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1 Department of Exercise Science, University of Georgia, Athens, Georgia 30602; 3 Department of Physiology and Biophysics, University of California, Irvine, California 92697-4560; and 2 Shepherd Center, Atlanta, Georgia 30309
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Spinal cord injury (SCI) results in muscle atrophy, which contributes to a number of health problems, such as cardiovascular deconditioning, metabolic derangement, and osteoporosis. Electromyostimulation (EMS) holds the promise of ameliorating SCI-related muscle atrophy and, therefore, improving general health. To date, EMS training of long-term SCI subjects has resulted in some muscle hypertrophy but has fallen short of normalizing muscle mass. The aim of this study was to compare the molecular responses of vastus lateralis muscles from able-bodied (AB) and SCI subjects after acute bouts of EMS-induced resistance exercise to determine whether SCI muscles displayed some impairment in response. Analysis included mRNA markers known to be responsive to increased loading in rodent muscles. Muscles of AB and SCI subjects were subjected to EMS-stimulated exercise in two 30-min bouts, separated by a 48-h rest. Needle biopsy samples were obtained 24 h after the second exercise bout. In both the AB and SCI muscles, significant changes were seen in insulin-like growth factor binding proteins 4 and 5, cyclin-dependent kinase inhibitor p21, and myogenin mRNA levels. In AB subjects, the mRNA for mechano-growth factor was also increased. Before exercise, the total RNA concentration of the SCI muscles was less than that of the AB subjects but not different postexercise. The results of this study indicate that acute bouts of resistance exercise stimulate molecular responses in the skeletal muscles of both AB and SCI subjects. The responses seen in the SCI muscles indicate that the systems that regulate these molecular responses are intact, even after extended periods of muscle unloading.
mechano-growth factor; insulin-like growth factor I; insulin-like growth factor binding protein; myogenin
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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INACTIVITY CAN LEAD TO A LOSS of muscle mass and function. Complete spinal cord injury (SCI) leads to inactivation and profound muscle unloading. The muscles of SCI patients are characterized by severe atrophy, as well as extensively altered metabolic and contractile protein profiles (6, 19, 40). For example, within several months of SCI, muscles and their constituent myofibers can be reduced to ~41% of the size of those of able-bodied (AB) individuals (16, 15). The loss in muscle mass and function can contribute to a number of health problems, such as decreased cardiorespiratory fitness, impaired glucose tolerance, and osteoporosis (37, 39).
Recognition of potential benefits to be garnered by maintaining or increasing muscle mass in SCI patients has lead to a number of studies aimed at using electromyostimulation (EMS) to induce contractile activity in the muscles of these patients. In AB subjects, EMS-induced resistance exercise has been shown to result in increases in muscle size and performance (13, 14, 41). Studies have also shown that the muscles of SCI patients can respond to EMS-mediated contractile activity with some degree of appropriate adaptation, including a modest hypertrophy (11, 17, 31, 36, 38, 40). However, the absolute changes in mass seen in long-term SCI subjects tend to be relatively small as a result of the atrophied state of the muscle at the start of training (e.g., Refs. 17, 31, 35, 36). For example, Mohr et al. (36) reported that EMS cycling evoked a 12% increase in cross-sectional area of the quadriceps femoris muscle in SCI subjects. Assuming the atrophied muscle was 40% of its preinjury size, a 12% increase would result in muscle that remained less than one-half the size of that expected for an AB subject. In contrast to the relatively small effects of EMS in long-term SCI patients, we instituted EMS training ~48 wk after the injury and were able to increase muscle mass to a state more directly comparable to that of ambulatory subjects in only 8 wk (22). Others have also reported that training initiated soon after SCI (~15 wk) maintained lower extremity muscle mass (9). It is not clear whether the differences between the ability of EMS training to rebuild vs. maintain skeletal muscle are a function of alterations in the physiology of the muscles or differences in the method of training used in the various studies. One possibility is that some of the molecular and cellular response systems involved with the response of muscle to increased loading are less responsive in the muscles of SCI subjects.
