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1Department of Physiology and Biophysics, University of California, Irvine at Irvine, California; and 2Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
Submitted 27 May 2004 ; accepted in final form 4 August 2004
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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muscle atrophy; mRNA; myosin; actin; insulin-like growth factor-I
In an attempt to ascertain the underlying mechanisms responsible for these changes in muscle structure and function, investigators have focused on a variety of cell and molecular markers to gain insight concerning the primary factors involved in these adaptive processes (17, 26). Recently, Haddad et al. (28, 29) used an animal model of near complete muscle inactivation/unloading, referred to as spinal isolation (SI), to dissect the subcellular events that are involved in the marked atrophy that occurs in this powerful model. These investigators demonstrated that factors affecting transcriptional, pretranslational, translational, and posttranslational processes were operative, thereby reducing total myosin heavy chain (MHC) and actin mRNA and protein levels, and that these alterations were centrally involved in the rapid muscle-wasting process (28, 29). Additional observations indicated that total RNA concentration (the bulk of which is ribosomal, which normally provides the primary machinery for protein translation) was significantly reduced in the atrophying muscles, especially in the early phases. Interestingly, there was little evidence to suggest that gene expression of growth factors such as insulin-like growth factor (IGF)-I was downregulated to contribute to the catabolic state that defined the SI state. On the other hand, other studies focusing on the anabolic processes that define the hypertrophic response to muscle overload also show that these same processes are impacted (3). However, under these latter conditions, the responses are directionally affected to provide an anabolic state to augment protein accumulation in the muscle fibers (3).
Given the importance of 1) maintaining muscle structural and functional homeostasis in the face of conditions that cause muscle deterioration such as during chronic states of muscle unloading and 2) preventing such a process via exercise of the resistance type, we conducted a study in which adult human subjects were exposed to the conditions of unilateral limb suspension (ULLS), a recognized model of inducing muscle atrophy (13, 31), ULLS plus RE (ULLS + RE), and RE alone to ascertain whether some of the same cellular/molecular markers indicative of muscle mass homeostasis that are operative in animal models also occur in humans. Therefore, we tested the working hypothesis that ULLS would induce reductions in MHC and actin mRNA expression as well as total RNA (ribosomal) concentration, thereby negatively impacting protein translational capacity, whereas resistance training of the concentric-eccentric type would blunt such alterations in the face of ULLS. The findings reported herein are largely consistent with this hypothesis. Moreover, the collective findings are in support of resistance training for space travelers, and further studies of molecular markers can be useful in deriving the mechanisms controlling atrophy and hypertrophy. Portions of this report have been reported elsewhere (36, 38).
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Thirty-one men and women, recruited from the greater Little Rock, AR, area, volunteered for this study. Although 21 individuals were subjected to unilateral unloading of the lower limb (see below) for 5 wk, 10 (7 men, 3 women) of these subjects, in addition, performed resistance exercise (RE) every third day using the unloaded limb (ULLS + RE) throughout the 5-wk experimental period for a total of 12 training sessions. The 11 subjects (7 men, 4 women) who performed unloading (ULLS) only refrained from any physical activity beyond their basic needs throughout the study. Ten ambulatory subjects (7 men, 3 women) carried out RE only using the same exercise regimen followed by the ULLS + RE group. Before this, subjects participated in three sessions over 2 wk to practice and become familiar with the different procedures, unloading, resistance training, and strength tests. To establish baseline data, all subjects then performed strength tests 1 day before the different interventions were initiated. With the use of magnetic resonance imaging, the volume of knee extensor muscles was measured before and on completion of the three different interventions. These measurements were always carried out before the muscle function tests. The RE program was completed 
72 h before any posttreatment (post) measurement. Muscle biopsies from vastus lateralis were obtained before and after any intervention immediately after the MRIs and before reloading. Samples were obtained from both the right leg (which served as an independent control) and the left leg (serving as the experimental, e.g., ULLS, ULLS + RE, and RE intervention). Changes in muscle function and volume have been reported in detail elsewhere (36, 38).
