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1Department of Physiology and Biophysics, The University of Alabama at Birmingham; 2Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center; and 3Department of Surgery, The University of Alabama at Birmingham, Birmingham, Alabama
Submitted 1 October 2004 ; accepted in final form 5 January 2005
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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sarcopenia; mechano-growth factor; p27kip; aging; resistance exercise
First characterized in 1997 (25), myostatin, or growth and differentiation factor-8 (GDF-8), is a member of the transforming growth factor-
superfamily that is known to play an essential role in the regulation of skeletal muscle mass. Myostatin mutation leads to massive hypertrophy and/or hyperplasia in developing animals, as evidenced by knockout experiments in mice (25) and by the well-known "double-muscling" phenotype seen in myostatin-null cattle (26). Additionally, myostatin mutation has been recently identified in a young child with overt muscle hypertrophy (32). Myostatin impairs muscle growth by inhibiting myoblast proliferation (36, 37) as well as differentiation (21, 30) in developing muscle. Additionally, myostatin has been shown to inhibit satellite cell activation (24), which would presumably limit growth of terminally differentiated adult myofibers. Myostatin may therefore play a key role in the inhibition of hypertrophic processes (17). Although the mechanisms are not fully understood, it most likely acts by modulating key regulators of the cell cycle such as cyclins (e.g., cyclins B1 and D1) and cyclin-dependent kinase inhibitors (e.g., p21cip and p27kip). For example, myostatin inhibition of satellite cell activation appears to be specific to negative regulation of G1-S progression (24), which we suggest may point to a potential interaction between myostatin and p27kip. Levels of myostatin mRNA expression have been found to be reduced after long-term resistance training (31) and elevated by disuse (29), with the magnitude of elevation significantly related to the magnitude of disuse myofiber atrophy. These findings suggest myostatin expression is tightly coupled to mechanical load.
The aims of the present study were to test the hypotheses that 1) acute RL using a regimen known to induce myofiber hypertrophy when performed 2–3 days/wk for several weeks (3 sets x 8–12 repetitions to volitional fatigue of squat, leg press, and knee extension) would suppress myostatin mRNA expression and elevate MGF mRNA expression in vastus lateralis samples and 2) the RL-mediated myostatin and/or MGF responses would be blunted in older women compared with both age-matched men and younger men and women. We studied additional transcripts involved in cell cycle progression (cyclins B1 and D1) and inhibition (p21cip and p27kip) to gain a better understanding of the influence RL exerts onto mitogenic processes. Expression levels of gene transcripts were determined by relative RT-PCR using 18S ribosomal RNA as an internal standard.
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METHODS |
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RL stimulus. We have described the RL stimulus in detail previously (4). Briefly, after a preexercise vastus lateralis muscle biopsy, subjects attended five successive visits to the laboratory on alternate days. The sequential sessions consisted of an introduction/familiarization to the 3 movements (squat, leg press, knee extension), a second familiarization session including practice one-repetition maximum (1RM) strength tests, 1RM assessment followed by 1 set x 8–12 repetitions of each exercise performed at 70% of 1RM, 2 sets x 8–12 repetitions to volitional fatigue, and, during the fifth session, 3 sets x 8–12 repetitions to volitional fatigue. All sets were separated by 90-s rest intervals. We designed this progressive protocol to prepare subjects for the full loading bout performed during the fifth exposure to the resistance exercises. As our objective was to study the effects of loading per se and not the effects of acute myofiber damage/inflammation, the progressive nature of this protocol was aimed at protecting subjects, at least in large part, from the acute inflammatory response that typically follows unaccustomed resistance exercise.
Body composition. Thigh lean mass (TLM), total body lean mass, and body fat percentage were determined by dual-energy X-ray absorptiometry (DEXA) using a Lunar Prodigy (model 8743; GE Lunar, Madison, WI). Analyses were conducted according to manufacturer's instructions using enCORE 2002 software (version 6.10.029). DEXA scans were performed on all but one young male (thus n = 37 for DEXA analyses). For age and gender comparisons, 1RM strength results were adjusted for TLM to yield estimates of specific strength.
