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HIGHLIGHTED TOPICS
Physiology of Aging
Departments of 1Medical Pharmacology and Physiology and 2Biomedical Sciences, and 3Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211
Submitted 2 May 2003 ; accepted in final form 17 September 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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-phos, p70 S6 kinase (p70S6k) -phos and -pan, calcineurin A-pan, STAT3-phos and -pan, p44 MAPK-pan, and p42 MAPK-pan. In contrast, Akt-pan, c-Jun NH2-terminal kinase-phos, and p38 MAPK-phos were observed to decrease from 10-day immobilization values to control levels. Also, Aktphos was unchanged among all groups. In a follow-up experiment in which muscle samples from both the present study and a previous study (Childs TE, Spangenburg EE, Vyas DR, and Booth FW. Am J Physiol Cell Physiol: 285: C391–C398, 2003) were reanalyzed together, the recovery-induced increase in p70S6k-phos from immobilization-atrophy was significantly attenuated in soleus muscles of the old group. atrophy; regulation; rehabilitation; recovery
Effective cellular communication plays an essential role in skeletal muscle plasticity. Previous studies have discovered many components are involved in the hypertrophy process such as growth factors [insulin-like growth factor I (IGF-I) and leukemia inhibitory factor] (1, 19, 20, 31), intracellular calcium (23, 27), and mechanical and oxidative stress (15, 21, 32). Interestingly, it is possible that multiple signaling pathways are integrated to influence the hypertrophy response. In normal skeletal muscle, each pathway appears to be utilized to transduce a variety of cellular signals that mediate the transcriptional and translational requirements for protein synthesis and degradation (6). For example, Bodine et al. (5) found that rapamycin, an mTOR inhibitor, blocked hypertrophy, and it was concluded that an IGF-I-sensitive pathway, phosphatidylinositol 3-kinase (PI3-kinase)/Akt/mTOR, is important for skeletal muscle hypertrophy. In addition, through an intramuscular injection of a constitutively active Akt construct, muscle hypertrophy was induced through downstream signaling proteins p70 S6 kinase (p70S6k) and eukaryotic initiation factor 4E binding protein (4E-BP1).
Alternatively, intracellular calcium levels also play a pivotal role in regulating muscular growth. Calcineurin (A and B), a calcium-sensitive enzyme serving as a phosphatase within the cell, has been shown to promote skeletal muscle hypertrophy through the IGF-I signaling pathway. Semsarian et al. (27) found that IGF-I-induced myotube hypertrophy through activation of the calcineurin signaling pathway. However, a controversy still exists over the relative contributions from Akt/mTOR and calcineurin during skeletal muscle hypertrophy (14, 16). It is not unreasonable to suggest that the hypertrophy process in skeletal muscle is dependent on the integrated communication of multiple signaling pathways.
Young muscle has the ability to proportionally enlarge its size more effectively after a given stimulus compared with old muscle (13), and this process may potentially occur through functioning cell signaling events. A recent report showed that a single bout of resistance exercise caused an increase in phosphorylation (phos) of the extracellular signal-related kinase 1 and 2 (ERK1/2), p90 ribosomal S6 kinase (p90RSK), and mitogen-activated protein kinase-interacting kinase-1 (Mnk-1) proteins in 22-yr-old male human subjects but decreased its ERK1/2, p90RSK, Mnk-1, p38 mitogen-activated protein kinase (MAPK), and c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) in the 79-yr-old men (33). Consequently, the responsiveness of these cell signaling pathways may continually become less efficient in response to muscle growth stimuli in aged muscle. Thus it is hypothesized that specific defects exist within a signaling pathway(s) in aged muscle and could limit potential muscle growth and contribute to a sarcopenic state.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Hindlimb immobilization and experimental model. A detailed procedure for the hindlimb immobilization model has been previously described (7). Briefly, on the day of casting, rats were lightly anesthetized by using isoflorane to attach plaster of Paris casts. The plantar flexor group of both legs was maintained in a shortened, nonstretched position during the immobilization period. The immobilized rats were checked daily for damage done to casting material, which was repaired if necessary. Rats were immobilized for a period of 10 days to allow comparison to earlier studies that used the same duration (11, 12). After 10 days of immobilization, the casts were completely removed. The rats were then returned to the same cage and allowed to ambulate freely until the date that they were killed. Recovery rats from the 10-day immobilization included a control group (n = 11) and 0-day (no recovery time) (n = 7), 3-day (n = 8), 6-day (n = 7), and 15-day (n = 8) recovery groups. Each rat represented an independent observation. The animals were euthanized on these days by using a drug cocktail containing ketamine (75 mg), xylazine (3 mg), and acepromazine (5 mg). On the day that the animals were killed, the soleus muscle from both legs was carefully excised, weighed, and frozen in liquid nitrogen for storage at -80°C. In a follow-up experiment, soleus muscle samples from 3- to 4-mo-old rats employed in a previous paper (12) were reanalyzed with old muscle samples in the present study.
