a maximal oxidative capacity (Vmax) calculated from the rate constant (k) of PCr resynthesis is equivalent to the Vmax from the steady-state measurements. Submaximal exercise is most often used as decreases in muscle pH with higher levels of exercise slow the rate of PCr recovery.14 15 Time constants of PCr recovery (1/k) in human calf muscle vary from 18 s for endurance athletes to 200 to 250 s in patients with severe peripheral vascular disease.16 The main advantage of the recovery test for measuring oxidative metabolism is that the measurements are relatively independent of exercise intensity, as long as muscle pH does not drop too much below 7.0. This means that the recovery test does not require accurate measurements of the amount of work being performed. This is an advantage in studies of human subjects, because it is often difficult to measure accurately the work performed by the specific muscle being measured by MRS. The disadvantage of the recovery test is that it requires good time resolution, with data points every 4 to 10 s for normal subjects.

Glycolytic metabolism is usually measured as the decrease in pH. The formation of lactate by glycolysis is associated with the production of protons. From this, the rate of glycolysis can be estimated from changes in muscle pH during exercise.17 During a short-duration bout of "maximal" exercise, sprint athletes demonstrated a twofold faster rate of decline of pH compared with endurance athletes.18 Other investigators have shown how measurements of pH and PCr before, during, and after exercise can be used to calculate buffering capacity and the rate of glycogenolytic ATP production.19 The exciting aspect of these kinds of measurements is that they can be combined with oxidative measurements to determine the energy flux through the three major energy pathways: oxidative metabolism, glycolytic metabolism, and the breakdown of PCr.17

The presentation of flux rates allows direct comparison of MRS results to traditional biochemical measurements, and a surprising amount of biochemical information can be obtained from signal changes, which are described in Figure 2 . However, the calculations and assumptions used to determine these flux rates often vary between investigators and are not always well described in the methods of papers. Thus, direct comparison of numbers between studies in different laboratories can be difficult. Simple ratios and concentrations have the advantage of at least showing the readers what that data looked like, but a study full of MRS ratios can be a difficult thing for traditional biochemists to understand.

Other Measurements That Can Be Made Using 31P MRS

Muscle fatigue is an area of study in which MRS measurements have provided some very interesting and useful information. Fatigue can occur at a number of different steps along the pathway of muscle excitation and contraction.20 One potential site of fatigue is the buildup of metabolic by-products, such as H+ and Pi, that inhibit muscle contraction.21 The decline in force is thought to be due to Pi shifting the equilibrium between cross-bridge attachment and detachment to a more detached state. A number of MRS studies in humans have demonstrated that the amount of the diprotonated form of Pi, namely, H2PO4-, is more closely related to the decline in force than measurements of pH or total Pi.22 The inclusion of MRS measurements along with other measures of fatigue promises to be a powerful approach in studying the relative contributions of various components of the fatigue pathway.23

Muscle injury has been monitored with 31P MRS. Strenuous exercise in normal subjects can cause a transient (1 to 7 days) elevation in the Pi/PCr ratio.24 This change has been associated with exercise-induced muscle injury and is also a common finding in patients with destructive muscle disorders.24

Age and developmental changes have been monitored with 31P spectra in resting muscle. The peaks of the phosphomonoester (PME) and phosphodiester (PDE) regions are generally considered to be markers of growth and senescence, respectively. The PME peak is very high relative to ATP early in life, and gradually it disappears in adolescents.25 The presence of PDE, as measured by the PDE/ATP ratio, has been shown to increase with age, roughly twofold every 20 years.26 However, the PME results suggest that age accounts for only 50% of the variance, thus further studies are needed before PME measurements can become useful as a biological marker of age.

MRS also has been used as a way to measure the metabolic cost per twitch.27 This is a measure of the efficiency of a muscle and is done by electrically stimulating the muscle and measuring the breakdown of PCr.

MRS and Respiratory Disease

It has become increasingly apparent that profound changes in peripheral muscle occur in patients with respiratory disease. For example, the thigh cross-sectional area has been found to be 24% smaller in patients with COPD than in control subjects,28 and the maximal strength of the knee extensors and flexors was reduced by 16 to 28%.28 29 COPD patients are reported to show a transformation in muscle fiber type from slow to fast twitch (a 42% decrease in slow-twitch fibers [type I]) and from high-oxidative to low-oxidative types.30 Along with the change in fiber type, decreases in the number of capillaries surrounding muscle fibers (as high as 40% for type I fibers) have been reported.30 Oxidative enzymes such as citrate synthase and reduced nicotinamide adenine dinucleotide show 30 to 40% declines, with glycolytic enzymes showing increases of a similar magnitude.31 32 These changes in peripheral muscle are thought to contribute to the limited exercise capacity seen in patients with COPD.29 33 34 The mechanisms for these changes in skeletal muscle are potentially multifactorial, with chronically reduced oxygen delivery, poor nutrition, and deconditioning as a result of reduced activity levels suggested as causes.26 Given that functionally relevant metabolic changes occur in peripheral skeletal muscle in COPD patients, it then becomes important to be able to monitor those changes.

