Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510
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ABSTRACT |
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To determine the
effect of insulin-like growth factor I (IGF-I) on cardiac contractile
protein synthesis in vivo, we measured L-[ring-2,6-3H]phenylalanine
incorporation into myosin heavy chain and actin during intravenous
infusions (4 h) of either saline or IGF-I (1 µg · kg1 · min
1)
in awake rats. After an overnight fast, IGF-I increased myosin synthesis by 29% compared with saline (11.5 ± 0.8 vs. 8.9 ± 0.6%/day, P < 0.01) and actin
synthesis by 26% (7.2 ± 0.3 vs. 5.7 ± 0.3%/day, P < 0.01), with similar effects in
left and right ventricles and a comparable effect on mixed cardiac
protein. When amino acids were infused with IGF-I, a further increase
in myosin synthesis was observed (P < 0.01). In fed rats, despite higher baseline synthesis rates than in
fasted rats (P < 0.01), IGF-I also
increased the synthesis of myosin (12.3 ± 0.5 vs. 9.9 ± 0.5%/day, P < 0.01) and actin (8.8 ± 0.3 vs. 7.5 ± 0.2%/day,
P < 0.01) compared with saline. IGF-I infusion had no hypoglycemic effect and did not change
heart rate or blood pressure. Thus relatively low-dose IGF-I has a
direct action in vivo to acutely increase heart contractile protein
synthesis in both fasted and fed awake rats.
heart; contractile proteins
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INTRODUCTION |
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INSULIN-LIKE GROWTH factor I (IGF-I) may have an important physiological role in the regulation of muscle protein synthesis in vivo. In the heart, IGF-I may also have beneficial pharmacological effects in the treatment of heart failure, as suggested by the improvement in cardiac function observed in rats with left ventricular failure treated with chronic IGF-I infusion (8). Clinical studies with IGF-I have not been performed, but IGF-I also mediates the cardiac effects of growth hormone, which may improve function in patients with dilated cardiomyopathy (13). Although the mechanisms underlying IGF-I's beneficial effects in heart failure remain somewhat unclear, these may include direct stimulation of heart growth, leading to an increase in cardiac mass (3, 8, 9).
Recent studies administering short-term infusions of IGF-I in vivo have
helped to elucidate the effects of IGF-I on skeletal muscle protein
turnover (15, 23, 29). IGF-I infusion acutely increases the synthesis
of mixed skeletal muscle protein in both humans (15) and rats (23). We
have shown that IGF-I also increases the synthesis of mixed myocardial
protein in the rat heart (23) at relatively low doses (1 µg · kg1 · min
1)
that are not associated with hypoglycemia (23). However, no previous
studies have examined the in vivo effects of IGF-I on the synthesis of
individual proteins, so that the effect of IGF-I on the specific
proteins responsible for cardiac contractile function remains uncertain.
The current study was therefore designed to determine whether short-term infusions of low-dose IGF-I directly stimulate cardiac myosin heavy chain and actin synthesis in vivo. Because changes in systemic hemodynamics may influence contractile protein synthesis (24, 26), we also examined whether the low dose of IGF-I used in these acute studies influences blood pressure or heart rate, and whether IGF-I has differential effects on left compared with right ventricular protein synthesis. We studied both fasted and fed rats to demonstrate that the stimulatory effect of IGF-I is not limited to more catabolic fasted animals, which have lower baseline rates of cardiac protein synthesis (28, 30).
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METHODS |
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Animal preparation. Male Sprague-Dawley rats (200-250 g body weight) were anesthetized with intraperitoneal injections of pentobarbital sodium (20 mg/kg); polyethylene and Silastic catheters were surgically inserted into the left carotid artery and right jugular vein, respectively, and then secured in the dorsum of the neck (23). Catheters were filled with polyvinylpyrrolidone in heparinized saline to maintain patency. The rats were allowed to recover for 7 days and were gaining weight before study. Rats were either fasted with access to water for 15 h or fed ad libitum before the experimental protocols, which were begun at 9 AM. Rats were awake and free to walk about in their cages during the experimental protocols.
Experimental protocols.
