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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60:28-34 (2005)
© 2005 The Gerontological Society of America

Effects of Long-Term Caloric Restriction on Early Steps of the Insulin-Signaling System in Mouse Skeletal Muscle

Danila P. Argentino1, Fernando P. Dominici1, Khalid Al-Regaiey2, Michael S. Bonkowski2, Andrzej Bartke2 and Daniel Turyn1,

1 Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
2 Departments of Physiology, Medicine, and Pharmacology, School of Medicine, Southern Illinois University, Springfield.

Address correspondence to Daniel Turyn, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956 (1113), Buenos Aires, Argentina. E-mail: dturyn{at}qb.ffyb.uba.ar


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
In this study, we analyzed the effects of long-term (14 months) caloric restriction (CR) on the first steps of the insulin signaling system in skeletal muscle of normal mice. CR induced a significant decrease in serum insulin and glucose levels, indicating an enhancement of insulin sensitivity. CR reduced the in vivo insulin-induced phosphorylation of the insulin receptor substrate (IRS)-1 by 27%, but this difference was not significant (p =.298). CR reduced insulin receptor (IR) abundance by 34% from the ad libitum values, but this difference did not reach significance (p =.246). The abundance of the p85 regulatory subunit of PI3K and glucose transporter 4 was unaltered after CR. However, IRS-1 abundance was significantly increased by 42% in muscle of mice exposed to CR. These findings indicate that the CR-induced improvement of insulin action in mice is not related to changes in glucose transporter 4, the p85 regulatory subunit of PI3K, or IR abundance in skeletal muscle but might be related to an increase in IRS-1 abundance in this tissue.

CALORIC restriction (CR) is the only known environmental intervention that retards aging and extends life span in a wide variety of both mammalian and nonmammalian species (1–5). A fundamental alteration observed in rats after CR is the augmented insulin-stimulated glucose transport in skeletal muscle (6,7). Insulin increases glucose uptake by stimulating translocation of glucose transporter 4 (GLUT4) from intracellular sites to the cell surface (8). Up to 75% of insulin-dependent glucose disposal occurs in skeletal muscle (8), and thus alterations in glucose metabolism in this tissue are important for the enhanced whole-body insulin sensitivity observed after CR. However, the mechanisms behind these alterations are not known. The signaling pathways by which insulin induces the translocation of GLUT4 to the cell surface include activation of the insulin receptor (IR). This is followed by autophosphorylation of the IR and the subsequent phosphorylation of several intracellular proteins including insulin receptor substrate (IRS)-1, an adaptor protein that appears to be essential for insulin action in skeletal muscle (8,9). Phosphorylated tyrosines in IRS-1 act as docking sites for various signaling molecules including phosphatidylinositol 3-kinase (PI3K) (8,9). Binding of tyrosine phosphorylated IRS-1 to the p85 regulatory subunit of PI3K (p85) results in the activation of this enzyme (8,9). This is a pivotal event in the metabolic actions of insulin in skeletal muscle (8,9).

Most of the research addressing the mechanism by which CR increases insulin sensitivity has been performed in rodents subjected to CR for short periods of time (5–28 days). The effects reported to date are as follows: with brief CR, there is no change in the number or binding affinity of the IR in skeletal muscle (10,11); there is also no effect on the tyrosine kinase activity of the IR (12). These effects suggest involvement of a postreceptor mechanism. However, subsequent research demonstrates that CR for 20 days increases insulin-stimulated phosphorylation of the IR and IRS-1 in skeletal muscle in rats (13) while inducing a decrease in the abundance of IRS-1 with no change in IRS-2 in skeletal muscle in rats and mice (6,14). Activation of PI3K, the next step in the insulin signaling pathway leading to glucose uptake, is also unaffected by short-term CR (15), along with the total amount of GLUT4 and p85 in skeletal muscle (6). However, researchers recently found that increased Akt2 phosphorylation plays a role in the CR-induced increase in insulin sensitivity in rat skeletal muscle (16). Reports on the effect of long-term CR on the insulin signaling system are scarce. Long-term CR has been shown to exert a pronounced increase in insulin sensitivity in rats (7,17). Similar results were found in humans subjected to a low-caloric diet for 2 years (18). In rhesus monkeys, long-term CR improved glucose tolerance and enhanced whole-body insulin sensitivity (19). In these animals, IRS-1 abundance tended to be greater in skeletal muscle, whereas the abundance of GLUT4 or p85 was unaltered (20). This result agrees with a study performed in rats in which GLUT4 levels were not affected by long-term CR (7). Thus, to provide a further insight into the molecular mechanisms involved in the enhancement of insulin action associated with long-term CR, the aim of our study was to determine the influence of prolonged CR in normal mice on the in vivo status of the first steps of the insulin signaling system in skeletal muscle. To this end, we evaluated the effects of consuming 70% of ad libitum intake for 14 months (starting at the age of 2 months) on the in vivo insulin-stimulated phosphorylation of the IR and IRS-1 in skeletal muscle of normal mice. Moreover, the effects of CR on the abundance of the IR, IRS-1, p85, and GLUT4 were evaluated in this tissue.


