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Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability (1997)

Chapter: 10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism

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Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
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10
Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism

V. R. Young,1Y-M. Yu, H. Hsu, J. W. Babich, N. Alpert, R. G. Tompkins, and A. J. Fischman

INTRODUCTION

The improved biochemical assessment of protein nutritional status and determination of quantitative dietary needs to maintain homeostasis and function in individuals, especially those who may be subjected to significant stress as in military combat situations, remain important research challenges for nutritional physiologists and biochemists. The advantages and limitations of approaches that have been taken so far to assess protein nutritional status have been discussed previously (Young et al., 1990). In that review it was proposed that an expanded application of stable isotope tracer techniques and of sophisticated

1  

V. R. Young, Laboratory of Human Nutrition, Massachusetts Institute of Technology, Cambridge, MA 02139; Shriners Burns Institute and Departments of Surgery and Radiology, Massachusetts General Hospital, Boston, MA 02114

The authors' studies were supported by grants from the Shriners Hospitals for Crippled Children and the National Institutes of Health (GM 21700, DK 15856, T 32-GM 07035, and T 32-CA 09362).

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

physicochemical measurements ought to offer an opportunity to make significant progress in nutritional evaluation. Therefore, this possibility has continued to be explored, and in this short review paper, particular attention will be given to presenting preliminary results from recent studies in this laboratory involving simultaneous use of stable isotope tracers and of imaging techniques involving positron emission tomography (PET).

To establish a reasonable framework for the discussion to follow, a general organization of body protein and amino acid metabolism is depicted in Figure 10-1; this includes some examples of the types of biochemical measures used to assess the status of the different metabolic-organ systems indicated. In the present context of a consideration of emerging technologies, however, the working hypothesis is that, by accumulating reliable data on the quantitative rates of protein anabolism and catabolism in various regions and organs of the body, practical new diagnostic tools can be developed for assessment of protein nutritional status in individuals under various pathophysiological states. Hence, the goal has been to refine, apply, and further develop noninvasive methods for determination of (1) protein turnover at the whole body and organ-tissue levels and (2) turnover of specific proteins in vivo. The principal analytical methods that have been exploited by this laboratory to date are those of isotope ratio and selected ion monitoring mass spectrometry and, more recently, positron emission tomography imaging.

FIGURE 10-1 A simplified organization of protein and amino acid metabolism, with an indication of the major systems involved and measures used to assess the status of these systems. CHI, creatine height index; Urea N, urea nitrogen; OH-Proline, hydroxyproline. SOURCE: Young et al. (1990) © J. Nutr. (120:1496–1502), American Society for Nutritional Sciences. Figure is based on G. Arroyave.

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

Because there has been substantial discussion previously, as well as elsewhere in these workshop proceedings, on the use of stable isotope tracer techniques in protein nutritional metabolic research (Halliday and Rennie, 1982; Matthews and Bier, 1983; Waterlow et al., 1978; Young et al., 1991), the major focus of attention in this paper will be with respect to PET. This is a technique familiar to many concerned with clinical nuclear medicine, but it is the authors' position that emission computed tomography has not yet been embraced sufficiently or understood as an experimental tool for nutritional metabolic research. Hence, it will first be indicated why it is an exciting prospect to use PET, and then a general account will be presented of the physical principles involved in PET and methods used for imaging. For this purpose, summary tables and figures will be used to illustrate major points and then discussion will turn briefly to some actual or potential applications of these techniques in nutritional research before a summary and a series of conclusions are drawn.

ISOTOPE TRACER ESTIMATES OF PROTEIN AND AMINO ACID TURNOVER IN VIVO

Stable Isotope Techniques

The advantages and disadvantages of use of stable isotope tracers for nutritional metabolic studies have been discussed by Bier in these proceedings (see Chapter 8) and also elsewhere (Matthews and Bier, 1983). However from the present perspective, it is pertinent to emphasize that these tracers have been applied extensively in studies of whole body protein (nitrogen) and amino acid kinetics in human subjects. A widely used model for estimation of whole body rates of protein turnover is the ''two-pool plasma precursor model" (Figure 10-2); this might involve, for example, use of [1-13C]leucine as tracer, with the rates then being based on isotopic data obtained with blood and expired air samples, following intravenous and/or oral administration of amino acids labeled with 13C or 15N and/or 2H (Garlick and McNurlan, 1994; Waterlow, 1995). In addition, 15N-end product methods have been applied for determination of rates of whole body protein synthesis, most often by giving [15N]glycine as tracer and then measuring the isotopic abundance of nitrogen in urinary urea and ammonia (Grove and Jackson 1995; Waterlow 1995). This latter approach is sufficiently safe and noninvasive to be applied in studies involving infants, pregnant women, and repeated measurements in other individuals or patients where blood sampling and/or venous puncture could not be justified or where it is not practical to do so. In both instances (precursor method and end-product method), whole body measurements of protein synthesis and breakdown rates are obtained. These parameters have been found to be quite valuable for enhancing understanding of human protein metabolism and nutrition, and it is clear that they represent a major investigative advance over information gained from the whole-body nitrogen balance method. However, they do not give any informa-

