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ENVIRONMENTAL, EXERCISE AND RESPIRATORY PHYSIOLOGY
1Nutrition, Exercise Physiology, and Sarcopenia Laboratory, Jean Mayer U.S. Department of Agriculture, Human Nutrition Research Center on Aging, Tufts University; and 2Human Physiology Laboratory, Department of Health Sciences, Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, Massachusetts
Submitted 15 April 2005 ; accepted in final form 18 November 2005
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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was increased immediately and 6 h after contraction in TA (1.6 ± 0.3- and 4.1 ± 0.8-fold, P < 0.05) and Pla (1.7 ± 0.2- and 2.1 ± 0.4-fold, P < 0.05) in Y rats and remained unaffected in O rats. Phosphorylation of GSK-3
was observed only immediately after HFES in TA (1.5 ± 0.2-fold, P < 0.05) in Y rats. Overall, eIF4E-eIF4G association and phosphorylation of 4E-BP1 and GSK-3 are increased after HFES in adult, but not in aged, animals. These observations suggest that the anabolic response to muscle stimulation is attenuated with aging and may contribute to the limited capacity of hypertrophy in aged animals. sarcopenia; exercise; signaling; hypertrophy
The mammalian target of rapamycin (mTOR) signaling kinase, which can be activated by Akt/protein kinase B, has emerged as a crucial regulator of skeletal muscle hypertrophy (8, 41). Acute and chronic effects of contractile activity have been described to increase the phosphorylation of mTOR and its downstream target, the 70-kDa ribosomal protein p70S6K1 (8, 10, 37, 40). p70S6K1 is pivotal in the control of translation, inasmuch as it regulates a subset of mRNAs containing 5'-terminal polypyrimidine tracts (TOP sequences), which encode ribosomal proteins and factors essential to the translational machinery (49). mTOR also phosphorylates eukaryotic initiation factor (eIF) 4E (eIF4E) binding protein (4E-BP1) (16). Hyperphosphorylation of 4E-BP1 prevents itself from binding to eIF4E, liberating eIF4E, which, in turn, binds to eIF4G. The eIF4E-eIF4G complex formation mediates association of the eIF4E-mRNA complex with the 40S ribosomal subunit, thereby triggering translation (38).
The phosphorylation of glycogen synthase kinase 3 (GSK-3) by Akt has also been implicated as an important signaling component in skeletal muscle hypertrophy in an mTOR-independent manner (11, 41). Inhibition of GSK-3 by phosphorylation promotes protein synthesis by releasing inhibition on the translation initiation factor eIF2B. eIF2B mediates the guanine nucleotide exchange on eIF2, which then aids the binding of methionyl-tRNA to the 40S ribosomal subunit to form the 43S preinitiation complex, thus promoting protein synthesis (21, 23).
The increase in phosphorylation of mTOR and p70S6K1 due to a single bout of exercise has previously been reported to be blunted in aged animals (36). These observations suggest that the anabolic response to a single bout of contraction is attenuated with aging and may help explain the limited capacity for hypertrophy in aged animals. The effect of aging on the other downstream targets of Akt, to our knowledge, has not been examined.
The intent of the present study was to determine how aging affects the regulation of the translation initiation pathway (4E-BP1/eIF4E-eIF4G) and the preinitiation complex formation pathway (GSK-3) in skeletal muscle subjected to contractile activity. Activation of these pathways was assessed in skeletal muscle from adult and aged rats immediately or 6 h after a single bout of sciatic nerve stimulation. We hypothesized that aging impairs the ability of contraction to stimulate 4E-BP1 phosphorylation, eIF4E-eIF4G formation, and GSK-3 phosphorylation.
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MATERIALS AND METHODS |
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/ (Ser21/9), GSK-3, phospho-4E-BP1 (Thr37/46), and 4E-BP1] were obtained from Cell Signaling Technologies (Beverly, MA); anti-eIF4G from Bethyl Laboratories (Montgomery, TX); anti-rabbit and anti-mouse horseradish peroxidase-conjugated secondary antibodies from Amersham Biosciences (Piscataway, NJ); and anti-rabbit BioMag IgG beads from Qiagen (Valencia, CA). All other chemicals were purchased from Sigma Chemical (St. Louis, MO) and Bio-Rad (Hercules, CA). Animals. Protocols for animal use were approved by the Institutional Animal Care and Use Committee of Boston University. Adult (6 mo old, n = 15) and aged (30 mo old, n = 15) male Fischer 344 x Brown Norway rats were purchased from the National Institute on Aging. The Fischer 344 x Brown Norway rat was chosen, because these animals exhibit a lower incidence of disease than other rat strains and demonstrate age-associated decrements in muscle mass and function that are similar to those seen in humans (7). On arrival, the animals were acclimatized for 3 days before experimentation and fasted overnight before the experimental protocol.
