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Proteolytic Gene Expression Differs At Rest and After Resistance Exercise Between Young and Old Women

Human Performance Laboratory, Ball State University, Muncie, Indiana.

Address correspondence to Scott Trappe, PhD, Human Performance Laboratory, Ball State University, Muncie, IN 47306. E-mail: strappe{at}bsu.edu

	Abstract

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Background. Skeletal muscle atrophy in rodents is associated with increased gene expression of proteolytic markers muscle-RING-finger protein 1 (MuRF-1) and atrogin-1. In humans with age-related muscle atrophy, known as sarcopenia, little is known about these key proteolytic biomarkers. Therefore, the purpose of this investigation was 2-fold: (i) measure messenger RNA (mRNA) expression of proteolytic genes MuRF-1, atrogin-1, forkhead box (FOXO)3A, and tumor necrosis factor- (TNF-) in young and old women at rest, and (ii) measure these proteolytic genes in response to an acute resistance exercise (RE) bout, a known hypertrophic stimulus.

Methods. A group of old women (OW: n = 6, 85 ± 1 years, thigh muscle = 89 ± 4 cm²) and young women (YW: n = 8, 23 ± 2 years, thigh muscle = 122 ± 6 cm²) performed three sets of 10 knee extensions at 70% of one-repetition maximum. Muscle biopsies were taken from the vastus lateralis before and 4 hours after RE. Using real-time reverse transcription–polymerase chain reaction (RT–PCR), mRNA was amplified and normalized to GAPDH.

Results. At rest, OW expressed higher mRNA levels of MuRF-1 (p =.04) and FOXO3A (p =.001) compared to YW. In response to RE, there was an age effect (p =.01) in the induction of atrogin-1 (OW: 2.5-fold). Both YW and OW had an induction (p =.001) in MuRF-1 (YW: 3.6-fold; OW: 2.6-fold) with RE.

Conclusions. These data show that the regulation of ubiquitin proteasome-related genes involved with muscle atrophy are altered in very old women (> 80 years). This finding is manifested both at rest and in response to RE, which may contribute to the large degree of muscle loss with age.

The underlying cause of sarcopenia is currently not known and likely multifaceted given the complex regulation of muscle growth and atrophy (6). To date, there is limited information on basal proteolytic regulation in aging human muscle, with evidence of higher proteolysis at rest (7). Cellular catabolic events include protein degradation through the ubiquitin/proteasomal pathway (UPP), calcium/calpain-dependent pathway, and lysosomal pathway, and cell death through apoptosis (8). In healthy humans, the UPP is responsible for the majority of intracellular protein degradation (9). The ubiquitination of a target protein is mediated by ubiquitin ligases, and skeletal muscle has specific ubiquitin ligases (E3) such as atrogin-1 and muscle-RING-finger protein 1 (MuRF-1) (10). Recently it has been shown that elevated gene expression of these two E3 ligases is highly associated with multiple atrophy models supporting the possibility of a common proteolytic program (11).

In humans with age-related muscle atrophy, little is known about proteolytic gene expression at rest and in response to resistance exercise (RE). Therefore, the purpose of this study was to examine the gene expression of well-established UPP markers (atrogin-1, MuRF-1, and forkhead box [FOXO]3A) and tumor necrosis factor- (TNF-) in skeletal muscle from individuals with sarcopenia, as well as skeletal muscle exposed to an acute bout of resistance training, an inducer of hypertrophic and proteolytic events (12). Based on current literature and the unique aspect of the current participant population (> 80 years), we were interested in two questions: (i) Do old women experiencing a large degree of sarcopenia express higher basal levels of selected atrophy-related genes compared to young women? (ii) Is there an effect of age in the induction of these markers after an acute bout of RE?

	METHODS

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Participants
Eight young (23 ± 2 years) and six old (85 ± 1 years) healthy women were recruited from the community for this investigation (Table 1). The criteria for subject qualification have previously been described (13). Prior to engaging in the experimental protocol, the women were informed of all procedures and risks associated with the protocol, and written informed consent was obtained from each participant. The Institutional Review Board of Ball State University and Ball Memorial Hospital approved the experimental design prior to the initiation of the study.

Whole Muscle Size (Computed Tomography)
Whole muscle cross-sectional area (CSA) of the right thigh was determined by computed tomography (CT) (CTI helical scanner; General Electric, Milwaukee, WI), as described previously (15).

1-RM Assessment
Bilateral muscle strength was assessed using an isotonic knee extensor device (CYBEX Eagle; CYBEX Inc., Medway, MA). The 1-RM procedure was performed with a gradual increase in weight, and the test continued until the participant was not able to maintain proper form and/or fully extend the knee with the given weight. The last weight successfully lifted to full extension was considered the 1-RM for each participant (Table 1).