Kutsuzawa et al35 used MRS in their study of the potential role of nutritional status on muscle metabolism in COPD patients. They examined normal weight and underweight (with an assumed poor nutritional status) patients and compared them to normal and underweight control subjects. MRS measurements were made of the forearm muscles during rhythmic handgrip exercise using a small magnet. They used steady-state measurements and compared normalized PCr and ATP levels between groups. Interestingly, they also normalized the subjects’ work levels to muscle mass using 1-h MRS to obtain the ratio of fat to muscle. This study’s conclusion was that nutritional status did not influence muscle metabolism in patients with COPD.

Mannix et al17 used MRS to examine energy flux through various metabolic pathways in patients with COPD and control subjects (Fig 4 ). They examined the calf muscles (plantar flexors) using a large whole-body magnet. Steady-state measurements taken during 90 s of isometric exercise were used, although the initial rate of PCr recovery was used in the calculations of oxidative metabolism. This study found that supplemental oxygen did not improve metabolism in mildly impaired COPD patients who were not receiving supplemental oxygen (FEV1/FVC, 46%) but did help severe COPD patients who were receiving supplemental oxygen (FEV1/FVC, 39%), suggesting different metabolic limitations in these two groups.



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  		Figure 4. Rate of ATP production from different energy pathways during exercise in two groups of COPD patients and in control subjects. Exercise consisted of sustained (90-s) isometric contractions with the plantar flexor muscles. Exercise was performed while breathing room air or 2 L/min supplemental oxygen. In this study, the patients with severe COPD showed a metabolic improvement with added oxygen (increased oxidative pathways, reduced glycolytic pathways), while the patients with mild COPD did not. Gly = glycolyisis. Figure modified from Mannix et al.17

 
MRS and the Control of Respiration

Increased respiratory drive is due in large part to metabolic stimuli arising from skeletal muscle.36 Numerous studies have addressed the mechanism for how the changes in metabolism in skeletal muscle stimulate respiration. It is not clear whether such stimulation occurs through central or peripheral pathways.37 Oelberg et al38 used MRS to show that skeletal muscle pH mediates the ventilatory chemoreflex in humans. They did this by using MRS to measure pH during exercise in the quadriceps muscles and measuring minute ventilation (E). They found in their study that E correlated with muscle pH but not with arterial pH.

MRS and Cardiovascular Disease

As with patients with COPD, patients with congestive heart failure show profound changes in exercise performance, muscle morphology, and muscle metabolism.39 In addition, abnormal muscle blood flow, independent of cardiac limitations, has been reported.39 MRS measurements have been made from both the forearm and calf muscle during exercise in patients with heart failure. The primary finding has been abnormal skeletal muscle metabolism, ie, reduced oxidative metabolism with an earlier shift to glycolytic metabolism.2 40 Figure 6 shows an early example of a study that demonstrated that forearm muscle metabolism in patients with heart failure was abnormal despite normal blood flow. This abnormality also appears to be independent of histochemical changes, muscle mass, or severe tissue hypoxia.39



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  		Figure 6. Comparison of MRS measurements and forearm blood flow with plethysmography in normal subjects and in patients with heart failure. Increases in Pi/PCr ratios (top) indicate reduced oxidative capacity, decreases in pH (middle) indicate greater glycolysis, and the lack of change in forearm blood flow (bottom) suggests that the metabolic abnormalities are not a result of reduced blood flow. N = 5 in all measurements. Figure modified from Wiener et al.41

 
Summary

MRS has become an increasingly valuable tool to study skeletal muscle physiology. This is due to its ability to obtain real-time measurements of the intact muscle (in vivo). In addition, the noninvasive nature of MRS lends itself to a wider range of studies than the traditional invasive methodologies. Given the critical role of skeletal muscle physiology in the study of the control of breathing (and vice versa), it is not surprising that MRS has been used in a number of important studies on respiratory control. In addition, MRS has been used in a number of interesting studies on the effect of chronic pulmonary disease and chronic coronary disease on exercise capacity and skeletal muscle function. The similarities of the metabolic findings between pulmonary and coronary disease suggest the potential for some interesting common pathways, especially because in both conditions impaired muscle function is in excess of what is predicted by central limitations in oxygen delivery. While the highly prized goal of making MRS measurements of respiratory muscles is currently not feasible, the rapid pace of development in MRS technology should allow these kinds of studies in the near future.



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  		Figure 5. The correlation between E and quadriceps muscle pH measured with MRS. The data are from three exercise bouts in one subject. A bilateral lower-extremity positive pressure of 45 mm Hg was used to separate out the effects of arterial pH, pain, and central motor command. • = results acquired during bilateral use of lower-extremity positive pressure; {circ} = results acquired without use of lower-extremity positive pressure. Go modified from Oelberg et al.38

 
Footnotes

Abbreviations: ADP = adenosine diphosphate; ATP = adenosine triphosphate; k = rate constant; MRS = magnetic resonance spectroscopy; PCr = phosphocreatine; PDE = phosphodiester; Pi = inorganic phosphate; PME =phosphomonoester; E = minute ventilation

References

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