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The Journal of Nutrition Vol. 128 No. 2 February 1998,
pp. 356S-359S
Departments of Surgery and * Medicine, State University of New York, Stony Brook, NY 11794
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ABSTRACT |
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Abstract
Introduction
References
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This paper examines the role of hormones in the normal responses of muscle protein synthesis to nutrient intake and the use of hormones to improve the effects of nutritional therapies in patients with protein-wasting conditions. In growing rats, the increase in muscle protein synthesis after feeding seems to be mediated by the rise in plasma insulin and also by an enhanced sensitivity of the muscle to insulin brought about by the amino acid leucine. In adult rats, however, the responsiveness of muscle to both feeding and insulin is much reduced, suggesting that changes in protein degradation play an important role in the response to feeding. Similarly, in adult humans, muscle protein synthesis is not affected by insulin, but is stimulated by insulin-like growth factor (IGF)-I and growth hormone (GH). The effect of GH treatment has been studied in a number of different groups of patients suffering from protein wasting, and improvements in nitrogen balance and lean body mass have been reported. In a study of patients with acquired immunodeficiency syndrome (AIDS), however, GH treatment for 2 wk caused a fall in muscle protein synthesis in the patients with wasting, despite an increase in healthy controls, suggesting that the responsiveness of muscle to the hormone may be altered by the stage of the disease.
KEY WORDS: protein synthesis · insulin · growth factors · rats · humans
At present, there is considerable interest in modulating protein metabolism with hormones to enhance the effect of nutritional therapies in protein-wasting medical conditions such as surgical trauma, sepsis and acquired immunodeficiency syndrome (AIDS).3 Nutritional support alone is insufficient to prevent the protein loss, mainly from skeletal muscle, associated with infection and inflammation (Garlick and Wernerman 1997 During nutrient absorption, amino acids are taken up by muscle and retained as muscle protein. Measurements of muscle protein synthesis rates in young rats have shown that 12 h of food deprivation results in a 40% fall in the rate of protein synthesis, with rapid restoration within 1 h of a meal (Garlick et al. 1983
Effects similar to those of insulin on muscle protein synthesis are observed with insulin-like growth factor (IGF-I). The data in Figure 1 were obtained in adult mice that were fed, postabsorptive (12 h), or postabsorptive and infused with insulin, IGF-I or saline (control). The figure shows that both insulin and IGF-I restore the rate of muscle protein synthesis in fasted animals to that seen in the fed group. Previous experiments, with a 3-h period between injection of insulin or IGF-I and measurement of protein synthesis, showed smaller stimulations, probably because of the short half-lives of these hormones in the circulation (Sandström et al. 1995
INTRODUCTION
Abstract
Introduction
References
). In this article, we will first examine the role of hormones, especially insulin, in the normal response of muscle protein synthesis and degradation to nutrient intake. Second, we will describe the effects of the growth factors, insulin-like growth factor-I (IGF-I) and growth hormone (GH), on muscle protein synthesis and discuss their use to promote protein retention in wasting diseases.
MEDIATORS OF THE RESPONSE
TO NUTRIENT INTAKE
). Because insulin is the prominent hormone controlling the metabolism of carbohydrate and fat after a meal, its role in the stimulation of protein synthesis by feeding has been investigated. Experiments on isolated muscle in vitro have shown that insulin can stimulate protein synthesis and inhibit protein degradation (Fulks et al. 1975, Jefferson et al. 1974). Moreover, injection of a single dose of insulin (100 mU) into fasting rats in vivo also stimulated muscle protein synthesis, but only transiently (Garlick et al. 1992). When insulin levels were maintained by intravenous infusions of insulin, the stimulation of muscle protein synthesis was prolonged (>1 h) even without the provision of additional nutrients (Garlick et al. 1983). The magnitude of stimulation was similar to that produced by feeding; in addition, it could be blocked by injection of anti-insulin serum (Preedy and Garlick 1986), suggesting that insulin might be mediating the response to nutrient intake. However, infusion of insulin at a rate that resulted in a plasma insulin concentration comparable to that of the fed animal gave no stimulation of protein synthesis: a twofold higher concentration of the hormone was required for the effect on protein synthesis (Garlick et al. 1983). Further studies showed that this insensitivity to insulin in fasting animals could be alleviated by infusion of amino acids together with the insulin (Garlick and Grant 1988), with most of the effect attributable to the branched-chain amino acids, particularly leucine (Garlick and Grant 1988, Garlick et al. 1992). The conclusion from this series of experiments was that the stimulation of muscle protein synthesis by feeding in the young rat is mediated by an increase in insulin secretion plus a leucine-induced increase in the sensitivity of the muscle to insulin.