Muscle protein extraction and concentration measurements. The muscle tissue was homogenized on ice with buffer that included 50 mM HEPES (pH 7.4), 0.1% Triton X-100, 4 mM EGTA, 10 mM EDTA, 15 mM Na4P2O7·H2O, 100 mM -glycerophosphate, 25 mM NaF, 50 µg/ml leupeptin, 50 µg/ml pepstatin, 40.4 µg/ml aprotinin, and 1 mM Na3VO4. After homogenization, the samples were stored at -80°C. The protein concentration of the samples was determined in triplicate via the Bradford procedure (Bio-Rad protein assay, Hercules, CA).
SDS-PAGE, Western blotting, and immunodetection. Homogenates of the muscle were solubilized at a concentration of 1.25 mg/ml in loading buffer (2.5 mM Tris·HCl, pH 6.8, 20% glycerol, 2% SDS, 5% -mercaptoethanol, and 0.025% bromophenol blue) and boiled at 98°C for 5 min. A 100-µg aliquot of total protein was loaded (100 µg·sample-1·lane-1) onto 10% SDS-PAGE gels with the following exceptions: 25 µg/sample for GSK-3 and a 15% SDS-PAGE gel for calcineurin B. All gels were run at 150 mV for 30 min and at 200 mV for 1.5 h to separate proteins. The gels were then transferred onto nitrocellulous membranes (Osmotics, Westborough, MA) at 51 V for 2.5hat4°C in transfer buffer (25 mM Tris-base, 192 mM glycine, and 20% methanol). To confirm successful transfer of protein and equal loading of lanes, which occurred in all cases, the membranes were stained with Ponceau S (data not shown). After successful transfer, the membrane was placed in blocking buffer [5% nonfat dry milk in Tris-buffered saline-0.1% Tween-20 (TBS-T)] for 1 h at room temperature, serially washed (3 x 5 min), and incubated with primary antibody in dilution buffer (5% BSA in TBS-T) overnight at 4°C. After another serial wash with TBS-T (1 x 10 min, 4 x 5 min), the membranes were incubated with both a horseradish peroxidase (HRP)-conjugated secondary antibody and a HRP-linked anti-biotin antibody in blocking buffer for 1 h followed by another serial wash with TBS-T (1 x 10 min, 4 x 5 min). Enhanced chemiluminescence reagent (Perkin Elmer Life Sciences, Boston, MA) was used to detect the HRP activity by exposure to Kodak-XAR5 autoradiographic film for the appropriate durations to keep the integrated optical densities (IODs) within a linear and nonsaturated range for all bands of each membrane. The IODs were quantified by using ImageQuant densitometry software (Molecular Dynamics; renamed Amersham Biosciences, Sunnyvale, CA). To correct the sample IODs for various exposure differences, the same quality control sample was loaded onto every gel. Representative blots are shown only under signaling response graphs where statistical difference occurred.