Muscle Biopsy
Muscle biopsy samples were obtained, processed, and placed in 0.5 mL of RNAlater (Ambion, Austin, TX) and stored at –20°C until RNA extraction.

Total RNA Extraction and RNA Quality Check
All the methods for RNA extraction and real-time reverse transcription–polymerase chain reaction (RT–PCR) have been described in detail previously by our laboratory (13,14). Total RNA was extracted in TRI reagent (Molecular Research Center, Cincinnati, OH). The quality and integrity of extracted total RNA was evaluated using an RNA 6000 Nano LabChip kit on an Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA).

RT and Real-Time PCR
Oligo (dT) primed first-strand complementary DNA (cDNA) was synthesized using SuperScript II RT (Invitrogen, Carlsbad, CA) optimized for sensitive RT–PCR on low amounts of RNA. Quantification of messenger RNA (mRNA) transcription (in duplicate) was performed in a 72-well Rotor-Gene 3000 Centrifugal Real-Time Cycler (Corbett Research, Mortlake, NSW, Australia). GAPDH was used as a housekeeping gene (HKG) for internal control after validation (13). All primers used in this study were mRNA-specific (on different exons and/or crossing over an intron) and designed for gene expression real-time PCR analysis using Vector NTI Advance 9 software (Invitrogen) (Table 2).

Relative Quantification of Real-Time PCR Assay
The gene expression in relation to age and exercise was evaluated by a relative quantification method, as described by us previously (13,14). To avoid inter-assay variability, each real-time PCR run contained samples from both age groups (young and old) and both experimental conditions (pre- and postexercise). To monitor the efficiency of each real-time PCR run, a serial dilution (1; 0.5; 0.250; 0.125; 0.062; 0.031) of cDNA for each gene of interest (GOI) and the HKG GAPDH was amplified using gene-specific primers. The amplification calculated by Rotor-Gene software was specific, highly efficient, and similar for each real-time PCR run (mean ± standard error [SE]) (efficiency = 0.998 ± 0.013; R² = 0.984 ± 0.005; slope = 3.33; coefficient of variation [%CV] = 4.94 ± 0.83). The average duplication intra-assay %CV value for the old women was 0.47 ± 0.16, and for the young women it was 0.37 ± 0.14.

The data were analyzed using and methods (17). As described by us previously (13), to compare the relative gene expression between young and old women at baseline, the method was used. This method generates a value in arbitrary units (AU) of GOI expression normalized to HKG expression (C_T = C_{T GOI} – C_{T HKG}). The method was used to calculate the fold changes in gene expression as a result of the RE. In this method, GOI expression is normalized to HKG expression and calibrated to control pre-exercise value (C_T = (C_{T GOI timeX} – C_{T HKG timeX}) – (C_{T GOI average time zero} – C_{T HKG average time zero})) within each age group. Using this analysis, the fold changes at time zero (control = pre), if not influenced by external stimulus, should be very close to 1.

The validation of GAPDH was performed to ensure that its expression was unaffected by RE and age, as described by us previously (13). In our group of women, age had no effect on GAPDH expression, because cDNA produced on 50 ng of total RNA generated C_T values that were almost identical (old women [OW]: 12.97 ± 0.26 vs young women [YW]: 12.89 ± 0.18). Also, the fold change of GAPDH as a result of RE was 1.14 ± 0.14 and 1.14 ± 0.17 (i.e., no change) for OW and YW, respectively.

Statistical Analysis
Data are presented as means ± SE. For each gene, the fold changes in mRNA expression ( data) were compared using a 2 x 2 analysis of variance (ANOVA), with factors of time (pre- to postexercise) and age (young and old). In the presence of 2 x 2 ANOVA interaction, paired Student t tests were used as post hoc analysis. For analysis of gene expression baseline differences, using the method (AU), an independent Student t test was performed. An independent Student t test was also used for all participants' characteristics comparisons. Normality of data was achieved by logarithmic data transformation; therefore, the parametric analyses were used. Significance was set at p <.05 for all analyses.

	RESULTS

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Muscle Profile
OW were weaker (p =.02) (1-RM: 38.8 ± 2.6 kg vs 60.2 ± 5.9 kg) and had a smaller (p =.004) muscle size (89.4 ± 3.7 cm² vs 122.0 ± 5.6 cm²) compared to YW (Table 1).

Basal Level Gene Expression
At rest, skeletal muscle of OW expressed higher levels (AU ± SE) of FOXO3A (OW: 25 ± 3 vs YW: 10 ± 2) (p =.001, 95% confidence interval [CI], 19–31) and MuRF-1 (OW: 59 ± 8 vs YW: 41 ± 3) (p =.04, 95% CI, 43–75) compared to young women (Figure 1). There was no effect of age on the mRNA expression of atrogin-1 (p =.17) and TNF- (p =.38).