Tissue collection. Muscle samples were collected in the Pittman General Clinical Research Center at UAB. Muscle tissue was removed under local anesthetic (1% Lidocaine) from vastus lateralis muscle by percutaneous needle biopsy using a 5-mm Bergstrom biopsy needle under suction as previously described (9). To avoid any residual effects of the initial biopsy taken from the left leg, the postexercise biopsy was taken from the right leg 24 h after the first full bilateral loading bout (4 progressive bouts preceded this one). Samples were quickly blotted with gauze, dissected free of visible connective and adipose tissues, weighed, and snap-frozen in liquid nitrogen. All samples were stored at –80°C.
Total RNA isolation. Frozen muscle samples (average = 35 mg) were homogenized, and total RNA was extracted using the TRI Reagent (Molecular Research Center, Cincinnati, OH) according to the company's protocol, which is based on the method by Chomczynski and Sacchi (7). Extracted RNA was precipitated from the aqueous phase with isopropanol and, after two ethanol washes, dried and suspended in nuclease-free water (Promega, Madison, WI) at a ratio of 0.8 µl/mg muscle. RNA concentration was determined with a fluorometer (TD-700, Turner Designs, Sunnyvale, CA) using the RiboGreen RNA Quantitation Kit (Molecular Probes, Eugene, OR) according to the manufacturer's protocol. RNA concentration of each sample was determined by linear regression using ribosomal RNA standards from the RiboGreen RNA Quantitation Kit and expressed as total RNA per milligram of muscle. RNA samples were stored at –80°C for the subsequent analyses of specific mRNAs by relative RT-PCR procedures.
RT. One microgram of RNA was reverse transcribed in a total volume of 20 µl using SuperScript II Reverse Transcriptase (Invitrogen, GIBCO-BRL, Carlsbad, CA) with a mix of oligo(dT) (100 ng/reaction) and random primers (200 ng/reaction), according to the method described by Bickel et al. (5). After the RT reaction, mixtures were incubated at 45°C for 50 min, they were heated at 90°C for 5 min to discontinue the reaction and then stored at –80°C for subsequent PCR analyses.
PCR. A relative RT-PCR method was applied in the present study using 18S ribosomal RNA as an internal standard (Invitrogen) to determine relative expression levels of mRNAs for myostatin, MGF, cyclin B1, cyclin D1, p21cip, and p27kip. The primer sequences for the specific target mRNAs are shown in Table 1. Primers were designed using the Primer Select computer program (DNAStar, Madison, WI) and prepared by Invitrogen (GIBCO). In preliminary experiments, we confirmed that each target mRNA primer set was compatible with the alternate 18S primers.
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Statistical analysis. Data are reported as means ± SE. Between-group differences in preexercise descriptive variables were tested using age x gender ANOVA. All variables measured before and after loading were analyzed using age x gender x load repeated-measures ANOVA. For each ANOVA model with a significant main or interaction effect, Tukey HSD tests were performed post hoc to localize the effect(s). Zero-order correlations were tested between levels of lean body mass (LM) or TLM and resting levels, as well as load-mediated changes, for each transcript studied. Correlations were also tested between load-mediated changes in mRNA levels for myostatin, MGF, cyclin B1, cyclin D1, p21cip, and p27kip mRNA. For each correlation, we tested for the presence of outliers by residual analysis using a standard residual >2.5 SD. If one or more outliers were identified, these subjects were excluded and the correlation was retested. Results are summarized with the appropriate sample size for each correlation after removing outliers (if any). Statistical significance was accepted at P < 0.05 for all tests.
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RESULTS |
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Correlational analyses revealed some noteworthy associations. Using residual analysis to detect outliers as described in METHODS led to the removal of no more than one outlier from any given correlation. For all subjects, the relative concentration of myostatin mRNA in resting VL muscles was positively related to LM (r = 0.45, P < 0.01, n = 37) and TLM (r = 0.49, P < 0.01, n = 37; Fig. 5A). Furthermore, the magnitude of reduction in myostatin mRNA correlated with LM (r = –0.42, P < 0.05, n = 36) and TLM (r = –0.47, P < 0.01, n = 36). Interestingly, these findings appeared to have been mainly driven by males. In men, resting myostatin levels were positively related to LM (r = 0.68, P < 0.005, n = 18) and TLM (r = 0.63, P < 0.01, n = 18; Fig. 5B), and there was a negative relationship between load-induced reduction in myostatin mRNA and muscle mass (TLM) (r = –0.80, P < 0.01, n = 17; Fig. 6A).