Antibodies. The primary antibodies Ser473-Akt-phos (1:500 dilution), Akt (1:1,000), Ser9-GSK3-phos (1:1,000), GSK-3 (1:2,500), Thr389-p70S6K-phos (1:500), p70S6K (1:500), Thr202/Tyr204 (p44/p42 MAPK) or ERK1/2 (1:1,000), p44/42 MAPK or ERK1/2 (1:1,000), Thr183/Tyr185-SAPK/JNK-phos (1:500), SAPK/JNK (1:1,000), Thr180/Tyr182-p38 MAPK-phos (1:1,000), p38-MAPK (1:1,000), Tyr705-signal transducer and activator of transcription 3 (STAT3)phos (1:1,000), STAT3 (1:1,000), and anti-biotin antibody (1:4,000) were purchased through Cell Signaling Technologies (Beverly, MA). Calcineurin A (1:10,000) and calcineurin B (1:4,000) were purchased through Sigma-Aldrich (St. Louis, MO) and Affinity Bioreagents (Golden, CO), respectively. Anti-rabbit and anti-mouse secondary antibodies (1:7,500) were purchased from Amersham Biosciences (Piscataway, NJ). Antibody specificity was verified by molecular weight, positive controls [GSK-3-phos, p70S6k-total concentration of specific signaling proteins (pan), calcineurin B-pan, and p38-phos], blocking peptides (GSK-3-phos and p38-phos), and absence of immunoreactivity from secondary antibody signal in the absence of the primary antibody (all molecules).
Statistical analysis. All data are expressed as means ± SE. Muscle mass data was analyzed by using a one-way analysis of variance and a Tukey's post hoc test. The Western blotting values were analyzed nonparametrically by a Kruska-Wallis test, and a post hoc analysis was done by using a Dunn's multiple-range test with P < 0.01 as statistical marker of significant difference. The baseline comparison among experimental groups was selected to be the group at the end of the 10 days of hindlimb immobilization because this value allowed two statistical comparisons to be made; one for atrophy (preimmobilization control vs. 10-day immobilization) and the second for recovery [10-day immobilization (which also was the 0-day recovery) value vs. 3, 6, and 15 recovery days].
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Phosphorylation levels and total protein expression of various signaling proteins in atrophying and postimmobilization old soleus muscles. The number of rats per group is equal to the number of independent observations made for every signaling protein except for the 10-day immobilized group, which had only six rats instead of seven for p38, STAT3, calcineurin A, and calcineurin B measurements.
PI3-kinase pathway. Significant differences in Akt-pan included the preimmobilization control group, which was 52% lower than the 10-day immobilization group (Fig. 2A). This was followed by a 56 and 65% decrease in the 6-day and 15-day recovery groups, respectively. Akt-phos was not significantly different among any of the groups. GSK-3-phos (Ser9) increased by 91% only in the 6-day recovery group (Fig. 2B) relative to the 10-day immobilized group. Also, p70S6k-phos (Thr389) increased by 3,030 and 1,940% in the 6-day and 15-day recovery time points, respectively, compared with the 10-day immobilization group (Fig. 2C). p70S6k-pan values were significantly higher in the preimmobilization controls and the sixth day of recovery by 102 and 195%, respectively, compared with the 10-day immobilization group.
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Calcineurin A and B. Calcineurin A-pan was higher than the 10-day immobilization group by 180, 463, and 219% in control, 6-day, and 15-day groups, respectively, compared with the 10-day immobilization group (Fig. 3A). Calcineurin B-pan values were 114% higher at 3 days and 57% higher at 6 days of recovery (Fig. 3B) compared with the 10-day immobilization group.
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JAK2-STAT3 pathway. STAT3-phos (Tyr705) increased at the sixth day of recovery and was significantly different from control and fifteenth day of recovery by 69 and 68%, respectively (Fig. 4). STAT3-pan was increased by 90 and 87% in the 6-day and 15-day recovery groups, respectively, compared with the 10-day immobilization group.