Subjects
Subjects were healthy men (n = 21) and women (n = 10), age 30–56 yr (Table 1). At the time of recruitment, the subjects did not participate in any regular training program. A medical examination excluded women who were on contraceptives or hormone replacement therapy, as well as individuals who were hypertensive or reported past or present knee pathology. Subjects were then matched by gender, body size, and age and knee extensor strength, and they were assigned to ULLS, ULLS + RE, or RE groups. All subjects complied with the prescribed unloading and resistance training protocols (see below).
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Unilateral Lower Limb Unloading
Twenty-four hours per day, unilateral unloading of the left lower limb was accomplished using the model introduced in our laboratory (13) and subsequently modified (30, 38). In brief, in performing any upright or ambulatory activity, short-length crutches, aided by handgrip and forearm support distal to the elbow (Swereco Rehab, Sollentuna, Sweden), were used. The right foot was equipped with a shoe that had a 10-cm-thick sole, which removes weight bearing from the left unloaded limb.
As prophylaxis to venous thromboembolism, subjects received a daily dose of 325 mg of aspirin. In addition, they wore knee-length compression stockings during any ambulatory activity. As reported elsewhere (38), three men assigned to the ULLS group were admitted to ultrasound-Doppler examinations due to acute leg pain. Clinical assessments did, however, exclude suspected deep venous thrombosis. Daily injections of low-molecular weight heparin (Fragmin 2500 IE) were then administered, and the reported symptoms subsided. All subjects completed the study without any disruption.
RE
Unilateral RE, using the left limb, was performed at regular 3-day intervals spanning 12 exercise sessions. A flywheel RE system (14), constructed for the seated knee extension (YoYo Technology, Stockholm, Sweden), and a protocol, described in detail elsewhere (36), were employed. In brief, after a warm-up, each session consisted of four sets of seven maximal, coupled concentric and eccentric knee extensions from a knee joint angle of 90° to almost full extension. An electrogoniometer, affixed onto and aligned with the rotational center of the machine lever arm, and a miniature compression load cell (model 276A, K-toyo, Seoul, Korea) measured joint angle and force during each exercise session. Subjects received verbal encouragement, and, by producing force and joint angle signals on a personal computer display, instant performance feedback was provided during exercise. An analog-to-digital converting system (MuscleLab, Ergotest, Langesund, Norway), which was interfaced to the personal computer, integrated these signals and logged performance during training.
Percutaneous Muscle Biopsies
Tissue samples were obtained from the lateral aspect of the right and left vastii muscle using the percutaneous needle biopsy technique (15) before and after any intervention and before subjects resumed weight bearing. Samples were immediately frozen and subsequently stored in liquid nitrogen until analyzed.
Molecular Analyses
Total RNA isolation.
Total RNA was extracted from preweighed frozen muscle samples using the TRI Reagent (Molecular Research Center, Cincinnati, OH) according to the company’s protocol, which is based on the method described by Chomczynski (20). Extracted RNA was precipitated from the aqueous phase with isopropanol and, after washing 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 the conversion factor of 40 µg/ml per unit of optical density of 260 nm). The muscle total RNA concentration was calculated based on total RNA yield and the weight of the analyzed sample. The RNA samples were stored frozen at –80°C and were used subsequently in determining total mRNA [poly(A)], total MHC mRNA, and 
-skeletal actin mRNA expression using slot blotting procedures, and IGF-I, IGF-I receptor (IGF-R), and IGF-I binding protein 4 mRNAs using RT-PCR methods.
RNA slot blotting.