In the initial series of experiments, which assessed the effects of
IGF-I on heart contractile protein synthesis during fasting, rats were
assigned to one of three protocols. The rats received a simultaneous
4-h continuous intravenous infusion of
L-[ring-2,6-3H]phenylalanine
(Amersham, Arlington Heights, IL) at a rate (1 µCi/min) sufficient to
label cardiac contractile proteins adequately for determining their
specific activities. The first group received an intravenous infusion
of saline and served as the control group (n = 14). The second group received a
continuous intravenous infusion of recombinant human IGF-I (rhIGF-I,
Genentech, S. San Francisco, CA) at a rate of 1 µg · kg1 · min
1
for 4 h (n = 14). Because IGF-I's
anabolic effects on muscle in vivo may depend on substrate availability
for protein synthesis (16, 23, 29), we also assessed whether amino acid
infusion would augment IGF-I effects in fasted rats. Thus a third group (n = 8) received IGF-I with coinfusion
of mixed amino acids (10% Travesol, Clintec Nutrition, Deerfield, IL)
at a rate (0.01 ml/min) designed to prevent hypoaminoacidemia during
IGF-I infusion (23). Hearts from 3-5 rats, whose bulk protein
synthesis rates in skeletal muscle and heart have previously been
reported (23), were further analyzed for contractile protein specific
activity and were included in each of the above groups. The animals
included from this previous study had received an adequate tracer
infusion to permit this analysis and otherwise had been treated
identically to the rats in this study.
Plasma analytic measurements. Plasma glucose concentration was determined using the glucose oxidase method (Beckman Instruments, Palo Alto, CA). Plasma amino acid concentrations were measured in sulfosalicylic acid extracts with an automated ion exchange chromatography analyzer (Dionex D-500, Sunnyvale, CA) or HPLC (in the fed rats, which permitted the measurement of basic amino acids). Plasma insulin was measured by radioimmunoassay with rat insulin standards and anti-rat antibodies (Linco Research, St. Charles, MO). Plasma IGF-I was measured by radioimmunoassay with human IGF-I as a standard and antibodies that cross-react with both rat and human IGF-I (Nichols Institute Diagnostics, San Juan Capistrano, CA); this assay underestimates rat IGF-I concentrations by ~20% compared with those that use rat IGF-I-specific antibodies. Plasma phenylalanine concentration was measured using a reverse-phase HPLC technique, as previously described (25, 33). Radioactivity in the HPLC eluent phenylalanine peak was measured by liquid scintillation counting and used to calculate the phenylalanine specific activity.
Heart contractile protein analysis.
Phenylalanine specific activity in actin and myosin heavy chains was
assessed in proteins isolated using the method of Esser (11). A 10%
homogenate was prepared in 62.5 mM Tris buffer (pH 6.8) with a polytron
homogenizer. An equal volume of sample buffer containing 125 mM Tris,
4% SDS, 20% glycerol, 10% -mercaptoethanol, and 0.001%
bromophenol blue was then added before the protein suspension was
dissolved at 100°C for 3 min. The samples were filtered and had a
final protein concentration of ~1 mg/ml. Preparative SDS-polyacrylamide gel electrophoresis was performed on 7% acrylamide gels (14 × 13 × 0.3 cm). Samples (300 µg) were
run at 100 V for 5 h. Gels were stained with Coomassie blue, and actin
and myosin heavy chain bands were identified by reference to purified
protein standards (Sigma, St. Louis, MO). When proteins were extracted from the actin and myosin heavy chain bands and subjected to repeat electrophoresis and silver staining, >95% was present within their single distinct bands.
Calculations. Plasma [3H]phenylalanine specific activity was calculated by dividing the phenylalanine radioactivity (dpm/ml) by its concentration (nmol/ml). Fractional rates of protein synthesis (ks, expressed as %/day) were calculated from the ratio of the specific activity in protein to that in plasma during the 240-min [3H]phenylalanine infusion with the following equation (23, 25)
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Statistical analysis. Statistical significance was determined using analysis of variance (with Dunnett's or Newman-Keuls tests to evaluate intergroup differences) or t-tests. Statistical significance was defined as P <0.05. Variance is expressed as SE.
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RESULTS |
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Substrate and hormone concentrations during IGF-I infusion in fasted rats. In fasted rats, IGF-I infusion increased total plasma IGF-I concentrations by 34% but had no significant insulin-like hypoglycemic effects (Table 1). As expected, plasma insulin concentrations fell by 59% in rats receiving IGF-I alone (P < 0.01; Table 1). Infusion of IGF-I resulted in a 25% decrease in circulating amino acids available for protein synthesis (P < 0.01; Table 2). When amino acid infusions were given together with IGF-I, overall amino acid supply and insulin concentrations were maintained close to fasting levels (Tables 1 and 2).