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For all subjects, there was a positive correlation between load-mediated increases in MGF and cyclin D1 mRNA levels (r = 0.60, P < 0.01, n = 37). As cyclin D1 has been used extensively as a general marker of cell cycle activity, and MGF is a muscle-specific, load-sensitive mitogen, this relationship is suggestive of a load-induced increase in mitogenic activity within a population of myogenic cells. Partitioning by age or gender revealed significant relationships in young subjects (r = 0.80, P < 0.01, n = 19) and in males (r = 0.54, P < 0.05, n = 19).
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DISCUSSION |
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The capacity of young men for resistance training-induced myofiber hypertrophy is well known. Additionally, much of the recent work demonstrating acute load-mediated increases in proteins and/or mRNAs thought to be important for long-term growth/regeneration has been conducted in young men (14, 28, 41, 42). Our unique model enabled us to assess potential influences of age and/or gender on key transcriptional activities following loading. The overall trend of these data is that young men responded most positively to the loading program, demonstrating robust and consistent changes in factors thought to promote (MGF, cyclin D1, cyclin B1) and inhibit (myostatin, p27kip) the processes of growth and regeneration. The other age/gender groups showed some, but not all, of these favorable responses, with the least responsive group appearing to be older women.
Although these data provide important insight regarding age and gender influences on load-mediated gene expression, two limitations are notable. First, our postloading analysis was limited to one timepoint (24 h). Additional postloading biopsies both earlier and later than 24 h may have revealed additional age and/or gender differences. With serial biopsies ranging from 0 to 48 h postloading, Psilander et al. (28) clearly demonstrated (in young men) that temporal postloading responses vary among transcripts. Second, our analyses were limited to mRNAs. Although our work is certainly not unique in this regard (5, 28), coupled analysis of both mRNA and its protein product is certainly a strength. However, we previously showed using the same model that 24 h after loading is probably too early to detect a host of changes at the protein level (4). A protocol with multiple postloading biopsies would have addressed both of these limitations but was simply not feasible.
Myostatin and general cell cycle inhibitors. We found no significant age differences in resting levels of myostatin mRNA, a finding that has been shown previously in men (39). One important finding was that, in response to the same relative loading stimulus, older women had an impaired ability to downregulate myostatin expression. Older men, however, showed a load-induced reduction in myostatin similar in magnitude to both younger men and women. We recently reported that older females showed a blunted myofiber hypertrophic response along with a blunted strength gain after 26 wk of progressive resistance training compared with older males (3). If myostatin downregulation is key to the promotion of hypertrophic processes, an attenuated acute response to loading in older women may contribute to an impaired long-term growth adaptation. Interestingly, older women have also been shown to be more susceptible to detraining following resistance training compared with young men, young women, and older men (18). A study of polymorphic variation in a cohort of older women showed that myostatin polymorphic variants were related to differences in strength levels in older women (34). This group further demonstrated that women with a less common myostatin allele exhibited a 68% larger increase in muscle volume in response to strength training (17), suggesting this allele resulted in either lower amounts of myostatin protein or an alternate protein product with reduced efficacy as a negative regulator.
Reductions in myostatin mRNA have been shown previously following 9 wk of resistance training (31). On the basis of our finding of markedly reduced myostatin mRNA levels following acute RL, we suggest the bulk of the reduction found after 9 wk of training may have occurred very early in the training program (e.g., first 1–3 exercise bouts). In contrast to our findings and to those of Roth et al. (31), Willoughby (41) recently reported increased levels of myostatin protein and mRNA after both 6 and 12 wk of resistance training. One major difference in protocol design, however, was the collection of 6- and 12-wk biopsies only 15 min after an exercise bout (compared to 24 h in the current study).