Electrical stimulation. The high-frequency electrical stimulation (HFES) model has been previously described (37) and was chosen on the basis of its efficacy in stimulating protein translation and muscle hypertrophy in vivo (2). The HFES model used in the present study produced 10 sets of 10 contractions with an overall protocol time of 30 min. This protocol results in concentric (shortening) contraction of the plantaris (Pla) and eccentric (lengthening) contraction of the tibialis anterior (TA). TA and Pla muscles were chosen, because contractile activity has previously been shown to induce mTOR signaling in these muscles after HFES (37). In addition, the HFES model allows a comparison of the effects of different types of contractions in adult and aged muscle. Animals were killed by a lethal dose of pentobarbital sodium at baseline (n = 5 adult, n = 5 aged) or immediately (n = 5 adult, n = 5 aged) or 6 h (n = 5 adult, n = 5 aged) after HFES.
Preparation of skeletal muscle tissue lysates.
TA and Pla muscles were rapidly dissected, trimmed of connective tissue, weighed, frozen in liquid nitrogen, and stored at –80°C. Samples for Western blot analyses were homogenized in 10 volumes of lysate buffer containing 50 mM Tris·HCl, 100 mM NaF, 10 mM EDTA, 50 mM -glycerophosphate, 1 mM Na3VO4, 3 mM benzamidine, 1 mM phenylmethylsulfonyl fluoride, and 10 µg/ml each of aprotinin, leupeptin, and pepstatin. Homogenates were centrifuged at 10,000 g for 10 min at 4°C, and aliquots were stored at –80°C. The protein concentration was determined by the Bradford assay with BSA as a reference (Bio-Rad).
Immunoprecipitation.
The association of eIF4E with eIF4G and the association of eIF4E with 4E-BP1 were quantified by a modification of the method described by Kimball et al. (25). Briefly, an anti-eIF4E antibody was used for immunoprecipitation of eIF4E-eIF4G and 4E-BP1 complexes from 400 µg of muscle protein. The antibody-antigen complex was collected by incubation for 1 h at 4°C with 500 µl of goat anti-rabbit BioMag IgG beads. Before they were used, the beads were washed three times with low-salt buffer [LSB; 20 mM Tris·HCl (pH 7.4), 150 mM NaCl, 5 mM EDTA, 0.5% Triton X-100, and 0.1% -mercaptoethanol] on a magnetic rack, and half of the original volume was reconstituted with LSB-0.1% nonfat dry milk. After the incubation, the beads were washed twice with LSB and once with high-salt buffer [50 mM Tris·HCl (pH 7.4), 500 mM NaCl, 5 mM EDTA, 1% Triton X-100, 0.5% sodium deoxycholate, 0.1% SDS, and 0.04% -mercaptoethanol]. The beads were washed in 100 µl of SDS sample buffer, and the sample was boiled for 5 min to elute protein bound to the beads. Supernatants were collected using a magnetic rack, and 20-µl aliquots were subjected to electrophoresis on a 7.5% polyacrylamide gel for quantification of eIF4G or 4E-BP1 [eIF4G and 4E-BP1 antibodies diluted 1:200 and 1:50,000, respectively, in 5% BSA in Tween 20-Tris base sodium (TTBS)] or a 15% polyacrylamide gel for quantification of total eIF4E (diluted 1:10,000 in 5% BSA in TTBS).
Western blotting. Equal amounts of protein (20 or 40 µg) were resolved by SDS-PAGE using 15% gel for GSK-3 and 4E-BP1. Proteins were transferred to polyvinylidine difluoride membranes (Bio-Rad), and equal protein loading was verified by Ponceau S staining. Membranes were blocked for 1 h in TTBS containing 5% milk and then incubated with the appropriate primary antibody (diluted 1:1,000 in 5% BSA in TTBS) overnight at 4°C. After they were washed several times in TTBS, the membranes were incubated with anti-rabbit or anti-mouse horseradish peroxidase-conjugated secondary antibodies (diluted 1:10,000 in blocking buffer) for 1 h at room temperature. Protein signals were detected with Enhanced Chemiluminescence Plus reagents (Amersham, Piscataway, NJ). Images were scanned, and band intensities were quantified by densitometry (Bioquant Image Analysis, Nashville, TN).