One microgram of total RNA was placed in 20 µl of denaturing buffer (10% formaldehyde, 67% formamide, and 0.5x MOPS, pH 7) at 60°C for 15 min. Samples were brought up to a 100-µl volume with 6x SSC and were applied onto a positively charged nylon membrane (GeneScreen plus, NEN) using a slot blot apparatus (Schleisher and Schuell). Each sample was loaded in duplicates on two separate membranes. After ultraviolet fixation, these membranes were hybridized with three different probes consecutively as follows. 1) An antisense -skeletal actin mRNA probe was used to determine -skeletal actin mRNA expression, or a common antisense MHC mRNA probe was used to determine the total MHC mRNA expression. The MHC probe is complementary to the coding region 500 nucleotides upstream from the stop codon of type I MHC mRNA. This region is 100% identical in all the MHC isoforms, and the obtained signal corresponds to the total population of MHC mRNA expressed in human muscle. 2) An oligo(dT) probe (12–18 mer, Life Technology) was used to detect poly(A) RNA (total mRNA population). 3) An antisense 18S ribosomal RNA probe in which the signal is directly proportional to the amount of total RNA that was used to normalize for possible variability in the amount of loaded RNA per slot. Probes were 5' end-labeled with P32 using 
-ATP and T4 polynucleotide kinase. Hybridization and washing procedures were carried out as described previously (27). Hybridization signals were detected and analyzed using a phosphorimager and Image Quant analysis software (Molecular Dynamics). For each sample, the MHC mRNA, actin mRNA, and dT (polyA) signals were normalized to the corresponding 18S signal. The slot blot hybridization signal for these probes was strongly correlated with the amount of loaded total RNA ranging from 0.25 to 2 µg per slot. The sequence of oligonucleotides probes used for hybridization is reported in Table 2. Total MHC mRNA, total -skeletal actin mRNA, and total mRNA were expressed as concentration per gram of muscle in arbitrary units. This latter value was obtained on the basis of total RNA concentration and the specific signal generated relative to the corresponding 18S per 1 µg of total RNA.
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PCR. A relative RT-PCR method, using 18S as an internal standard (Ambion, Austin, TX), was applied to study the expression of specific mRNAs for IGF-I, IGF binding protein-4 (BP-4), and the IGF-R. The sequences for the various primers used for the specific target mRNAs are shown in Table 2, and these primers were purchased from Life Technology (Invitrogen, Carlsbad, CA). In each PCR reaction, the 18S ribosomal RNA was coamplified with the target cDNA (mRNA) to serve as an internal standard and to allow correction for any differences in starting amounts of total RNA. PCR procedure and quantification methods were conducted as described previously (16, 40).
Statistics
All values are presented as means ± SE. For all parameters, the post-value was compared with its corresponding pre-value within a group using a paired t-test. This approach tested whether the manipulation was able to induce a change per se in the studied parameter. In addition, the post to pretreatment (pre) value change for a given parameter was compared among groups using one-way ANOVA followed by a Newman-Keuls post hoc test. These latter comparisons enabled us to detect differential response of a parameter due to the different manipulations (ULL, ULL + RE, and RE). Differences were considered significant when P < 0.05.
Although the number of women in each group was small (n = 3 or 4 per group), based on gender means within groups, there appeared to be no influence of gender on the responses. Thus determinations on male and female subjects were combined.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Changes in muscle volume and strength have been reported elsewhere (36, 38). Because these findings serve as important background information relative to the biochemical analyses presented below, they are briefly summarized as follows. Quadriceps muscle volume of the left limb decreased by 8.8% (P < 0.05) in ULLS group, whereas the ULLS + RE group showed a 7.7% increase (P < 0.05) (36, 38). RE alone produced a 6.1% increase (P < 0.05) as reported previously (36, 38). In neither group did volume of the weight-bearing right limb change (P > 0.05) (36, 38).
