SCHOLARLY REVIEWS. Muscle Damage: Nutritional Considerations. Eccentric Exercise. William J. Evans Tufts University

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1 SCHOLARLY REVIEWS International journal of Sport Nutrition, 1991, 1, Muscle Damage: Nutritional Considerations William J. Evans Tufts University Most exercise results in some skeletal muscle damage. However, unaccustomed exercise andlor eccentric exercise can cause extensive damage. This exercise-induced muscle damage causes a response that can be characterized by a cascade of metabolic events. Within 24 to 48 hours, delayed onset muscle soreness and weakness, the most obvious manifestations of the damage, peak. Increased circulating neutrophils and interleukin-1 occurs within 24 hours after the exercise, with skeletal muscle levels remaining elevated for a much longer time. There is a prolonged increase in ultrastructural damage and muscle protein degradation as well as a depletion of muscle glycogen stores. These metabolic alterations may result in the increased need for dietary protein, particularly at the beginning of a training program that has a high eccentric component such as strength training. The delay in muscle repair and glycogen repletion following damaging exercise should cause coaches and athletes to allow an adequate period of time between competition for complete recovery. Unaccustomed exercise generally results in delayed onset muscle soreness (DOMS). This delayed soreness begins within 24 hours after the exercise and may be mild or severe depending on the intensity of the activity and the individual's previous activity levels. While there has been much speculation of the cause of DOMS, currently there is agreement that it is likely the result of exerciseinduced muscle damage. This exercise-induced muscle damage initiates a remarkable metabolic response, with the ultimate result being the repair of the damaged muscle tissue. This review will focus on the nutritional implications of exercise-induced skeletal muscle damage and subsequent adaptive responses. Eccentric Exercise Muscle contraction and shortening produces a concentric action; however, when skeletal muscle lengthens as it produces force, the result is an eccentric muscle action. An example of this is lifting a weight (concentric action) and lowering it (eccentric action). At the same power output, the oxygen cost of eccentric exer- William J. Evans is with the USDA Human Nutrition Research Center on Aging, Tufts University, 71 1 Washington St., Boston, MA

2 Muscle Damage: Nutritional Considerations / 21 5 cise is lower than that of concentric exercise (1). Despite the lower oxygen cost, eccentric exercise has been demonstrated to be a potent cause of muscle damage (38, 40), DOMS, and increased circulating creatine kinase (CK) activity (17). The reason why eccentric exercise causes far greater amounts of muscle damage than concentric exercise may be due to different fiber recruitment patterns. Newham et al. (39) measured the integrated EMG (IEMG) during chair stepping exercise. They asked their subjects to perform the exercise with one leg raising the body and the contralateral leg lowering the body. Fewer motor units were recruited during eccentric exercise and, unlike the concentric leg, the IEMG rose progressively during the eccentric exercise. They concluded that "the fact that greater tension per muscle fibre is generated under eccentric contraction conditions provides a situation where relatively few fibres are recruited and are producing relatively large forces" (p. 60). It thus appears that when an individual performs eccentric exercise that he or she is not accustomed to, there is far greater forcelfiber than during concentric exercise producing similar amounts of force. Increased circulating CK activity has been used by many investigators as an indicator of skeletal muscle damage (9, 17, 20, 36). The magnitude and duration of the increase is affected by the type and intensity of the activity and the previous level of the subjects' activity. Downhill running (45 min, 57% VO,max, -10% incline) caused a 351 % increase in circulating CK activity whereas level running caused no change. Evans et al. (17) saw a large fifty-fold average increase in circulating CK activity in sedentary men following only 45 minutes of eccentric cycling (250 W); this increase did not return to preexercise levels until 11 days following the exercise. Endurance