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Shriners Burns Hospital and University of Texas Medical Branch Galveston, Texas 77550
Address all correspondence and requests for reprints to: R. R. Wolfe, Ph.D., Shriners Burns Institute, 815 Market Street, Galveston, Texas 77550.
Abstract
We have investigated the relationships between the rates of muscle protein synthesis and degradation and of transmembrane transport of selected amino acids in leg skeletal muscle of 19 severely burned patients and 18 normal controls in the postabsorptive state. Patients were studied on the 14 ± 5 postburn day, and their mean burn size was 66% ± 18% of total body surface area. Methods were based on the leg arteriovenous balance technique in combination with biopsies of the vastus lateralis muscle and infusions of isotopic tracers of amino acids. Net muscle protein breakdown was greater in the patients because of an 83% increase in the rate of muscle protein degradation. The rate of muscle protein synthesis was also increased in the patients but to a lesser extent than protein degradation, i.e. by 50% with the arteriovenous phenylalanine balance technique and by 49% with the direct tracer incorporation method. The absolute values of inward transport of phenylalanine, leucine, and lysine were not significantly different in the two groups. However, the ability of transport systems to take up amino acids from the bloodstream, as assessed by dividing inward transport by amino acid delivery to leg muscle, were 50–63% lower in the patients. In contrast, outward phenylalanine and lysine transport were 40% and 67% greater in the patients than in the controls, respectively. We conclude the primary alteration in muscle protein metabolism is an acceleration of protein breakdown, and the increase in protein synthesis likely is due to increased intracellular amino acid availability as a result of accelerated breakdown. Transmembrane transport in the outward direction is accelerated, presumably to facilitate the export of amino acids from muscle to other tissues. In contrast, transmembrane transport in the inward direction is impaired relatively to the increased delivery of circulating amino acid to skeletal muscle secondary to accelerated blood flow.
THE RESPONSE OF skeletal muscle in critical illness is characterized by a rapid decrease in protein content in skeletal muscle and accelerated amino acid release. Studies at the molecular level suggest that in skeletal muscle of acutely ill patients, proteolytic enzymes are up-regulated (1, 2), protein synthetic capacity is impaired at the transcriptional and posttranscriptional levels (3, 4, 5, 6), and amino acid transport system activity is decreased (7, 8, 9, 10). However, when the rates of protein synthesis and degradation were assessed in vivo at the whole-body level by isotopic tracers of amino acids, patients with trauma, sepsis, or burns exhibited parallel increases of the rates of both proteolysis and protein synthesis (11, 12, 13). Such accelerated whole-body protein turnover in acute diseases states is, at least in part, a reflection of interorgan amino acid fluxes from tissues characterized by an increase of net protein breakdown (14) to tissues characterized by an increase of protein synthesis (15, 16, 17, 18). However, it is not known whether the simultaneous accelerations of protein degradation and synthesis observed at the whole-body level can also be observed within an individual tissue such as skeletal muscle (19). Furthermore, the role of transmembrane transport kinetics in the accelerated interorgan amino acid exchange of critically ill patients remains to be established.
To determine the rates of protein synthesis and degradation and of transmembrane transport of selected essential amino acids in skeletal muscle of severely burned patients, we have used techniques based on the arteriovenous catheterization, muscle biopsy, and stable isotopic tracers. Patients were studied in the postabsorptive state during the flow phase after injury, i.e. a relatively stable clinical and metabolic period characterized by elevation in energy expenditure and increased protein catabolism.
Subjects and Methods
Subjects
We studied 18 normal volunteers and 19 patients with severe burns in the postabsorptive state. The volunteers [17 males and 1 female; aged 28 ± 10 (mean ± SD) yr] were considered to be healthy by medical history and physical examination. They were receiving no medications. Their body mass index was 24 ± 2 kg/m2. Leg volume (10,353 ± 1701 ml) was estimated using an anthropometric approach (20). Subjects were admitted to the Clinical Research Center at the University of Texas Medical Branch the morning of the study after an overnight fast.