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

FIGURE 10-2 The two-pool model that is used widely to calculate rates of whole body protein synthesis and degradation (turnover) from data obtained with stable isotope (e.g., 15N or 13C) labeled amino acids. This diagram indicates that the turnover of whole body proteins is the sum of those occurring in the different organs and tissues. In separate or simultaneous studies, along with stable i sotope tracers, rates in these specific regions might be determined from arteriovenous (A-V) difference studies, by measurement of incorporation of labeled tracers into and their loss from proteins and/or by positron emission tomography, using a short-lived radionuclide such as 13N. SOURCE: Adapted from Garlick and McNurlan (1994).

tion about the quantitative contribution made by the major organs and tissues that collectively contribute to the status of whole-body protein balance and its integrity, nor do the parameters elucidate the changes occurring within those organs and tissues, possibly in different directions. Attempts are made to emphasize this point in Figure 10-2, which attempts to convey the need to dissect the kinetic parameters of whole body protein turnover into its major components, particularly by developing estimates of protein synthesis and breakdown in the principal protein-active organs such as liver, muscle, and the intestines.

Indeed, various approaches have been used to examine the dynamic status of protein and amino acid metabolism within individual tissues and organs, and these basically involve (1) arteriovenous (A-V) balance determinations across an organ (Tessari et al., 1995; Yu et al., 1990) or limb (Biolo et al., 1995; Cheng et al., 1985), while infusing a labeled amino acid such as 2H-phenylalanine or [15N, 13C]leucine, or (2) a direct measurement of the incorporation of a labeled amino acid into tissue protein by taking a biopsy of the specific tissue (e.g., Essen et al., 1992; Nair et al. 1988, 1995; Welle et al., 1993; Yarasheski et al.,

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

1992, 1993). Although analytical developments now allow these types of studies to be conducted with much smaller tissue samples than were required previously (Calder et al., 1992), both of these major approaches are invasive, which limits their broad and convenient application in human nutritional-metabolic research.

Finally, in relation to an understanding of the integration of amino acid metabolism in vivo and how stressful conditions might compromise metabolism and homeostasis, it would be of considerable interest to develop a detailed picture of the quantitative metabolic fate of the individual amino acids within and among various organs. As illustrated in Figure 10-3, there is an organ specificity or orientation to the metabolism of the individual amino acids (e.g., Munro 1983; Young and El-Khoury, 1995), and the nutritional status of the individual will depend in part on how well the roles of the organs involved and their interactions with other organs are maintained. These could well be affected by dietary, hormonal, and other factors, including infection and physical and psychological stressors. Furthermore, the status of protein and amino acid metabolism within discrete areas of an organ, including the brain (Williams et al., 1994), also might be affected by such factors. It is within this metabolic framework that investigators in this laboratory have turned recently to an exploitation of PET for assisting in the inquiry into human protein metabolism under different conditions of health and disease. Therefore, the principles and some of the practical issues involved in PET and its application to nutritional research will now be

FIGURE 10-3 A simplified outline of the organ fate and origin of various amino acids.

SOURCE: Adapted from Munro (1983).

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

considered in brief. This is done to help the informed reader, who may nevertheless be unfamiliar with PET, to perhaps better appreciate both its advantages and limitations. The discussion is, therefore, somewhat superficial, but consultation of the references will serve to elaborate upon the points made here.

Positron Emission Tomography

PET is a technique for measuring the concentration of a positron-emitting radio isotope, within a three-dimensional body, via external detection of the radiation emerging from the isotope. Positron-emitting radio nuclides of carbon, nitrogen, oxygen, and fluorine can be prepared readily, and because these elements are present in compounds that are relevant to the study of in vivo aspects of amino acid-protein metabolism, PET offers an opportunity to enhance current investigations of specific organ and tissue protein metabolism by the noninvasive means that will be discussed below. The basic principles of PET and measurement techniques are as follows, while the reader is referred to more extensive discussions for further detail (Christian, 1994; Daghighian et al., 1990; Fowler and Wolf, 1986; Hoffman and Phelps, 1986; Links, 1994; Ter-Pogossian et al., 1980).

Positron Decay and Coincidence Detection of Radiation Annihilation

Proton-rich nuclides decay to a more stable isotope by two possible decay processes: (1) by electron capture and (2) by positron decay, which is the particular emission of interest in this paper. In this latter process, a proton (p) is converted to a neutron (n), a positron (a positive electron, ß+), a neutrino (v), and energy, as follows:

The emitted positron, after traveling a short distance, combines with an electron in the surroundings, resulting in an annihilation interaction.2 This latter event converts all of the mass of the positron and electron into electromagnetic energy, which results in the emission of two 0.511-MeV photons (gamma rays) (Christian, 1994). These two gamma rays travel in very nearly opposite directions (Figure 10-4), penetrate the surrounding tissue, and are recorded outside of the subject by a circular array of detectors, which permit measurement of both the quantity and the location of the positron-emitting radio isotope (Daghighian et al., 1990; Links, 1994). Because the two annihilation photons are created si-

2  

In an annihilation interaction, the rest mass of the electron-positron pair disappears and is replaced by the two 511-KeV photons, in accord with conservation of energy and momentum.

