Clinical Trials for the Treatment of Secondary Wasting and Cachexia

Perspectives on Exercise and Wasting1

Elsworth R. Buskirk
Physiological Research Center, The Pennsylvania State University, University Park, Pennsylvania 16802
ABSTRACT Recommendations for endpoints in clinical trials of wasting that involve exercise should involve selection that clearly identies the effects of exercise. Broad endpoints such as morbidity and mortality must be corrected for the effects of age, smoking, hypertension, etc. in order to gain adjusted information pertinent to exercise. Selection of variables related to physiological function although more specic i.e., maximal oxygen uptake, must still be viewed from the perspective that other variables may contribute to the values measured. Nevertheless, physiological information obtained from performance tests may well provide useful endpoints. In this max, heartrate and pulmonary ventilation at xed work loads, muscular strength, reaction time, regard, V 02 exibility, blood gases, cardiac output, stroke volume, serum lactate, and properties of skeletal muscle such as mitochondria concentration and components related to muscle energetics, e.g., adenosine triphosphate. In addition exercise will denitely impact body mass and composition as well as conguration. The latter is assessable through utilization of somatogramography. Analysis of muscle depends on muscle biopsy and magnetic resonance spectroscopy. Neither of these methods has been employed in clinical trials to the best of our knowledge. Thus, one needs evidence that exercise in the clinical trial provides a discrete effect on performance capabilities, body status and biologically important variables. J. Nutr. 129: 295S302S, 1999. KEY WORDS: exercise wasting cardiovascular disease semi-starvation somatogramography magnetic resonance

bed rest

skeletal muscle

It is common knowledge that exercise develops and/or improves functional capacity and delays many disabilities that accompany old age. Chronic diseases are postponed through regular exercise. It is quite likely that physical activity and tness are directly linked to the maintenance of health and longevity. A variety of trials have shown that regular physical activity leads to improvements in risk factors such as blood lipid proles, hypertension, poor glucose tolerance, etc. Both morbidity and mortality have been shown to be favorably impacted by regular exercise (Blair et al. 1989, Kushi et al. 1997, Lee and Paffenbarger 1996, Paffenbarger et al. 1994, Paffenbarger and Lee 1996). Thus, exercise has proven a valuable behavioral/environmental adjunct in the diagnosis and treatment of a variety of conditions/diseases. While not universally utilizable, properly prescribed regular exercise can produce meaningful positive changes in body composition,

metabolism, energetics, self sufciency and general well-being in both healthy and compromised individuals. Specic endpoints in relation to the effect of exercise on the prevention of wasting or recovery from wasting involve decision making in regard not only to morbidity and mortality but to body composition, systems performance and physiological function. Selection of endpoints involves selection of discrete meaningful variables that provide information solely attributable to exercise. Such selection is no easy task. Attention here will be paid to some previous investigations, their ndings and some suggestions particularly in regard to skeletal muscle. In the limited space available I have also chosen to briey review two conditions that produce wasting ie semi-starvation and bed rest, provide a brief focus on skeletal muscle and wasting, and mention a simple analytical technique for evaluating body conguration in wasting (somatogramography) as well as a more complicated evaluation of muscle energetics and metabolism with magnetic resonance spectroscopy. RELATIVE RISK/MORTALITY The value of regular exercise has been conclusively demonstrated in recent years through the efforts of several epidemiologists who have evaluated results from several large groups who differed in regular physical activity. Three of the many available studies are summarized here with a focus on mortality and relative risk. In general relative risk was inversely propor-

1 Presented at the workshop entitled: Clinical Trials for the Treatment of Secondary Wasting and Cachexia: Selection of Appropriate Endpoints, May 2223, 1997, Bethesda, MD. The workshop was sponsored by the Food and Drug Administration, Ofce of AIDS Research, National Cancer Institute, National Institute of Mental Health, Bristol-Meyers Squibb, Abbott Laboratories, Serono Laboratories, Inc., American Institute for Cancer Research, Roxane Laboratories, National Institute of Drug Abuse, SmithKline Beecham, National Institute of Aging, Eli Lilly Company and the American Society for Nutritional Sciences. Workshop proceedings are published as a supplement to The Journal of Nutrition. Guest Editors for this supplement publication were D. J. Raiten and J. M. Talbot, Life Sciences Research Ofce, American Society for Nutritional Sciences, Bethesda, MD.

