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From the Clinical Research Centers |
Departments of Surgery (A.A.F., M.S.-M., R.R.W.) and Internal Medicine (C.A.S.), University of Texas Medical Branch, Galveston, Texas 77550
Address all correspondence and requests for reprints to: Dr. Arny A. Ferrando, Metabolism, SHC, 815 Market Street, Galveston, Texas 77550. E-mail: aferrand{at}sbi.utmb.edu
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Abstract |
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31 µg/dL). After 14 days of strict BR, hypercortisolemia
increased phenylalanine efflux from muscle by 3-fold (P <
0.05). The augmented negative amino acid balance was the result of an
increased muscle protein breakdown (P < 0.05) without a
concomitant change in muscle protein synthesis. Muscle efflux of
glutamine and alanine increased significantly after bed rest due to a
significant increase in de novo synthesis (P <
0.05). Thus, inactivity sensitizes skeletal muscle to the catabolic
effects of hypercortisolemia. Furthermore, these effects on healthy
volunteers are analogous to those seen after severe injury. |
Introduction |
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A traumatic insult is also associated with increased cortisol secretion (4). The increase in blood cortisol concentrations correlates with the severity of the injury (4) and often persists for weeks after injury (4, 5). Although trauma is accompanied by increased circulating concentrations of glucagon and catecholamines (6), the loss of muscle nitrogen is likely due primarily to the effects of cortisol (7). The effects of cortisol on skeletal muscle are to increase net protein breakdown (8, 9, 10) and efflux of amino acids (8, 10).
Severe injury most often entails prolonged periods of inactivity or bed rest (BR). Inactivity alone in healthy volunteers has been shown to result in a loss of body nitrogen (11, 12) and lean body mass (11, 12, 13, 14). We have previously noted that the loss of lean body mass with BR is due to a decrease in skeletal muscle protein synthesis, while muscle protein breakdown remains unchanged (11). Despite a difference in the underlying mechanisms for loss of muscle nitrogen between severe injury and inactivity alone, the net effect is a loss of lean body mass. However, the accompanying hormonal environment is quite different. Whereas BR does not alter anabolic or catabolic hormonal profiles (11), the same is not true of trauma or surgery. In the case of trauma or postsurgical intervention (15), recovery is associated with both hypercortisolemia and periods of inactivity. Although it has been hypothesized that the effects of BR on muscle protein are of minor impact during severe stress (16), a clinical interaction is thought to exist. For this reason, conventional postsurgical treatment dictates a prompt return to an ambulatory state to enhance the healing process. However, it is unclear the extent to which the BR component contributes to the response of skeletal muscle in patients after surgery or trauma who are hypercortisolemic. Therefore, we have investigated the hypothesis that BR amplifies the normal catabolic effect of hypercortisolemia. To this end, we studied the effects of a cortisol challenge on six normal volunteers before and after 14 days of strict BR.
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Methods |
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Six healthy males [26 ± 6 (SD) yr; 76 ± 6 kg; 179 ± 5 cm] were studied before and after 14 days of BR. Written consent was obtained on all subjects, and the protocol was approved by the Institutional Review Board at the University of Texas Medical Branch.
Experimental Protocols
This study involved a 20-day stay at the General Clinical Research Center (GCRC) at University of Texas Medical Branch. The first 5 days served as a diet stabilization period before 14 days of strict BR. Subjects were not permitted to deviate from BR and were continuously monitored by the GCRC staff. Excretory and hygiene functions were accomplished while strict BR was maintained. Subjects were not permitted to sit up at any time, and eating was accomplished by elevating and supporting the head with one arm. Subjects were fed a mixed diet based on the Harris-Benedict equation and designed to maintain body weight throughout the study. The energy intake was adjusted during BR to account for the reduced activity and energy expenditure. The energy distribution of the diet was approximately 14% protein, 27% fat, and 59% carbohydrate, with protein intake standardized at 1.5 g/kg·day. Care was taken to insure that the study diets were very similar to the subject’s normal diet, as ascertained by GCRC dietitian interview. Meal patterns were very similar between subjects with some accommodation of individual aversions. During the 5-day diet stabilization period and the day after BR, body mass was determined by dual energy x-ray absorptiometry (DEXA; Hologic QDR-1000; Hologic, Waltham, MA) with regional analysis (Specialized Region of Interest Software; Hologic).