Skeletal muscle can respond to changes in loading state via alteration in myofiber size as well as qualitative changes in contractile and metabolic characteristics. As in the case of SCI, unweighting and inactivity result in a decrease in muscle size as a result of myofiber atrophy (16). Conversely, increased muscle loading can result in myofiber hypertrophy and alterations in the expression profile of contractile and metabolic proteins (12). It is clear that changes in loading patterns result in the adaptation of only the affected muscles. This has lead to the recognition that specific adaptations that occur in skeletal muscle appear to be regulated primarily by intrinsic mechanisms (e.g., local cellular mediators as opposed to central or circulating factors).
We have previously shown that, in rodent muscle, cellular and molecular events indicative of a hypertrophic response can be detected after a single bout of resistance-type exercise (25). In that study, we also demonstrated that multiple bouts of exercise result in the summation of these cellular and molecular responses. In the present study, we have attempted to evaluate the response of some of these molecular markers to acute bouts of EMS-induced resistance exercise in both healthy subjects and long-term SCI patients to uncover potential SCI-induced changes. Our hypothesis was that SCI-induced defects in mechanisms by which skeletal muscle adapts to increased loading would be detectable as differential molecular level responses to acute resistance exercise.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. Seven AB (age 27 ± 1.6 yr, height 177 ± 3.3 cm, weight 80 ± 7.0 kg, 1 woman, means ± SE) and eight SCI (age 36 ± 1.9 yr, height 178 ± 2.9 cm, weight 83 ± 6.8 kg) subjects participated in this study. SCI level of injury ranged from C4 to T10, and the average time postinjury was 9 ± 2.1 yr. All subjects were motor and sensory complete, with the exception of one who was motor complete only. SCI and AB subjects had no history of lower extremity pathology and signed informed consent before testing. AB subjects were recreationally active and not currently involved in lower extremity resistance exercise. Methods were approved by the Institutional Review Boards of the University of Georgia and Shepherd Center and the University of California-Irvine.
EMS protocol. The vastus lateralis (VL) muscle was stimulated essentially as described previously (4, 16, 30). Subjects were seated in a custom-built chair with the hip and knee secured at ~70° of flexion. The leg was firmly secured to a rigid lever arm with an inelastic strap to ensure that the knee extensors could only perform isometric contractions. As with our previous animal studies, isometric mode contractions were used to minimize the potential for muscle injury (3). The moment arm was established by placing a load cell (model 2000A, Rice Lake Weighing Systems, Rice Lake, WI) parallel to the line of pull and perpendicular to the lever arm. Torque was recorded from the load cell by using a MacLab analog-to-digital converter (model ML 400, ADInstruments, Milford, MA) sampling at 100 Hz and interfaced with a portable Macintosh computer (Apple Computer, Cupertino, CA). Two 8 × 10-cm surface electrodes (Uni-Patch, Wabasha, MN) were placed on the proximal and distal portions of the VL. This electrode placement has previously been shown to allow sufficient recruitment of the VL in AB subjects and is essentially as done previously (5, 30). A commercial stimulator (TheraTouch model 4.7, Rich-Mar, Inola, OK) was used for EMS. The initial torque was determined in the following manner. The AB controls performed a maximum voluntary contraction (MVC) for isometric knee extension prior to EMS. The subjects were highly motivated, and all had prior experience with knee-extension MVC. We have previously established that the VL muscle constitutes roughly 30% of the total quadriceps group cross-sectional area (28). Accordingly, electrical current sufficient to elicit ~30% of the observed isometric knee-extension MVC was determined and used for the subsequent EMS protocol in the AB subjects. For SCI patients, the torque was determined by increasing current incrementally until torque no longer increased, thereby ensuring that the entire VL was activated. The EMS protocol consisted of 5-s contractions separated by 15 s for 30 min at these previously determined current levels. An identical stimulation bout was performed 48 h later. For both groups, contractions were evoked with 50-Hz trains of 450-µs biphasic pulses.
Biopsy technique.
Muscle samples were obtained from all subjects immediately before the
initial stimulation and 24 h after the second stimulation bout.
Biopsies were taken from the VL by using the percutaneous biopsy
technique, as done previously (16, 28). Samples were immediately cooled with liquid nitrogen and then stored at 
70°C until analyzed.
Total RNA isolation.