The average force generated during concentric and eccentric actions increased by 11% (P < 0.05) over the 12 exercise sessions in both the RE and ULLS + RE groups (36, 38). Muscle strength of the left limb as determined based on the maximal voluntary isometric force decreased by 25% (P < 0.05) in the ULLS group and was maintained in the ULLS + RE group (36, 38). RE alone was associated with an 11% increase (P < 0.05) in muscle strength (36, 38). In all groups, the right limb showed no change in strength (P > 0.05) in post vs. pre measurements (36, 38).
Responses of Cellular/Molecular Markers
Total RNA and mRNA. Total extractable muscle RNA was used as an index representing the protein translational capacity of the muscle, because over 85% of the total RNA pool consists of ribosomal RNA. As shown in Fig. 1A, the ULLS group (left leg) showed a significant reduction in total RNA concentration relative to the preexperimental condition (e.g., before unloading). Contrary to this response, in both the ULLS + RE and RE groups, there was an increase in RNA concentration indicating that those muscles exposed to the RE stimulus were able to either maintain or augment the total RNA pool relative to the pretraining state. Pre vs. post sample analyses for the right (control side) were not impacted statistically (Fig. 1A). Determinations of the total poly(A) mRNA (e.g., the total message pool) showed similar responses as that seen for the total RNA (Fig. 1B).
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Total MHC and Actin mRNA
MHC and actin protein accounts for 60–70% of the protein pool comprising the myofibril fraction, which, in turn, accounts for 50% of the total protein pool of the muscle fibers. Thus these two structural/regulatory proteins clearly represent the most abundant proteins expressed in muscle fibers. Because, in steady state, there is a strong agreement between the level of MHC and actin protein that is expressed relative to their respective abundance of mRNA expression within the muscle (28, 29), it would appear that the mRNA levels for these two proteins represent two critical pretranslational markers for maintaining the mass of the fiber. In the ULLS experimental muscle (left leg), total MHC and actin mRNA expression were reduced (P < 0.05) in the post state as shown in Fig. 2. In contrast, in both the ULLS + RE and RE groups, MHC and actin mRNA concentrations were not different from the pretraining values. However, it was somewhat surprising that the actin and MHC posttraining value (especially for total MHC) for the control right leg were clearly lower relative to the pretraining values for all three experimental groups. At present, we do not have an explanation for this peculiar response. One-way ANOVA analyses to compare the changes among the three groups show that the change in MHC and actin mRNA expression in the ULLS were significantly different for the changes occurring in the ULLS + RE and RE groups in the experimental leg. In contrast, the changes in right (control) leg were not different from each other across the experimental groups.
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Previous studies have shown that IGF-I, in and of itself, is a potent growth factor that can induce muscle hypertrophy (8), and this factor is upregulated at both the mRNA and peptide level under loading conditions that result in muscle hypertrophy (1, 4, 22). However, when animal muscles become unloaded, IGF-I mRNA expression and peptide levels do not appear to be reduced (9, 29). In the context of these observations, it was of interest to examine the IGF-I mRNA profiles in the muscles of the three experimental groups. As shown in Fig. 3A, muscle IGF-I mRNA expression was not altered by ULLS or ULLS + RE but was increased in the RE group (P < 0.05). This observation was, however, confounded by the anomaly whereby the control muscles, e.g., right leg of the ULLS and ULLS + RE groups, also demonstrated high levels. The reason for this is not readily apparent (see DISCUSSION). In the context of these alterations in IGF-I expression, we also examined expression of the IGF-R. Our findings, presented in Fig. 3B, suggest an upregulation of the receptor under the condition of ULLS, which might represent a negative feedback response to the unloading state, since previous studies on unloaded, inactivated rodent skeletal muscle show the same response (29).
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Comparing changes that occurred for each variable in each group using ANOVA analyses showed that the alterations in IGF-I, IGF-R, and IGF BP-4 were not significantly different among the three different groups.