0022-3166/99 $3.00 1999 American Society for Nutritional Sciences.

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TABLE 1
Rates and relative risks of all-cause mortality by gradients of physical activity or physical tness. For the period 1970 1985 amoung men in the aerobics center longitudinal study
Physical tness Least Fit Second Third Four Most Fit 5TH 5TH 5TH 5TH 5TH No. of deaths 75 40 47 43 35 Deaths per 10,000 man-years 64.0 25.5 27.1 21.7 18.6 Relative risk* 3.44 1.37 1.46 1.17 1.00 (Referent)

Age standardized Adapted from Blair et al., 1989 Data from Women essentially comparable

subjects by kcal wkn-1 of regular physical activity. The relative risk of cardiovascular death was approximately halved if 2,500 kcalwk-1 or more was utilized for regular physical activity as compared to those who utilized less than 1,000 kcal wk1 for activity (Table 3). Kushi et al. (1997) studied a large group of postmenopausal women in Iowa. The women were grouped on the basis of a physical activity index as determined by questionnaire. The adjusted relative risk of total mortality was highest among those citing low activity and least among those with high activity. The same observation held for all three age groups studied ie less than 60 years, 60 to 64 years and 65 years and older. Although the risk reduction was not as great for the postmenopausal women (RR 0.66 to 0.74) in the three age groups as it was for the men studied by Blair and Paffenbarger and their colleagues, it was highly signicant among the most active women (Table 4). PERSPECTIVES FROM CDC AND THE SURGEON GENERALS REPORT Overall perspectives in regard to the status of physical activity participation in the United States have recently been summarized in the Centers for Disease Control (1996) and the Surgeon Generals Report (see U. S. Department of Health and Human Services 1996 [Report of the Surgeon GeneralPhysical Activity and Health]). In addition, the benets of regular physical activity regardless of the circumstances (i.e., wasting) are presented in bullet identied statements (Tables 5, 6, and 7). Although wasting per se is not mentioned several conditions/diseases that are associated with wasting are presented. It is obvious from the statements offered that exercise should be considered as an adjunct in preventing, controlling or intervening therapeutically in situations involving wasting. EXERCISE DETERMINATION/PRESCRIPTION In the assessment of exercise it is difcult to ascertain how much daily exercise and of what type is pursued by a given individual. A variety of techniques have been devised as illustrated in Table 8 but none is entirely satisfactory, particularly when one would like to know what type of exercise and how much is useful in either preventing or recovering from wasting (Buskirk et al. 1980). Yet such knowledge is critical if exercise is to be maximized as a useful therapeutic procedure. The bottom line is that prescription of exercise for any particular circumstance should be well thought out and competently administered to maximize potential effectiveness. So many options are currently available through rehab programs in hospitals, diagnostic laboratories, health clubs with appropriately trained personnel and institutional programs such as

tional to amount of physical activity. Blair et al. (1989) found that among men who participated in the Aerobics Center Longitudinal Study from 1970 to 1985 the relative risk of dying was more than three-fold higher among the least t subjects than among those most t (Table 1). Quintiles of physical tness were developed and in general relative risk decreased with greater tness. In a more recent analysis covering the period 1970 to 1989 Blair et al. (1995) reported lesser relative risk among those who were regarded as physically t at the rst exam in 1970 and still t at the second exam in 1989. Again those who were unt initially and remained unt had three-fold greater relative risk (Table 2). Paffenbarger et al. (1994), Paffenbarger and Lee (1996), and Lee and Paffenbarger (1996) presented data that divided TABLE 2
Rates and relative risks of all-cause mortality (1970 1989) in the aerobics center longitudinal study with respect to changes in physical tness between 1970 and 1989
Physical Fitness 1st Exam Unt Unt Fit Fit 2nd Exam Unt Fit Unt Fit No. of deaths 32 25 9 157 Mortality rate (per 10.000) 122.0 67.7 63.3 39.6 Relative risk 1.00 (referent) 0.56 0.52 0.33

