Protein and Amino Acids, 1999
Pp. 279-284. Washington, D.C.
National Academy Press
Alterations in Protein Metabolism Due to the Stress of Injury and Infection
Robert R. Wolfe1
During severe injury or infection an overall metabolic response occurs that results in a loss in lean body mass. However, each tissue has a specific response that may be unique, and net protein synthesis may even be increased in some tissues. Thus, protein synthesis is accelerated in the liver (for the production of acute phase proteins), the immune system, and wound repair requires rapid protein synthesis. The catabolic response largely occurs in the skeletal muscle. Over a short period of time, the muscle has an adequate reserve of protein to maintain normal function despite accelerated catabolism. However, when the catabolic response is extended over several days or weeks, severe debilitation can occur. This is reflected by the fact that currently only 50 percent of patients
discharged from an intensive care unit return to normal function, including work, within 2 years (Bams and Miranda, 1985). The persistent disability following severe burn injury is also well documented (Chang and Herzog, 1976). Although many factors may contribute to these statistics, loss of muscle strength and function is central to the problem of rehabilitation. This chapter interprets the goal of nutritional and metabolic support during acute hospitalization following severe injury and the period immediately following discharge to be a rapid return to normal physiological function. Therefore, the focus here will be on the response of muscle.
The net synthesis or catabolism of muscle protein depends on the balance between the rate of protein synthesis and breakdown. The precursors for protein synthesis are derived from either protein breakdown or from transmembrane transport from the plasma. The amine acids resulting from protein breakdown can either be re-incorporated into protein or released into plasma. Exogenous amine acids given in nutrition can only be incorporated into protein after being transported into the muscle cells from the blood. Thus, the processes of protein synthesis, breakdown, and transmembrane amine acid transport are linked, and it is necessary to evaluate the response to stress by quantifying these three related processes. Consequently, results will be presented from a technique involving the infusion of tracer amounts of amine acids labeled with heavy stable isotopes of carbon (13C) or hydrogen (2H) and sampling from the femoral artery and vein and from the intramuscular pool of the vastus lateralis (obtained by biopsy) (Biolo et al., 1995a). This approach allows quantification of transmembrane transport rate of various amine acids, as well as the rates of muscle protein synthesis and breakdown.
The negative protein balance caused by severe injury results from a large increase in the rate of protein breakdown. Although synthesis is also increased, the increase is insufficient to offset the increased rate of breakdown. The increase in muscle protein breakdown is coupled with an increase in the outward transport of amine acids, which is consistent with the role of the muscle to provide amine acid precursors for synthesis elsewhere in the body. The negative amine acid balance persists across the muscle even for a person in the fed state. Furthermore, increasing the amount of protein intake has no effect on the rate of muscle protein synthesis.
The alteration in transport kinetics across the muscle cell membrane may be central in the altered muscle protein kinetics. The inward transport of phenylalanine and leucine in severely burned patients is less than half the normal rate. This explains the inefficiency of amine acid or protein intake in stimulating synthesis, because the exogenous amine acids must enter the cells before they can be incorporated into protein. This point can be seen clearly in the case of glutamine. The intramuscular glutamine concentration is decreased in severely burned patients to about one-third its normal value. This is in large part due to an accelerated rate of outward transport, as the intracellular appearance from protein breakdown is double the normal rate and de novo
synthesis is not markedly suppressed. Nonetheless, the infusion of glutamine directly into the femoral artery of adult burn patients did not increase the intramuscular concentration of glutamine, despite a three-fold increase in the femoral venous concentration of glutamine.
Because of the altered amino acid transmembrane kinetics, it is clear that greater-than-normal protein intake is not effective in curtailing the catabolic response of muscle (Patterson et al, 1997). Therefore, there is no reason to believe that more than 100 g/d of protein will provide any additional benefit. However, with regard to the question of whether protein requirements increase with military operational stressors and what is the optimum protein intake, it is nevertheless clear that protein requirements have increased. This is because normal protein intake is insufficient to alleviate catabolism. Further, it is possible that an optimal formulation of amino acids would be beneficial (Sakurai et al, 1995). However, given the deficiencies in inward transport, it is unlikely any amount or particular mix of amino acids would make any difference without concurrent manipulation of the metabolic state of the tissue. In this author's experience, these observations apply equally to men and women. However, it is possible that metabolic manipulation with hormone therapy could make the muscle more responsive to the stimulatory effect of amino acids on protein synthesis, thereby providing a rationale for increasing protein intake and optimizing the formulation of an amino acid mixture.