). Conversely, sensitivity of muscle protein synthesis to food deprivation and refeeding is high during suckling, but declines over the weaning period (Davis et al. 1991 and 1993). These findings have led us to suggest that the sensitivity of muscle protein synthesis to feeding and insulin may be a characteristic of growth, because it is most pronounced during the rapid growth phase and blunted in fully adult animals (Baillie and Garlick 1992, Garlick et al. 1992).
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Fig 2.
Rates of muscle protein synthesis in healthy volunteers and in HIV and AIDS patients, measured after an overnight fast, before and after 2 wk of treatment with GH (6 mg/d). Groups are (left to right) healthy volunteers, HIV+ patients, AIDS patients with <10% weight loss and AIDS patients with >10% weight loss. *Denotes a significant change after GH treatment (P < 0.05).
). Smaller increases in the rate of whole-body protein degradation result in enhanced protein deposition at higher intakes (Mitton and Garlick 1992). By contrast, studies in adult humans have shown that whole-body protein degradation is more sensitive to food intake than is protein synthesis, which shows little change when fasting subjects are fed (McNurlan and Garlick 1989, Melville et al. 1989, Motil et al. 1981).
), appears to be increased in response to feeding (Halliday et al. 1988). However, measurement with an injection of a large amount of [1-13C]leucine (Garlick et al. 1989) indicates no significant change in protein synthesis with feeding (McNurlan et al. 1993). The flooding method, the same approach as that used for measurement in rats (Garlick et al. 1980), was used in these studies because the short period of measurement facilitates the detection of transient changes and minimizes the potential for error due to compartmentation of free amino acid pools within the tissue (Garlick et al. 1994). Conclusions about insulin's effect on human muscle, however, are not method dependent. No change in muscle protein synthesis has been detected in a variety of studies with either method (McNurlan et al. 1994, Gelfand and Barrett 1987, Fryburg et al. 1990, Bennet et al. 1990). In general, therefore, the human studies are consistent with those in rats, showing little effect of feeding or insulin on muscle protein synthesis.
, Svanberg et al. 1996; see Fig. 1). There is no obvious difference in experimental protocol or method to explain why the mouse should be so responsive to food deprivation and refeeding, when rats and humans are not, except that the mouse is ~10-fold smaller that the rat. Although it is tempting to assume that the mouse is more sensitive to nutrient supply because its relatively higher metabolic rate per unit body weight (Brody 1945) will deplete nutrient stores more rapidly during fasting, this explanation is not borne out by studies in small birds (white crowned sparrows, similar in body weight to mice). These birds do not alter muscle protein synthesis over the diurnal cycle (Murphy and Taruscio 1995; Murphy, M. E., personal communication) and even changing the light/dark periods from 6 to 18 h of light per day did not demonstrate that the altered cycle of feeding and fasting influenced muscle protein synthesis. We conclude, therefore, that in adults of a variety of species, including rats, sparrows and humans, the accretion of muscle protein during feeding is achieved more by a depression of protein degradation than by an increase in protein synthesis. Adult mice, by contrast, respond like immature animals of other species, by increasing rates of muscle protein synthesis.
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Fig 1.
Rates of muscle protein synthesis in skeletal muscle of adult mice that were postabsorptive (fasted) or fed, or were postabsorptive and infused with either saline (fasted), insulin or IGF-I for 1 h. Muscle protein synthesis was measured during the last 10 min of infusions. The bars represent mean values ± SEM; *denotes significant differences from control (P < 0.001). Redrawn from Sandström et al. 1995 and Svanberg et al. 1996.