9777 men aged 20 82 years, 6819 healthy, 2958 unhealthy Adapted from Blair et al., 1995

TABLE 3
Relative risks of cardiovascular disease by gradients of physical activity. Rates and relative risks of CVD death among 14,623 male Harvard alumni aged 45 84 years at entry, in a 12-year follow-up, 19771988, by physical activity in kcal wk1
Physical activity (kcal wk1) 1000 10002499 2500 Man-years (%) 31 39 30 No. of CVD deaths 512 317 170 CVD deaths per 10,000 man-years 78.8 56.3 43.0 Relative risk of CVD death 1.00 0.71 0.54 P 0.001 0.001

Standardized for age, cigarette habit, hypertension, obesity, alcohol consumption, early parental mortality, and selected chronic diseases (CHO, stroke, chronic lung disease, diabetes and cancer). Adapted from Paffenbarger et al., 1994, Paffenbarger and Lee, 1996, and Lee and Paffenbarger, unpublished.

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TABLE 4
MultivariateAdjusted relative risks (RR) of total mortality according to physical activity index, stratied for age, among postmenopausal women in Iowa and excluding baseline disease and the rst 3 years of follow-up, 1986 1992
Age group 60 y Cohorts Low activity Med. activity High activity P value (for trend) Deaths 298 133 89 0.02 RR 1.00 0.88 0.74 Deaths 471 175 147 6064 y RR 1.00 0.74 0.67 Deaths 540 211 179 65 y RR 1.00 0.74 0.66

0.001

0.001

For 60 y, n 13,148; for 60 64 y, n 13,044; for 65 y, n 10,850. Adapted from Kushi, et al. 1977.

those offered by special institutes (Coopers Aerobus Center) or organizations (YMCA, YWCA). WASTING Some of the non-disease conditions that are conducive to wasting are identied in Table 9. All have been studied parTABLE 5
Overall perspective re physical activity in the U.S. report of the Surgeon General Physical Activity and Health, 1996
Facts More than 60 percent of U.S. adults do not engage in the recommended amount of activity. Approximately 25 percent of U.S. adults are not active at all. Physical inactivity is more common among: Women than men. African American and Hispanic adults than whites. Older than younger adults. Less afuent than more afuent people. Social support from family and friends has been consistently and positively related to regular physical activity.

tially though in many instances with rather gross techniques. Nevertheless, valuable insights have been obtained. Some of the techniques that have been employed in various clinical trials involving exercise are listed in Table 10. Many of these same techniques are applicable in the assessment of the effects of wasting. There are numerous methods for appraisal of the degree of wasting and recovery from wasting. Some of these are listed in Table 11 and many have been discussed by the presenters at this workshop. Sufce it to say that most of the methods have only been incompletely pursued particularly in view of the many causes and types of wasting that occur. Rejeski et al. (1996) make the point that physical activity has global contributions to make re health-related quality of TABLE 7a
Older adults: Physical Activity and Health Report of the Surgeon GeneralPhysical Activity and Health, 1996
Facts The loss of strength and stamina attributed to aging is in part caused by reduced physical activity. Inactivity increases with age. By age 75, about one in three men and one in two women engage in no physical activity. Among adults aged 65 years and older, walking and gardening or yard work are, by far, the most popular physical activities. Social support from family and friends has been consistently and positively related to regular physical activity.