As increased mechanical load has been shown to reduce myostatin, one might expect increased myostatin levels during states of reduced loading. Findings in both humans (29) and rodents (20) support this concept. Significantly elevated myostatin mRNA levels were observed in the vastus lateralis muscle of 12 patients with chronic disuse atrophy of type II myofibers (29). Furthermore, muscle atrophy during spaceflight has been shown to be associated with increased myostatin mRNA and protein levels (20).
Striking from the present study was the finding that thigh muscle mass in healthy sedentary adults, irrespective of age or gender, was positively related to resting levels of muscle myostatin mRNA. At odds with this finding are reports that serum levels of a "myostatin-immunoreactive protein" are higher in older adults and inversely related to muscle mass (44) and lean mass in frail elderly women (33) and to lean mass in HIV-positive men suffering from cachexia (11). However, the sequence of the 26-kDa "immunoreactive protein" has not been confirmed, and whether this protein is in fact myostatin in any form has been questioned (45). Our findings of a positive association between resting myostatin mRNA levels and muscle mass were revealed in a fairly large subject cohort. Although further study is certainly needed (including protein-level analyses), we consider this result combined with the finding that load-induced reductions in myostatin mRNA were greatest in subjects with higher muscle mass as a possible indicator of hypertrophic potential. It is also possible that the positive relationship seen between resting myostatin mRNA and thigh muscle mass was, in part, driven by myofiber type distribution. Previous studies in rodents have indicated preferential expression of myostatin in type II plantaris muscle (38) and a positive relationship between myostatin mRNA expression and MHCIIb abundance (6). Whether myostatin is more abundant in type II muscle among humans is unknown. If so, it is certainly possible that subjects with greater thigh muscle mass in our study also possessed a greater type II myofiber area distribution. In an ongoing study of over 40 young and older participants similar in age to the current subjects, we have found that the type II atrophy associated with sarcopenia is most notable in type IIx myofibers (M. Bamman, J.S. Kim, and D. Kasek, unpublished observations).
The cell cycle is regulated by a number of cyclin-dependent kinase inhibitors including the INK4 family and the CIP/KIP family (p21cip, p27kip, p57kip). p27kip is typically considered an inhibitor of cell cycle initiation (G1) (22), while p21cip inhibits the cell cycle at multiple control points, including progression through the G2-M boundary. In the present study, a load-induced reduction was found for p27kip mRNA levels as indicated by an overall main effect of loading. The mean data in Fig. 4A show that all groups except OM contributed to this effect. We reported a similar load-mediated reduction in p27kip protein concentration in women using the same acute loading model (4). Spangenburg et al. (35) previously suggested that p27kip may be a molecular mediator in the progression of age-related sarcopenia based on the findings that p27kip expression is higher in older satellite cells, and p27kip overexpression arrests cultured satellite cells in G1 despite the overexpression of IGF-I, a potent mitogen.
Lin et al. (22) previously demonstrated the inhibitory influence of p27kip on myogenic cells and its association with myostatin in developing muscle, as p27kip knockout mice showed markedly increased gastrocnemius muscle mass and a reduction in myostatin mRNA levels. This finding suggests that p27kip deficiency-induced muscle hypertrophy may be partially mediated by decreased myostatin. We report herein that not only were p27kip and myostatin mRNA levels reduced by mechanical load, the magnitudes by which these transcripts declined were positively related in men and especially in young men. If, in fact, p27kip and myostatin work in concert, our findings may provide some basis for a greater load-induced hypertrophic potential in young men vs. older women, as no coordinated decline in the two transcripts was seen in older women nor in all women combined.