The patients with burns (16 males and 3 females), ranging in age from 16 to 64 yr (mean ± SD, 31 ± 18 yr), were studied 8–30 d (mean ± SD, 15 ± 11 d) after injury. The proportion of body surface burned ranged from 40% to 92% (mean ± SD, 66% ± 18%). The extent of third-degree burns was 53% ± 29% of total body surface area. Patient’s body mass index was 23 ± 5 kg/m2 and their leg volume was 7366 ± 2427 ml (P < 0.001 vs. normal volunteers). In 13 patients (total body surface burned: 69% ± 19%), burn wounds were present in both legs. In these patients the arteriovenous catheterization of the femoral vessels was performed in the less injured leg (total leg surface burned: 66% ± 18%). Six patients (total body surface burned: 59% ± 12%) did not exhibited burn wound in their legs.
The patients were admitted either to the University of Texas Medical Branch (n = 15) or to the Shriners Burns Hospital in Galveston (n = 4) within 48 h after injury. Fluid resuscitation had been provided, and excision of the burn wound and grafting had been done within 4 d after the injury, as previously described (21). Our studies were performed at least 2 d after the most recent surgical excision. Each patient was maintained in an environmentally controlled room. The patients were studied during a relatively stable clinical and metabolic period when they were ascertained to be in the phase of response generally characterized by elevation in cardiac rate (128 ± 20 beats/min), core temperature (38.3 ± 0.4 C), and metabolic rate (25% ± 8% increase of resting energy expenditure above the expected values calculated with the Harris-Benedict equation). All patients received continuous enteral feeding of milk via a duodenal feeding tube at a rate to provide 7531 kJ/m2 (1800 kcal/m2) of body surface area per day plus 9205 kJ/m2 (2200 kcal/m2) of body surface area burned per day. All forms of nutritional support were stopped 8 h before the start of isotope infusion.
All normal volunteers, patients, or patients’ parents gave informed written consent before participating in the study, which was approved by the Institutional Review Board of the University of Texas Medical Branch at Galveston.
Indwelling catheters were placed in the left antecubital vein of one arm for infusion of isotopes and in the femoral artery and vein of one leg for blood sampling. The femoral arterial catheter was also used for the primed-continuous infusion of Indocyanine green (Becton Dickinson and Co. Microbiology Systems, Cockeysville, MA) to measure leg blood flow (20). Indocyanine green recycling was assessed by measuring dye concentration in the wrist or antecubital vein of the right arm. The patients had the arterial and most of the venous catheters in place for clinical purposes. After obtaining a blood sample for measurement of background amino acid enrichment and indocyanine green concentration, the infusion protocol was initiated. First, a primed-continuous infusion of L-[ring-13C6]phenylalanine (Cambridge Isotope Laboratories, Woburn, MA) followed at 60 min by L-[1-13C]leucine (Cambridge Isotope Laboratories) and L-[2-15N]lysine (Cambridge Isotope Laboratories). Tracer infusions were maintained constant throughout the experiment. The following tracer infusion rates (IRs) and priming doses (PDs) were used in the patients and in the controls: L-[ring-13C6]phenylalanine: IR = 0.075 and 0.050 µmol/kg per min, respectively; PD = 3.0 and 2.0 µmol/kg, respectively; L-[1-13C]leucine: IR = 0.150 and 0.080 µmol/min, respectively; PD = 9.0 and 4.8 µmol/kg, respectively; L-[2-15N]lysine: IR = 0.180 and 0.080 µmol/kg per min, respectively; PD = 16.2 and 7.2 µmol/kg, respectively. PDs and IRs of tracers were greater in the burned patients because previous evidence (11) indicated that their whole-body rates of amino acid turnover were more than double that those in the controls.
The experimental protocol was designed to simultaneously assess in skeletal muscle the kinetics of intracellular free amino acids and the fractional synthetic rate (FSR) of protein (20). The calculation of the intracellular amino acid kinetics required isotopic steady state in the free amino acid pools in blood and muscle at the end of the study, i.e. between 180 and 240 min of infusion. Measurement of FSR by the incorporation of L-[ring-13C6]phenylalanine required steady-state enrichment of the precursor during the incorporation period, i.e. between 60 and 240 min. Isotope infusions were not started simultaneously because the equilibration period of each tracer varied. L-[ring-13C6]phenylalanine required 1 h primed-continuous infusion to reach isotopic steady state in the intracellular pool, whereas L-[1-13C]leucine and L-[2-15N]lysine were infused for 3 h (20).