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Substrate and hormone concentrations during IGF-I infusion in fed rats. Fed rats had significantly higher initial plasma IGF-I concentrations (P < 0.01), which increased further (by 54%) with IGF-I infusion (P < 0.01) and decreased by 28% with saline infusion (P < 0.01; Table 1). Plasma glucose concentrations were higher in fed rats compared with fasted rats (P < 0.01). The fed rats exhibited a similarly slight decrease in plasma glucose in the course of both the IGF-I and saline infusions during which they did not receive food (Table 1). Plasma insulin concentrations, which were initially twofold higher in fed compared with fasted rats (P < 0.01), fell by 50% during IGF-I (but not saline) infusion (P < 0.01) but did not reach the hypoinsulinemic levels seen in fasted rats during IGF-I infusion (Table 1). Baseline plasma amino acids were similar in fed and fasted rats (Table 2) and generally fell less during infusion of IGF-I in fed compared with fasted rats (Table 2). However, there was a small decrease in the concentrations of several individual essential amino acids in fed rats during IGF-I infusion (Table 3). Individual amino acid concentrations from fasted rats during IGF-I infusion have been previously reported (23).
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Hemodynamic effects of IGF-I infusion. The mean carotid arterial pressures and heart rates measured in fasted and fed rats during the saline and IGF-I infusions are shown in Fig. 1. Blood pressures and heart rates remained stable throughout the 4-h IGF-I infusion and were not significantly different from those in rats receiving saline infusion.
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Plasma phenylalanine specific activity. Arterial plasma phenylalanine specific activity rapidly approached steady-state values (Fig. 2). The steady-state specific activity was similar during saline and IGF-I infusions, indicating that IGF-I had no effect on whole body proteolysis. As would be anticipated, the steady-state phenylalanine specific activity was lower with the combined infusions of IGF-I and the amino acid mixture that contained unlabeled phenylalanine.
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Effects of IGF-I on heart myosin heavy chain and actin synthesis in fasted rats. Fractional rates of myosin heavy chain and actin synthesis in total (left and right) ventricular myocardium from fasted rats are shown in Fig. 3. Infusion of IGF-I alone increased the rate of myosin synthesis by 29% (11.5 ± 0.8 vs. 8.9 ± 0.6%/day, P < 0.01) and actin synthesis by 26% (7.2 ± 0.3 vs. 5.7 ± 0.3%/day, P < 0.01) compared with saline. This increase in myocardial contractile protein synthesis with IGF-I was paralleled by a comparable increase (30%) in mixed protein synthesis in the heart (12.5 ± 0.9 vs. 9.6 ± 0.6%/day, P < 0.005). Amino acid replacement potentiated IGF-I's stimulation of contractile protein synthesis. In rats receiving combined IGF-I and amino acid infusions, myosin synthesis rates increased further to 16.4 ± 1.0%/day (P < 0.01 compared with IGF-I alone), values which were nearly twofold higher than those in rats receiving saline. Actin synthesis rates were also somewhat, but not significantly, higher (8.2 ± 0.6%/day) than with IGF-I alone.
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Effects of IGF-I on heart myosin heavy chain and actin synthesis in fed rats. In fed rats, the fractional protein synthesis rates were measured in left ventricular myocardium and were higher than in fasted rats for myosin (9.9 ± 0.5 vs. 8.0 ± 0.6%/day, P < 0.05), actin (7.5 ± 0.3 vs. 5.7 ± 0.4%/day, P < 0.01), and total protein (12.7 ± 0.4 vs. 10.3 ± 0.2%/day, P < 0.01). Synthesis rates in saline-infused fed rats were in fact comparable to those in fasted rats receiving IGF-I infusion. Despite the higher baseline synthesis rates in the fed rats, IGF-I increased myosin heavy chain synthesis by 24% (12.3 ± 0.5 vs. 9.9 ± 0.5%/day, P < 0.01) and actin synthesis by 18% (8.8 ± 0.3 vs. 7.5 ± 0.2%/day, P < 0.01) compared with saline (Fig. 5). This increase in contractile protein synthesis with IGF-I was also reflected in an increase in total heart protein synthesis (14.2 ± 0.3 vs. 12.7 ± 0.4%/day, P < 0.05).