TABLE 6
From the Centers for Disease Control and prevention CDCs National Physical Activity initiative, 1996
Facts People with disabilities are less likely to engage in regular moderate physical activity than people without disabilities, yet they have similar needs to promote their health and prevent unnecessary disease. Social support from family and friends has been consistently and positively related to regular physical activity. Benets of Physical Activity Reduces the risk of dying from coronary heart disease and of developing high blood pressure, colon cancer, and diabetes. Can help people with chronic, disabling conditions improve their stamina and muscle strength. Reduces symptoms of anxiety and depression, improves mood, and promotes general feelings of well-being. Helps control joint swelling and pain associated with arthritis. Can help reduce blood pressure in some people with hypertension.

TABLE 7b
Older adults: Physical Activity and Health Report of the Surgeon GeneralPhysical Activity and Health, 1996
Benets of Physical Activity Helps maintain the ability to live independently and reduces the risk of falling and fracturing bones. Reduces the risk of dying from coronary heart disease and of developing high blood pressure, colon cancer, and diabetes. Can help reduce blood pressure in some people with hypertension. Helps people with chronic, disabling conditions improve their stamina and muscle strength. Reduces symptoms of anxiety and depression and fosters improvements in mood and feelings of well-being. Helps maintain healthy bones, muscles, and joints. Helps control joint swelling and pain associated with arthritis.

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TABLE 8
Methods of appraisal of physical activity
Questionnaires/Diaries Direct Observation Activity Monitoring Devices Pulse Rate Pulmonary Ventilation Foot-strike Sensors Laboratory Testing and Activity Simulation Doubly Labeled Water

TABLE 11
Methods of appraisal of degree of wasting and recovery from wasting
Body Composition Analysis Physiological Function Analysis Metabolic, (Aerobic, Anaerobic) Endocrine Cardiovascular Pulmonary Renal Performance Analysis Flexibility Strength Endurance Coordination Somatograms, Anthropometry

life and that there are cognitive, emotional and social dimensions that should be included in any thorough examination of current status whether or not wasting has been involved (see Table 12). STARVATION/SEMI-STARVATION The classic book Biology of Human Starvation (Keys et al. 1950) reveals major concern about the rehabilitation process following 24 weeks of semi-starvation. During the rehabilitation or recovery period of 12 weeks, physical tness related variables were followed at intervals. Those being rehabilitated were given marginal or adequate caloric intakes. Two tness variables, (1) performance on the Harvard tness test, and (2) maximal oxygen intake, were utilized and the results are summarized in Table 13. As expected the adequate caloric intake supplemented with minerals and vitamins provided signicantly better recovery response. A point is made that the rate of return of the maximal oxygen intake was substantially improved on a per liter basis but this gain was not evident on a per kg basis where the recovery of body tissue paralleled the capacity to transport and utilize oxygen. Grande and Taylor (1965) summarized the effect of various biological stresses on the maximal oxygen intake. Their observations are presented in Table 14. All of the stresses adTABLE 9
Conditions conductive to wasting, non disease related
Starvation Semi-starvation Bedrest Disabling injury Weightlessness Sustained stress

versely affected the ability to deliver oxygen to working muscle with semi-starvation for six months having the greatest effect. Experimental malaria also produced a major reduction as did 21 days of bed rest. Acute starvation for four or ve days produced a signicant decline as did semi-starvation at 580 kcal d-1 for 12 days. The point is that the physiological assessment of aerobic capacity proved a good marker of the impact of the imposed biological stress. BED REST Saltin et al. (1968) conducted an evaluation of a 50-day recovery period of physical training following a 20-day period of bed rest among ve young men. Both interval and continuous exercise was employed throughout the week except on Sundays. Training was conducted utilizing from 65 to 90% of the maximal oxygen uptake. Nutrition was ad lib. A summary

TABLE 12
Content dimensions for physical activity and health-related Quality of Life
I. II. Global indices of HRQL Physical function Difculties with ADLs and other performance-related domains Physical self-concept Health-related perceptions Physical symptoms/states Pain discomfort Fatigue Energy Sleep Emotional function Depression Anxiety Anger/hostility Self-esteem Mood/affect Social function Social dependency Leisure-time pursuits Family/work roles Cognitive function Memory Attention Problem-solving/decision making Adapted from Reieski et al. (1996)

III.