Isotope Infusions
The day before BR, subjects were fasted after dinner
(approximately 1800 h) until the end of the study at 1200 h
the following day. A 20-gauge polyethylene catheter was inserted into
an antecubital vein at approximately 2300 h. Just before 2400
h, baseline blood samples were obtained for measurement of background
amino acid enrichment, indocyanine green concentration, plasma glucose,
and serum cortisol concentrations. A systemic infusion of
hydrocortisone sodium succinate (Solu-Cortef; Upjohn, Kalamazoo, MI) at
120 µg/kg·h was started at 2400 h (Fig. 1
) and maintained throughout the study.
At 0500 h, a blood sample was obtained for glucose and cortisol
concentrations, and a primed (63 µmol/kg) constant (0.35
µmol/kg·min) infusion of L-[5-15N] glutamine was
given. At 0700 h, blood was again sampled for glucose and cortisol
concentration, and three additional tracers were started at the
following priming dose (PD) and infusion rates (IR):
L-[ring-2H5]phenylalanine, IR = 0.05
µmol/kg·min, PD = 2 µmol/kg; L-[1-13C]alanine,
IR = 0.35 µmol/kg·min, PD = 35 µmol/kg, and
L-[2H3]ketoisocaproic acid, IR = 0.1
µmol/kg·min, PD = 4.8 µmol/kg. All isotopes were purchased
from Cambridge Isotope Laboratories (Andover, MA).
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65°C for measurement of
systemic concentration of indocyanine green. At 0900 h, a biopsy of the vastus lateralis was performed as described previously (17). Immediately after the biopsy, a primed (2 µmol/kg) continuous (0.05 µmol/kg·min) infusion of L-[15N]phenylalanine was initiated and maintained until 1100 h. The arterial and intracellular L-[15N]phenylalanine enrichments at plateau and during the decay were used to determine the fractional breakdown rate (FBR). At 1100 h, blood was obtained for glucose and cortisol concentrations and amino acid enrichments, and the L-[15N]phenylalanine was then discontinued. Additional biopsies of the vastus lateralis were taken at 1130 and 1200 h.
Arteriovenous blood samples were drawn at 20-min intervals throughout the last hour (1100 to 1200 h) to determine amino acid kinetics. In addition, leg BF was determined by indocyanine green infusion during this hour. To measure leg BF, a continuous infusion (IR = 0.5 mg/min) of indocyanine green was started 15 min before the kinetic hour. Subsequent sampling was performed simultaneously from the femoral vein and the heated wrist over this hour. Arterial samples for amino acid kinetics were always taken after those from the femoral vein and wrist to avoid interference with BF measurement. After each sampling, indocyanine green infusion was uninterrupted for at least 10–15 min before the next BF measurement.
At the conclusion of the isotope infusion study, the subjects were fed and remained in bed for the next 14 days. At 2400 h on day 13 of BR, the above protocol was repeated. When the study was concluded on day 14, subjects were again fed but allowed to ambulate. Subjects remained at the GCRC until the following day for the post-BR DEXA, then discharged.
Analysis of Samples
Blood. The concentrations of unlabeled phenylalanine, glutamine, and alanine, as well as the enrichment of their isotopic counterparts, were simultaneously determined by gas chromatography-mass spectrometry in blood using the internal standard approach (17). Whole blood samples from the femoral vein and artery were immediately precipitated in preweighed tubes containing 15% sulfosalicylic acid. A known internal standard mixture (100 µl/mL blood) was added to the tube and thoroughly mixed. The composition of the internal standard was: 49.4 µmol/L L-[ring-13C6]phenylalanine, 330.7 µmol/L L-[2H4]alanine, and 562.6 µmol/L L-[13C5]glutamine. The tubes were reweighed for determination of blood volume, centrifuged, and the supernatant was removed and frozen at -80°C until analysis. On thawing, 500 µl of the sulfosalicylic extract was passed over a cation exchange column (Dowex AG 50W-8X, 100–200 mesh H+ form; Bio-Rad Laboratories, Richmond, CA) and dried under vacuum using a Speed Vac (Savant Instruments, Farmingdale, NY). To determine the enrichments of the infused tracers and internal standards, the tert-butyldimethylsilyl derivative was prepared as described previously (11). The isotopic enrichment of free amino acids in blood were determined on an HP Model 5989 gas chromatography-mass spectrometry (Hewlett-Packard Co., Palo Alto, CA) by electron impact ionization and selected ion monitoring (18). Data were expressed as tracer to tracee ratio, with correction for overestimation of enrichment (skew) due to isotopomer distribution and for "overlapping" contribution of isotopomers of small weight to the apparent enrichment of isotopomers of greater mass (18).