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DISCUSSION |
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This study demonstrates that relatively low-dose infusions of IGF-I acutely increase heart myosin heavy chain and actin synthesis in awake, fasted rats. This stimulation of contractile protein synthesis occurs despite the fall in plasma amino acid and insulin concentrations that accompanies IGF-I infusion in vivo, although amino acid replacement does potentiate IGF-I's effect. Both left and right ventricular contractile protein synthesis is stimulated, indicating a global action of IGF-I. In addition, IGF-I's effect extends to fed animals, whose baseline contractile protein synthesis rates are higher than those in more catabolic fasted animals. Insofar as these doses of IGF-I do not alter heart rate or blood pressure, it is likely that IGF-I has a direct effect on the heart to stimulate contractile protein synthesis in vivo.
The current results are consistent with the increased synthesis of mixed protein (18, 20) and contractile proteins (5) seen in cardiac myocytes with IGF-I stimulation in vitro. However, isolated neonatal myocytes (20) and quiescent adult myocytes (5) appear to have greater responsiveness to insulin and other growth factors than intact hearts in adult animals, which are performing physiological work and are subject to the influence of circulating hormones. It is also difficult to extrapolate results obtained with high concentrations of IGF-I in vitro, in the absence of IGF-I-binding proteins that modulate IGF-I's action in vivo, to the intact organism. Thus the current findings provide strong evidence for a direct action of IGF-I to stimulate contractile protein synthesis in the heart in vivo. Furthermore, they also extend earlier in vivo studies from our laboratory and others, showing a stimulatory effect of IGF-I on the overall synthesis of mixed muscle protein in both heart (7, 23) and skeletal muscle (15, 16, 23).
It is noteworthy that IGF-I stimulates the synthesis of the myosin heavy chain, which not only is the major cardiac contractile protein but also is localized to myocytes within the heart. IGF-I also increased actin synthesis in the heart to the same extent as myosin heavy chain synthesis, suggesting that IGF-I stimulates cardiac sarcomeric actin synthesis. Although it is possible that IGF-I may also have stimulated the synthesis of non-cardiac-derived actin, it is unlikely that this contributed significantly to the synthesis rates measured in this study, and it might be noted that IGF-I suppresses smooth muscle actin in cultured cardiocytes (6). Myosin heavy chain and actin together represent 20-25% of total cardiac protein by mass (12) and would account for a significant fraction (15-20%) of the total cardiac protein synthesized during IGF-I infusion, as estimated from their respective synthetic rates. The finding of similar increases in mixed protein and contractile protein synthesis rates indicates that IGF-I also has a comparable effect on generalized cardiac myocyte protein synthesis. IGF-I may also increase the synthesis of nonmyocyte proteins, but it is unlikely that IGF-I preferentially increases the synthesis of nonmyocyte proteins, because no increase in interstitial matrix or fibrosis is observed after chronic IGF-I administration in rats (3).
We chose to study a lower infusion rate of rhIGF-I for these acute studies than that which was previously found to lead to cardiac hypertrophy when administered subcutaneously over 2-4 wk to rats (3, 8). This lower rate of IGF-I administration avoids the potential for hypoglycemia associated with higher intravenous infusion rates, which may lead to catecholamine release and confound the results of the study. The lower rate of IGF-I infusion also resulted in only a 30% increase in total plasma IGF-I concentrations compared with the two- to threefold increase in previous chronic studies (8). It might be noted that the baseline IGF-I levels measured in these and other rat studies (8, 9, 23, 35) are higher and somewhat more variable than in human studies (1), reflecting species differences and the assay used to measure IGF-I. In addition, we observed significantly lower IGF-I levels in 15-h-fasted compared with fed rats, consistent with prior reports that IGF-I levels fall with fasting (35). The physiological role of IGF-I in normal cardiac protein homeostasis in the adult animal is unknown. However, it is of interest that the higher baseline IGF-I levels may have contributed to the higher rates of heart contractile protein synthesis rates that we observed in the fed compared with fasted rats.