TABLE 10
Endpoints in clinical trials: Impact of exercise
Decreased Mortality Decreased Morbidity Decreased Risk Factors (for several diseases) Increased Functional Capacity Flexibility Mobility Strength Endurance Coordination Increased Self-sufciency Prevention of Injury Preservation of Muscle Mass, FFM Promotes Psychological WellBeing IV.

V.

VI.

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TABLE 13
Effect of kcal rehabilitation on two tness variables
Test Harvard Fitness (sec) Low High VO2 max (cc kg1) Low High Control S24 R5 R12 % Recovery @ R12

248.7 258.5 47.5 51.2

81.7 81.3 33.8 38.6

15.5 39.4

59.0 79.4 4.0 4.4

35.5 44.8 29.1 32.0

n 8. Low kcal intake 1600 or 2000 kcal d1. High kcal intake 2400 or 2800 kcal d1. Adapted from Keys et al., 1950.

max charges during training during recovery is of the V 02 presented in Figure 1. Two of the subjects who were initially TABLE 14
Effect of various biological stresses on the maximal oxygen uptake
max V 02 (L min1) Condition Bed rest Malaria Acute Strav. Semi Strav.* Semi Strav. Duration (days) 21 10 45 12 180 Before 3.85 3.69 3.45 3.50 3.11 After 3.18 2.95 3.19 3.32 1.95 % Decrease 17.4 20.1 7.5 5.1 37.3

* 580 kcal d1. 1600 kcal d1. Adapted from Grande and Taylor, 1965

better trained reached their pre-bed rest values by 40 to 50 days of recovery. Those who were initially in poorer physical condition actually exceeded their pre-bed rest values and had equaled them by 10 days of training. Figure 2 shows various cardiovascular variables plotted in relation to exercise intensity as assessed by oxygen intake. Maximal-values of cardiac output, arterio-venous oxygen difference and stroke volume were all enhanced by training during recovery whereas heart rate was signicantly reduced. Recently bed rest has been given comprehensive coverage in the Handbook of Physiology: Environmental Physiology (see Fortney et al. 1996). For example a summary of the impact of max appears in Figure 3. Effects on several variables on V 02 heart rate, stroke volume, and arterial and venous oxygen concentrations are depicted. Bone loss and muscle hypotrophy are also discussed implicating neuronal, endocrine and enzymatic alterations all of which can be somewhat modied during the recovery process, but the role of exercise in recovery remains only partially known.

FIGURE 1 Changes in maximal oxygen uptake, measured during running on a motor-driven treadmill, before and after bed rest and at various intervals during training; individual data on ve subjects. Arrows indicate circulatory studies. Heavy bars mark the time during the training period at which the maximal oxygen uptake had returned to the control value before bed rest. (From Saltin et al. 1968.) (Adapted from Astrand and Rodahl 1977).

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FIGURE 2 Mean values of cardiac output, arteriovenous oxygen difference, stroke and heart rate in relation to oxygen uptake during running at submaximal and intensity before (c), after (b) a 20-day period of bed rest, and again after a 50-day period (t). (Modied from Saltin et al. 1968.) (Adapted from Astrand and Rodahl 1977.)

SKELETAL MUSCLE It is assumed that both strength and endurance training (aerobic) are necessary to compensate for losses of muscle mass