At 60 min the first muscle biopsy was taken from the vastus lateralis muscle using a 4-mm Bergström biopsy needle (Stille, Stockholm, Sweden) to measure isotopic carbon enrichment of bound and free phenylalanine in muscle. To measure leg blood flow, at 165 min a primed-continuous infusion of indocyanine green dye (IR = 0.5 mg/min; PD = 5 mg) into the femoral artery was started and maintained until the end of the experiment. Between 180 min and 240 min, blood samples were taken every 20 min from the femoral vein, arterialized wrist vein, and femoral artery to measure glucose, amino acid, and dye concentrations as well as amino acid enrichments. To allow sampling from the femoral artery, the dye infusion was stopped for less than 10 sec and than quickly resumed. Arterial samples were always taken after samples from the femoral and wrist veins to avoid interferences with the blood flow measurement. At 240 min, after the last blood sample was taken and before stopping the tracer infusion, the second muscle biopsy was taken.
Analysis
Concentrations of selected amino acids (phenylalanine, leucine, and lysine) and isotopic enrichment of infused tracers were measured in whole-blood samples taken from the femoral artery and vein as described (20). The stable isotopes L-[ring-2H5]phenylalanine, L-[1,2-13C2]leucine, L-[1,2-13C2,6,6-2H2]lysine were added to the tubes as internal standards (20). To determine the enrichment of the infused tracers and the internal standards of free phenylalanine, leucine, lysine, and alanine in the whole blood, the nitrogen-acetyl-n-propyl esters were prepared as described (20). Blood samples from the femoral and arterialized wrist veins were collected to measure indocyanine green concentration in serum, as described (20). Leg plasma flow was calculated from steady-state values of dye concentration in the femoral and arterialized wrist veins (20). Leg blood flow was calculated from the hematocrit.
Each tissue sample was weighed and muscle protein was precipitated with 0.5 ml 10% trichloroacetic acid. An internal standard solution containing the same isotopes as those used for the blood samples, but in different proportion, was added to the tissue and thoroughly mixed (20). The free amino acid enrichments were then determined as on the nitrogen-acetyl-n-propyl derivatives as described previously (20). Intracellular amino acid concentrations and enrichments were calculated assuming that the ratio of intracellular to extracellular spaces averaged 0.16 [as previously measured in normal volunteers (20)] and that amino acid concentrations and enrichments in the interstitial fluids equaled blood values in the femoral vein. We (20) have previously shown that assumptions relative to interstitial fluid have minimal effect on the calculation of the model parameters (see below) even in the case of differences of tissue fluid distribution between the two groups of patients and controls. The protein-bound phenylalanine was isolated by HPLC, and the enrichment determined after combustion using an isotope-ratio mass spectrometer (VG Isogas, VG Instruments, Middlewich, England) as described (20). Enrichments were expressed as tracer/tracee ratio, with correction for the contribution of isotopomers of small weight to the apparent enrichment of isotopomers with a greater mass (20).
