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J Appl Physiol 98: 1562-1566, 2005. First published September 10, 2004; doi:10.1152/japplphysiol.00870.2004
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HIGHLIGHTED TOPICS
Biomechanics and Mechanotransduction in Cell and Tissues

Aging does not alter the mechanosensitivity of the p38, p70S6k, and JNK2 signaling pathways in skeletal muscle

Troy A. Hornberger,1 R. D. Mateja,1 E. R. Chin,2 J. L. Andrews,1 and K. A. Esser1

1School of Kinesiology, University of Illinois Chicago, Chicago, Illinois; and 2Pfizer Global Research and Development, Groton, Connecticut

Submitted 11 August 2004 ; accepted in final form 6 September 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The capacity for skeletal muscle to recover its mass following periods of unloading (regrowth) has been reported to decline with age. Although the mechanisms responsible for the impaired regrowth are not known, it has been suggested that aged muscles have a diminished capacity to sense and subsequently respond to a given amount of mechanical stimuli (mechanosensitivity). To test this hypothesis, extensor digitorum longus muscles from young (2–3 mo) and old (26–27 mo) mice were subjected to intermittent 15% passive stretch (ex vivo) as a source of mechanical stimulation and analyzed for alterations in the phosphorylation of stress-activated protein kinase (p38), ribosomal S6 kinase (p70S6k), and the p54 jun N-terminal kinase (JNK2). The results indicated that the average magnitude of specific tension (mechanical stimuli) induced by 15% stretch was similar in muscles from young and old mice. Young and old muscles also revealed similar increases in the magnitude of mechanically induced p38, p70S6k (threonine/serine 421/424 and threonine 389), and JNK2 phosphorylation. In addition, coincubation experiments demonstrated that the release of locally acting growth factors was not sufficient for the induction of JNK2 phosphorylation, suggesting that JNK2 was activated by a mechanical rather than a mechanical/growth factor-dependent mechanism. Taken together, the results of this study demonstrate that aging does not alter the mechanosensitivity of the p38, p70S6k, and JNK2 signaling pathways in skeletal muscle.

stretch; mechanotransduction; growth; hypertrophy; atrophy

AGING IS ASSOCIATED WITH A loss of skeletal muscle mass (sarcopenia), and the effects of sarcopenia appear to be exacerbated by an impaired recovery of muscle mass following periods of unloading (i.e., limb immobilization or bed rest) (9, 16). This hypotheses is supported by numerous animal-based studies that have consistently shown that muscles from aged animals lose their ability to regain mass (regrowth) following a period of unloading (13, 15, 23). Although the mechanisms responsible for impaired regrowth in animals are not known, it has been proposed that aging may result in a diminished capacity of skeletal muscle to sense and subsequently respond to a given amount of mechanical stimuli (mechanosensitivity) (13, 21).

Several studies have reported data that are consistent with the hypothesis that aging alters the mechanosensitivity of skeletal muscle. For example, contraction-induced changes in gene expression, as well as signaling through the MAPKs, have been reported to change with aging (7, 14, 21). Furthermore, overload-induced signaling through ribosomal S6 kinase (p70S6k), a molecule implicated in the regulation of muscle mass, has been reported to decline with aging (13). All of these reports are consistent with the hypothesis that aging alters the mechanosensitivity of skeletal muscle; however, any conclusions about mechanosensitivity from these studies are limited because the magnitude of mechanical stimuli applied to the muscles was not directly controlled.

The purpose of this study was to determine whether differences in mechanosensitivity exist between young and aged muscles of rodents. We hypothesized that mechanosensitivity is attenuated in muscles from aged compared with young mice. To test this hypothesis, an organ culture device capable of applying well-defined mechanical stimuli (passive-specific tension) to skeletal muscle was used. Mechanotransduction was assessed by measuring changes in the phosphorylation state of several signaling molecules that have been implicated in the transcriptional and translational control of cell growth [stress-activated protein kinase (p38), p54 jun N-terminal kinase (JNK2), and p70S6k] (1, 18–20). The data presented in this study indicate that the mechanosensitivity of the p38, p70S6k, and JNK2 signaling pathways is similar in muscles from young (2–3 mo) and old (26–27 mo) mice.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Materials.   Peroxidase-conjugated anti-rabbit antibody was purchased from Vector Laboratories (Burlingame, CA). Phospho-specific JNK2 antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). All other antibodies were purchased from Cellular Signaling (Lake Placid, NY). Polyvinylidene difluoride membranes were purchased from Millipore (Bedford, MA). Enhanced chemiluminescence detection reagent was purchased from Amersham Pharmacia Biotech (Buckinghamshire, UK). Detergent-compatible protein assay kit was purchased from Bio-Rad (Hercules, CA). Dulbecco's modified Eagle's medium was purchased from Invitrogen (Carlsbad, CA). Force measurements and stretch movements were produced on a 300-BLR force transducer/dynamometer (Aurora Scientific, Aurora, ON). Data from the force transducer were integrated with a PCI-MIO analog-to-digital board (National Instruments, Austin, TX) and interfaced with LabView software for data analysis (National Instruments). Muscle field stimulations were delivered through a Grass stimulator (Grass Telefactor, West Warwick, RI).