(related to strength) and mitochondrial concentrations (related to aerobic capacity and endurance). This brings up the question of the capacity of myonuclei in skeletal muscle bers to supply either structural or oxidative proteins for rebuilding of muscle. Presumably, some transcriptional changes by myonuclei can occur with training leading to muscle ber coexpression of myosin heavy chain isoforms. Any compromise or loss of coordination of protein expression by myonuclei may well be due to poor communication among myonuclei (Tseng et al. 1995). Lessened load-bearing for 30 days reduced satellite cell number by 45% in the soleus muscle of young rats (Darr and Schultz 1989). An insufcient number of satellite cells may not permit a hypotrophied muscle to regrow to its former size. Research is needed to determine whether the number of functional satellite cells becomes limiting re maintenance or restoration of musclemass. Can strength training, whether intermittent or continuous, affect the satellite cell concentrations in a constructive way in any rehabilitation regimen? Is one procedure better than another recruitment or activation of a signicant number of satellite cells? Booth et al. (1994) cite the observation that older individuals have a loss of a-motoneurons, motor units, muscle bers and muscle mass plus ber type regrouping and rearrangementthus meeting the criteria for a neuromuscular syndrome of wasting. They characterize muscle wasting with age as a neuromuscular disease that is worthy of considerably more research support because of the increased disability that affects the aged. Based on review of the literature Tseng et al. (1995) offer the following conclusions particularly as they relate to exercise and the aging/wasting issue. The rate of skeletal muscle loss can be slowed and/or maintained by strength training. Aerobic training improves the quality of life by resisting the cascade of disability presumably through the preservation of mitochondrial concentrations. A list of muscle properties that undergo charges with wasting and therapeutic treatment for wasting appears in Table 15. There are a great many questions that arise re wasting of skeletal muscle. Both Dutta and Hadley (1995) and Carlson

FIGURE 3 Adaptive responses of prolonged bed rest that inuence maximal oxygen uptake. Adapted from Fortney et al. 1996.

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TABLE 15
Muscle properties that undergo changes with wasting and rehabilitation
Mass Fiber type Insulin sensitivity Glucose uptake/utilization Strength Isometric Peak torque Rate of torque development Fatiguability ATP production Impact absorption

(1995) have reviewed the wasting problem and suggest the following: What causes the loss of motor neurons? How long do denervated muscle bers survive? Do denervated bers become functional if reinnervated? Are motor units remodeled with rehabilitation? Does denervation of a muscle ber stimulate axonal sprouting? What markers in skeletal muscle are best to assess neuromuscular remodeling? What are the dynamics of satellite cell contributions to the reversal of denervation atrophy or muscle hypertrophy? Is satellite cell number dependent on neural inuences? If so how can these inuences be maximized? ANTHROPOMETRY: SOMATOGRAMOGRAPHY One simple type of appraisal that has been inadequately explored is one dealing with anthropometry and construction of somatograms that characterize the individual. Since wasting involves body mass and conguration changes, these can be visualized via somatogramography. The procedure was rst proposed by Behnke et al. (1959). It was later rened by Behnke et al. (1978) and a summary of the technique is discussed by Katch (1992). Although no attempt will be made to describe the technique in detail here the general principle

is outlined. The current denition comprises the ponderal somatogram PSOM with its two components: (1) ponderal equivalent muscular component (PEM), which includes the shoulder, chest, biceps, forearm, thigh and calf; and (2) ponderal equivalent nonmuscular component (PENM), which includes two abdominal measurements and their average as well as hips, knee, wrist and ankle. Constants are calculated from the data for the reference man and woman. Also utilized is a ponderal equivalent (PE) expressed in kg for each girth and a d-value or deviation from a reference man or woman. The system appears to be a relatively valid approach for partitioning a matrix of girths into muscularly related and nonmuscularly related components that characterize the individual. Thus, comparisons can be made of how an individual changes over time, e.g., during or recovery from wasting. Katch (1992) also implies considerable utility for the squared matrix of girths multiplied by stature. An example of the original plus the PSOM plot for a body builder is presented in Figure 4. MAGNETIC RESONANCE SPECTROSCOPY One method of studying skeletal muscle under a variety of conditions is the utilization of magnetic resonance spectroscopy (MRS). Kent-Braun et al. (1995) has reviewed the utility of MRS as well as technical aspects of following the energetics of muscle on a continuous and non-invasive bases (see Figure 5). One limitation is the connement of evaluation to relatively small muscle groups. The variables of concern are inorganic phosphate (Pi), phosphocreatine (PCr) and , and -adenosine triphosphate (ATP). Calculated ratios are utilized, e.g., Pi/PCr, as are derived values for such compounds as adenosine diphosphate (ADP). Labeled chemicals can be employed such as 13C for studying glycogen utilization and synthesis. Studies of fasting and muscle metabolism during fatiguing exercise have found Pi/PCr and pH changes to be dampened perhaps due to shifts from carbohydrate to fatty acid and ketone utilization. A lesser acid environment may explain lower Pi/PCr due to the effect of acidosis on the creatine kinase reaction. Thus, studies in malnourished subjects who are challenged by exercise may well reveal metabolic/energetic abnormalities that are hard to discern with other techniques. A variety of condition/diseases have been studied with MRS as well as the effectiveness of treatment. Exercise has been used as part of the therapeutic process but seldom to a