Statistical analyses. The differences in phosphorylation and eIF4E-eIF4G and 4E-BP1 association band intensity were calculated between experimental muscles and corresponding control muscles for each individual animal as follows: change = (experimental intensity – control intensity)/control intensity. From this, a fold-change score was derived: fold change = (control intensity/control intensity) + change. For the baseline comparisons of TA to Pla and adult to aged animals, the differences in intensity were compared in a similar manner: change = (TA intensity – Pla intensity)/Pla intensity; fold change = (Pla intensity/Pla intensity) + change; change = (adult intensity – aged intensity)/aged intensity; fold change = (aged intensity/aged intensity) + change. Values are means ± SE of five rats per group. Differences between control and experimental muscles in both age groups were also determined by a paired t-test. Differences in baseline parameters between age groups were determined by an unpaired t-test. Differences were considered significant at P < 0.05.
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RESULTS |
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GSK-3 phosphorylation after contractile activity in adult and aged animals.
GSK-3 and GSK-3 phosphorylation was not different between TA and Pla muscles at baseline [1.2 ± 0.17-fold (P = 0.4) and 1.2 ± 0.16-fold (P = 0.4) in adult and aged rats, respectively, for GSK-3 and 1.1 ± 0.15-fold (P = 0.8) and 1 ± 0.07-fold (P = 0.5) in adult and aged rats, respectively, for GSK-3] or between adult and aged rats [0.9 ± 0.05-fold (P = 0.5) and 1.0 ± 0.3-fold (P = 0.7) in TA and Pla, respectively, for GSK-3 and 0.9 ± 0.08-fold (P = 0.3) and 0.9 ± 0.17-fold (P = 0.5) in TA and Pla, respectively, for GSK-3]. Total GSK-3 protein was used as the internal control for phosphorylated GSK-3 and phosphorylated GSK-3, inasmuch as it was not altered at baseline or with contractile activity in either age group. GSK-3 phosphorylation increased immediately and 6 h after exercise in TA [1.6 ± 0.3-fold (P < 0.05) and 4.1 ± 0.8-fold (P < 0.01)] and Pla [1.7 ± 0.2-fold (P < 0.01) and 2.1 ± 0.4-fold (P < 0.05)] muscles in adult rats, but no significant change was observed in aged rats (Fig. 1). GSK-3 phosphorylation remained unaffected by contractile activity, except in adult TA muscle at 0 h compared to control (1.5 ± 0.2-fold, P < 0.05).
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-form (unphosphorylated), -form (phosphorylated), and 
-form (hyperphosphorylated). Phosphorylated 4E-BP1 expressed two bands, representing the - and -forms. 4E-BP1 phosphorylation was normalized to the total 4E-BP1 protein by measurement of the ratio of phosphorylated to total band intensity. 4E-BP1 phosphorylation was not different between TA and Pla muscles at baseline [0.9 ± 0.06-fold (P = 0.2) and 1.2 ± 0.36-fold (P = 0.8) for adult and aged, respectively] or between adult and aged rats [1.03 ± 0.22-fold (P = 0.6) and 1.09 ± 0.11-fold (P = 0.7) for TA and Pla, respectively]. A significant increase in 4E-BP1 phosphorylation was observed 6 h after exercise in TA muscle (5.0 ± 2.0-fold, P < 0.05) in adult, but not in aged, rats (Fig. 2). Although there was a 66% increase immediately after and a fivefold increase 6 h after HFES in Pla muscle of adult rats, these changes were not statistically significant. In addition, no change in 4E-BP1 phosphorylation was observed in Pla muscle of aged rats. The association of 4E-BP1 with eIF4E was not affected by age or contractile activity.
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DISCUSSION |
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phosphorylation, 4E-BP1 phosphorylation, and eIF4E-eIF4G complex formation in young animals but that this response is blunted in older animals. In adult rats, activation of mTOR/p70S6K1 occurs immediately and 6 h after contraction in Pla muscle, but only 6 h after contraction in TA muscle (37). This difference in the pattern of activation in Pla and TA muscles may partially be due to the difference in the type of contraction (concentric and eccentric, respectively) induced by HFES. In the present study, eIF4E-eIF4G complex formation followed a similar pattern of activation. Formation of the eIF4E-eIF4G complex is considered a crucial step in the initiation of protein translation: eIF4G has been suggested to act as a "bridge" between mRNA and the 40S ribosomal subunit, because it contains binding sites for eIF4E (which binds directly to the m7GTP cap structure of the 5'-end of mRNAs) and eIF4A (which has ATP-dependent RNA helicase activity) as well as for eIF3 associated with the ribosome (25, 28).