Animal care and use.   All experimental procedures were approved by the University of Illinois at Chicago Animal Care Committee. For aging experiments, male CB6F1 mice (Harlan, Indianapolis, IN) of 2–3 mo of age were used for the young group, and mice of 26–27 mo of age were used for the old group. It should be noted that longevity studies with this strain of mice indicate that the median life span is ~28.5 mo of age (6). Male C57BL10 mice (Jackson Laboratories, Bar Harbor, MA), 2–4 mo of age, were used for the conditioned media experiments. All animals were allowed free access to food and water. Animals were anaesthetized with pentobarbital sodium (40 mg/kg), and the extensor digitorum longus (EDL) muscle of the right hindlimb was exposed. Sutures (4-0 silk) were tied at the proximal and distal myotendonus junctions of the EDL. A lever arm for attachment to a force transducer/dynamometer was attached to the suture at the distal end of the EDL, and a lever arm for attachment to a micromanipulator was attached to the suture at the proximal end of the EDL. The EDL was excised and immediately placed in an organ culture bath.

Organ culture.   The design of the organ culture bath system (mechanical stimulator) was based on work described by Reeds et al. (17) and consisted of a refined myograph system (Kent Scientific, Torrington, CT) with DMEM (high glucose) cell culture media at 37°C maintained under continuous 95% O2 and 5% CO2 gassing, as previously described (5). It should be noted that the EDL muscle in this system remains viable for at least 2 h, as determined by stability in [ATP], [phosphocreatine]/[total creatine] (where brackets denote concentration), twitch tension, and rates of protein synthesis (5).

With the lever arms attached to the force transducer and micromanipulator, the EDL was adjusted to optimal length (Lo). Lo was initially determined in pilot experiments by stimulating the muscle with a 0.5-ms, 10-V pulse, and twitch tension was measured. The length of the muscle was adjusted until a peak in twitch tension was observed, and the passive tension at this length was recorded. The results from these experiments indicated that the passive tension on the muscle at Lo was 6.7 ± 0.9 mN for young and 7.2 ± 1.0 mN for old mice (n = 5/group). Therefore, in all subsequent experiments, muscle length was adjusted until a passive tension of 7.0 mN was obtained, and this length was assumed to be at approximately Lo. Fresh media was added to the bath at 30-min intervals.

Stretch paradigm.   Following a 30-min preincubation at Lo, muscles were subjected to 90 min of stretch or static conditions, as previously described (5). Briefly, muscles were subjected to 15% stretch by using a 50-ms ramp, with a 100-ms holding pattern. This pattern of stretch was repeated once every 3 s for 90 min while control muscles were held static at Lo. The passive tension of the muscle was continuously monitored throughout the experimental period and normalized to physiological cross-sectional area (PCSA) to obtain a value for specific passive tension [tension (mN)/PCSA (cm2)]. PCSA was estimated with the following formula:

Fiber length was estimated by multiplying the measured muscle length by the fiber length to obtain the muscle length ratio (0.44 ± 0.02 young and 0.42 ± 0.03 old). Fiber length-to-muscle length ratios were determined from muscles pinned at Lo following digestion in 30% HNO3, as described by Ref. 11. A value of 1.056 g/cm3 was used for the density of skeletal muscle (12), and it was assumed that aging did not affect this value.

Coincubations.   In some experiments, static muscles were coincubated with stretched muscles, as previously described (5). In these experiments, the right EDL muscle was connected to the lever arms of the mechanical stimulator and adjusted to Lo. The EDL muscle from the left leg was connected to lever arms of a motionless apparatus that allowed for the muscle to be fixed at a chosen length. The length of the left EDL was adjusted to match that of the right EDL on the mechanical stimulator. The left EDL was then coincubated with the right EDL by positioning the muscles parallel to one another in the organ culture bath (≤1.5 mm of space between the two muscles). The right EDL was then subjected to stretch or static conditions on the mechanical stimulator while the left EDL was maintained in a static state. It should be mentioned that, due to a limited availability of CB6F1 mice, the coincubation experiments in this study were performed on muscles from c57BL10 mice. The decision to use muscles from the CB6F1 mice was justified by previous work from our laboratory (5), which had extensively characterized the signaling response of muscles from c57BL10 mice and demonstrated that muscles from these mice displayed the same signaling responses as the muscles from the CB6F1 mice used for the aging portion of this study.