FIGURE 4 Left. Original somatogram (SOM). There is no distinction between muscular and nonmuscular components. Scores within a range of 2 percentage deviations from the zero reference line are considered to be within normal limits of variation compared with the reference man and woman standards. Right. Ponderal somatogram (PSOM) for a 35-year-old world champion body builder with extraordinary upper body development. The largest deviations are 88.6 % for the biceps, 62.8% for the chest, and 58.8% for the shoulders. (Adapted from Katch 1992.)

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Blair, S. N., Kohl, H. W., III, Barlow, C. E., Paffenbarger, R. S., Jr., Gibbons, L. W. & Macera, C. E. (1995) Changes in physical tness and all-cause mortality: a prospective study of healthy and unhealthy men. J.A.M.A. 273: 10931098. Blair, S. N., Kohl, H. W., III, Paffenbarger, R. S., Jr., Clark D. G., Cooper, K. H. & Gibbons, L. W. (1989) Physical tness and all-cause mortality: a prospective study of healthy men and women. J. Am. Med. Assoc. 262: 23952401. Booth, F. W., Weeden, S. H. & Tseng, B. S. (1994) Effect of aging on human skeletal muscle and motor function. Med. Sci. Sports Exerc. 26: 556 560. Buskirk, E. R., Hodgson, J. & Blair, D. (1980) Assessment of daily energy balance: Some observations on the methodology for indirect determinations of energy intake and expenditure. In: Assessment of Energy Metabolism in Health and Disease (Kinney, J. M., ed.), pp. 113117. Carlson, B. M. (1995) Factors inuencing the repair and adaptation of muscles in aged individuals: Satellite cells and innervation. J. Gerontology 50A(Special issue): 96 100. Centers for Disease Control (CDC). (1996) National Physical Activity Initiative. U.S. Dept. of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA. Darr, K. C. & Schultz, E. (1989) Hindlimb suspension suppresses muscle growth and satellite cell proliferation. J. Appl. Physiol. 76: 18271834. Dutta, C. & Hadley, E. C. (1995) The signicance of sarcopenia in old age. J. Gerontology 50A(Special issue): 1 4. Fortney, S. M., Schneider, V. S. & Greenleaf, J. F. (1996) The physiology of bed rest. In: Handbook of Physiology, Section 4 Environmental Physiology, Vol. II, (Fregley, M. J. & Blatteis, C. M. eds.), pp. 889 939. Oxford University Press, New York. Grande, F. & Taylor, H. L. (1965) Adaptive changes in the heart, vessels and patterns of control under chronically high loads. In: Handbook of Physiology, Section 2 Circulation, Vol. III, (Hamilton W. F. & Dow, P. (eds.), American Physiological Society, Waverly Press and Williams and Wilkins Company, Baltimore, MD. Katch, F. I. (1992) New approaches to body composition evaluation and some relationships to dynamic muscular strength. In: Body Composition and Physical Performance (Marriott, B. M. & Grumstrap-Scott, J. eds.), pp. 119 139. National Academy Press, Washington, D.C. Kent-Braun, J. A., Miller, R. G. & Weiner, M. W. (1995) Human skeletal muscle metabolism in health and disease: Utility of magnetic resonance spectroscopy. In: Exercise and Sports Sciences Reviews (Holloszy, J. O., ed.), pp. 305347. Williams and Wilkins, Baltimore, MD. Keys, A., Brozek, J., Henschel, A., Mickelsen, O. & Taylor, H. L. (1950) The Biology of Human Starvation. University of Minnesota Press, Minneapolis, MN. Kushi, L. H., Fee, R. M., Folsom, A. R., Mink, P. J., Anderson, K. E. & Sellers, T. A. (1997) Physical activity and mortality in postmenopausal women. J. Am. Med. Assoc. 277: 12871292. Lee, I-M. & Paffenbarger, R. S., Jr. (1996) Do physical activity and physical tness avert premature mortality? In: Exercise and Sports Sciences Reviews (Holloszy, J. O., ed.), pp. 135171. Williams and Wilkins, Baltimore, MD. Paffenbarger, R. S., Jr., Kampert, J. B., Lee, I-M., Hyde, R. T., Leung, R. W. & Wing, A. L. (1994) Changes in physical activity and other lifeway patterns inuencing longevity. Med. Sci. Sports Exerc. 26: 857 865. Paffenbarger, R. S. & Lee, I-M. (1996) Physical activity and tness for health and longevity. Res. Quart. Exerc. Sport 67(Suppl. 3): 1128. Rejeski, W. J., Brawley, L. R. & Shumaker, S. A. (1996) Physical activity and health related quality of life. In: Exercise and Sports Sciences Reviews (Holloszy, J. O., ed.), pp. 71108. Williams and Wilkins, Baltimore, MD. Saltin, B., Blomqvist, G., Mitchell, J. H., Johnson, R. L., Jr., Wildenthal, K. & Chapman, C. B. (1968) Response to exercise after bed rest and after training. Circulation 38(Suppl. 75): VIII78. Tseng, B. S., Marsh, D. R., Hamilton, M. T. & Booth, F. W. (1995) Strength and aerobic training attenuate muscle wasting and improve resistance to the development of disability with aging. J. Gerontology 50A(Special issue): 113 119. U. S. Department of Health and Human Services (1996) Physical Activity and Health: A Report of the Surgeon General. U. S. Dept. of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion.