   METHODS
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Materials
The reagents and apparatus for sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE) and immunoblotting were obtained from Bio-Rad (Hercules, CA). HEPES, Tris, phenylmethylsulfonyl fluoride (PMSF), aprotinin, Triton X-100, Tween 20, porcine insulin, bovine serum albumin (fraction V), and polyvinylidene difluoride (PVDF) membranes were obtained from Sigma Chemical Co. (St. Louis, MO). Protein A-Sepharose 6 MB was obtained from Pharmacia (Uppsala, Sweden), and enhanced chemiluminescence (ECL) was obtained from Amersham (Piscataway, NJ). The monoclonal antiphosphotyrosine antibody ({alpha}PY, PY99), the polyclonal anti-IR ß-subunit antibody ({alpha}IR, C-19), the polyclonal antibody raised against GLUT4, goat antirabbit immunoglobulin G (IgG) conjugated with horseradish peroxidase (HRP) and goat antimouse IgG HRP secondary antibodies were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). The antirat carboxy-terminal IRS-1 antibody ({alpha}IRS-1) and the antibody to p85 ({alpha}p85) were obtained from Upstate Biotechnology (Lake Placid, NY).

Animal Care and Feeding
Normal female mice were used in this study in a closed colony with a heterogeneous genetic background. This stock was derived from crossing 129 Ola - BALB/c background mice with a line derived from C57BL/g x C3H hybrids. Animals from this stock were used in our previous studies of insulin signaling (21). The animals were weaned at 21 days of age and were housed in groups of 4–5 per cage in plastic "shoe box type" cages with wood chips in a room with a controlled 12:12 day/night cycle (lights on from 6 AM to 6 PM) and a temperature of 22 ± 2°C. Each cage was equipped with an individual filter top (microisolator unit). Sentinel animals were housed in the same room and were used in testing for antibodies to all major murine pathogens. The results of the tests were uniformly negative. Starting at 2 months of age, animals were divided into two groups: ad libitum (AL) or CR. AL (control) animals had constant access to food (Rodent Laboratory Chow 5001; not autoclaved; 23.4% protein, 4.5% fat, 5.8% crude fiber; purchased from LabDiet, PMI Feeds, Inc., St. Louis, MO). Using a previously described protocol (22,23), we gradually decreased the caloric intake of the CR animals by 30%. CR animals received 90% of the caloric intake of their AL counterparts for the first week, 80% for the second week, and 70% for the remainder of the study. We calculated the AL animals' average daily food consumption by monitoring their food consumption weekly per cage, and the CR animals were fed daily, at approximately 5:00 PM, 70% of the average amount of food consumed daily by AL animals during the preceding week (22,23). Both groups were given tap water ad libitum. Animals were used at the age of 16 months, after 14 months of dietary treatment. The stages of the estrous cycle were not monitored because, at 16 months of age, mice usually do not exhibit cyclic change in the cellular composition of vaginal smears. All animal studies were approved by the Southern Illinois University Animal Care and Use Committee.