Blood glucose was determined on a YSI 2300 Stat (Yellow Springs Instruments, Yellow Springs, OH) glucose analyzer after collection into tubes containing glycolytic inhibitors. Measures for each time point were done in duplicate and averaged.
Serum cortisol concentration was determined by commercial radioimmunoassay (DPC, Los Angeles, CA). All samples were analyzed with one respective assay with an intra-assay coefficient of variation of 3.4%.
Muscle. Tissue biopsies of the vastus lateralis were
immediately blotted and frozen in liquid nitrogen. Samples were then
stored at -80°C until processed. On thawing, the tissue was weighed
and protein was precipitated with 0.5 ml of 10% perchloroacetic acid.
To simultaneously determine the intracellular concentrations of certain
amino acids, an internal standard containing 2.6 µmol/L
L-[ring-13C6]phenylalanine, 5.7 µmol/L of
L-[2H4]lysine, 5.8 µmol/L
L-[13C6]leucine, and 730.8 µmol/L
L-[13C5]glutamine was added (2 µl/mg wet
tissue) and thoroughly mixed. The tissue was then homogenized and
centrifuged, and the supernatant was collected. This procedure was
repeated two more times, and the pooled supernatant (1.5 ml) was
processed as the blood samples described in Blood. To
determine intracellular enrichment of infused tracers, the
tert-butyldimethylsilyl derivative was prepared as described
above. Intracellular enrichment was determined by correction for
extracellular fluid based on the chloride method (19).
The remaining pellet was processed, and the protein bound L-[ring-2H5]phenylalanine and L-[2H3]leucine enrichments were determined using chemical impact ionization with methane gas, as described previously (20). The ions monitored for L-[ring-2H5]phenylalanine were m/z 407 and 409 and for L-[2H3]leucine m/z 202 and 203. These ions are the m + 3 and m + 5 and m + 3 and m + 2 enrichments for phenylalanine and leucine, respectively, where m + 0 is the lowest molecular weight of the ion. These ratios were used because they are more sensitive than using the traditional m + 5/m + 0 (used for plasma phenylalanine samples). Enrichments from the protein-bound samples were determined using a linear standard curve of known m + 5/m + 3 or m + 3/m + 2 ratios and correcting back to the absolute change in m + 5/m + 3 enrichments over the incorporation period. The m + 3 leucine is analyzed because [2H3]ketoisocaproic acid (m + 3) is transaminated in muscle to form leucine, which in turn is incorporated into tissue protein.
Calculations
This protocol was designed to simultaneously determine in
skeletal muscle, amino acid kinetics of free amino acids, and
fractional synthetic and breakdown rates of mixed muscle protein. Leg
amino acid kinetics were calculated according to a three-pool
compartment model that was derived (21) in our laboratory and has since
become our standard methodology for expressing amino acid kinetics (1, 17, 20, 22, 23). Therefore, the model parameters are briefly outlined:
Amino acids enter and leave the leg via the femoral artery
(Fin) and femoral vein (Fout);
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Intercompartment flow of free amino acids can occur between the artery
(A), vein (V), and muscle (M). For example, FM,A refers to
the net amino acid movement from the artery to the muscle, whereas
FV,M refers to the movement from the muscle to the vein.
These terms describe inward and outward tissue transport, respectively.
Thus,
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Fractional Synthetic Rate (FSR) of Muscle Protein. Skeletal
muscle FSR was calculated from the determination of the rate of tracer
incorporation into the protein and the enrichment of the intracellular
pool as the precursor:
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Fractional Breakdown Rate (FBR) of Muscle Protein. The
derivation and assumptions of the calculation for FBR are described in
detail elsewhere (24) and used previously (20). Briefly, however, this
new method for measuring fractional protein breakdown uses a variation
of the traditional precursor-product method. In this case, the product
is free intracellular amino acids and the precursors are arterial blood
and tissue protein. The following equation was used for the calculation
of FBR:
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Data Presentation and Statistical Analysis
Data are presented as means ± SEM. Pre- and post-bed rest studies were compared by paired t test with Bonferroni correction (Family error rate). A P value is presented where appropriate and considered significant when <0.05.