Measurements of total RNA content provide insights on the translational
capacity of tissue. Total RNA was extracted from preweighed frozen
muscle samples by using the TRI Reagent (Molecular Research Center,
Cincinnati, OH), according to the company's protocol, which is based
on the method described by Chomczynski and Sacchi (18).
Extracted RNA was precipitated from the aqueous phase with isopropanol
and after being washed with ethanol, dried, and suspended in a known
volume of nuclease-free water. The RNA concentration was determined by
optical density at 260 nm (using an optical density 260-nm unit
equivalent to 40 µg/ml). The muscle total RNA concentration is
calculated on the basis of total RNA yield and the weight of the
analyzed sample. The RNA samples were stored frozen at 80°C to be
used subsequently in determining specific mRNA expression by using
relative RT-PCR procedures.
RT.
One microgram of total RNA was reverse transcribed for each muscle
sample by using the SuperScript II RT from GIBCO-BRL and a mix of
oligo(dT) (100 ng/reaction) and random primers (200 ng/reaction) in a
20-µl total reaction volume at 45°C for 50 min, according to the
provided protocol. At the end of the RT reaction, the tubes were heated
at 90°C for 5 min to stop the reaction and then were stored at
80°C until they were used in the PCR reactions for specific mRNA
analyses (see below).
PCR.
A relative RT-PCR method using 18S as an internal standard (Ambion,
Austin, TX) was applied to study the expression of mRNAs for
insulin-like growth factor (IGF)-I, mechano-growth factor (MGF), IGF-I
receptor, IGF binding proteins (IGFBP-4 and -5), myogenin, cyclin D1,
and p21. The sequence for the various primers used for the specific
target mRNAs is shown in Table 1. These primers were designed by using Primer Select computer program (DNA
Star), purchased from Life Technology (GIBCO) and were tested for their
compatibility with the alternate 18S primers.
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Statistical analysis. All values are reported as means ± SE. For each time point, treatment effects were determined by ANOVA with post hoc testing (Student Newman-Keuls) by using the Prism software package (Graphpad). Pearson's correlation analysis was used to assess the relationship between p21 and myogenin using the Prism software package. For all statistical tests, the 0.05 level of confidence was accepted for statistical significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Analysis of the torque output records indicated that, over the two exercise bouts, the AB subjects were stimulated to produce 36 ± 1% of their previously measured isometric MVC. Over the course of the stimulation protocol, the torque of the AB subjects declined by 42 ± 6%, whereas that of the SCI subjects decreased 64 ± 9%.
The mRNAs for several components of the IGF-I system were altered in
response to the acute bout of EMS-induced resistance exercise. Compared
with the preexercise sample, the expression and/or accumulation of MGF,
the loading-sensitive isoform of IGF-I (26), was
significantly increased in the muscles of SCI subjects after EMS (Fig.
2A). The expression of the
mRNA for IGFBP-4 was significantly increased in both the
able-bodied control and SCI muscles, whereas that of IGFBP-5 was
significantly depressed (Fig. 2, B and D). There
were no significant alterations in the expression of the mRNAs for
either IGF-I (data not shown) or type 1 IGF-I receptor (Fig.
2C).
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The expression of two markers of cellular differentiation was increased
as a result of EMS. The mRNA for p21, a general marker of cellular
differentiation, was significantly increased in the postexercise
samples from both control and SCI subjects (Fig. 3A). In addition, p21 mRNA
expression was significantly higher in the muscles of SCI patients
before the EMS exercise (Fig. 3A). The expression of
myogenin mRNA, a putative muscle-specific marker of cellular
differentiation, was increased to a similar extent in both control and
SCI subjects (Fig. 3B). The observed increases in cyclin D1
expression, a marker of cellular proliferation, did not reach
statistical significance in either the AB or SCI subjects (data not
shown).
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Compared with preexercise, the concentration of total muscle RNA was
not significantly altered by EMS (Fig.