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

FIGURE 10-4 Annihilation of positron and electron produces two 0.511-MeV gamma photons. υ, neutrino; , antineutrino. SOURCE: P. E. Christian in Nuclear Medicine, Technology and Techniques, 3d ed., D. R. Bernier, P. E. Christian, and J. K. Langan, eds., St. Louis, 1994, Mosby.

multaneously, as well as being emitted at 180° angles to each other, the electronics of the detectors are arranged so as to count only coincident events in the opposite detectors (i.e., within a 5 billionth of a second). This, then, is the principle of annihilation coincidence detection (Figure 10-5) (Hoffman and Phelps, 1986). Gamma rays originating outside of the space between the two detectors interact with only one of the detectors per annihilation, and these rays are not counted, also as illustrated in Figure 10-5. It might be appreciated, therefore, that the accuracy of the tissue localization of activity and the detection efficiency depend on the size and cross-sectional geometry of the detectors and the detector materials used in their construction. These factors influence the cost of the equipment used in measurements, with scanners generally now costing over $2 million. Additional details concerning detector systems and image reconstruction are given elsewhere (Daghighian et al., 1990; Links, 1994), but it should be evident that PET can be used to image, in a quantitatively functional context, in vivo aspects of tissue metabolism, blood flow, and receptor occupancy, for example. However, PET cannot distinguish among different chemical (metabolic) species since it only measures radioactivity concentration. This is a major limitation of this technique, where, for example, specific meta-

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

FIGURE 10-5 Schematic diagram of the principle of annihilation coincidence detection. SOURCE: Hoffman and Phelps, "Positron emission tomography: Principles and quantitation" in Positron Emission Tomography and Autoradiography: Principles and Applications for the Brain, 1986, pp. 237–286, reprinted with permission of Lippincott-Raven Publishers.

bolic interconversions are of particular interest in addition to where they are occurring within body tissues and organs.
Nuclide Production and Radiotracer Synthesis

While a large number of positron-emitting radionuclides exist, the physical properties of some positron (ß+)-emitters are summarized in Table 10-1. Additionally for comparison, information also is listed here about the more traditional radioisotopes, 14C and 3H. The half lives of the four positron emitters given in this table range from 2 minutes (15O) to 110 minutes (18F), and these physical properties offer some flexibility in tailoring the design of metabolic PET studies. For example, it is possible to use H215O to measure blood flow in a particular tissue or organ and then, after a short while, to give 18F-deoxyglucose

TABLE 10-1 Physical Properties of 11C, 15O, 13N, 18F, 3H, and 14C

Nuclide

Half Life

Decay Mode

11C

20.4 min

ß+

15O

2.07 min

ß+

13N

9.96 min

ß+

18F

109.7 min

ß+

3H

12.35 yr

ß-

14C

5,730 yr

ß-

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

as a tracer to measure the glucose metabolic rate in the same organ. These nuclides are produced within a cyclotron whose design varies, and this determines cost and production capability (Fowler and Wolf, 1986). However, this aspect of PET-related technology will not be detailed further here.

With respect to carbon-11 (11C), it is produced by 11B (p,n)11C and 14N (p,a)11C nuclear reactions (Table 10-2), with 11C-labeled carbon monoxide (11CO), carbon dioxide (11CO2), and cyanide (11CN) being used as precursors for radiotracer synthesis (Table 10-3). 13N is also cyclotron produced, generally via the 16O (p,a)13N nuclear reaction, which is performed using a water target to yield a [13N]nitrate ion (Quaim et al., 1993). 13N-ammonia can be produced directly by deuteron bombardment of methane and then, following purification, can be used for the synthesis of 13N-labeled amino acids or other compounds using both biosynthetic and synthetic strategies (Fowler and Wolf, 1986). Some examples of the types of 11C-, 13N-, and 18F-labeled compounds that can be made and could, perhaps, be used as probes of protein amino acid and substrate metabolism in vivo are listed in Table 10-3. This table was generated from data presented in the extensive review about positron-emitter tracers by Fowler and Wolf (1986).