Calculations
Whole-body amino acid rates of appearance were calculated according to standard equations, i.e. tracer infusion rates divided by arterial enrichments. Whole-body rates of appearance of the essential amino acids, phenylalanine, leucine, and lysine, are indexes of whole-body proteolysis. The kinetics of free amino acids in leg muscle have been determined according to the model described (20). Briefly, amino acids enter and leave the leg via the femoral artery and femoral vein, respectively. The rate of amino acid delivery to the leg is calculated from the product between whole-blood concentrations in the artery and the rate of leg blood flow. The unidirectional flow of free amino acids among artery, vein, and intracellular muscle compartment is determined by the model. The rate of inward and outward amino acid transport is calculated as the rate of net amino acid movement from artery to intramuscular compartment of free amino acid and from muscle to vein, respectively. The rate of intracellular appearance for the essential amino acids phenylalanine, leucine, and lysine defines the rate of release from protein breakdown (Eq. IV). Because phenylalanine and lysine are not oxidized in muscle (20), the rate of intracellular utilization for these amino acids refers to the rate of utilization for protein synthesis (Eq. V). In the case of leucine, this figure does not represent utilization for protein synthesis but the sum of protein synthesis and oxidation. The rate of net amino acid balance defines protein balance in the case of phenylalanine and lysine (Eq. VI). Nonetheless, despite the fact that different marker amino acids are potentially used to determine muscle protein kinetics, phenylalanine yields the most reliable information because of the rapid transmembrane transport and the small pool size of this amino acid (20).
Each kinetic parameter is defined as follows [see (20) for the derivation of the equations]:
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Where CA and CV are free amino acid concentrations in the femoral artery and vein, respectively; EA, EV, and EM are amino acid enrichments in the femoral artery, femoral vein, and vastus lateralis muscle, respectively, and BF is leg blood flow. The rate of inward transport was related to regional amino acid delivery to assess transport system ability to take up amino acids from the circulation, as follows:
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The rate of outward transport was related to intracellular amino acid concentration to assess transport system ability to release amino acids into circulation, as follows:
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Where CM is free amino acid concentrations in muscle. This kinetic parameter has the same meaning as clearance and is expressed in the same units (liter/minute).
The rate of glucose uptake was calculated from the arteriovenous difference of glucose concentration multiplied by leg blood flow. Glucose transport activity was obtained from the ratio between glucose uptake and arterial glucose delivery (arterial concentration times leg blood flow).
Muscle protein FSR was calculated by dividing the increment in enrichment in the product, i.e. protein-bound L-[ring 13C6]phenylalanine tracer/tracee ratio, by the enrichment of the precursor, i.e. free intracellular L-[ring 13C6]phenylalanine tracer/tracee ratio (20). Delta increments of protein-bound L-[ring 13C6]phenylalanine enrichment during the 3-h incorporation periods were obtained from the isotope ratio mass spectrometry measurements of the protein-bound phenylalanine enrichment in the first and second biopsy as described (20). Then FSRs were calculated as follows (20):
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Where EM(1) and EM(2) are the L-[ring 13C6]phenylalanine enrichments in the free muscle pool in the biopsies at the beginning and end of the incorporation period, respectively. Average values between EM(1) and EM(2) were used as precursor enrichments for muscle protein synthesis. T indicates the time interval (minutes) between first and second biopsy. The factors 60 (min/h) and 100 are needed to express the FSR in percent per hour.
Statistical analysis
Data were expressed as mean ± SD of the mean (SD). Previous observations indicate that the determination of muscle protein and amino acid metabolism is not significantly affected by the presence of a burn wound in the catheterized leg (14, 22). Thus, data of patients with burned or unburned legs were pooled together and compared with control subjects. Comparison between patients with unburned and burned legs are shown (see Table 6
. Statistical analysis was performed by means of the nonparametric Mann-Whitney two-sample test.
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Amino acid concentrations and enrichments in the femoral artery and vein were in steady-state conditions over the last 40 min of the study period in both burned patients and normal controls. In Tables 1 and 2, average values of free amino acid concentrations and enrichments in the femoral artery and vein and muscle are reported. Blood phenylalanine concentrations were greater in the patients with burns than in the controls. In skeletal muscle of patients, phenylalanine and leucine concentrations were 43% and 74% greater, respectively, whereas muscle concentration of lysine was 28% lower. The rates of tracer infusion were greater in the patients than in the controls (see Subjects and Methods); thus, the values of amino acid enrichments in the two groups cannot be directly compared (Table 2). Nonetheless, the ratios between amino acid enrichments in muscle and the artery were lower (P < 0.05) in the patients than in the controls (phenylalanine: 0.55 ± 0.08 vs. 0.63 ± 0.09; leucine: 0.44 ± 0.16 vs. 0.57 ± 0.13; lysine: 0.35 ± 0.10 vs. 0.41 ± 0.10). The rate of whole-body proteolysis was 2 to 3 times greater in the patients than in the controls, depending on each individual amino acid (Fig. 1). Figure 2 shows the rates of appearance from whole-body proteolysis of the essential amino acids phenylalanine, leucine, and lysine.