trained runners performing the same exercise showed only an average twofold increase for only 24 hours after the exercise. The preexercise circulating CK activity of the runners in this study was significantly greater than that seen in the sedentary men. One single bout of eccentric exercise will reduce the DOMS and elevation in circulating CK activity for up to 6 weeks in previously sedentary subjects following subsequent bouts of eccentric exercise (5). This "protection" against further eccentric exercise-induced damage may result from an increased number of muscle fibers recruited, so that the ratio of force to fiber is reduced. Komi and Buskirk (29) demonstrated that during eccentric exercise training the IEMG showed a linear, significant increase while the IEMG of concentric and isometric exercise did not change. An alternative hypothesis was proposed by Newham et al. (36), who speculated that the dramatically reduced enzyme efflux in response to a second exposure to eccentric exercise is due to the elimination of weak or susceptible muscle fibers by the first exposure. There is a large intersubject variability in the rise in circulating CK activity (9, 10, 16, 37), however, indicating that CK is not an accurate predictor of skeletal muscle damage. Subjects who appear to be quite similar when performing the same amount of eccentric exercise can have changes in circulating CK activity that are different by orders of magnitude. Clarkson and Ebbeling (10) pointed out that the increase in circulating CK is "unrelated to either the development of muscle soreness, the amount of strength loss after exercise, fitness level of the subject, or lean body weight" (p. 257). Manfredi et al. (31) found no difference in circulating CK response following high intensity eccentric

3 216 / Evans exercise that produced very different amounts of skeletal muscle damage as assessed by electron and light microscopy of muscle biopsies, even when circulating CK was corrected for total muscle mass. It is quite likely that the postexercise rise in circulating CK activity is a manifestation of skeletal muscle damage but not a direct indicator of it. Ultrastructural Damage Running a marathon can cause extensive skeletal muscle damage (25, 46). Warhol and co-workers (46) showed a characteristic pattern of muscle damage, with tearing of sarcomeres at the Z-band level followed by movement of fluid into the muscle cells in biopsies taken in the days following the race. Mitochondrial and myofibrillar damage showed progressive repair by 3 to 4 weeks after the marathon. Late biopsies (8 to 12 weeks after the race) showed central nuclei and satellite cells characteristic of a regenerative response. The damage seen by these investigators is very similar to the ultrastructural changes in skeletal muscle resulting from eccentric exercise. The extent of the ultrastructural evidence of damage is greater well after the initial damaging exercise. Friden et al. (19) found more damaged muscle fibers 3 days after when compared to those seen only 1 hour after high tension eccentric exercise. Newham and co-workers (38) also showed that eccentric exercise caused immediate damage but that biopsies taken 24 to 48 hours after the exercise showed more marked damage. These data are indicative of an ongoing process of skeletal muscle repair consisting of increased degradation of damaged proteins and increased rate of protein synthesis. Metabolic Events Following Eccentric Exercise Following one bout of high intensity eccentric exercise (17), previously sedentary men show a prolonged increase in the rate of muscle protein breakdown, evidenced by an increase in urinary 3-methylhistidinelcreatinine which peaked 10 days later. In addition, we measured an increase in circulating interleukin-1 (IL-I) levels in these subjects 3 hours after the exercise. Endurance trained men, performing the same exercise, did not display increased circulating IL-1 levels. However, their preexercise plasma IL-1 levels were significantly higher than those seen in the untrained subjects. Damage to tissue as well as infection itself stimulates a wide range of defense reactions, known as the acute phase response (28). The acute phase response is critical for its antiviral and antibacterial actions as well as promoting the clearance of damaged tissue and subsequent repair. Within hours of injury or exercise (8), the number of circulating neutrophils can increase manyfold. Neutrophils migrate to the site of injury where they phagocytize tissue debris and release factors known to increase protein breakdown such as lysozymes and oxygen radicals (2). Greater neutrophil increases have been observed after eccentric exercise than after concentric exercise (44). While neutrophils have a relatively short halflife (1 or 2 days within tissue) (3), the life span of monocytes may be 1 to 2 months after migration to damaged tissue (26). Substantial monocyte accumulation in skeletal muscle was found after completion of a marathon. Following eccentric