Western blots.   Muscles were removed from the organ culture bath and immediately frozen with liquid nitrogen-cooled tongs. Frozen muscles were homogenized by a Polytron in a buffer containing 20 mM Tris (pH 7.5), 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Nonidet NP-40, 50 mM {beta}-glycerolphosphate, 1 mM Na3VO4, 1 µg/ml leupeptin, and (0.2 mM) 1 mM PMSF. Protein concentration was determined by the detergent-compatible protein assay (Bio-Rad Laboratories). From the homogenate, samples containing 15-µg protein were dissolved in Laemmli buffer and subjected to electrophoretic separation by SDS-PAGE on 7.5% acrylamide gels, as previously described (4). Following electrophoretic separation, proteins were transferred to a polyvinylidene difluoride membrane, blocked in 5% blotto [5% powdered milk in TBST (Tris-buffered saline, 1% Tween 20)] for 3 h followed by an overnight incubation at 4°C with primary antibody. After overnight incubation, membranes were washed for 30 min in TBST and then probed with anti-rabbit antibody for 45 min at room temperature. Following 30 min of washing in TBST, the blots were developed by using enhanced chemiluminescence. Once the appropriate image was captured, membranes were stained with Coomassie blue to verify equal loading and transfer in all lanes. Densitometric measurements were carried out by using the FluorS Max Imager with QuantityOne Software (Bio-Rad).

Statistical analysis.   All values are expressed as means ± SD. Statistical significance was determined by using ANOVA followed by Student Newman-Keuls post hoc analysis. Differences between groups were considered significant if P ≤ 0.05.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Characteristics of EDL muscles from young and old mice.   The EDL muscles from old mice weighed significantly more than the muscles from young mice (young = 12.03 ± 1.54 mg, old = 13.3 ± 1.06 mg, n = 10/group, P ≤ 0.05); however, when normalized to body weight, the muscles from old mice revealed a significant 24.6% reduction in the muscle weight-to-body weight ratio (young = 0.42 ± 0.01 mg/g, old = 0.32 ± 0.01 mg/g, n = 10/group, P ≤ 0.05).

The passive tension of the EDL muscle at Lo was 6.7 ± 0.9 mN for young and 7.2 ± 1.0 mN for old (n = 5/group). At the immediate onset of the 15% stretch protocol, the peak-specific passive tension in the old muscles was 28.8% greater than in young muscles (P ≤ 0.05) (Fig. 1A). No significant difference in average peak-specific passive tension applied throughout the 90-min stretch protocol was observed (Fig. 1B). These results indicate that, with the exception of the initial time point, muscles from young and old mice were subjected to a similar average magnitude of mechanical stimuli (peak-specific passive tension) throughout the 90-min stretch protocol.



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  		Fig. 1. Time course of peak-specific passive tension in young and old muscles. A: the peak-specific passive tension in extensor digitorum longus (EDL) muscles from young (open bars) and old (shaded bars) mice at various time points during a 30-min preincubation at optimal length, followed by 90 min of intermittent 15% passive stretch (STR; n = 10/group). B: the average peak-specific passive tension in EDL muscles from young and old mice during the 90 min of intermittent 15% passive STR (n = 10/group). Values are means + SD. *Significantly different from young muscles (P ≤ 0.05).

 
Mechanically induced p38 phosphorylation is similar in young and old muscles.   It has been suggested that aged muscles have a reduced capacity to sense and subsequently respond to mechanical stimuli. To test this hypothesis, alterations in p38 phosphorylation were evaluated following 90 min of intermittent stretch in young and old muscles. It was determined that intermittent stretch produced similar increases in p38 phosphorylation in muscles from young (6.8 ± 1.2-fold) and old mice (8.3 ± 1.2-fold) (Fig. 2). These results indicate that the mechanosensory/mechanotransduction pathway responsible for activating p38 phosphorylation is not altered with aging.



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  		Fig. 2. Mechanically induced p38 phosphorylation is similar in young and old muscles. Western blot analysis of phosphorylated p38 (P-p38) following 90 min of control (CNT, Stretch –, open bars) or intermittent STR (Stretch +, shaded bars) conditions in EDL muscles from young and old mice is shown. Values are means + SD expressed as a percentage of the values obtained in the aged-matched CNT muscles (n = 4–5/group). *Significantly different from aged-matched CNT muscles (P ≤ 0.05).