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MAPK pathways. The level of JNK-phos (Thr183/Tyr185) decreased by 96% in the 15-day recovery group compared with the 10-day immobilization group (Fig. 5A). ERK1-pan (p44 MAPK) increased 114% after 6 days of recovery compared with the 10-day immobilization group (Fig. 5B). Also, ERK2-pan (p42 MAPK) increased by 56 and 40% in the 6-day and 15-day recovery groups, respectively (Fig. 5C). Compared with 10-day immobilization group, p38 MAPK-phos (Thr180/Tyr182) was 85% lower in controls and 66% lower at 15 days of recovery (Fig. 5D). p38 MAPK-pan was 27% lower in the control group.
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Comparison of young vs. old. The increase in p70S6k-phos was significantly attenuated at the third recovery day in the soleus muscle from old compared with young rats (Fig. 6). No significant differences for GSK-3-phos, STAT3-phos, or p38-pan during recovery were found between young and old soleus muscles.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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After 10 days of immobilization, the soleus muscle had atrophied by 19.2% in the old animals. This percentage of atrophy is much less than the 38.5% previously observed in young rats (12). The lower percentage of muscle atrophy observed in the old soleus muscle after the immobilization period suggests the muscle had already lost a substantial amount of mass over time. Previously, Chakravarthy et al. (11) documented that gastrocnemius muscle from old rats failed to show any significant regrowth of the gastrocnemius muscle for 77 days after a limb immobilization-induced stimulus. Here, we confirm a similar finding in the soleus muscle, the major load-bearing muscle of the hindlimb. We have also confirmed that, even after 30 days of recovery in 30-mo-old rats, no significant muscle mass was regained (25). This unexpected observation is in agreement with reports that aged animals have attenuated (2, 13, 10, 24) or cannot increase their muscle mass after mechanical overload produced by surgical ablation (4). Specifically, 15 days after the removal of the immobilization material, the soleus muscle had failed to show any regrowth in the old animals. However, our laboratory previously found that after 6 and 15 days of reload in the soleus muscle of young animals that mass had recovered by 37 and 40%, respectively, after the same bout of atrophy (12). These data indicate that soleus muscle does not regrow at the same rate in old animals during the 15-day recovery period from limb immobilization as it does in young animals. This observation has potential clinical relevance because the reduction of muscle growth in old animals may be contributing to the inability to recover preatrophy function from an atrophy-inducing stimulus. Therefore, the goal of this study was to determine the status of various signaling pathways during recovery in old rats after limb immobilization.
Interestingly, Akt phosphorylation did not increase at anytime point in the reloaded, old muscle. Using direct gene injection, Bodine et al. (5) found that Akt is an important regulator of muscle hypertrophy in skeletal muscle. In addition, Bodine et al. found that Akt-phos was significantly elevated after 14 days of compensatory hypertrophy in young animals. Akt is thought to contribute to muscle hypertrophy through activation of mTOR-p70S6K (5) and/or deactivation of the GSK-3 (5). Therefore, the lack of change in Akt phosphorylation postimmobilization may limit the regrowth of old soleus muscle.
In the old muscle, GSK-3 phosphorylation significantly increased 91% at the sixth day of recovery compared with the 10-day immobilization group. [The 10-day immobilization/0-day recovery value was selected for baseline comparison because it allowed statistical comparisons for atrophy (preimmobilization control vs. the baseline of 10-day immobilization group) and recovery (baseline vs other recovery groups).] GSK-3 is a downstream signaling target in the PI3-K pathway known to affect various cell functions such as metabolism, gene transcription, and cell cycle regulation (18). Hardt and Sadoshima (18) also described GSK-3 as a novel regulator of cardiac hypertrophy. Active or nonphosphorylated GSK-3 phosphorylates a transcription factor, nuclear factor of activated T cells (NFAT), and initiates NFAT removal from the nucleus. Vyas et al. (30) recently found that active GSK-3 negatively regulated skeletal myotube hypertrophy by potentially reducing NFAT transcriptional activity. However, after phosphorylation of GSK-3 at Ser9 by Akt, GSK-3 is inactivated and potentially allows NFAT to remain active within the nucleus to induce the transcription of necessary hypertrophy genes. Therefore, the phosphorylation of GSK-3 might be a crucial signaling mechanism for skeletal muscle regrowth, and its function appeared intact in the old rats. However, an alternative signaling pathway besides Akt may be regulating the activity of GSK-3 due to Akt's lack of phosphorylation during muscle recovery.