Taken together, the results presented herein suggest that the differential loading conditions imposed on the vastus muscle of the three test groups (left leg) reflect changes in gene expression of key contractile proteins coupled with changes in total RNA concentration that could impact key processes, e.g., translational processes. These responses could impact the differential changes in muscle volume and strength that occurred across the three experimental groups. In contrast, the changes in the IGF-I system are not clear cut and suggest a more complex role in the regulation of this system as discussed below.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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As described herein and elsewhere (2, 13, 37), the ULLS model represents a unique approach to unloading the muscles of the lower limb in human subjects, whereby one limb is prevented from weight bearing with the use of crutches. Effective muscle unloading results in a loss of muscle mass and strength. RE is a common countermeasure and is designed to prevent the loss in muscle function. The goal of this study was to determine whether the effects of ULLS and RE can also be observed at the molecular level with muscle biopsy analyses for total RNA and contractile protein mRNA.
In the ULLS experimental design, the unloading suspension is designed to affect only the left leg, and theoretically the right leg should serve as untreated control. However, with the use of the crutches, the ground reaction forces become attenuated on the control right limb so that it cannot in reality be considered as a normal control. With the possibility of obtaining biopsies before (pre) and after (post) the 5-wk treatment program, we were able to compare pre- with posttreatment measurement in both left and right leg. Although the right leg did not appear to be significantly different in post- to pretreatment comparisons based on volume or strength measurements (5, 13, 30, 38), our results show that the right leg underwent some subtle posttreatment changes that made it unsuitable to be used as a control. Consequently, our experimental design, from the biochemical perspective, treated each limb as a separate entity, with each limb, more or less, being analyzed independently of one another. The reason for this response in the right untreated leg for some of the molecular measurements is unclear at present, but such a pattern may reflect the fact that normal weight-bearing activity was compromised by the use of the crutches when the subject performed any ambulatory movements. Nevertheless, these subtle changes at the cellular level should not confound the findings observed, and the conclusion made concerning results on the biopsy samples of the test limb.
Cellular Markers Impacting the Homeostasis of Muscle Mass
It is well known that muscle unloading leads to muscle atrophy as a result of a negative protein balance; however, it is not clear how this protein imbalance is achieved and how it impacts structural muscle proteins, particularly the total MHC and actin expression at the pretranslational level. Protein expression can be generally regulated at several levels in the cascade, linking a gene’s transcriptional activity to its protein product. These include 1) transcriptional/posttranscriptional/pretranslational processes that impact the quantitative level of expression of mRNA, 2) translational processes that modulate the conversion of the mRNA blueprint into protein, and 3) posttranslational/degradative processes that impact the stability or half-life of the protein product. In a recent study, Bickel et al. (16) reported that muscle of long-term spinal cord-injured patients express less total RNA per unit muscle mass, which is indicative of a lower anabolic potential. Interestingly, two 30-min bouts of resistance training in the form of electromyostimulation were effective in ameliorating the RNA deficit in these spinal cord-injured muscles (16). However, that study did not examine the expression of specific muscle protein mRNA such as actin and MHC. In this study, we have examined the MHC and actin mRNA concentrations as markers for pretranslational processes in regulating muscle protein homeostasis, as well as the total RNA concentration as a general marker for the protein translation capacity of the cell. Our results show that, after 5 wk of unloading (ULLS), the muscle total RNA concentration was decreased by 13% (P < 0.05), total MHC mRNA concentration was decreased by 41% (P < 0.05), and actin mRNA concentration was decreased by 28% (P < 0.05). These observations are consistent with the idea that protein imbalance is due, in part, to a decrease in pretranslational and translational processes. Specifically, the reduction in total RNA, the majority of which is ribosomal, represents a reduction in the machinery that is necessary for translating mRNA into protein. This deficiency is further worsened with the decrease in the message substrates encoding the two most abundant proteins expressed in skeletal muscle, e.g., MHC and actin. RE was effective in completely blunting those molecular alterations (Fig. 2), and this response is in agreement with muscle volume and strength data reported previously (36, 38).