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shows the rates of muscle protein balance, proteolysis, and protein synthesis as determined by the arteriovenous balance technique and the phenylalanine tracer. The patients were in a hypercatabolic state, as indicated by their significantly higher rate of net muscle protein loss, compared with that in the normal volunteers. The accelerated net muscle protein catabolism was due to an 83% increase in the absolute rate of muscle proteolysis. In fact, the rate of muscle protein synthesis was actually increased but to a lesser extent than the acceleration in proteolysis, i.e. by 50% with the arteriovenous phenylalanine balance technique and 49% with the direct tracer incorporation method (Fig. 3).
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The rate of leg blood flow was more than double (P < 0.05) in the patients than in the controls (7.79 ± 2.12 and 3.51 ± 1.41 ml/min per 100 ml leg volume, respectively). Consequently, the rates of amino acid delivery to the leg muscle (blood flow times arterial concentrations) were 2 to 3 times greater (P < 0.05) in the patients than in the controls (phenylalanine: 518 ± 162 vs. 167 ± 82; leucine: 942 ± 309 vs. 411 ± 193; lysine: 1368 ± 552 vs. 686 ± 267 nmol/min per 100 ml leg volume, respectively). Table 3 shows the rates of inward and outward transmembrane transport of phenylalanine, leucine, and lysine in the patient and control groups. Despite the fact that amino acid delivery was increased, the absolute values of inward amino acid transport were not significantly different in the two groups. Consequently, the ability of transport systems to take up amino acids from the bloodstream, as assessed by normalizing inward transport for the rate of amino acid delivery to leg muscle, was 50–63% lower in the patients (Fig. 4).
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) were 40% and 67% greater in the patients than in the controls, respectively. The ability of transport systems to release amino acids into the bloodstream was assessed by normalizing the absolute values of outward transport by intracellular amino acid concentrations (Fig. 5). Outward transport activities of phenylalanine and leucine were not statistically different in the burned patients and controls, whereas outward transport activity of lysine was twice greater in the patients (Fig. 5).
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shows the relative contribution of protein degradation and inward transport to the rate of intracellular amino acid appearance. The contribution of inward transport from the bloodstream to intracellular amino acid appearance was significantly decreased for all the amino acids studied.
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). Glucose transport activity was not significantly different in the two groups.
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the results of selected parameters of leg muscle protein and amino acid kinetics in burned patients with or without leg injury are reported. Our data indicate that the rates of muscle protein synthesis and degradation and of inward and outward (data not reported) amino acid transport are not significantly affected by the presence of burn wound in the catheterized leg. Discussion
Patients with severe burn injury were studied in the postabsorptive state during the flow phase in conditions of accelerated metabolic rate and muscle protein catabolism. We found that muscle protein turnover was accelerated with a greater increase of the rate of protein breakdown (about 80%) than that of synthesis (about 45%). Thus, the net protein loss of our patients was entirely explained by the failure of muscle protein synthesis to increase sufficiently to offset the increase in breakdown. Expressed differently, it appears the increase in breakdown is the primary defect leading to catabolism. In contrast to protein turnover, the rates of inward amino acid transport from the bloodstream into skeletal muscle were normal in absolute terms but decreased relatively either to arterial amino acid delivery or to intracellular amino acid turnover.
Evidence indicates that the rate of muscle blood flow can influence amino acid and glucose transport into cells by increasing substrate delivery to membrane transport systems (23, 24). In our study the rate of leg blood flow was more than double in the patients. However, despite the fact that the rates of arterial amino acid delivery to leg muscle were 2 o 3 times greater in the patients than in the controls, the absolute values of the rates of inward transport of essential amino acids were similar. Consequently, the fractional inward transport of phenylalanine, leucine, and lysine were 2 to 3 times lower in the burned patients than in the controls. In contrast to amino acid transport, the absolute rate of glucose transport increased in the patients as previously described (25). Such increase was proportional to the accelerations in blood flow and glucose delivery. In fact, the fractional glucose transport rate was similar in the burn and control groups.