4). However, total muscle RNA
concentration was significantly lower in SCI vs. control muscles before
exercise (Fig. 4). This difference was no longer significant after the
EMS exercise bouts.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Individual skeletal muscles adapt to alterations in loading, allowing for the development of task-specific functional characteristics. These adaptations can include an increase or decrease in mass, as well as alterations in contractile characteristics. Enforced unloading and/or inactivity can lead to adaptations that have negative impacts. In the case of SCI patients, extensive loss of muscle mass can contribute to cardiovascular deconditioning, metabolic derangement, and osteoporosis (37, 39). A number of studies have attempted to evaluate the utility of EMS to increase the muscle mass of long-term SCI patients (6, 9, 11, 13-17, 19, 22, 30, 31, 36-40). Whereas the general consensus appears to be that EMS training can result in improvement in various measures of muscle function, it is not clear that the benefits are proportional to the time and effort the patients must invest in EMS training. Some portion of this uncertainty most likely results from the inconsistency of the published results. In turn, much of the variability in the published research in this field can be attributed to differences in experimental design and methodology. For example, the protocols imposed during various EMS training studies have included no loading, endurance types of activity (cycle ergometery), and a few attempts at true resistance types of exercise (e.g., Refs. 9, 31, 35-40). As a result, the ability of the muscles of long-term SCI patients to hypertrophy has not been systematically examined. Of particular interest, there have been some reports that suggest that EMS may be more effective at normalizing muscle mass and function when applied a relatively short time after the injury. This raises the possibility that the muscles of long-term SCI patients may exhibit physiological responses to EMS training that differ from those of ambulatory subjects.
Few studies involving direct comparisons between the exercise response of the muscles of SCI and AB subjects have been reported (15, 22, 30, 39). Where they exist, such studies have followed traditional approaches to the evaluation of resistance exercise and relied on end-state measures, such as strength, muscle size, or protein level biochemistry (22, 30). The temporal resolution of such measurements is generally on the scale of weeks or months, requiring many exercise sessions. In the present study, we used changes in the expression of various mRNAs as indicators of the cellular-level responses to the exercise stimulus with a temporal resolution on a scale of hours to compare the responses of AB vs. SCI subjects. These experiments were patterned on our previous work in rodents in which changes in the expression of markers of both myogenic and anabolic processes were detected after a single bout of resistance exercise (25). In that study, we found that two bouts of exercise, separated by 48 h, provided a summation of cellular and molecular signaling responses, such that the magnitude of a given response was greater than that seen after a single exercise bout. In the present study, the two-exercise-bout model was used to ensure that a sufficient stimulus was delivered.
A limitation of the present study is that, unlike our previous rodent studies, which provided relatively large amounts of muscle (e.g., >500 mg), analysis was limited to mRNA changes due to the smaller amount of tissue available from human biopsy samples (3). In addition, the number of biopsy samples and, therefore, time points when it was feasible to collect from human subjects were limited compared with those from our animal studies. Therefore, we could not be certain that we had chosen the optimal parameters (e.g., exercise stimulus, sample collection time) to ensure that the response was fully realized. Nonetheless, we were able to detect changes in a number of molecular signals indicative of a hypertrophy response in the EMS-exercised muscles of both AB and SCI subjects.
IGF-I axis. IGF-I has been shown to stimulate anabolic and myogenic processes associated with the development of skeletal muscle hypertrophy (1). In skeletal muscle, the IGF-I system has also been shown to be sensitive to increased loading (1-3, 25). In muscle, the IGF-I axis consists of locally expressed IGF-I and MGF, the type I IGF-I receptor, and a number of IGFBPs. Modulation of the various components of this system appears to be important for the development of a compensatory hypertrophic response (1, 7, 8, 10, 20, 24, 26, 33, 44). In animal studies, increased muscle loading has been shown to result in an upregulation of the expression of IGFBP-4 and downregulation of IGFBP-5 (7, 25). The same pattern of changes was seen in these mRNAs in muscle samples from both the AB and SCI subjects in the present study (Fig. 2). Using a similar EMS training protocol in rats, we had previously observed that MGF mRNA was increased at very early time points (e.g., 6-12 h) after contractile activity (25). In the present study, the muscles from the SCI subjects exhibited an approximately twofold increase in MGF mRNA 24 h after the second bout of EMS-induced resistance exercise. This contrasts to the muscles of the AB subjects in whom no MGF response was evident at this time point. One possibility for this difference might be that some cellular transduction and signaling mechanisms, which mediate the MGF response, may have an increased sensitivity in the muscles of the SCI subjects.