The pattern of 4E-BP1 phosphorylation was somewhat more variable. In TA muscle, 4E-BP1 phosphorylation remained unaffected immediately but increased fivefold 6 h after HFES, suggesting that eIF4E-eIF4G complex formation after HFES may be mediated by mTOR/4E-BP1 signaling. However, in the Pla muscle, 4E-BP1 phosphorylation increased 66% immediately and fivefold 6 h after HFES in Pla muscle, but neither was statistically significant. These differences between TA and Pla muscles were not explained by baseline differences in 4E-BP1 phosphorylation. This response may be related to the variability in the response observed in the Pla and the TA muscle and also may have been influenced by differences in the mode of contraction between the TA (eccentric) and the Pla (concentric) muscle. Kubica et al. (27) reported that the Thr37 and Thr46, but not the Thr70, phosphorylation sites were phosphorylated with resistance exercise (16 h after exercise). This finding, along with the lack of change in 4E-BP1-eIF4E association and eIF4E-eIF4G association, suggests a lack of involvement of this pathway in the increased protein synthesis observed in this study. However, the time of assessment (16 h after contraction) and the nature of the exercise protocol (4 bouts of contractions performed over a 10-day period) limit our ability to make direct comparisons between studies. Future studies are needed to clarify the temporal changes in the pattern of 4E-BP1 phosphorylation and their association with muscle protein synthesis.
Although Akt has been demonstrated to phosphorylate Ser2448 of mTOR (33, 44, 45), previous studies have failed to show that HFES results in a sustained increase in Akt phosphorylation (37). Because 4E-BP1 phosphorylation and, more importantly, eIF4E-eIF4G complex formation occurred in a similar pattern over the course of time, mTOR may be phosphorylated in an Akt-independent manner. Recently, Hornberger et al. (19) demonstrated that mechanically induced phosphorylation of downstream targets of mTOR occurs by a mechanism independent of phosphatidylinositol 3-kinase and Akt in skeletal muscle. Although Akt is the only kinase identified to phosphorylate Ser2448 of mTOR, additional control mechanisms of mTOR via Akt have been suggested, through tuberous sclerosis complexes 1 and 2 (TSC-1 and TSC-2). TSC-1 and TSC-2 form a complex that represses mTOR, and this inhibition can be reversed when TSC-2 is phosphorylated by Akt (30, 34). TSC-2 is a GTPase-activating protein for the small G protein Ras homolog enriched in brain (Rheb). Rheb can activate mTOR when bound to GTP. Several mechanisms have been proposed to explain Rheb activation of mTOR, including activation of an mTOR binding protein, facilitation of amino acid transport, and/or activation of an unknown kinase of mTOR (29, 48). An alternative mechanism of mTOR activation has been proposed by Holz et al. (18), who suggested that p70S6K directly phosphorylates Ser2448 and Thr2446, suggesting a direct pathway of mTOR phosphorylation independent of Akt that is controlled by protein kinase C (18). The role of this alternative pathway of mTOR phosphorylation after contraction in muscle remains to be determined.
Amino acids, especially leucine, have been shown to increase mTOR signaling and protein synthesis (6, 22, 24), although it is unknown whether amino acid availability or sensitivity increases with contractile activity. It has been reported that AMP-activated protein kinase (AMPK) can inhibit protein synthesis via signal repression through mTOR (9, 26, 39) by activation of TSC-2 (20). During resistance exercise, the activity of mTOR could be acutely blunted by AMPK, thus inhibiting protein synthesis and enhancing amino acid availability for energy metabolism. During recovery from resistance exercise, the inhibition of mTOR by AMPK is suppressed, allowing amino acids to activate mTOR and increase protein synthesis (14).