APPLICATIONS OF PET

Although PET has not yet found extensive use in nutritional or metabolic research, its spatial resolution and quantitative features allow quantification of metabolic parameters in volumes of tissue as small as 1.0 cm3. Thus, PET techniques have been validated for measurement of regional blood flow, blood volume, pH, and oxygen utilization (Huang et al., 1986) and applied in studies of glucose metabolism in the brain (Phelps et al., 1986), for measuring blood flow (Huang et al., 1983; Raichle et al., 1983), glucose metabolism and tricarboxylic acid cycle activity in the myocardium (Huang and Phelps, 1986; Schelbert and Schwaiger, 1986), and regional glucose uptake (leg, arm, and heart) (Nautila et al., 1993). Only limited studies using PET have been conducted on amino acid metabolism in peripheral tissues (e.g., Hawkins et al., 1989; Planas et al., 1992),

TABLE 10-2 Production of Positron-Emitting Radionuclides

Nuclide

Production

11C

14N(p,a )11C

15O

14N(a,n)15O

13N

16O(p,a )13N

18F

18O(p,n)18F

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

TABLE 10-3 Some Positron-Labeled Compounds that Have Been Synthesized for Biomedical Studies

Compound

Labeled Precursor

[11C] Amino Acids

 

L-[1-11C]phenylalanine

H[11C]N

L-[1-11C]alanine

[11C]O2

L-[methyl-11C]methionine

[11C]O2

L-[1-11C]leucine

H[11C]N

18F-Labeled Compounds

 

2-deoxyl-2[18F]fluoro-D glucose

[18F]F2

3-deoxy-3-[18F]fluoro-D glucose

H[18F]anhydrous

13N-Labeled Compounds

 

L-[13N]asparagine

[13N]H3

L-[13N]leucine

[13N]H3

L-[13N]methionine

[13N]H3

 

SOURCE: Adapted from Fowler and Wolf (1986).

although this technique is particularly attractive because in principle it is possible to make sequential, site-specific, time-dependent physiological and biochemical measurements within the same subject. More importantly, due to its relatively noninvasive nature, PET measurements can be made routine for application in experiments with human subjects.

L-methyl-[11C]methionine (11C-Met) has been found to be a useful tracer with PET for evaluation of amino acid kinetics in vivo (e.g., Stalnacke et al., 1982) and for detection of tumors (Bustany et al., 1986; Kubota et al., 1985; LaFrance et al., 1987; Mosskin et al., 1987). Therefore, and because it was possible to prepare 11C-Met without a considerable synthetic or analytical research developmental effort (Figure 10-6), this laboratory has explored recently whether and how 11C-Met might be used to estimate the rate of mixed protein synthesis in skeletal muscle. The major reasons for doing this and a summary of the initial results are given below.

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

FIGURE 10-6 A general outline of one route of synthesis of L-[11C-methyl]methionine. Further details given in Fowler and Wolf (1986) and Meyer et al. (1993).

Muscle Protein Synthesis as Measured with PET
Importance of Skeletal Muscle

The maintenance of lean body mass is critical for continued cell and organ function, whether this relates to the physical performance of the individual or the capacity to withstand a stressful condition, such as systemic infection. A major contributor to the total lean mass of the body is the skeletal musculature. This accounts for about 40 percent of body weight (Forbes, 1987, 171) and approximately 52 percent of the combined protein in the muscle and nonmuscle mass of the body (Cohn et al., 1980). Hence, it might be predicted that changes in the size and metabolic status of the skeletal musculature would have significance for the well-being and functional capacity of the individual. For example, in reference to energy metabolism, the skeletal musculature (1) is the principal site of facultative thermogenesis in response to excess carbohydrate (Astrup and Christensen, 1992), (2) acts as a buffer to maintain glucose homeostasis during postprandial energy-yielding substrate storage (Taylor et al., 1993), (3) is a major determinant of daily basal energy expenditure (Zurlo et al., 1990), and (4) accounts (Tzankoff and Norris, 1977) for a large proportion, if not all, of the decline in basal or resting energy expenditure during aging (McGandy et al., 1966; Vaughan et al., 1991; Young, 1992). Further, the skeletal musculature plays a key role in the regulation, maintenance, and integration of whole-body nitrogen homeostasis (Young, 1970). An example of this latter point is depicted in Figure 10-7, which shows that branched chain amino acids, glutamine, and arginine metabolism interact via the active participation of the skeletal musculature, intestines, kidney, and liver. The point to be emphasized here is that there are metabolically significant interactions and signaling among these major anatomic regions, in amino acid and protein metabolism. Hence, it is important to

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

FIGURE 10-7 Outline of the metabolism of arginine, with reference to the cooperative involvement of the skeletal musculature intestines, kidney, and liver. SOURCE: Adapted from Brusilow and Horwich (1989).

learn how changes in the size, and possibly metabolic status, of the musculature under various physiological and stressful conditions affect the integrity of these metabolic interrelationships and, in consequence, the ability of the individual to cope with the environment.

Additionally, body protein wasting is a significant contributor to morbidity and death in a variety of catabolic disease states (Hill, 1992; Manning and Shenkin, 1995), with the major source of this loss being from skeletal muscle (Kinney, 1995; Kinney and Elwyn, 1983; Rennie, 1994). However, it should be pointed out that Muller et al. (1995) did not find that either the absolute level of muscle mass or the change in muscle mass during the advancing years in male subjects, who were participants in the Baltimore Longitudinal Study of Aging, was related to all-cause mortality. Perhaps, upon more detailed examination, muscle may be found to be more important in relation to morbidity and death due to infection and trauma while less so in relation to that associated with de-

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

generative disease, including cardiovascular and arteriosclerotic disease and cancers at some organ sites.