Glucose and Insulin Concentrations
We measured circulating insulin concentration in 10- to 20-µL serum samples by using an RIA kit for insulin (Linco Research, Inc., St. Charles, MO). Serum glucose was measured in single 10-µL samples with the glucose oxidase procedure (Trender; Sigma Chemical Co.).

Insulin Administration and Tissue Homogenization
Food was withdrawn for 16 hours. Mice were anesthetized with isoflurane (Baxter Pharmaceutical Products, Inc., Deerfield, IL). After anesthesia was induced, a sample of blood under basal conditions was drawn by cardiac puncture as previously described (21,24,25). Afterward, the portal vein was exposed and 10 IU of porcine insulin per kilogram of body weight in saline vehicle (0.9% NaCl) in a final volume of 0.1 mL was injected via this vein. Control mice in both CR and AL groups were injected with vehicle to obtain data under basal conditions. Approximately 3 minutes after injection, hind-limb skeletal muscle was removed, coarsely minced, and homogenized in 10 volumes of solubilization buffer A [1% Triton, 100 mM Tris (pH 7.4), 100 mM sodium pyrophosphate, 100 mM sodium fluoride, 10 mM EDTA, 10 mM sodium vanadate, 2 mM PMSF, and 0.1 mg/ml aprotinin] at 4°C as described previously (24,25). Muscle extracts were centrifuged at 100,000 g for 1 hour at 4°C to eliminate insoluble material, and protein concentration was measured using the Bradford method (24,25).

Immunoprecipitation and Immunoblotting
Equal amounts of muscle protein were incubated at 4°C overnight with {alpha}IR or {alpha}IRS-1 (4 µg/ml final concentration for all antibodies). Immune complexes were collected by incubation with protein A-Sepharose, washed with solubilization buffer A, boiled in Laemmli sample buffer, and stored at –70°C until electrophoresed. Resolution of proteins by SDS–PAGE and Western transfer of proteins to PVDF membranes was performed as previously described (24,25). Membranes were blocked by incubation with a blocking buffer composed of Tris-buffered saline–Tween 20 (TBS-T) buffer [10 mM Tris–HCl (pH 7.6), 150 mM NaCl, and 0.02% Tween 20] containing either 3% bovine serum albumin (fraction V) (for phosphotyrosine detection) or 5% nonfat dry milk (for protein detection). The membranes were then incubated for 4 hours at room temperature with {alpha}PY (1 µg/ml), {alpha}IR (1 µg/ml), or {alpha}IRS-1 (1 µg/ml). Finally, membranes were incubated with goat antimouse IgG HRP secondary antibody (for PY detection) or with goat antirabbit IgG HRP (for protein detection), and specific bands were detected by ECL. The intensities of the bands were quantitated by optical densitometry.

To determine the abundance of p85 and GLUT4 in skeletal muscle, we denatured equal amounts of solubilized muscle protein (80 µg) by boiling them in reducing sample buffer, resolving them by using SDS–PAGE, and subjecting them to immunoblotting with {alpha}p85 (1:2000 dilution) or {alpha}GLUT4 (1:200 dilution). Membranes were incubated with goat antirabbit IgG HRP, proteins were detected with ECL, and the intensities of the specific bands were quantitated by optical densitometry.

Statistical Analysis
Results are presented as means ± SEM, except where otherwise indicated. Experiments were performed by analyzing all groups of animals in parallel. Data were analyzed using analysis of variance (ANOVA) followed by the Tukey–Kramer test using GraphPad InStat (version 3.0 for Windows 95; GraphPad Software, Inc., San Diego, CA). Student's t test was used when the values of two groups were analyzed. The level of significance was set at p <.05.


   RESULTS
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Animal Characteristics
The effects of CR on body weight and circulating levels of glucose and insulin are shown in Table 1. Animals subjected to CR (CR mice) exhibited a moderate (33%) decrease in circulating glucose levels and a more profound decrease in insulin levels (60%) as compared to ad libitum-fed animals (AL mice) (p <.05 and p <.003, respectively). The mean body weight of CR mice was 28% lower than that of AL mice (p <.005).