The anabolic action of growth hormone on muscle in children is well established. The acute, intravenous infusion of growth hormone in burned children has been shown to increase muscle protein synthesis to the same extent as a pharmacological dose of insulin, but the effect of the two hormones was not additive (Gore et al., 1991). The effect of growth hormone on adult muscle protein metabolism is less clear. It has been recently shown that growth hormone replacement in growth hormone-deficient adults increased lean body mass after six months, but not after 1 month, of growth hormone supplementation (Solomon et al., 1989). However, it is not clear that this response reflected increased muscle mass, and in fact it could have been due to water retention. In contrast, a period of 5 days of growth hormone treatment in normal volunteers receiving a diet containing only 50 percent of caloric requirement induced a switch from a negative, whole-body N balance to a positive, whole body N balance (Manson and Wilmore, 1986). Furthermore, N balance improved in some (e.g., Wilmore et al., 1974), but not all (e.g., Belcher et al., 1989) studies in which growth hormone was administered to burn patients. However, none of these studies assessed the effect of growth hormone on muscle per se. The only studies in which muscle protein synthesis was directly measured failed to show an effect of growth hormone either in normal (Yarasheski et al., 1993b) or elderly volunteers (Yarasheski et al., 1995).
Insulin is the most important anabolic hormone on an hour-to-hour basis in normal human physiology. Local hyperinsulinemia to an extent comparable to that achieved during a normal meal caused a significant increase in muscle protein synthesis and inward transmembrane transport of phenylalanine (Sakurai et al., 1995). To extend this observation to the clinical setting, severely burned adults were infused for 7 days at a rate high enough to maintain plasma insulin concentrations of approximately 500 μU/ml. Additional glucose was given as needed to maintain euglycemia. Patients were studied according to a crossover design, with half of the patients receiving the insulin therapy in the fast week, and half receiving the insulin therapy in the second week. Patients were used as their own controls and were studied in the fed state. Insulin therapy reversed the negative amine acid balance across the muscle, primarily by stimulating muscle protein synthesis. Paradoxically, protein breakdown also increased, thereby blunting the net anabolic effect of insulin. It is possible that the stimulation of protein synthesis exceeded the availability of intracellular amine acids, leading to an acceleration of protein breakdown in order to maintain the intracellular pools. If this was the case, it may be that in severely burned patients, an increased intake of amine acids might be more effective during insulin therapy than when insulin is not given, particularly since insulin greatly stimulated the rate of inward amine acid transport. However, the interaction of insulin therapy and the amount of amine acid or protein intake has not been investigated.
In patients given the control diet the first week and insulin therapy the second week, growth hormone was given throughout the third week, without interruption of the insulin. No additional effect of growth hormone beyond that elicited by insulin was observed (Sakurai et al., 1995).
Testosterone is well known for its ability to stimulate muscle anabolism in normal subjects when taken in large doses. However, testosterone is also effective in stimulating muscle protein synthesis when given to normal volunteers in an amount sufficient to increase the plasma concentration to the high-normal range. The effect of testosterone is likely to be exerted on the transcription of mRNA, as suggested by the observations of a significant increase in muscle protein synthesis observed 5 days after the intramuscular injection of 200 mg, while no effect was observed during the intravenous infusion of the same amount of testosterone over 5 hours (Ferrando, et al, 1998). Transcriptional effects are likely to take days to be effective. The effectiveness of testosterone in critically ill or rehabilitating patients is unknown, but it is pertinent that in adult male burn patients the serum concentration of testosterone is reduced more than 80 percent below the normal control value. Further, it is possible that an interactive effect between testosterone and insulin might be anticipated, since they appear to operate via different mechanisms. However, this possibility remains unexplored.
AUTHOR'S CONCLUSIONS AND RECOMMENDATIONS
The catabolic response of muscle is characterized by an outward efflux of amino acids from muscle that minimizes the effectiveness of any nutritional protocol. It is therefore reasonable to explore the interaction of hormonal and nutritional therapy. In adult patients, only insulin therapy has been shown to stimulate muscle protein synthesis, but results from normal volunteers given testosterone are quite promising. Future areas of investigation should involve quantification of hormonal effects on muscle, and interactive effects between hormones and diet. Thus, it is possible that whereas a higher than normal protein intake in injured patients normally doesn't provide an added benefit beyond that achieved with a normal intake, a higher protein intake becomes beneficial when the system is ''primed" by testosterone and/or insulin therapy.
Based on currently available data, a diet is recommended for severely injured patients of 1.5 g protein/kg day, with carbohydrate given at a rate that supplies approximately the caloric equivalent of the resting energy expenditure. Fat should be given only as needed to avoid fatty acid deficiency (approximately 2 percent of daily caloric intake). Exogenous insulin should be given to maintain euglycemia. Men and women should be given the same treatment, and it is unlikely the particular source of protein is important provided that it has a reasonable balance of essential amino acids.
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