For these various reasons a detailed, quantitative understanding of the regional distribution of protein and amino acid utilization and of the ways by which imbalances between protein synthesis and breakdown occur in the major organs will be required if more effective nutritional-pharmacological strategies for attenuating these losses and for improving upon the tools used for assessment of nutritional status are to be developed. Furthermore, a more complete and secure understanding of the metabolic etiology for changes in muscle mass under various conditions might begin with reliable in vivo estimates of the rates of myofibrillar and sarcoplasmic protein synthesis and breakdown under various pathophysiological conditions. For example, recent studies using 13C-leucine as a tracer, followed by tissue biopsy, have shown that the fractional rate of mixed muscle or myofibrillar protein synthesis is significantly lower (about 30–40%) in elderly subjects (Welle et al., 1993; Yarasheski et al., 1993) as compared with younger adults. This age-related change in synthesis might represent an important mechanism that accounts for the diminished muscle mass in the elderly (Muller et al., 1995). However, a greater research effort needs to be focused on the in vivo regulation of muscle protein and amino acid metabolism, including determination of protein synthesis and breakdown rates, in adult human subjects under various pathophysiological conditions, such as those conditions experienced by military personnel in field operations. This is made more pertinent because measurements of protein synthesis may correlate with muscle strength, as suggested by the recent studies of Urban et al. (1995) concerning the effects of testosterone on muscle function and metabolism in elderly men. Of course, it also is equally important to determine whether and to what extent inflammatory mediators, such as interleukin-1 and tumor necrosis factor, determine the status of protein synthesis and breakdown (e.g., Goodman, 1991; Roubenoff and Rall, 1993; Zamir et al., 1992a, b) in skeletal muscle and to identify the multiple proteolytic pathways that might be involved (Goldberg and St. John, 1976; Sugden and Fuller, 1991; Thorne and Lockwood, 1993). These mediators are altered by infection as well as by vigorous exercise.

Initial Studies with PET

For the various reasons given above, as well as to establish a basis for the design and conduct of a series of studies in healthy adult control subjects and in preparation for later studies in different groups of hospitalized patients, an initial experiment was carried out with the aid of PET using 11C-Met (Hsu et al., 1996) on the transport and metabolism of methionine in the skeletal muscle of anesthetized dogs. Data analyses were performed by fitting tissue-and metabolite-corrected, arterial blood-time-activity curves to a three-compartment model. The model structure included vascular space, tissue precursor, and protein compartments. The results of the PET measurements then were compared with data

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

from simultaneous studies using A-V difference measurements during primed constant infusion of L-[1-13C-methyl-2H3]methionine (13C-2H3 -Met). The A-V difference-stable isotope tracer approach has been applied by this laboratory and other investigators to quantify muscle protein metabolism within the limbs of human subjects (e.g., Biolo et al., 1995; Cheng et al., 1985; Tessari et al., 1991).

The details of this approach and the methods involved are presented in a recent publication (Hsu et al., 1996), but a few points might first be made before a summary of the results of this laboratory is presented below. First, the decision to conduct an initial study with 11C-Met as a tracer was made, in part, because it has been shown that while isoenzymes of methionine adenosyltransferase, which catalyze synthesis of S-adenosylmethionine, are active in liver, kidney, and bone marrow, the specific activity of this enzyme is about 30-fold lower in heart and skeletal muscle (Finkelstein, 1990; Mudd et al., 1965). Therefore, it is reasonable to assume that most of the radioactivity that is retained in skeletal muscle following a dose of 11C-Met would reflect its incorporation into proteins. Furthermore, in contrast to some other 11C-labeled tracers, such as 1-11C-leucine, analysis of PET studies with 11C-Met, at least with reference to muscle, is not complicated by a contribution of 11CO2 to total blood radioactivity (Hawkins et al., 1989; Ishiwata et al., 1988). Nevertheless, much research remains to be carried out with respect to determination and evaluation of the choice and application of specific positron emitter-labeled amino acids for studies of regional aspects of body protein and specific amino acid metabolism in the human subject.

Second, for purposes of data analysis, the compartmental model that is illustrated in Figure 10-8 was applied. The rate constants K1 (or K2,1) and k2 (or k1,2) represent forward and reverse transport of methionine between plasma and tissue, and k3 (or k3,2) represents incorporation of the label into proteins, nucleic acids, creatine, and lipids. Due to the expected low level of transmethylation in

FIGURE 10-8 Kinetic model for 11C-Met utilization by skeletal muscle. The model assumes that the rates of transamination and transmethylation of methionine in this tissue are low and it contains vascular space, tissue precursor, and protein compartments. The rate constants K1 (K2,1) and k2 (k1,2) represent forward and reverse transport of methionine between plasma and tissue, and k3 (k3,2) represents incorporation into proteins. SOURCE: Hsu et al. 1996. Measurement of muscle protein synthesis by positron emission tomography with L-[methyl11C]methionine. Proc. Natl. Acad. Sci. USA 93:1841–1846. Copyright (1996) National Academy of Sciences, U.S.A.