We found no evidence to suggest that the acute effects of IGF-I were mediated by hemodynamic changes, insofar as both arterial blood pressure and heart rate remained stable. Previous studies have shown that IGF-I has vasodilatory effects, significantly increasing forearm blood flow when infused into the brachial artery in humans (17). However, such effects may depend on the route, dose, and duration of administration. A previous study (3) reported decreased peripheral vascular resistance in anesthetized rats after 4 wk of treatment with doses of IGF-I that were twofold higher than in our study, whereas another study demonstrated a small increase in arterial blood pressure in awake rats after 9 days of treatment with IGF-I (8). Although we cannot exclude a selective vasodilatory effect of IGF-I in the current study, a generalized effect seems unlikely, since it would have been expected to produce some change in blood pressure. An increase in contractility has also been reported in perfused hearts from rats receiving chronic IGF-I administration (31), but there is no evidence that an increase in contractility alone results in an increase in cardiac protein synthesis in vivo. Furthermore, IGF-I also increases protein synthesis in quiescent myocytes in vitro, which are not subject to changes in contractility (4).
Coinfusion of amino acids with IGF-I prevented the decline in circulating amino acids used for protein synthesis that otherwise occurs during IGF-I infusion (1, 10, 22, 23) and potentiated IGF-I's stimulation of heart contractile protein synthesis in the fasted rats. These findings are consistent with our prior observations that amino acid infusion significantly augmented IGF-I's effect on skeletal muscle and heart mixed protein synthesis in the rat (23). Similar effects of amino acids have also been reported with respect to IGF-I's effect on human skeletal muscle protein synthesis (16, 29). It might be noted that amino acid infusion per se, even at an eightfold higher rate than used in this study, does not increase phenylalanine incorporation into heart protein (25). Thus the effect of amino acid infusion to blunt the fall in both plasma amino acid and insulin concentrations, which occurs with IGF-I infusion, may be important in potentiating the effect of IGF-I on muscle protein synthesis (23). IGF-I also stimulated contractile protein synthesis in fed rats that had higher rates of heart protein synthesis than the fasted rats. As expected, the fed rats had higher basal insulin concentrations and did not develop severe hypoinsulinemia or hypoaminoacidemia, presumably reflecting continued absorption of amino acids from the gut. These features of the fed state may have potentiated the effect of IGF-I in these rats. In addition, these findings provide important evidence that IGF-I's stimulatory effect on contractile protein synthesis is not limited to more catabolic fasted animals.
The current studies are of clinical interest in view of recent data suggesting that IGF-I and growth hormone promote heart growth and may have favorable effects on cardiac function in heart failure (2, 3, 8, 9). Growth hormone alone has little direct growth-promoting effect on cardiac myocytes (20), but when administered in vivo, it increases circulating IGF-I concentrations (19) as well as local muscle production of IGF-I (32), which are thought to play an important role in mediating growth hormone's action on the heart. However, growth hormone action in vivo on the heart may not simply be mediated by IGF-I but may also involve interactions with other hormones, such as insulin, which may modulate IGF-I's effects directly or through changes in IGF-I-binding proteins (27). In this regard, recent studies are also of note, in that they have shown different patterns of cardiac hypertrophy in rats receiving chronic infusions of IGF-I, growth hormone, or the combination of both IGF-I and growth hormone (3).
We did not measure synthesis rates of specific myosin heavy chain
isoforms in the current study, but the normal rat at this age
predominantly expresses the higher activity -isoform (21). In
contrast, in cultured rat cardiocytes (14) and quiescent rabbit
myocytes (5), which predominantly express
-myosin heavy chain, IGF-I
increases
-myosin heavy chain synthesis in vitro. The extent to
which the stimulatory effects of IGF-I on contractile protein synthesis
reflect generalized translational effects on the adult heart in vivo,
or more specific transcriptional regulation of individual proteins,
remains uncertain. However, the parallel increase observed in the
synthetic rates of mixed myocardial protein makes it likely that IGF-I
activates factors controlling protein translation in the heart. The
effect of IGF-I on these pathways and the signaling mechanisms
responsible for IGF-I's effect on the heart warrant further
investigation, given the important physiological effects of IGF-I
demonstrated in these studies.
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ACKNOWLEDGEMENTS |
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We thank Drs. Raymond Russell and Patrick McNulty for review of the manuscript.
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FOOTNOTES |
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This study was supported by grants from the American Diabetes Association and National Institute of Diabetes and Digestive and Kidney Diseases (RO1-DK-40936). The rhIGF-I was generously supplied by Genentech (Palo Alto, CA).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: L. H. Young, Section of Cardiovascular Medicine, 323 FMP, Yale Univ. School of Medicine, 333 Cedar St., New Haven, CT 06520-8017.
Received 5 May 1998; accepted in final form 30 September 1998.
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