4 Muscle Damage: Nutritional Considerations exercise, monocyte accumulation in muscle was not seen until 4 to 7 days later (27,42). In addition to the capability to phagocytize damaged tissue, monocytes secrete cytokines such as IL-1 and tumor necrosis factor (TNF). These and other cytokines mediate a wide range of metabolic events, having an effect on virtually every organ system in the body. Elevated cytokine levels during infection or injury have different and selective effects. IL-1 mediates an elevated core temperature during infection (7). In laboratory animals IL-1 and TNF increase muscle proteolysis and liberation of amino acids (34), possibly providing substrates for increased hepatic protein synthesis. While circulating IL-1 has been shown to increase acutely as a result of eccentric exercise (17), by 24 hours after the exercise it returns to resting levels. Biopsies of the vastus lateralis taken before, immediately after, and 5 days after downhill running showed an immediate and prolonged increase in IL-1B (6). This study implicates muscle IL-1B in the postexercise change in protein metabolism. Protein Metabolism Eccentric exercise-induced increases in muscle hydrolase activity (45), intracellular Ca2+ (14), IL-lb, and urinary 3-methylhistidine levels indicate that muscle protein turnover is also increased. Fielding et al. (18) used a primed, constant infusion of 1-13C-leucine before as an indicator of whole-body protein metabolism, immediately after, and 10 days after a single bout of high intensity eccentric exercise in previously sedentary old and young men. They found that leucine oxidation and flux were significantly elevated (compared to preexercise samples) at both postexercise time points, indicating a prolonged increase in protein turnover. These results tend to support those showing that previously sedentary young men consuming 1 g proteinokg-'*day-' showed an increased urinary nitrogen excretion and a prolonged period of negative nitrogen balance when beginning a vigorous exercise program (24). These studies indicate that the need for dietary protein may be high at the beginning of training. Frontera et al. (23) demonstrated that older (ages years) sedentary men have the capacity to significantly increase both the size and strength of their muscles. Using a progressive resistance training (PRT) program (80% of the 1- repetition max, 3 days a week, 12 weeks), Frontera et al. demonstrated that muscle hypertrophy was associated with a significant posttraining elevation in urinary 3-methylhistidinelcreatinine. This PRT program had a substantial eccentric component, which almost certainly resulted in significant damage in the knee extensor and flexor muscles. Half of the men who participated in this study were given a daily proteinlcalorie supplement (S) providing an extra 560f 16 kcallday (16.6% protein, 43.8 % carbohydrate, and 40.1 % fat) in addition to their normal ad lib diet. The rest of the subjects received no supplement (NS) and consumed an ad lib diet. By the 12th week of the study, dietary calorie (2, in S vs. 1,620_+80 kcal in NS) and protein (1 18k 10 in S vs g/day in NS) intake was significantly different between the S and NS groups. Composition of the midthigh was estimated by computerized tomography and showed that the S group had greater gains in muscle than did the NS men (Figure 1). In addition, urinary creatinine excretion was greater at the end of the