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  		Table 1. Characteristics of Animals Used.

 
Tyrosine Phosphorylation and Protein Levels of IR
For comparison and evaluation, the value of insulin-stimulated AL mice was set at 100%. Basal IR phosphorylation values were similar in CR and AL mice. As determined by immunoblotting with an antiphosphotyrosine antibody, the phosphorylation level of the IR in skeletal muscle of AL mice after an in vivo bolus injection of insulin was increased by 54% (p <.05 vs basal AL mice; n = 3) (Figure 1, A and B). IR phosphorylation in skeletal muscle of CR mice showed a similar extent of increase (50%) after an in vivo insulin stimulation when compared to the respective basal value (p <.05) (Figure 1A and B). Moreover, both groups had a similar level of IR after insulin stimulation (Figure 1A and B), suggesting that CR did not affect the response to insulin at this level.



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  		Figure 1. Insulin receptor (IR) tyrosine phosphorylation and protein levels in skeletal muscle of ad libitum (AL) and caloric-restricted (CR) mice. A sample of muscle was obtained after injecting insulin (+) or its diluent (–) into the portal vein. Equal amounts of solubilized protein obtained as described in the Methods section were immunoprecipitated with an anti-insulin receptor antibody ({alpha}IR), run on SDS–PAGE (sodium dodecyl sulfate–polyacrylamide gel electrophoresis), and analyzed by Western blotting with phosphotyrosine antibody ({alpha}PY) (A) or {alpha}IR (C). (B and D) Data quantification by scanning densitometry: means ± SEM of the number of independent experiments are indicated. IR tyrosine phosphorylation is expressed as a percentage; we assigned a value of 100% to the mean of insulin-stimulated (AL) mice (B). The level of IR is expressed as relative to values found in AL mice, which were set at 100% (D)

 
As compared to that in AL mice, IR abundance after CR was numerically greater with a difference of 34%. However, this apparent change did not reach statistical significance (p =.246, n = 6; Figure 1C and D). Although IR abundance appeared to be increased in skeletal muscle of CR mice, when the data were normalized for the amount of receptor protein in muscle, the muscular receptor phosphorylation in CR mice was numerically lower (reduced by 30%) when compared to values measured in AL mice. This difference did not reach statistical significance (p =.06; Figure 3).



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  		Figure 3. Ratio between in vivo phosphorylated IR and IRS-1 and total immunoprecipitable quantity of receptor or IRS-1 in muscle from AL and CR mice. Data are expressed as means ± SEM (standard error of mean). * p <.01 vs AL mice

 
Tyrosine Phosphorylation and Protein Levels of IRS-1
In skeletal muscle of CR animals, the basal level of phosphorylation of IRS-1 was numerically decreased by 50% when compared to the respective AL values, but this change did not reached statistical significance (Figure 2A and B). After stimulation with insulin, a similar level of IRS-1 tyrosine phosphorylation was found in both groups of animals (Figure 2A and B; n = 3). In spite of the similarity in the response to insulin at the level of IRS-1 phosphorylation, there was a significant change in the abundance of IRS-1 in skeletal muscle of CR mice. When compared to AL mice, IRS-1 abundance in skeletal muscle was increased by 42% in CR mice (p <.05; n = 6; Figure 2C and D). In comparison to animals fed AL, the ratio between the in vivo phosphorylated IRS-1 and the total amount of IRS-1 in muscle of CR mice was significantly reduced (50% of AL values; p =.012; Figure 3).