Myogenic markers.
In rats, increased loading has been shown to result in the
proliferation and differentiation of satellite cells (reviewed in Refs.
24, 42). There is an increasing body of
evidence that indicates that these myogenic processes are an obligatory component of the compensatory hypertrophic response (2,
21). In the present study, we used the mRNA for cyclin D1 as a
marker of the intent of some cell population within muscle to enter the cell cycle. In contrast to our previous studies conducted in rats, we
did not detect statistically significant increases in the expression of
cyclin D1 mRNA in the muscles from either the AB or SCI subjects (25). It is possible that the failure to detect a
significant cyclin D1 response was related to the limitation imposed by
selecting a single time point for sample collection. In our rodent
studies, we have found that the cyclin D1 response is delayed compared with other measures. Our laboratory has previously reported that one of
the earliest responses to increased muscle loading is marked increase
in myogenin mRNA (2, 3, 25). Myogenin is a member of the
myogenic regulatory factor family and, as such, is important for
the expression of muscle-specific proteins (24, 42). In the present study, the expression and/or accumulation of myogenin mRNA
was increased in both the AB (~3-fold) and SCI (~2-fold) subjects
24 h after the second EMS-induced resistance exercise bout (Fig.
3). In fully innervated skeletal muscle, increased expression of
myogenin is thought to indicate that a population of myogenic cells is
differentiating (3, 23, 27, 34, 42, 43, 46). In support of
this, the increase in myogenin mRNA in the present study was highly
correlated with the mRNA for p21, a general cell-type marker of
differentiation, in both AB and SCI subjects (Fig.
5). This result suggests that the
exercise-induced response of the muscles in both the AB and SCI
subjects included the differentiation of some class of myogenic
precursor cell. This result, correlation between the increase in p21
and myogenin, is similar to that seen in our laboratory's previous
rodent studies (2, 3, 25).
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Total RNA. The majority of the RNA present in muscle cells consists of ribosomal RNA. Therefore, the concentration of RNA in skeletal muscle provides an indication of the synthetic potential of the cells that make up that tissue. It should be noted that potential differences in translational efficiency would not necessarily be reflected in this measurement. The concentration of RNA in the muscles of SCI subjects before the exercise bouts was significantly lower than that in the muscles of the AB subjects. The postexercise SCI RNA concentration was not statistically different from the preexercise value; however, it was no longer significantly different from that of the AB subjects. Decreased anabolic potential of the SCI muscles is not a particularly surprising finding. However, the possibility that this parameter might begin to respond after just two exercise bouts suggests that the anabolic potential of the muscles from long-term SCI subjects may be capable of recovery, given appropriate stimuli.
In summary, the primary divergence in the observed molecular level responses between the AB and SCI subjects was a potentially exaggerated response in the abundance of MGF mRNA in the muscles of the SCI subjects. In this context, it should be noted that the actual duty cycle of the contractile activity in this study was 7.5 min per training bout. This would most likely represent a relatively small proportion of the total daily contractile activity, albeit at higher forces, for the muscles of the AB subjects, but an essentially infinite increase (i.e., from nothing to something) for the muscles of the SCI subjects, and thus a greater loading-induced response would not be unexpected. In this respect, it is probably more surprising that the various additional indicators did not demonstrate a differential responses. Taken together, the results of this study suggest that, at the molecular level, the muscles of long-term SCI subjects appear to respond to increased contractile activity in a very similar fashion to the muscles of AB subjects.| |
ACKNOWLEDGEMENTS |
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The authors thank the subjects for participation in this study and Anqi Qin for technical assistance with the molecular analysis.
Funding was provided, in part, by the Foundation for Physical Therapy (to C. S. Bickel) and National Institute of Child Health and Human Development Grants HD-37439-S and HD-39676 (to G. A. Dudley).
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. R. Adams, Dept. of Physiology & Biophysics, Univ. of California, Irvine, 346-D Medical Sciences 1, Irvine, CA 92697-4560 (E-mail: gradams{at}uci.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.
First published February 28, 2003;10.1152/japplphysiol.00014.2003
Received 7 January 2003; accepted in final form 6 February 2003.
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DISCUSSION
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