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Results |
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Cortisol infusion resulted in an 8-fold increase (P =
0.0001) in blood cortisol concentrations that was maintained throughout
the isotope infusion study (Fig. 2).
Concomitant plasma glucose increased significantly over background
values (P = 0.02), but remained within normal fasting
values throughout the entire study (Fig. 2).
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Amino acid kinetics are presented in Table 1. Net amino acid balance was more
negative in response to cortisol after 14 days of inactivity. De
novo synthesis of alanine and glutamine were also increased after
BR. Model-derived calculation of protein breakdown (FM,O)
demonstrated an increase that approached significance at
P = 0.06. To compare the arteriovenous model
calculation of protein breakdown with the direct method (FBR),
FM,O (nmol·min-1·100 mL
leg-1) derived from phenylalanine was converted to FBR
(%/h) on the basis of phenylalanine content in muscle [233 nmol/mg
dried tissue (17)], the protein content in muscle [25% (17)],
and the assumption that muscle accounts for 60% of leg volume in
normal subjects (25). Both methods resulted in essentially the same
value, with no statistical differences at either time point between the
direct FBR calculation and the FM,O to FBR conversion
value. Prebed rest-direct FBR was 0.09 ± 0.005%/h, and the
converted value for FM,O was 0.108 ± 0.02%/h,
whereas BR14-direct FBR was 0.108 ± 0.005%/h, and the converted
FM,O was 0.135 ± 0.08%/h. Because there is agreement
between methods, it is likely that the depicted increase in protein
breakdown by the arteriovenous model (FM,O) is significant
despite P = 0.06.
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Discussion |
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Investigation of protein metabolism by these independent methodologies have proven reliable and accurate. We have demonstrated that FSR and FBR measures in fasted individuals yield similar results (20) and that model-derived and direct incorporation calculations produce essentially similar values (17, 20). The FSR and FBR calculations describe fractional rates that are independent of the amount of muscle present. Thus, the loss of leg lean mass with BR would not affect the accuracy or validity of these values. The issue of tracer recycling from protein must be addressed because the second isotope infusion study was conducted 14 days after the first. Given that muscle protein turns over approximately 2%/day (see Results), then only 2% of the tracer enrichment could be derived from the first study. As a worse case, this would serve to underestimate only FBR calculations because FSR is unaffected since it is calculated by the difference in enrichment over time (Eq IX). In relation to this study, the possibility of an underestimation only strengthens the findings of increased protein breakdown with inactivity. In reality, however, a relative error of 2% is negligible in the calculation of FBR.
The BR model has been shown to mimic the loss of LBM associated with space flight and microgravity (11, 12, 26). In this respect, BR results in LBM losses, which are comparable with those noted in space (26). Although not included in the present study, "control" subjects who have experienced bed rest alone have been previously investigated by our laboratory (11). In the previous study, we demonstrated that the loss of LBM in normal, healthy volunteers is due to a decrease in whole-body and skeletal muscle protein synthesis, whereas protein breakdown remains unchanged (11). The interactive effect of hypercortisolemia and BR on protein breakdown is six times greater than that of BR alone. Furthermore, even though net amino acid balance across the muscle becomes more negative after BR alone (11), the combined effects of inactivity and hypercortisolemia are again 6-fold worse. It must be noted that both space flight and BR studies investigate fundamentally healthy individuals. However, BR in a healthy population is not clinically relevant. Prolonged BR or inactivity is an integral aspect of recovery from severe injury or illness, and the accompanying physiological and metabolic alterations are distinctly different than BR alone. Severe injury can result in a persistent hypercortisolemia that may last for weeks or months (4, 28). The present study demonstrates that after only 14 days of inactivity, hypercortisolemia exacerbates the loss of nitrogen from skeletal muscle.