Findings Compared With Animal Models of Unloading
In rodent studies involving limb unloading coupled to markedly reducing neuromuscular activity of the muscle by the intervention of SI, one of the hallmarks of the adaptive muscle wasting that occurs involves both a reduction in total RNA concentration and a reduced transcriptional activity (and corresponding pre- and mature mRNA levels) for both actin and myosin (29). These two alterations likely contribute to the rapid loss in both MHC and actin protein in this model of muscle wasting. During SI, although there is no clear-cut evidence that there is repression of growth factor expression such as IGF-I (29), the prevailing evidence suggests that the IGF-I signaling pathway cannot compensate for the reduced capacity for protein synthesis and the likely augmentation of protein degradation (based on analyses of protein degradation markers), the collection of which causes the net catabolic state of the muscle. The observations obtained on the ULLS group is consistent with this mechanism of catabolism, because the IGF signaling cascade was not elevated to the levels seen in the RE groups. In the context of the above-mentioned alterations, it is important to note that, when rodent skeletal muscle is chronically overloaded by synergistic ablation, IGF-I expression, at both the mRNA and peptide levels of expression, are markedly elevated to relative levels that are significantly greater than those reported herein for the human ULLS and RE subjects as well as those reported on unloaded animal muscles (29). Thus the maintained level of IGF-R gene expression on the contralateral right leg and the increase in the IGF-R expression in the ULLS group may be part of a compensatory response to maintain an anabolic response in the face of an insufficient chronic weight-bearing state. Clearly, more research is needed on this interesting phenomenon.
Historical Perspectives
From a historical perspective, the findings in this study add insight into the underlying mechanism(s) thought to impact muscle protein balance during unloading states. For example, in 1990, Thomason and Booth (39) published a classic working model of muscle atrophy. The essence of that model detailed a process whereby there was an initial transient decrease in protein translation, which was subsequently followed by an increase in degradation until the muscle reached a new steady state of reduced mass. These findings suggested that the atrophy process was temporally linked to both an initial contribution of decreased protein synthesis followed by increased protein degradation. Subsequently, Haddad et al. (28) demonstrated that, in the robust atrophy model of SI, pretranslational processes impacting key sarcomeric proteins, e.g., MHC and actin mRNAs, occurred throughout the unloading process until a new steady state was reached. These latter observations suggested that pretranslational processes likely contribute significantly to loss of protein throughout the process of atrophy until a new steady state is reached. Thus, in agreement with the observation of Haddad et al. (28), the present study extends the above findings on animal models by demonstrating that after 5 wk of unloading (ULLS) a reduction in total RNA, MHC, and actin mRNA is maintained throughout the period of unloading. Thus these findings suggest that human muscles respond similarly to atrophy stimuli as those of animals when weight-bearing activity is reduced.
Collectively, the findings reported herein suggest three important findings at the subcellular/molecular level concerning the effects of altered loading states imposed on human skeletal muscle that are consistent with previous findings seen in animal models: 1) unloading of skeletal muscle reduces gene expression of the two primary contractile proteins that make up the contractile apparatus of skeletal muscle cells at a strategic level of regulation; 2) such an adaptive process is impacted further by the reduction in total RNA (and ribosomal), which should further impose a reduced translational capacity of the unloaded muscle; and 3) a training paradigm consisting of concentric-eccentric actions spaced apart at regular 3-day intervals is capable of reversing these alterations at the molecular level, thereby affecting key processes likely involved in ameliorating the deficits in muscle mass/volume occurring in these subjects. These conclusions would have been strengthened if additional markers were examined; however, this was precluded by the amount of muscle available for analyses. Thus it is apparent from the present study that molecular analyses of human muscle biopsies can provide insight into the underlying mechanisms that impact skeletal muscle during adaptive change in response to alerted loading states and to RE.
Finally, the findings reported herein clearly support in-flight resistance training for space travelers and that molecular markers may provide insight in fine tuning such in-flight exercise protocols
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GRANTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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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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