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

muscle as already noted above, k2,3 is taken to reflect the rate of total protein synthesis in this tissue (PSR = Protein Synthetic Rate). Radioactivity in the vascular compartment was represented by a blood volume fraction parameter; the model parameters were estimated by least squares fitting of the predicted tissue concentrations of methionine (based on measured whole blood 11C radioactivity and the concentration of free labeled methionine plasma) to the tissue concentrations measured by PET (Hsu et al., 1996). Third, in the PET component of this PET-stable isotope tracer investigation, it was possible to assess the rate of muscle protein synthesis in two regions of the skeletal musculature: in the paraspinal muscles and in those in the hind leg. This was accomplished by first carrying out a 90-min 11C-Met tracer study with the scanner oriented over the paraspinal muscle region. Then a second injection of 11C-Met was given followed with a 90-min study and imaging over the hind leg region.

The Results and Their Interpretation

Estimated model parameters and values for PSR and T1/2 (half life) of the tissue precursor (methionine) pool from PET for paraspinal and hind limb muscles are summarized in Table 10-4. No significant differences between hind limb and paraspinal muscles were detected for K2,1; k1,2; k3,2; and PSR, and as shown in Figure 10-9, PSRs calculated for hind limb and paraspinal muscle were highly correlated.

PSRA-V in the limb, as determined using a primed constant infusion of 13C-2H3-Met together with A-V difference measurements of methionine isotopomer concentrations across the hind limb, was equivalent to 0.27 ± 0.05 nmol methionine min-1·g-1. Hence, these results results demonstrate that PSRA-V, expressed in relation to the weight of limb tissue, is somewhat, but not greatly, higher than that based on the PET approach. Since the stable isotope procedure

TABLE 10-4 Kinetic Parameters for L-[Methyl-11C]Methionine Metabolism in Paraspinal and Hind Limb Muscles

Muscle Region

K2,1 (ml·min-1·g-1)

k1,2 (min-1)

k3,2 (min-1)

PSR (nmol·min-1·g-1)

Paraspinal

0.0154*

0.0266

0.0124

0.172

 

± 0.0058

± 0.0094

± 0.0049

± 0.062

Hind Limb

0.0170

0.0304

0.0155

0.208

 

± 0.0055

± 0.0100

± 0.0058

± 0.048

* Mean ± SEM.

SOURCE: Adapted from Hsu et al. (1996).

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

FIGURE 10-9 Relationship between the estimate of PSRs determined by PET for hind limb and paraspinal muscle. SOURCE: Hsu et al. 1996. Measurement of muscle protein synthesis by positron emission tomography with L-[methyl11C]methionine. Proc. Natl. Acad. Sci. USA 93:1841–1846. Copyright (1996) National Academy of Sciences, U.S.A.

measures methionine utilization across the entire limb, whereas the PET-derived estimate is for muscle tissue specifically, some of the difference appears to be explained by bone marrow methionine metabolism and by the higher fractional rate of protein synthesis in the skin (Biolo et al., 1994).

Whole-body methionine kinetics also were measured in these dogs (Unpublished data, Y-M. Yu, Shriners Burns Institute, Boston, Mass., 1996), and so it was possible to estimate the relative contribution made by hind limb protein synthesis to the whole-body protein synthesis rate. A summary of these findings is presented in Table 10-5. According to these data, about 7 percent of the whole-body protein breakdown was accounted for by the breakdown of proteins in the left leg. This is a value that seems to be in reasonable line with the anticipated contribution by skeletal muscle to body protein metabolism if it can be compared with data for the adult human, where the entire skeletal musculature accounts for about 25 percent of total whole-body protein turnover. This latter value was arrived at by assuming (1) a whole-body protein breakdown rate of approximately 4 g·kg-1·day-1 (Waterlow, 1995), (2) a muscle protein mass of 3.8 kg (Cohn et al., 1980), and (3) a muscle mixed protein fractional synthesis rate of about 1.95 percent per day (Garlick and McNurlan, 1994; Smith and Rennie, 1990).

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

TABLE 10-5 Rates of Protein Synthesis and Breakdown in the Whole Body and Hind Leg of Dogs Given a Constant Intravenous Infusion of L-[2H3-methyl-1-13C]Methionine

Parameter

Value

Whole body (g·kg-1·day-1)

 

Protein synthesis

3.4 ± 0.5*

Protein breakdown

4.5 ± 0.5

Hind limb as percentage of whole body

 

Protein synthesis

7.3 ± 0.7

Protein breakdown

8.0 ± 0.5

* Mean ± SEM for seven dogs.

The whole-body rate was based on the model of Storch et al. (1988) and the values for the hind leg based on the approach described by Yu et al. (1990) for leucine and as discussed in Hsu et al. (1996).