5 218 1 Evans Supplemented Control Figure 1 - Relative increases in muscle mass as assessed by computerized tomagraphy after 12 weeks of progressive resistance training, showing a greater gain in muscle mass in the supplemented men (P<0.05). Supplemented men received 560 f 16 kcallday (16.6% protein, 43.8% carbohydrate, and 40.1% fat) in addition to their normal ad lib diet. The control subjects consumed an ad lib diet with no supplement (32)- training in the S group than in the NS group (32), indicating a greater muscle mass in the S group. There was no difference in strength gains between the two groups. Exercise has been shown to cause an increase in the need for dietary protein in endurance trained men. Using nitrogen balance to estimate dietary protein requirement, Meredith et al. (33) found that habitual endurance exercise was associated with dietary protein needs greater than the current recommended dietary allowance of 0.8 kg- '*day-' and averaged g kg-' *day-'. Protein requirements expressed as a percent of energy needs (averaging 3,910f 240 kcallday) showed that these subjects needed only 6.9f 0.5% of total dietary calories as protein. This suggests that well trained individuals consuming an average American diet (12-15 % protein) and adequate amounts of energy are not likely to have an inadequate dietary protein intake. However, Nelson et al. (35) have also shown that amenorrheic athletes reported consuming low amounts

6 Muscle Damage: Nutritional Considerations of calories (1, kcal) and protein (0.7f 0.1 g-kg-'-day-'), implicating inadequate dietary calories andlor protein as a cause of athletic amenorrhea. Carbohydrate Metabolism The importance of skeletal muscle glycogen as a substrate for energy metabolism during exercise is well known. Muscle glycogen depletion during exercise is associated with the onset of fatigue, and for this reason a diet rich in carbohydrate has been the basis of most dietary recommendations for endurance athletes. Concentric exercise stimulates a rapid increase in muscle glycogen stores during recovery (4), which is most likely the result of increased sensitivity of the exercised muscles to insulin and a concomitant increase in glucose transport. This phenomenon has been termed glycogen supercompensation. However, exercise that results in muscle damage may also result in impaired glycogen synthesis. An association has been described between delayed ultrastructural muscle damage and impaired glycogen repletion in marathon runners consuming a high carbohydrate diet before and after the race (43). Twenty-four hours after running a marathon, muscle glycogen levels were depleted to 40% of precompetition levels. Five days after the race, glycogen stores returned to normal levels for trained runners; however, they were still only 67% of prerace levels. This is despite the fact that muscle glycogen synthase levels were normal and the subjects did not exercise and consumed a high carbohydrate diet following the race. Kuipers et al. (30) examined well-trained cyclists and found that 24 hours after 30 minutes of eccentric exercise, muscle glycogen levels were below preexercise values. O'Reilly et al. (40) examined the effects of 45 minutes of eccentric exercise on muscle glycogen levels immediately after and 10 days after the exercise. The glycogen content of the 10-day postexercise biopsy was rnrnollkg wet wt, which was significantly lower than the resting preexercise level and not different from the immediate postexercise level (Figure 2). This lack of glycogen repletion was seen despite the fact that these subjects did not exercise for the 10-day postexercise period and consumed a diet that was relatively high in carbohydrate (54% of total calories). Costill et al. (11) examined the effects of varying dietary carbohydrate intake following high intensity eccentric exercise and found that while a higher carbohydrate intake increased the amount of glycogen synthesized, 3 days after the exercise the muscle glycogen stores were consistently lower than those seen in the contralateral leg, which was only exercised concentrically. O'Reilly et al. (40) have speculated that this delay in the restoration of muscle glycogen is likely due to a decrease in insulin sensitivity. Eccentric exercise causes damage to the sarcolemma (21, 22, 40), and it is likely that this alteration in membrane integrity decreases the rate of insulin-stimulated glucose transport. Glucose transport into the muscle cell has been shown to be the ratelimiting step in glucose utilization in resting muscle following exercise, and thus could result in decreased glucose availability in the cell for glycogen resynthesis (15,41). These studies indicate that muscle requires a prolonged period of time to recover from damage and that athletes should be cautious about competing too soon after an event that may have caused damage.