 
Mechanically induced p70S6k phosphorylation is similar in young and old muscles.   To further evaluate the mechanosensitivity of aged muscle, mechanically induced alterations in p70S6k threonine/serine 421/424 (p70S6k-421/424) and threonine 389 (p70S6k-389) phosphorylation were measured. Evaluation of both the 421/424 and 389 phosphorylation sites was conducted because previous reports have shown that they are regulated by different upstream mechanisms and can thus provide information about distinct mechanically induced signaling pathways. The results from these experiments indicated that the magnitude of mechanically induced p70S6k-421/424 phosphorylation was similar in muscles from young (2.3 ± 0.3) and old (2.8 ± 0.6) mice (Fig. 3A). The magnitude of the mechanically induced increase in p70S6k-389 phosphorylation was also similar in muscles from young (2.6 ± 0.6) and old (2.5 ± 0.5) mice (Fig. 3B). Taken together, these results provide further evidence that mechanosensitivity of skeletal muscle is not altered with aging.



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  		Fig. 3. Mechanically induced p70S6k(421/424) and p70S6k(389) phosphorylation is similar in young and old muscles. Western blot analysis of phosphorylated p70S6k on threonine/serine 421/424 (P-p70S6k 421/424) (A) and phosphorylated p70S6k on threonine 389 (P-p70S6k 389) (B) following 90 min of CNT (Stretch –, open bars) or intermittent STR (Stretch +, shaded bars) conditions in EDL muscles from young and old mice is shown. Values are means + SD expressed as a percentage of the values obtained in the aged-matched CNT muscles (n = 4–5/group). *Significantly different from aged-matched CNT muscles (P ≤ 0.05).

 
Mechanically induced JNK2 phosphorylation is similar in young and old muscles.   Measuring changes in the phosphorylation of JNK2 is another commonly used marker of mechanotransduction (10). Phospho-specific analysis of this protein indicated that the mechanically induced increase in JNK2 phosphorylation was similar in muscles from young (4.7 ± 0.3) and old (4.4 ± 1.0) mice (Fig. 4). It should be noted that muscles from old mice displayed a 3.5-fold greater level of phosphorylation in control (nonstretched) muscles (P ≤ 0.05) (See blot inset in Fig. 4). However, despite the higher basal level of phosphorylation in the old muscles, the magnitude of the mechanically induced increase in JNK2 phosphorylation was not affected.



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  		Fig. 4. Mechanically induced p54 jun N-terminal kinase (JNK2) phosphorylation is similar in young and old muscles. Western blot analysis of phosphorylated JNK2 (P-JNK2) following 90 min of CNT (Stretch –, open bars) or intermittent STR (Stretch +, shaded bars) conditions in EDL muscles from young and old mice. Values are means + SD expressed as a percentage of the values obtained in the aged-matched CNT muscles (n = 4–5/group). Values at the top of the blot represent the relative optical densities that were determined for each group. *Significantly different from aged-matched CNT muscles (P ≤ 0.05).

 
A mechanically induced release of locally acting factors is not sufficient for the induction of JNK2 phosphorylation.   To determine whether signaling through JNK2 was elicited by a mechanically induced release of locally acting factors, static muscles were coincubated with muscles subjected to intermittent stretch. In the coincubation experiments, muscles subjected to intermittent stretch revealed a significant increase in JNK2 phosphorylation, an effect that was not observed in the static muscles that were coincubated with stretched muscles (Fig. 5). The results from these experiments indicate that a mechanically induced release of locally acting factors was not sufficient for the activation of JNK2 phosphorylation.



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  		Fig. 5. A mechanically induced release of locally acting factors is not sufficient for the induction of JNK2 phosphorylation. Western blot analyses are of P-JNK2 from experiments in which EDL muscles were attached to the mechanical stimulator or a motionless device. The muscles on both devices were adjusted to optimal length and coincubated (CoInc) in the culture bath. A: muscles on the mechanical stimulator were held at optimal length for a 30-min preincubation followed by an additional 90 min of either CNT or STR conditions. B: muscles on the motionless device were held at optimal length and CoInc with CNT (open bars) or STR (shaded bars) muscles on the mechanical stimulator. Values are means + SD expressed as a percentage of the CNT conditions (n = 3–4/group). *Significantly different from CNT (P ≤ 0.05).