FIGURE 5 Schematic of the general relationship between power or force and Pi/PCr (or [ADP]) during progressive exercise. As the workload increases, there is a concomitant increase in Pi/PCr as the muscle responds to the increased energy demand. The initial, linear portion of this curve (workload red with untrained subjects, there is less of an increase in Pi/PCr at any given relative workload, thus indicating an improved ability to keep pace with energy needs by means of oxidative phosphorylation. In contrast, in persons with disease that impairs muscle metabolism (either directly or indirectly), the initial slope of work versus Pi/PCr is decreased, indicating a poor capacity for oxidative metabolism.

denitive extent. According to Kent-Braun et al. (1995) all of the following have been investigated in part: muscle injury, metabolic myopathies, neuromuscular degeneration, muscular dystrophy, multiple sclerosis, postpolio rehabilitation, limited muscle oxygenation (heart failure, peripheral vascular disease), chronic fatigue syndrome, diabetes mellitus, AIDS, thyroid conditions. and miscellaneous other afictions. The major disadvantages in utilizing MRS in the evaluation of wasting are the limited number of adequate facilities, experienced personnel, high cost and the necessity to visit major hospitals or other large laboratories for in-house studies. An illustration of the impact of disease on the Pi/PCr ratio is given in Figure 5. Impaired muscle metabolism in disease is reected by a lesser slope of work versus Pi/PCr which indicates a poorer capacity for oxidative metabolism in the involved muscle. LITERATURE CITED
Astrand, P. O. & Rodahl, K. (1977) Textbook of Work Physiology, McGraw-Hill Book Company, New York. Behnke, A. R., Guttentag, O. E. & Brodsky, C. (1959) Quantication of body weight and conguration from anthropometric measurements. Hum. Biol. 31: 213234. Behnke, A. R., Katch, F. I. & Katch, V. (1978) Routine anthropometry and arm radiography in assessment of nutritional status; its potential. J. Parenter. Enteral. Nutr. 2: 532553.