In the present study, p38MAPK phosphorylation in the 10-day immobilization group of old rats was significantly higher than controls and the 15-day recovery groups. Because the soleus muscle was shown to significantly atrophy during the 10-day immobilization time period, we speculate that the activation of p38 MAPK could be promoting the loss of muscle tissue. Childs et al. (12) observed a similar rapid increase of p38-phos during atrophy of the young soleus muscle. p38 is a member of the SAPK cascade of the MAPK pathway and has been shown to significantly increase in phosphorylation after bouts of exercise and muscle overload (22). Carlson et al. (9) demonstrated that p38 MAPK-phos was elevated for 24 h after a functional overload in the soleus muscle of young rats. p38 may also act to prevent or retard muscle atrophy; however, it is clearly not an effective hypertrophy agent under immobilization conditions on the basis of the present study and our laboratory's previously published data (12). It is concluded that p38 MAPK could act to stimulate soleus muscle atrophy during disuse, and the sustained activation of p38MAPK in old muscle recovery could inhibit the regrowth process.
STAT3 phosphorylation increased after 6 days of reloading in the old animals, which suggests its signaling may be functional. As a member of the Janus kinase 2(JAK2)/STAT3 pathway, STAT3 is known to regulate the intracellular actions of various growth factors and also induce satellite cell proliferation in vitro (29). STAT3 is a transcription factor known to homodimerize and translocate to the nucleus after phosphorylation (Tyr705) by an upstream kinase, JAK2.
We hypothesized that one or more cell signaling pathways may become defective during the reloading of skeletal muscle in aged animals. This could provide a potential molecular mechanism for lack of muscle regrowth observed in the old animals. To test this possibility, soleus muscle samples from the 3- to 4-mo-old rats in a previous report of Childs et al. (12) were reanalyzed by loading them on the same gel with samples from old rats. Those signaling proteins chosen for follow-up experimentation were qualitatively assessed as having a differential response between age groups. Each gel consisted of samples for all five time points for both ages. The increase in p70S6k-phos was significantly attenuated at the third recovery day in the soleus muscle from old compared with young rats (Fig. 6). p70S6k is a downstream signaling component of the PI3-kinase pathway and is thought to be a significant contributor to protein synthesis (28). The smaller upregulation of IGF-I-1Eb mRNA (local muscle IGF-I) expression observed in the overloaded plantaris muscle of old vs. young rats by Owino et al. (24) may contribute to lesser p70S6k-phos observed in the nonregrowing soleus muscles of older rats in the present study. Baar and Esser (3) have previously reported a tight correlation between the activation of p70S6 and the long-term increase in muscle mass. It has been suggested that the phosphorylation of p70S6k may serve as an important marker for the phenotypic changes that characterize load-induced muscle hypertrophy. The delayed activation of p70S6K in the old muscle observed in the present study could represent a slowed initiation of protein synthesis during the recovery time period. As a result, this specific signaling pathway designates a potential translational defect for skeletal muscle growth in aged animals.
Limitations of the present study include the following: 1) later time points beyond 15 days of recovery may reveal regrowth and additional changes in signaling molecules, and 2) no intervention was provided for the rats to facilitate muscle regrowth postimmobilization. However, because many older humans undergo no exercise training after periods of physical inactivity, the aim of the present study was to provide baseline data.