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Mechanosensitivity was defined as the ability of a skeletal muscle to sense and subsequently respond to a given amount of mechanical stimuli. Therefore, measuring the magnitude of mechanical stimuli applied to each muscle was a prerequisite for determining whether aging alters mechanosensitivity. In this study, intermittent 15% passive stretch was used as the source of mechanical stimulation, and the magnitude of mechanical stimulation was measured by recording the peak-specific passive tension (force/PCSA). The decision to apply passive tension as opposed to active tension (i.e., eccentric contractions) was based on previous reports that have demonstrated that aging results in alterations in motor unit composition of skeletal muscle (3). Changes in motor unit composition, as well as other age-associated changes in excitation-contraction coupling, may have complicated the interpretation of our results. Therefore, we choose to apply 15% passive stretch and measure peak-specific passive tension. The results from these measurements indicated that the average magnitude of mechanical stimuli applied to young and old muscles was similar throughout the 90-min stretch protocol, and thus correcting for differences in the magnitude of mechanical stimuli was not required for determining whether aging altered the mechanosensitivity of skeletal muscle.

The ability of skeletal muscle to sense and subsequently respond to mechanical stimulation was assessed by changes in p38, JNK2, and p70S6k phosphorylation. The selection of these markers of mechanotransduction was based on previous reports, which have implicated their respective roles in the transcriptional and translational control of cell growth (1, 18–20). In addition, using the stretch protocol employed in this study, we have previously characterized the temporal activation of the p38 and p70S6k molecules and demonstrated that these molecules are highly responsive to mechanical stimuli, and their activation appears to result from a purely mechanical rather than mechanical/growth factor-related mechanisms (5). In this study, we extend those results and found that a mechanically induced release of locally acting factors was also not sufficient for the induction of JNK2 phosphorylation. This was considered to be an important point because aged muscles have been reported to have a diminished sensitivity to certain growth factors such as IGF-I (8, 22). By choosing markers of mechanotransduction that were dependent on mechanical rather than mechanical/growth factor-related mechanisms, we were able to avoid this potentially confounding variable and conclude that, in skeletal muscle, the mechanosensitivity of several growth-related signaling pathways is not altered with aging.

The conclusion that aging does not alter the mechanosensitivity of skeletal muscle is consistent with previous reports that have shown that the host environment rather than properties intrinsic to aged muscle produce certain deficits that are observed with aging. For example, Carlson and Faulkner (2) used cross-transplantation studies to demonstrate that chronological age alone is not a factor that limits the intrinsic ability of skeletal muscle to regenerate. Instead, the poor regeneration of skeletal muscles in old animals is a function of the environment for regeneration provided by the old host (2). By performing our experiments ex vivo, we avoided any variables that may have been associated with the age of the host environment. This may help explain why signaling through the MAPKs (p38 and JNK2), as well as p70S6k, in old animals revealed a normal response to mechanical stimuli in our studies, whereas others have reported an impaired response when assessing these markers in vivo (13, 21). Other considerations could include the muscle that was studied (i.e., EDL vs. soleus) and the possibility that the old mice employed in this study had not aged enough to observe a decrease in mechanosensitivity, and, under more extreme aging conditions (i.e., >27 mo of age), a decrease in mechanosensitivity may exist.

In summary, the results from this study indicate that aging does not alter the mechanosensitivity of the p38, p70S6k, and JNK2 signaling pathways in skeletal muscle. This conclusion is only valid when comparing young and old muscles that are not undergoing regrowth, and, therefore, we propose that the impaired regrowth observed with aging results from deficits that are either 1) distal from the point of mechanotransduction, or 2) a consequence of disuse-induced atrophy and age-associated alterations in mechanosensitivity that arise only after an atrophic event. Distinction between these two hypotheses will be important to determine.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This research was supported by funding from National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR-45617 and from Pfizer to K. A. Esser and by the AFAR-Glenn Foundation to T. A. Hornberger.

Present addresses: T. A. Hornberger, Department of Bioengineering, University of California San Diego, La Jolla, CA 92093-0435; K. A. Esser, Department of Physiology, University of Kentucky, Albert B. Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0298; J. L. Andrews, Department of Physiology, University of Kentucky, Albert B. Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0298; and E. R. Chin, Research Pharmacology, Pfizer Global Research & Development, 10724 Science Center Drive, San Diego, CA 92121.


   FOOTNOTES
 

Address for reprint requests and other correspondence: T. A. Hornberger, Dept. of Bioengineering, Univ. of California San Diego, La Jolla, CA 92093-0435 (E-mail: thornb1{at}bioeng.ucsd.edu)

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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 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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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.
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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.
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G. C. Sieck
Commentary
J Appl Physiol, April 1, 2005; 98(4): 1541 - 1541.
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