Potential mechanisms accounting for the observed decrease in inward amino acid transport relative to arterial delivery include an impaired ability of transport systems to take up amino acids from the extracellular space and an increased shunting of leg blood flow from artery to vein through nonnutritive routes. However, an increased shunting would have decreased the fractional transport of both amino acids and glucose to the same extent. The fact that in our study the fractional transport of glucose was not different in the two groups suggests that the decrease in the fractional amino acid transport observed in the patients should have been, at least in part, accounted for by an impaired function of transport systems.
In the patients with burn injuries, the rates of amino acid transport were decreased not only in relation to extracellular amino acid delivery but also to the intracellular turnover of each individual amino acid. Phenylalanine, leucine, and lysine are essential amino acids. Release from proteolysis and inward transport account for their intracellular appearance. In normal subjects inward transport accounted for 40–60% of total intracellular appearance, depending on the individual amino acid. In the burned patients this figure decreased for all the studied amino acids by approximately 15–20%.
In our study the rate of synthesis of skeletal muscle proteins has been determined by two different methodologies. Both methods were in agreement and demonstrated that the rate of muscle protein synthesis was about 45% greater in the patients with burns than in the healthy controls. This observation is in apparent contrast with a number of studies at the molecular level showing a down-regulation of the synthetic capacity of muscle protein in critical illness, as expressed by the cellular levels of total RNA (3), rRNA (4), or specific mRNA of myofibrillar proteins (5, 6). Thus, despite the fact that the protein synthetic pathways could have been down-regulated at the transcriptional level, an increased availability of intracellular amino acid derived from a greatly accelerated rate of protein breakdown may have stimulated protein synthesis by a posttranscriptional mechanism. The role of increased amino acid availability as a stimulus of muscle protein synthesis is well established (24). However, protein synthesis was not accelerated sufficiently to match the increase in breakdown and prevent the severe protein loss of our patients. This presumably reflects the accelerated outward transport, and perhaps oxidation, of amino acids released from breakdown. Alternatively, it may be that synthesis is in fact limited, and the increase in response to the extra availability of amino acids is less than would have been the case in normal muscle presented with that amount of extra amino acids. This would explain why patients with less severe critical illness with milder changes in protein breakdown than those in our study would have a suppression in the rate of protein synthesis (18, 26, 27).
In agreement with previous observations (28), the burned patients in our study exhibited increased intramuscular concentrations of free phenylalanine and leucine but depressed concentration of lysine. The absolute rates of outward amino acid transport were increased in the patients with burn injuries. However, when these rates were normalized by the values of intracellular amino acid concentrations, outward transport activities of phenylalanine and leucine were similar in the two groups, whereas outward transport activity of lysine was twice greater in the patients. These results of amino acid transport kinetics can explain the discrepancies among the different intracellular levels of phenylalanine, leucine, and lysine.
In conclusion, in this study we have simultaneously determined the kinetics of proteins and of transmembrane amino acid exchange in skeletal muscle of postabsorptive burned patients. We have shown that there is an accelerated rate of intracellular amino acid appearance from protein breakdown. The rate of protein synthesis is increased in absolute terms, possibly because an increased intracellular amino acid availability, but it is much lower than the rate of breakdown. Transmembrane transport in the outward direction is accelerated to facilitate the export of amino acids from muscle to other tissues. In contrast, transmembrane transport in the inward direction is impaired relatively to the increased delivery of circulating amino acid to skeletal muscle secondary to accelerated blood flow.
Footnotes
Present address for G.B.: Clinica Medica, University of Trieste, Ospedale di Cattinara, Trieste, Italy. E-mail: gianni.biolo@clmed.univ.trieste.it.
Abbreviations: FSR, Fractional synthetic rate; IR, infusion rate; PD, priming dose.
Received June 14, 2001.
Accepted April 2, 2002.
References
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