Impaired activation of 4E-BP1 and eIF4E-eIF4G complex formation in aged rats follows the same time course as the impaired activation of mTOR/p70S6K1. This strongly suggests that downregulation of mTOR with age is the cause for the inability of the eIF4E-eIF4G complex to form after HFES. This reduced association of eIF4E-eIF4G may play a role in the age-associated limitation in the capacity for muscle hypertrophy. Conversely, because the stimuli by which mTOR can be upregulated after muscle contraction are not identified, the mechanism by which all downstream components of mTOR signaling can be downregulated with age remains unresolved. One potential candidate, AMPK, is more phosphorylated in aged rats after chronic overload, contributing to the decreased activity of mTOR (50). The impaired activity of mTOR by age may also result from the reduced availability of circulating or local growth factors, as well as cytokines (35, 51). Alternatively, the impairment may be due to the resistance to these growth factors or amino acids (12, 13) at the receptor level.
GSK-3 phosphorylation has been discussed as an important component of hypertrophy and is increased after muscle contraction (31, 41, 43). The preference for phosphorylation of the -isoform (Ser21) over the -isoform (Ser9) as an acute response to muscle contraction has been reported previously (43, 46). In adults, we report that phosphorylation of GSK-3 increased 
1.5-fold immediately after muscle stimulation in TA and Pla muscles and four- and two-fold 6 h after muscle stimulation in TA and Pla muscles, respectively. On the other hand, phosphorylation of GSK-3 remained unaffected, except immediately after contraction in Pla muscle. Therefore, we confirm here that GSK-3 is the principal dominant isoform that is phosphorylated acutely in response to HFES.
The lack of temporal association between the activation of Akt and GSK-3 phosphorylation has been described previously (42, 43). This suggests that an alternative pathway may exist by which contraction can phosphorylate GSK-3 at Ser21. Several candidates have been suggested to phosphorylate GSK-3 at Ser21 (32), and several, including p70S6K1, MAP kinase-activated protein kinase-1, and c-Jun NH2-terminal kinase, are increased with contractile activity (11, 17, 46, 47). However, the specific mechanism by which GSK-3 is phosphorylated with contraction is not well understood.
In aged rats, neither GSK-3 nor GSK-3 was phosphorylated after contraction. Because GSK-3 phosphorylation is thought to promote protein synthesis by increasing activity of eIF2 to form the 43S preinitiation complex (21, 23), the decrease in phosphorylation of GSK-3 with age may result in decreased activity of eIF2, which ultimately can contribute to the decreased protein synthesis. Recently, mTOR-dependent activation of eIF2B has been reported (27). Because GSK-3 and mTOR phosphorylation are decreased with age, it is most likely that formation of the 43S preinitiation complex is inhibited in aged animals and humans after contraction.
Although we have reported a consistent suppression of several key regulators of protein translational capacity in aged skeletal muscle, a limitation of the present study was a lack of direct measures of muscle protein synthesis. However, the results of the present study are supported by two studies examining the relation between activation of Akt/mTOR signaling and changes in muscle protein synthesis in vivo (1, 12). Recently, Cuthbertson et al. (12) demonstrated a reduction in the increase in skeletal muscle protein synthesis in response to a 40-g dose of essential amino acids in older humans and a corresponding reduced phosphorylation of mTOR and its downstream target p70S6K1 compared with young individuals. Atherton et al. (1) also reported that the increase in mTOR, GSK-3, and 4E-BP1 in response to HFES was associated with an increase in fractional muscle protein synthesis, and this response was absent in response to low-frequency electrical stimulation. These data suggest that changes in the phosphorylation state of downstream targets of Akt/mTOR signaling are temporally related to differences in skeletal muscle protein synthesis. These responses need to be confirmed in the present model system.
Overall, we report that phosphorylation of GSK-3 and GSK-3 and 4E-BP1 and eIF4E-eIF4G complex formation are increased in skeletal muscle after a single bout of in situ muscle contractile activity induced by HFES in adult animals, but these responses are attenuated in aged animals. These observations suggest that the anabolic response to muscle contraction is decreased with aging and may explain the limited capacity of hypertrophy in aged individuals. Future studies should investigate the upstream mechanism by which these cellular pathways are activated by HFES and the resultant impact on skeletal muscle protein synthesis.
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ACKNOWLEDGMENTS |
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Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the U.S. Department of Agriculture.
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FOOTNOTES |
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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. Section 1734 solely to indicate this fact.
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REFERENCES |
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or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation. FASEB J 19: 786–788, 2005.
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76 yr old. Am J Physiol Endocrinol Metab 277: E118–E125, 1999.This article has been cited by other articles:
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