USE OF GROWTH HORMONE AND IGF-I IN TREATMENT OF MUSCLE WASTING DISEASES
, Svanberg et al. 1996).
). In these studies, IGF-I infusion for 6 h caused positive amino acid balance, both by inhibiting protein degradation and stimulating protein synthesis (Fryburg 1994). This differs from the effect of insulin, which does not stimulate synthesis (Bennet et al. 1990, Fryburg et al. 1990, Gelfand and Barrett 1987, McNurlan et al. 1994). Therefore IGF-I possesses the insulin-like property of inhibiting degradation, but in addition can stimulate protein synthesis (Fryburg 1991). This ability of IGF-I to stimulate protein synthesis resembles the action of GH, which was shown in separate studies on volunteers to stimulate protein synthesis without affecting protein degradation (Fryburg et al. 1991, Fryburg and Barrett 1993). Although it is often believed that the effects of GH are mediated through IGF-I, this cannot be the case entirely. First, the effects of the two hormones were different, in that GH did not change protein degradation. Second, the effect of GH was observed with little or no change in systemic IGF-I and GH concentrations because the GH was infused directly into the brachial artery (Fryburg et al. 1991).
). Improvements in nitrogen balance and muscle protein synthesis, measured with stable isotopic tracers, were observed in a study of burned patients treated with GH for 2-3 wk (Gore et al. 1990). However, 3 d of treatment with GH in cancer patients resulted in no improvement in either protein synthesis or protein degradation in the whole body (Wolf et al. 1992).
), and 3 mo of GH treatment resulted in an increase in lean body mass, as measured by bioelectrical impedance (Krentz et al. 1993). However, when AIDS patients were given GH plus IGF-I for 3 wk, no change in either total body potassium or total body nitrogen could be observed (Ellis et al. 1996). Although each of these studies involved weight-losing patients, the results are not consistent. The variability in these results might arise from the different doses of GH given, which ranged from 0.7 to ~6 mg/d. In particular, the study that failed to show differences was the one that employed the lowest dose of GH (although IGF-I was also given; Ellis et al. 1996). In addition, the effect of GH might be time dependent. Lieberman et al. (1994) reported initial nitrogen retention, but only transiently, in AIDS patients treated with IGF-I for 10 d.
). Protein synthesis was measured by flooding with [2H5]phenylalanine followed by blood sampling and muscle biopsy (McNurlan et al. 1994) before and after the 2-wk period of treatment. As shown in Figure 2, the rate of protein synthesis before GH was no different in controls than that in patients who were HIV-positive, had AIDS with no weight loss or had AIDS with >10% weight loss. However, their responses to GH were very different. In the healthy controls, there was a significant increase in protein synthesis after GH, but in patients with AIDS and weight loss, there was a significant decrease. Responses in the HIV-positive and AIDS-without-weight-loss groups were intermediate. The rank correlation between individual changes in protein synthesis and their numerical group assignment (taking controls as group 1 through to AIDS with weight loss as group 4) was highly significant (P < 0.002). This suggests that, as the disease progresses, the response of muscle protein synthesis to GH declines. Moreover, at the most advanced stage of disease, GH actually inhibits muscle protein synthesis.
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Fig 3.
The molar ratio of 3-methylhistidine (3-MH) to creatinine in 24-h urine samples collected before and after 2 wk of treatment with GH (6 mg/d). Groups are as described in Fig. 2. 
Significant change after GH treatment (P < 0.005); *pre-GH values significantly different than those of healthy and HIV+ groups (P < 0.05).
); a lack of sensitivity to GH was not present in this study, however, because the level of response of IGF-I to GH was the same in all groups. The overall conclusion from this study is that the ability of GH to stimulate IGF-I production remains intact in AIDS, but that the response of muscle is altered from an anabolic response in healthy subjects to a catabolic one in AIDS patients with wasting.
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FOOTNOTES |
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LITERATURE CITED |
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Abstract
Introduction
References
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-ketoisocaproate during a L-[113C]leucine infusion in man: a method for measuring human intracellular leucine tracer enrichment.
Metabolism
1982;
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