7 220 / Evans Pre I-Post IOD-Post Figure 2 - Skeletal muscle glycogen levels from subjects before, immediately after, and 10 days after 45 minutes of high intensity eccentric exercise (250 W). There was a prolonged glycogen depletion following the exercise (40). *Significantly different from preexercise levels (P<0.05). Vitamin E Our laboratow has recentlv examined the effects of vitamin E on exerciseinduced muscie damage in old and young men (8). It was our hypothesis that eccentric exercise results in an increase in the production of neutrophil-generated oxygen radicals and causes the exercise-induced increase (12, 13) in lipid peroxidation. We expected that increased rates of lipid peroxidation would then contribute to increased membrane permeability and increased leakage of muscle proteins. Because of the well-known properties of vitamin E as an antioxidant and oxygen radical scavenger, it might reduce the eccentric exercise-caused increase in circulating CK activity. We examined older (55 to 74 years old) and young (22 to 29 years old) subjects after they received 800 IU of vitamin E for 48 days in a double-blind placebo controlled fashion. The subjects ran downhill on an inclined treadmill (-16% grade) for 45 minutes. The results were contrary to our expectations. There was a clear difference in CK release and neutrophilia between the young and older placebo groups, with the young subjects demonstrating a significantly

8 Muscle Damage: Nutritional Considerations greater circulating CK activity and neutrophil count following the eccentric exercise. However, vitamin E affected only the older subjects by increasing their responses, eliminating the differences between the two age groups. At the time of peak concentrations in the plasma, CK correlated (r =0.75 1, P<0.001) with superoxide release from neutrophils. The association of this circulating skeletal muscle enzyme with neutrophil mobilization and function supports the concept that neutrophiis are involved in the delayed increase in muscle membrane permeability after damaging exercise. These data indicate that vitamin E supplementation may affect the rate of repair of skeletal muscle following muscle damage and that these effects may be more pronounced in older subjects. Summary Exercise-induced skeletal muscle damage can have profound and longlasting whole-body and localized metabolic effects. These effects include prolonged muscle protein breakdown, whole-body nitrogen loss, and low muscle glycogen stores. The initiation of a vigorous exercise program for previously sedentary individuals or increasing training intensity will almost certainly increase the need for dietary protein. This increased need for protein results from increased muscle and whole-body protein turnover as well as increased oxidation of amino acids during and following exercise. In addition, since recovery of muscle glycogen stores requires a prolonged period of time following damaging exercise, sufficient recovery time should be allowed before resuming intense training or competition. This period of time may be highly variable (perhaps 2 to 12 weeks) from individual to individual, depending on the state of conditioning, amount of muscle damage, and nutritional habits of the athlete. References 1. Asmussen, E. Observations on experimental muscular soreness. Acta Rhum. Scand. 2: , Babior, B.M., R.S. Kipnes, and J.T. Curnutte. The production by leukocytes of superoxide, a potential bactericidal agent. J. Clin. Invest. 52: , Bainton, D.F. Phagocytic cells: Developmental biology of neutrophils and eosinophils. In Inflammation: Basic Principles and Clinical Correlates, J.I. Gallin, I.M. Goldstein, and R. Snyderman (Eds.), New York: Raven Press, 1988, pp Bergstrom, J., and E. Hultman. Muscle glycogen synthesis after exercise: An enhancing factor localized to the muscle cells in man. Nature, London. 210: , Byrnes, W.C., P.M. Clarkson, J.S. White, S.S. Hsieh, P.N. Frykman, and R.J. Maughan. Delayed onset muscle soreness following repeated bouts of downhill running. J. Appl. Physiol. 59: , Cannon, J.G., R.A. Fielding, M.A. Fiatarone, S.F. Orencole, C.A. Dinarello, and W.J. Evans. Interleukin-1S in human skeletal muscle following exercise. Am. J. Physiol. 257:R45 1-R455, Cannon, J.G., and M.J. Kluger. Endogenous pyrogen activity in human plasma after exercise. Science 220: , 1983.