The Implications and Some Comments

A number of additional comments might be made in reference to this initial PET study. First, this investigation into the use of PET for purposes of quantifying protein metabolism in vivo has encouraged this laboratory to begin to plan a preliminary series of studies in human subjects, especially because the available estimates of amino acid metabolism in specific organs and tissues have been derived mostly from A-V difference or tissue biopsy studies, as mentioned earlier. However, the A-V difference technique has several limitations when applied in human studies: (1) measurements cannot be performed in tissues and organs that do not have a discrete venous drainage; (2) for organs with a single venous drainage (such as kidney), the catheterization required for measuring A-V differences may be unsuitable for routine application; (3) the measurements have limited anatomic resolution (i.e., A-V differences across the entire region alone cannot be used to determine the individual contributions made by muscle, bone marrow, fat, and skin to substrate utilization); and (4) relatively long tracer infusion times (~5 hours) are required for many of these studies.

However, PET provides a rapid, routine noninvasive, in vivo method for the quantitative analysis of some tissue-specific biochemical processes. Compared then with the A-V difference techniques, PET has several advantages: (1) the measurements require only a metabolite-corrected arterial input function and imaging, (2) the anatomic resolution of PET allows measurements to be performed on tissue volumes as small as 1.0 cm3, and (3) due to the short half lives of the tracers, repetitive studies can be performed in the same subject. The limi-

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

tations of the PET methodology include: (1) an exposure of the subject to ionizing radiation, (2) inability to make a direct estimate of the specific metabolic pathways followed by the tracer, and (3) in comparison with the A-V difference method, PET does not provide a measure of protein breakdown.

The second comment is that the potential importance of the influence of blood flow rate and substrate delivery on metabolism emerges from these data. Thus, from the present stable isotope and leg weight data, the rate of protein synthesis in the total hind limb of these experimental animals was found to be equivalent to 7.3 ± 1.7 (mean ± SD) g·day-1. This compares with limited published values of about 3.2 g·day-1 (Barrett et al., 1987) and 8.6 to 11.5 g·day-1 (Biolo et al., 1992) for the hind limbs of dogs of comparable body weight. The authors believe that these differences might well be related to the blood flow rate across the limb during the study. In the study described here, PET measurements required that the leg of the dog be immobile. Hence, the dogs were heavily sedated and the hind limb restrained. These are procedures that could well have affected regional blood flow and the status of protein and amino acid metabolism in the limb. Recent reviews (Clark et al., 1995; Elia, 1995) emphasize the importance of blood flow on oxygen and substrate delivery in affecting metabolism in tissues and organs. In the present study, mean hind limb blood flow rate was 91 ml·min-1, whereas it was about 228 to 240 ml·min-1 in studies by Biolo et al. (1992, 1994) and 33 ml·min-1 in that of Barrett et al. (1987). Thus, when differences in blood flow rates are taken into consideration, the rate of limb protein synthesis measured in the present study appears to be similar to these other published values.

Of further relevance to these workshop proceedings is the fact that cold exposure induces changes in blood flow to the skin and extremities, and high-altitude exposure can result in reduced blood flow in peripheral tissues (IOM, 1996). As noted above, blood flow can be accurately measured using oxygen-15 [15O]water, and due to the short half life of 15O, this tracer permits blood flow measurements to be made in conjunction with other metabolic studies involving positron emitter-labeled compounds in physiological studies. A major limitation, of course, is that such blood flow studies have to be carried out in the physical proximity of the cyclotron.

Third, in this study, high levels of 11C-Met utilization by bone marrow also were noted (Hsu et al., 1996). This finding emphasizes the further potential value of PET in that it allows a simultaneous, discrete examination of the metabolic activity of different tissues within a particular organ.

Finally, in view of the authors' interest in the regulation of muscle protein mass and the metabolic basis that underlies changes in physical performance, it ought to be recognized that the PET approach described briefly above does not directly lead to an estimate of the rate of muscle protein breakdown. However, it would be entirely feasible to combine PET with one of the stable isotope protocols described elsewhere in this volume. The model that is proposed is the one described by Rathmacher et al. (1995), involving a bolus dose of L-3[2H3-

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

methyl]histidine given into the vein, followed by compartment modeling of the plasma tracer data. This is based on the principle that 3-methylhistidine, a component of actin and myosin, is a marker of muscle protein breakdown (Young and Munro, 1978). The model described by Rathmacher and coworkers (1995) is presented in Figure 10-10; for the present purpose it is shown to illustrate yet another example of the research value to be derived from a combined stable isotope-PET approach for in vivo assessment of protein metabolism in human subjects.