In conclusion, aged skeletal muscle exhibits an attenuated increase in the phosphorylation of p70S6K. With the development of this adverse modification in a cell signaling network, skeletal muscle may not effectively communicate the introduction of external stimuli (i.e., workloads) in old skeletal muscle. In the future, new strategies for reducing or eliminating the progression of sarcopenia will transpire from improving the efficacy of a dysfunctional signaling pathway or factor.
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ACKNOWLEDGMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Present address of E. E. Spangenburg: University of California-Davis, Exercise Biology Program, One Shields Ave., Davis, CA 95616 (E-mail: eespangenburg{at}ucdavis.edu).
GRANTS
This work was funded by National Institutes of Health (NIH) Grant AG-18881 (to F. W. Booth). E. E. Spangenburg was supported by NIH Grant AR-48514.
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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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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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negatively regulates skeletal myotube hypertrophy. Am J Physiol Cell Physiol 283: C545-C551, 2002.This article has been cited by other articles:
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  E. E. Spangenburg, D. Le Roith, C. W. Ward, and S. C. Bodine A functional insulin-like growth factor receptor is not necessary for load-induced skeletal muscle hypertrophy J. Physiol., January 1, 2008; 586(1): 283 - 291. [Abstract] [Full Text] [PDF]
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 Y.-W. Chen, C. M. Gregory, M. T. Scarborough, R. Shi, G. A. Walter, and K. Vandenborne Transcriptional pathways associated with skeletal muscle disuse atrophy in humans Physiol Genomics, November 14, 2007; 31(3): 510 - 520. [Abstract] [Full Text] [PDF]
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 M. Doucet, A. P. Russell, B. Leger, R. Debigare, D. R. Joanisse, M.-A. Caron, P. LeBlanc, and F. Maltais Muscle Atrophy and Hypertrophy Signaling in Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., August 1, 2007; 176(3): 261 - 269. [Abstract] [Full Text] [PDF]
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 K. M. Rice, D. L. Preston, D. Neff, M. Norton, and E. R. Blough Age-Related Dystrophin-Glycoprotein Complex Structure and Function in the Rat Extensor Digitorum Longus and Soleus Muscle J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2006; 61(11): 1119 - 1129. [Abstract] [Full Text] [PDF]
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D. M. Thomson and S. E. Gordon Impaired overload-induced muscle growth is associated with diminished translational signalling in aged rat fast-twitch skeletal muscle J. Physiol., July 1, 2006; 574(1): 291 - 305. [Abstract] [Full Text] [PDF]
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 M. D. Boppart, D. J. Burkin, and S. J. Kaufman {alpha}7beta1-Integrin regulates mechanotransduction and prevents skeletal muscle injury Am J Physiol Cell Physiol, June 1, 2006; 290(6): C1660 - C1665. [Abstract] [Full Text] [PDF]
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 F. Haddad and G. R. Adams Aging-sensitive cellular and molecular mechanisms associated with skeletal muscle hypertrophy J Appl Physiol, April 1, 2006; 100(4): 1188 - 1203. [Abstract] [Full Text] [PDF]
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E. E. Spangenburg and T. A. McBride Inhibition of stretch-activated channels during eccentric muscle contraction attenuates p70S6K activation J Appl Physiol, January 1, 2006; 100(1): 129 - 135. [Abstract] [Full Text] [PDF]
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M. Sitnick, A. M. Foley, M. Brown, and E. E. Spangenburg Ovariectomy prevents the recovery of atrophied gastrocnemius skeletal muscle mass J Appl Physiol, January 1, 2006; 100(1): 286 - 293. [Abstract] [Full Text] [PDF]
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T. A. Hornberger, R. D. Mateja, E. R. Chin, J. L. Andrews, and K. A. Esser Aging does not alter the mechanosensitivity of the p38, p70S6k, and JNK2 signaling pathways in skeletal muscle J Appl Physiol, April 1, 2005; 98(4): 1562 - 1566. [Abstract] [Full Text] [PDF]
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