9 222 1 Evans 8. Cannon, J.G., S.F. Orencole, R.A. Fielding, M. Meydani, S.N. Meydani, M.A. Fiatarone, J.B. Blumberg, and W.J. Evans. The acute phase response in exercise: Interaction of age and vitamin E on neutrophils and muscle enzyme release. Am. J. Physiol. 259:R1214-R1219, Clarkson, P.M., W.C. Byrnes, K.M. McCormic, and P. Triffletti. Muscle soreness and serum creatine kinase activity following isometric eccentric and concentric exercise. Int. J. Sports Med , Clarkson, P.M., and C. Ebbling. Investigation of serum creatine kinase variability after muscle damaging exercise. Clin. Sci. 75: , Costill, D.L., D.D. Pascoe, W.J. Fink, R.A. Robergs, S.I. Barr, and D. Pearson. Impaired muscle glycogen resynthesis after eccentric exercise. J. Appl. Physiol. 69:46-50, Davies, K.J.A., L. Packer, and G.A. Brooks. Free radicals and tissue damage produced by exercise. Biochem. Biophys. Res. Comm. 107: , Dillard, C.J., R.E. Litov, W.M. Savin, E.E. Dumelin, and A.L. Tappel. Effects of exercise, vitamin E, and ozone on pulmonary function and lipid peroxidation. J. Appl. Physiol. 45: , Duan, C., M.D. Delp, D.A. Hayes, P.D. Delp, and R.B. Armstrong. Rat skeletal muscle minochondrial [CA2+] and injury from downhill walking. J. Appl. Physiol. 68: , Elbrink, J., and I. Bihler. Membrane transport: Its relation to cellular metabolic rates. Science 188: , Evans, W.J. Exercise and muscle metabolism in the elderly. In Nutrition and Aging, M.L. Hutchinson and H.N. Munro (Eds.), San Diego: Academic Press, 1986, pp Evans, W. J., C.N. Meredith, J.G. Cannon, D.A. Dinarello, W.R. Frontera, V.A. Hughes, B.H. Jones, and H.G. Knuttgen. Metabolic changes following eccentric exercise in trained and untrained men. J. Appl. Physiol. 61 : , Fielding, R.A., C.A. Meredith, K.P. O'Reilly, W.R. Frontera, J.G. Cannon, and W.J. Evans. Enhanced protein breakdown following eccentric exercise in young and old men. J. Appl. Physiol. In press. 19. Friden, J., J. Seger, M. Sjostrom, and B. Ekblom. Adaptive response in human skeletal muscle subjected to prolonged eccentric training. Int. J. Sports Med. 4: , Friden, J., P.N. Sfakianos, and A.R. Hargens. Blood indices of muscle injury associated with eccentric muscle contractions. J. Orth. Res. 7: , Frideu, J., M. Sjostrom, and B. Ekblom. A morphological study of delayed muscle soreness. Experientia , Friden, J., M. Sjostrom, and B. Ekblom. Myofibrillar damage following eccentric exercise in man. Znt. J. Sports Med. 4: , Frontera, W.R., C.N. Meredith, K.P. O'Reilly, H.G. Knuttgen, and W.J. Evans. Strength conditioning in older men: Skeletal muscle hypertrophy and improved function. J. Appl. Physiol. 64: , GonFea, I., P. Sutzescu, and S. Dumitrache. The influence of muscle activity on nitrogen balance and the need of man for proteins. Nutr. Rep. Int. 10:35-43, Hikida, R.S., R.S. Staron, F.C. Hagerman, W.M. Sherman, and D.L. Costill. Muscle fiber necrosis associated with human marathon runners. J. Neuro. Sci. 59: , Johnston, R.B. Monocytes and macrophages. N. Engl. J. Med. 318: , 1988.