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  		Figure 2. Insulin receptor substrate (IRS)-1 tyrosine phosphorylation and protein levels in skeletal muscle of ad libitum (AL) and caloric-restricted (CR) mice. Animals received injections as per
Figure 1. Equal amounts of solubilized muscle protein were immunoprecipitated (IP) with an anti-IRS-1 antibody ({alpha}IRS-1), run on SDS–PAGE (sodium dodecyl sulfate–polyacrylamide gel electrophoresis), and analyzed by Western blotting with {alpha}PY (A) and {alpha}IRS-1 (C). (B and D) Data quantification by scanning densitometry: means ± SEM (standard error of mean) of the number of independent experiments indicated. IRS-1 tyrosine phosphorylation is expressed as a percentage; we assigned a value of 100% to the mean of insulin-stimulated AL-mice (B). IRS-1 protein level is expressed as relative to values found in AL mice, which were set at 100% (D). * p <.05 vs normal mice

 
Protein Levels of p85 and GLUT4
The total amount of p85 in skeletal muscle was not altered after CR (Figure 4A and B). When compared to AL mice, the amount of p85 in skeletal muscle of CR mice was numerically (32%) but not statistically higher (p =.270; n = 6; Figure 4A and B). No statistically significant differences were found in the muscle level of GLUT4 protein after CR (p =.839; Figure 4C and D).



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  		Figure 4. Protein levels of the p85 regulatory subunit of PI3K (p85) and GLUT4 in skeletal muscle of ad libitum (AL) and caloric restricted (CR) mice. Equal amounts of muscle protein were run on SDS–PAGE (sodium dodecyl sulfate–polyacrylamide gel electrophoresis) and subjected to Western blotting using antibodies against p85 ({alpha}p85) (A) or GLUT4 ({alpha}GLUT4) (C). (B and D) Data quantification by scanning densitometry: means ± SEM (standard error of mean) of the number of independent experiments indicated. Values are expressed as percentages; we assigned a value of 100% to the mean value in AL mice

 

   DISCUSSION
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Caloric restriction improves insulin action in peripheral tissues of many species including mice, rats, rhesus monkeys, dogs, and humans (5,17,18,26–28). Insulin and glucose serum levels were found to be decreased in CR mice, indicating an increased whole-body insulin sensitivity in these animals [reviewed in (5)].

The main purpose of this study was to evaluate the mechanisms by which long-term CR increases insulin sensitivity. To that end, the consequences of long-term CR on the abundance and functionality of the early components of the insulin signaling system were analyzed in skeletal muscle of normal mice.

Long-term CR resulted in an important reduction in both glucose and insulin levels, indicating an improvement in insulin sensitivity. Previous reports in other mammalian species such as rats and monkeys agree with these results (7,19,27). A striking result found in our study was that long-term CR failed to alter the response to in vivo insulin injection challenge in terms of maximal phosphorylation of IR and IRS-1 in skeletal muscle of normal mice. This contrasts with previous findings in rats exposed to short-term CR where both insulin-stimulated IR and IRS-1 phosphorylation were enhanced (13). Two conclusions can be drawn out of these observations: first, the increase in insulin sensitivity found after long-term CR in mice is apparently not associated with an enhancement in the functionality of the IR or the IRS-1, and second, the contrast between the previous studies performed in rats after short-term CR (13) and our current findings imply that the early steps of the insulin signaling system might be differentially modulated in rodents after short- or long-term CR.

The total amount of IR in muscle was not significantly changed by CR, in agreement with previous observations in rats subjected to short-term CR (10,13). A trend toward a decrease in the ratio of IR phosphorylation to the total amount of IR in muscle was found, suggesting a possibility of a reduced activation of the IR after long-term CR.

Another significant finding was that IRS-1 protein levels in skeletal muscle were increased in mice after 14 months of CR. This is similar to what was previously reported for rhesus monkeys subjected to long-term (6 years) CR, where there was a trend to an increase in the abundance of this protein (20). Collectively, our results and those found in monkeys (20) indicate that the increased expression of IRS-1 in skeletal muscle might be a common feature of animals subjected to long-term CR. Although IRS-1 appears to be essential for insulin action in skeletal muscle (8,9), it is not clear if the increase in the amount of IRS-1 detected in CR mice plays a role in the increased insulin sensitivity in these animals because the in vivo phosphorylation of IRS-1 attained after insulin injection was similar to that measured in AL mice. The ratio of IRS-1 phosphorylation to the total amount of IRS-1 in muscle in CR mice was significantly reduced, suggesting that CR did not improve the insulin signaling system at either IR or IRS-1 levels.