The importance of p27kip in the inhibition of cell growth has been demonstrated by Coats et al. (8), suggesting that the activity of cdk2, which is involved in progression throughout the entire cell cycle from G1 to M, is mainly inhibited by p27kip and to a lesser degree by p21cip. Levels of p21cip mRNA did not change in our model. By contrast, p21cip mRNA levels have been shown to increase markedly in response to mechanical load in rodents (2, 12) and in humans (5). These investigators considered an increase in p21cip as indicative of enhanced differentiation. In the work by Bickel et al. (5), muscle biopsies were collected 24 h after the second of two bouts of electrically evoked isometric contractions. The timing between stimulus and biopsy was identical to our model but the contraction paradigm differed substantially. We do not know whether this difference is responsible for the markedly different results in p21cip expression between the two studies; however, it is noteworthy that results of both total RNA concentration and cyclin D1 mRNA levels also differed, as total RNA concentration (µg RNA/mg muscle) increased 13% and cyclin D1 mRNA increased 34% after our dynamic RL regimen but did not change significantly in the isometric contraction model of Bickel et al.
The cdk inhibitors (p21cip, p27kip) we studied are often viewed as general markers of differentiation but, in addition to promoting withdrawal of actively proliferating cells, they specifically inhibit cell cycle initiation and/or progression. In a quiescent cell type such as satellite cells, our impression is that these cdk inhibitors may be responsible for inhibiting entry into the cell cycle (arresting in G1). Thus in the early response phase following loading, we speculate a suppression of cdk inhibitors might be advantageous by facilitating entrance into the cell cycle. Beyond an initial phase of proliferative activity (e.g., the first 24 h), an increase in cdk inhibitors may be advantageous to promote withdrawal (i.e., differentiation) of some cells as proliferation continues. The expression of p21cip mRNA has been shown to increase markedly within 12 h after the onset of compensatory overload (via synergist ablation) in rats (2). The compensatory overload model induces a much greater loading stimulus than our resistance exercise regimen, thus making it difficult to compare the two time courses.
MGF and general cell cycle promoters. In differentiated adult skeletal myofibers, RL-mediated myofiber hypertrophy involves increased muscle protein synthesis and activation of satellite cells. MGF is a load-sensitive autocrine/paracrine growth factor that likely works in concert with IGF-I to promote both of these processes (13, 15, 43). We found a marked increase in MGF mRNA expression (+49%) after acute RL; however, post hoc tests revealed a within-groups increase in young men only (91%). Others have also reported induction of MGF mRNA after acute RL in young men (5, 14, 28). Hameed et al. (14) found this acute response in young men only, as no change in MGF mRNA was noted in elderly men. In a separate study, however, this group found a substantial rise in MGF mRNA after 5 wk of resistance training in elderly men (13). The young men in the present study not only experienced the largest elevation in MGF but also the greatest reduction in myostatin mRNA, suggesting the muscles of young men were most responsive to the loading stimulus.
As markers of general proliferative activity, we examined cyclin D1 as integral to cell cycle initiation and cyclin B1 as an index of late cell cycle activity (i.e., progression through the G2-M boundary). Our data indicate that acute RL induced an overall increase in levels of cyclin D1 gene expression while only young subjects increased cyclin B1 mRNA levels. Others found increases in cyclin D1 mRNA levels after acute loading in rodents (12). Certainly these changes in cyclin expression cannot be uniquely attributable to satellite cell activation, as these general cell cycle markers may also point toward upregulation of mitotic activity in non-muscle cells (e.g., fibroblasts) that would seem necessary for growth/repair/regeneration of supporting tissues within the muscle. However, by assessing both cyclins D1 and B1, our data may provide some important insight into the overall growth/regenerative capacity of young and older men and women in response to acute loading. Based solely on cycle D1 mRNA levels (Fig. 3A), one might hypothesize that older women would have the greatest mitotic potential; however, by also studying late cell cycle activity (cyclin B1; Fig. 3B), younger men emerge as the group with the greatest combined response. In support of this, we noted positive relationships between increases in cyclin D1 and MGF only in young subjects and in men.