To understand the extent of this loss and its clinical significance,
Table 2 compares our present findings
with those from previous investigations of fasted volunteers (20) and
severely burned patients (1). The present study was designed to mimic
the hypercortisolemia noted in severely burned patients (5, 28). Table 2 demonstrates that before inactivity the hypercortisolemic effects on
skeletal muscle are indistinguishable from the values in overnight
fasted healthy volunteers. It seems that there are no additive effects
of hypercortisolemia and fasting in normal volunteers. The response to
cortisol is quite different after prolonged inactivity. Table 2
illustrates that the effects of hypercortisolemia on skeletal muscle in
fasted volunteers are very similar to those found in fed patients with
65% total body surface area burns (1). Skeletal muscle protein
breakdown (FM,O), protein synthesis (FO,M), and
net balance (NB) in these otherwise healthy, but inactive, volunteers
is metabolically similar to patients with severe burn injury. For
example, the apparent doubling of protein synthesis (FO,M)
is similar to that noted in burn patients (1). This increase in protein
synthesis is supported by the increased availability of amino acid
precursors from protein breakdown (FM,O), which is elevated
to the same extent in each group. The most prominent and
physiologically important similarity is the dramatic negative net amino
acid (phenylalanine) balance across the muscle, an unremitting
situation in severely injured patients that leads to significant losses
of LBM and impairs rehabilitative efforts (29).
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Further evidence for this combined influence of BR and hypercortisolemia can be seen in the resultant change of intramuscular glutamine concentrations. Glutamine has often been considered a conditionally essential amino acid after severe injury (32, 33) or surgical stress (33). In addition to its role in the interorgan transport of nitrogen, glutamine plays an important role in counteracting glucocorticoid-induced muscle loss (34), wound healing (35), and immune function (36). It has previously been demonstrated that after severe injury (2) or surgery (33) intramuscular glutamine can be depleted by as much as 40–75%. The current study demonstrated a significant decrease of intramuscular glutamine in response to hypercortisolemia after inactivity whereby levels were only 56% of normal. This dramatic decrease in intramuscular glutamine concentration is representative of the decrease noted after surgical stress (33). This provides further evidence that protein metabolism in skeletal muscle without an accompanying pathology can be made to represent severely injured muscle by combining hypercortisolemia and inactivity.
There is indirect evidence in animals that suggests that the ubiquitin-proteasome pathway may be involved in the catabolic effects of hypercortisolemia and inactivity on muscle protein breakdown. When fasted rats are injected with glucocorticoids, expression of ubiquitin protein mRNA increases within 6 h and is associated with a 25% increase in muscle protein degradation (37). In denervated (inactive) rat muscle, nonlysosomal proteolysis was 52% greater than an innervated control (38). When competitive inhibitors of the 26S (ubiquitin) proteasome were introduced, proteolysis was inhibited by 65% (38), indicating that proteolysis in inactive muscle is due in large part to this ubiquitin-proteasome pathway. Emerging evidence indicates that similar mechanisms are involved in the regulation of protein degradation in human muscle (39). A link between inactivity and increased protein oxidation has also been established in rats, where it is hypothesized that the decreased blood flow and oxidative damage with inactivity increases muscle breakdown (38). It is possible that this increased oxidative stress may also enhance the hypercortisolemic response during inactivity. Assuming similar pathways for protein degradation in human muscle, hypercortisolemia may exacerbate proteolytic pathways that are already "primed" by inactivity, thus accounting for the interactive effects. Although plausible, it must be noted that the role of the ubiquitin-proteasome pathway and these mechanisms in human muscle remain largely speculative at this point.
Thus, this study demonstrates that inactivity exacerbates the proteolytic effect of hypercortisolemia on skeletal muscle. The absence of muscular activity sensitizes skeletal muscle to the catabolic effects of cortisol. This predisposition to protein breakdown is such that skeletal muscle in healthy volunteers is metabolically analogous to severely injured or stressed patients. These findings provide a metabolic basis for the current surgical axiom of "getting the patient up and moving" as soon as possible after surgery. However, for a more severe injury, such as burns, prolonged bed rest is inherent, and efforts must focus on the preservation of LBM by ameliorating the catabolic effects of hypercortisolemia.
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Acknowledgments |
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Footnotes |
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Received April 28, 1999.
Revised June 15, 1999.
Accepted June 28, 1999.
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