AUTHORS' SUMMARY AND CONCLUSIONS

This paper has attempted to illustrate the potential, as well as the limitations, of PET as an investigative technique in nutritional research. Within the past 10 years, major improvements in the production and handling of short-lived isotopes have occurred (Stocklin and Pike, 1993), and this has gone in step with advances in the design and use of instrumentation for radiation detection and tomography. Now, more than a hundred PET groups have been established worldwide. It might be anticipated, therefore, that there will be an expanded use of PET in nutritional-metabolic research. However, at the same time, it is recognized that PET is not likely to become widely available to the entire nutri-

FIGURE 10-10 Schematic of a three-compartment model to analyze the kinetics of distribution, metabolism, and de novo production of 3-methylhistidine (3-MH) in human subjects. M1, M2, and M3 represent the mass of 3-MH in compartments 1, 2, and 3, respectively. L2,1, L1,2, L2,3, and L3,2 are fractional transfer rate coefficients of 3-MH within the system. The tracer, 3-[2H3-methyl]-methylhistidine (D33-MH), is injected into compartment 1. Sampling is performed from compartment 1(V). De novo production of 3-MH occurs in compartment 3. SOURCE: Adapted from Rathmacher et al. (1995).

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

tional research community, even in the United States, and so it will probably remain a valuable technique at a limited number of academic research centers during the foreseeable future.

Finally, in preparing this paper the authors were asked to address a number of questions that relate to the technology discussed, and these, together with their brief answers, are presented in Table 10-6. As pointed out by Faulkner et al. (1991), the technology associated with position imaging is extremely complex; a successful PET clinical research program requires a highly skilled team of scientists and technologists working in well-equipped, specialized laboratories and involves a significant annual financial expenditure. Nevertheless, the authors believe that it is entirely reasonable to suggest that, where the necessary mixture of technical expertise, collaborative interest and physical facilities exist, or where there is an obvious institutional commitment, PET must be considered among the exciting new and emerging technologies for nutritional and metabolic research.

TABLE 10-6 PET in Reference to Emerging Technologies: Some Questions and Answers

Will the technology be a significant improvement over current technologies?

There is no alternative to a noninvasive ''view" of the distribution of human amino acid metabolism in vivo.

How likely is the technology to mature sufficiently for practical use, and if so, how soon will it be available?

It is available now but only in selected medical-academic centers.

Cost-benefit ratio?

High cost: $2 million for camera, $2 million for cyclotron.

Benefit: Probably also very high, but who knows?

What about Small Business Innovative Research?

Certainly in the area of tracer development.

Practicality?

It is demanding and complex but exciting! Multidisciplinary.

Field-testing scenarios?

Not at all.

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

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Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
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Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
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Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
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DISCUSSION

DONALD McCORMICK: A couple of questions. One is that 30 mCi of labeled methionine did not sound like a heck of a lot, Vernon. How much methionine is delivered?

VERNON YOUNG: About 30 nmol methionine.

DONALD McCORMICK: In the case of a molecule where you label with an isotope like 11C, the decay is to nitrogen, is it not?

VERNON YOUNG: Yes, in that case.

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
×

DONALD McCORMICK: I am thinking of cases where you have a carbon and a nitrogen, and you generate an azide that is very toxic.

VERNON YOUNG: Oh, but the actual amount is so small. I thought what you were going to do was to ask me what the radiation load was, which I think is a very fair question. Well, I will tell you, since you did not ask. (Laughter)

I understand that in studies of this kind the radiation dose is roughly somewhere between a CAT scan and a barium enema. It is certainly in that range.

ARTHUR ANDERSON: I am intrigued by the bone marrow observations that you made. Have you gotten any preliminary evidence now about whether the protein synthesis is related to cell division versus antibody production?

VERNON YOUNG: Oh, no. That is a darned good question. What this [PET] actually does is that it gives you rates of biochemical processes, but it does not tell you what that process is. So this particular approach does have significant limitations, but I think the combination of approaches is extremely powerful.

DENNIS BIER: I do not want to ask a question, but earlier Vernon said he only had one regret, that he was getting on a plane. He was too embarrassed to tell you that, really, his other real regret is that as a young person and a British citizen, he was not a member of the United States military. (Laughter)

VERNON YOUNG: Nor was I member of the British military. (Laughter)

Suggested Citation:"10 Combined Stable Isotope-Positron Emission Tomography for In Vivo Assessment of Protein Metabolism." Institute of Medicine. 1997. Emerging Technologies for Nutrition Research: Potential for Assessing Military Performance Capability. Washington, DC: The National Academies Press. doi: 10.17226/5827.
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The latest of a series of publications based on workshops sponsored by the Committee on Military Nutrition Research, this book's focus on emerging technologies for nutrition research arose from a concern among scientists at the U.S. Army Research Institute of Environmental Medicine that traditional nutrition research, using standard techniques, centered more on complex issues of the maintenance or enhancement of performance, and might not be sufficiently substantive either to measure changes in performance or to predict the effects on performance of stresses soldiers commonly experience in operational environments. The committee's task was to identify and evaluate new technologies to determine whether they could help resolve important issues in military nutrition research. The book contains the committee's summary and recommendations as well as individually authored chapters based on presentations at a 1995 workshop. Other chapters cover techniques of body composition assessment, tracer techniques for the study of metabolism, ambulatory techniques for the determination of energy expenditure, molecular and cellular approaches to nutrition, the assessment of immune function, and functional and behavioral measures of nutritional status.

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