If we accept these molecular markers as representative of some key processes in the regulation of muscle mass, our combined findings may provide some molecular basis for disparate hypertrophic adaptations to long-term resistance training among gender- and age-specific populations. Based on the aforementioned assumption, we have drawn the following conclusions from these data. First, in resting and otherwise healthy muscle not induced to hypertrophy and not exposed to acutely atrophic conditions, the concentration of myostatin mRNA was positively related to muscle mass. This novel "paradox" may lead to a greater potential to reduce myostatin (among those with higher muscle mass) when a hypertrophic stimulus is imposed, as the magnitude of load-mediated reduction in myostatin was inversely related to muscle mass and this relationship was strengthened when only men were included. Second, as additional evidence for a link between resting muscle mass and mitogenic potential, load-mediated increases in cyclin D1 and decreases in p27kip mRNAs were related to TLM in men only. Third, concurrent reduction in myostatin and p27kip, as seen in young men, may be optimal as a permissive signal for the induction of myogenesis. Fourth, the greatest load-driven increase in MGF mRNA was found in young men, and the magnitudes of increase in MGF and cyclin D1 mRNAs were correlated in all subjects, suggesting coordinated mitogenic signaling between the two.
Overall, our findings suggest that high- to moderate-intensity RL serves as a natural inhibitor of myostatin gene transcription. Myostatin may act in concert with p27kip and reductions in these cell cycle inhibitors are coincident with enhancements in cell cycle progression (cyclins D1 and B1) and myogenic potential (MGF). Although these load-mediated myofiber hypertrophic signals appear to be optimal in young males, older women show impaired capacity to reduce myostatin and enhance MGF gene expression levels in response to the same relative loading stimulus. These acute molecular responses may underlie age and gender differences in the capacity for load-mediated hypertrophy. Thus an important next step would be the evaluation of these responses during long-term resistance training to determine whether indeed these acute events are predictive of satellite cell activation and myofiber hypertrophy.
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ACKNOWLEDGMENTS |
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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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superfamily member. Nature 387: 83–90, 1997.[CrossRef][Medline]
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L. B. Verdijk, R. Koopman, G. Schaart, K. Meijer, H. H. C. M. Savelberg, and L. J. C. van Loon Satellite cell content is specifically reduced in type II skeletal muscle fibers in the elderly Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E151 - E157. [Abstract] [Full Text] [PDF]
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J. K. Petrella, J.-s. Kim, J. M. Cross, D. J. Kosek, and M. M. Bamman Efficacy of myonuclear addition may explain differential myofiber growth among resistance-trained young and older men and women Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E937 - E946. [Abstract] [Full Text] [PDF]
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D. J. Kosek, J.-s. Kim, J. K. Petrella, J. M. Cross, and M. M. Bamman Efficacy of 3 days/wk resistance training on myofiber hypertrophy and myogenic mechanisms in young vs. older adults J Appl Physiol, August 1, 2006; 101(2): 531 - 544. [Abstract] [Full Text] [PDF]
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U. Raue, D. Slivka, B. Jemiolo, C. Hollon, and S. Trappe Myogenic gene expression at rest and after a bout of resistance exercise in young (18-30 yr) and old (80-89 yr) women J Appl Physiol, July 1, 2006; 101(1): 53 - 59. [Abstract] [Full Text] [PDF]
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V. G. Coffey, A. Shield, B. J. Canny, K. A. Carey, D. Cameron-Smith, and J. A. Hawley Interaction of contractile activity and training history on mRNA abundance in skeletal muscle from trained athletes Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E849 - E855. [Abstract] [Full Text] [PDF]
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G. F. Martel, S. M. Roth, F. M. Ivey, J. T. Lemmer, B. L. Tracy, D. E. Hurlbut, E. J. Metter, B. F. Hurley, and M. A. Rogers Age and sex affect human muscle fibre adaptations to heavy-resistance strength training Exp Physiol, March 1, 2006; 91(2): 457 - 464. [Abstract] [Full Text] [PDF]
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J.-s. Kim, D. J. Kosek, J. K. Petrella, J. M. Cross, and M. M. Bamman Resting and load-induced levels of myogenic gene transcripts differ between older adults with demonstrable sarcopenia and young men and women J Appl Physiol, December 1, 2005; 99(6): 2149 - 2158. [Abstract] [Full Text] [PDF]
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P. M. Siu and S. E. Alway Subcellular responses of p53 and Id2 in fast and slow skeletal muscle in response to stretch-induced overload J Appl Physiol, November 1, 2005; 99(5): 1897 - 1904. [Abstract] [Full Text] [PDF]
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