The upregulation of IRS-1 observed in our study could be the consequence of decreased insulin levels. A negative correlation between IRS-1 content and insulin concentrations was observed in vitro (29,30). However, IRS-1 abundance in skeletal muscle is decreased in some hypoinsulinemic states (24,31). Moreover, increased abundance of IRS-1 has been found to be associated with the hyperinsulinemic–insulin-resistant state induced by either a high-fat or a high-salt diet (32,33). It is interesting that a major decrease in the content of IRS-1 in skeletal muscle has been found in rodents exposed to short-term CR (6,14). Therefore, an important conclusion from our study is that the levels of IRS-1 may be differentially affected after short- or long-term CR. The role of IRS-1 regulation in the modulation of insulin sensitivity in response to dietary treatment in mice remains to be clearly defined, as short-term CR was reported to increase insulin sensitivity in IRS-1 knockout mice (14).

Regarding our current results, we hypothesize that the increase in IRS-1 levels found in mice after 14 months CR could represent an adaptation to prevent these animals from becoming hypoglycemic in response to a treatment that enhances insulin sensitivity. Only a small number of studies have explored the effect of CR on skeletal muscle p85 protein abundance in mammals. The evidence accumulated so far indicates that the total amount of p85 in skeletal muscle is not changed after either short-term CR in mice (6) or long-term CR in rhesus monkeys (20). In agreement with those reports, we found in our study that p85 levels were not significantly altered in skeletal muscle of mice subjected to chronic CR. Insulin-stimulated association of p85 with IRS-1 was previously shown to be unaltered after short-term CR in rats (15). Moreover, short-term CR does not alter the insulin stimulation of IRS-1-, IRS-2-, or phosphotyrosine-associated PI3K in skeletal muscle (13,15), suggesting that CR improves insulin action through mechanisms that do not involve PI3K activation.

Skeletal muscle is the most important tissue involved in the insulin-dependent clearance of whole-body glucose and glucose transport emerges as the apparent rate- limiting step of this action (8). It has been reported that CR improves insulin-dependent glucose transport in skeletal muscle of normal rats by a mechanism that does not involve up-regulation of GLUT4, regardless of the duration of the dietary treatment (6,7). Further support of this conclusion was provided by a recent report demonstrating unaltered levels of GLUT4 in skeletal muscle from rhesus monkeys subjected to long-term CR (20). However, short-term CR leads to an increased number of cell-surface GLUT4 transporters in rat skeletal muscle after insulin stimulation (6). In our study, the insulin-induced translocation of GLUT4 was not analyzed, but the results are consistent with the available information on the effects of long-term CR on muscle GLUT4 content in both rats and rhesus monkeys (7,20).

CR mice appear as an important model in research on aging, and an extensive evaluation of insulin and IGF-1 signal transduction in this mammalian model of delayed aging and increased life span could allow researchers to determine whether the status of the insulin signaling system and insulin action is related to the duration of life in mammals.

Our study is the first to report the analysis of the in vivo status of the proximal insulin signaling steps in skeletal muscle of mice subjected to long-term CR. In summary, we determined that long-term CR induced a decrease in body weight, as well as a reduction in serum glucose and insulin levels. CR did not alter the in vivo insulin-induced phosphorylation of IR or IRS-1, nor the amount of GLUT4 transporter, p85, or IR. However, IRS-1 abundance was significantly increased in CR mice.


   Acknowledgments
 
Daniel Turyn and Fernando Pablo Dominici are Career Investigators from Consejo Nacional de Investigaciones Científicas y Tecnológicas of Argentina (CONICET). They received grant support from the University of Buenos Aires, CONICET, Fundación Antorchas, and Agencia Nacional de Promoción Científica y Tecnológica of Argentina (ANPCYT). Danila P. Argentino is a research fellow from CONICET. Andrzej Bartke received support from the National Institute on Aging (AG 19899) and from the SIU Geriatric Medicine and Research Institute.


   Footnotes
 
Decision Editor: James R. Smith, PhD

Received April 12, 2004

Accepted July 19, 2004


   References
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 Methods
 Results
 Discussion
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