10 Muscle Damage: Nutritional Considerations Jones, D.A., D. J. Newham, J.M. Round, and S.E. J. Tolfree. Experimental human muscle damage: Morphological changes in relation to other indices of damage. J. Physiol. (London). 375: , Kampschrnidt, R. Leukocytic endogenous mediatorlendogenous pyrogen. In The Physiologic and Metabolic Responses of Ihe Host, M.C. Powanda (Ed.), Amsterdam: ElsevierINorth Holland, 1981, pp Komi, P.V., and E.B. Buskirk. Effect of eccentric and concentric muscle conditioning on tension and eletrical activity of human muscle. Ergonomics , Kuipers, H., H.A. Keizer, F.T.J. Verstappen, and D.L. Costill. Influence of a prostaglandin-inducing drug on muscle soreness after eccentric work. Znt. J. Sports Med. 6: , Manfredi, T.G., R.A. Fielding, K.P. O'Reilly, C.N. Meredith, H.Y. Lee, and W.J. Evans. Serum creatine kinase activity and exercise-induced muscle damage in older men. Med. Sci. Sports Exer. In press. 32. Meredith, C.N., W.R. Frontera, and W.J. Evans. Effect of diet on body composition changes during strength training in elderly men. J. Am. Geriatr. Soc. In press. 33. Meredith, C.N., M.J. Zackin, W.R. Frontera, and W.J. Evans. Dietary protein requirements and body protein metabolism in endurance-trained men. J. Appl. Physiol. 66: , Nawabi, M.D., K.P. Block, M.C. Chakrabarti, and M.G. Buse. Administration of endotoxin, tumor necrosis factor, or interleukin 1 to rats activates skeletal muscle branched-chain a-keto acid dehydrogenase. J. Clin. Invest. 85: , Nelson, M.E., E.C. Fisher, P.D. Catsos, C.N. Meredith, R.N. Turksoy, and W.J. Evans. Diet and bone status in amenorrheic runners. Am. J. Clin. Nutr. 43: , Newham, D.J., D.A. Jones, and P.M. Clarkson. Repeated high-force eccentric exercise: Effects on muscle pain and damage. J. Appl. Physiol. 63: , Newham, D.J., D.A. Jones, and R.H.T. Edwards. Large delayed plasma creatine kinase changes after stepping exercise. Muscle Nerve 6: , Newham, D.J., G. McPhail, K.R. Mills, and R.H.T. Edwards. Ultrastructural changes after concentric and eccentric contractions of human muscle. J. Neur. Sci. 61: , Newharn, D. J., K. R. Mills, B.M. Quigley, and R.H.T. Edwards. Pain and fatigue after concentric and eccentric muscle contractions. Clin. Sci , O'Reilly, K.P., M.J. Warhol, R.A. Fielding, W.R. Frontera, C.N. Meredith, and W.J. Evans. Eccentric exercise-induced muscle damage impairs muscle glycogen repletion. J. Appl. Physiol. 63: , Richter, E., L. Garetto, M. Goodman, and N. Ruderman. Muscle glucose metabolism following exercise in the rat. J. Clin. Invest. 69: , Round, J.M., D.A. Jones, and G. Cambridge. Cellular infiltrates in human skeletal muscle: Exercise induced damage as a model for inflammatory muscle disease? J. Neurol. Sci , Sherman, W., D. Costill, W. Fink, F. Hagerman, L. Armstrong, and T. Murray. Effect of 42.2-km footrace and subsequent rest or exercise on muscle glycogen and enzymes. J. Appl. Physiol. 55: , Smith, L.L., M. McCammon, S. Smith, M. Charnness, R.G. Israel, and K.F. O'Brien. White blood cell response to uphill walking and downhill jogging at similar metabolic loads. Eur. J. Appl. Physiol. 58: , 1989.

11 224 1 Evans 45. Vihko, V., A. Salrninen, and J. Rantarnaki. Exhaustive exercise, endurance training, and acid hydrolase activity in skeletal muscle. J. Appl. Physiol. 47:43-50, Warhol, M.J., A.J. Siegel, W.J. Evans, and L.M. Silverman. Skeletal muscle injury and repair in marathon runners after competition. Am. J. Pathol. 118: ,1985. Acknowledgments This project has been funded at least in part with federal funds from the U.S. Department of Agriculture, Agricultural Research Service, under contract no. 53-3K , and by grants from Ross Laboratories and Hoffmann-La Roche. The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.