View larger version (9K): [in this window] [in a new window]   Figure 1. Comparison of baseline messenger RNA (mRNA) levels (arbitrary units) (mean ± standard error [SE]) from skeletal muscle of young and old women. FOXO3A = forkhead box 3A; MuRF-1 = muscle-RING-finger protein 1. *p <.05 between age groups

View larger version (7K): [in this window] [in a new window]   Figure 2. Effect of resistance exercise on gene expression from skeletal muscle tissue of young and old women. Represented as fold changes (mean ± standard error [SE]). FOXO3A = forkhead box 3A; MuRF-1 = muscle-RING-finger protein 1. *p <.05 main time-effect for young and old women combined. #p <.05 time effect for old women

	DISCUSSION

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Effect of Age on Basal Level Gene Expression
The current data, using a targeted gene expression approach, support the existing microarray data suggesting that old individuals tend to express higher levels of mRNA in a number of gene categories including the UPP (19–21). In particular, microarray data indicate that FOXO3A is one of the genes being expressed at higher levels in old individuals (20,22), which is in agreement with the current data. Recent findings showing that FOXO transcription factors are active in atrophy models (23,24) also support the observed elevated basal levels of FOXO3A in the OW used in the current study.

In the current investigation, there were higher levels of MuRF-1 mRNA in the OW compared to the YW, whereas no significant difference was found for the atrogin-1 gene. This is in slight contrast to the induced atrophy models involving rodents (11,25) and humans (26,27) that have consistently shown higher mRNA levels of both MuRF-1 and atrogin-1. In aging rodent muscle there are data indicating both increased (28) and decreased gene levels (29) of these E3 ligases. These findings suggest that older sarcopenic individuals do not have as robust of a proteolytic program as has been reported in induced atrophy models (11,25–27). Perhaps the less robust proteolytic program is related to the rate of muscle loss because humans gradually lose muscle mass over a period of decades compared to days or weeks in the atrophy models of rodents and humans. The current study data also contrast those of Whitman and colleagues (18), who reported similar basal levels in MuRF-1 and atrogin-1 gene expression between young and old adults. Muscle mass was not reported from those old persons (72 years); however, there was no difference in muscle fiber size (18). The age difference between studies may have impacted the findings because individuals > 80 years old have a greater magnitude of sarcopenia compared to individuals only a decade younger (5). Collectively, these previous research studies combined with the current investigation point to differences in basal proteolytic gene induction that may be related to the degree of muscle mass loss.

Effect of Age on Gene Expression After RE
To our knowledge, this is the first study on proteolytic gene expression after RE in young and octogenarian women. An interesting finding of the current study was the robust mRNA induction (14 of 14 participants) of MuRF-1 with an acute RE bout in both YW and OW. Interestingly, this is the third group of participants in whom our laboratory has observed a strong induction of MuRF-1. Yang and colleagues (30) recently reported an upregulation of MuRF-1 in both myosin heavy chain (MHC) I and IIa fibers in young men, after an identical RE bout. The consistent upregulation of MuRF-1 among participant groups suggests that it is an important component in the protein breakdown occurring in the hours after unaccustomed RE (12).

A novel finding in the current study was the upregulation of atrogin-1 following exercise, which was specific to the OW. The lack of an atrogin-1 induction in the YW is consistent with our recent data in young men (30). This age-related exercise response in atrogin-1 is indicative of a greater proteolytic challenge to the skeletal muscle, which may promote protein breakdown after RE in OW to a greater extent than in YW. Interestingly, the induction of both MuRF-1 and atrogin-1 genes with exercise parallels the elevated basal state observed during rapid atrophy models as discussed earlier. One plausible explanation for the age differences observed in atrogin-1 induction could be due to an age-impairment in the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway, although that was not measured in this study. Limitations in this particular signaling pathway have been found in aging rodents after electrical stimulation (31,32). Given the regulation of FOXO3A through the PI3K/Akt pathway, and FOXO3A's regulation of atrogin-1 transcription (23,24), an age impairment in the PI3K/Akt pathway would support the upregulation of atrogin-1 found in the OW. If a sufficient anabolic stimulus is lacking due to pathway limitations, nuclear exclusion of FOXO3A will not occur and FOXO3A can still perform as a transcription factor, which results in increased mRNA levels of atrogin-1. This potential regulation of FOXO3A in aging human skeletal muscle warrants further investigation.

Apart from our laboratory's data, reports on MuRF-1 and atrogin-1 mRNA expression after RE is scarce in young persons and not available in old adults. In young individuals, atrogin-1 appears to either not change (26,30,33), or decrease (34), after a hypertrophic stimulus. Combined, these data suggest that atrogin-1 is not involved in the acute phase of protein breakdown after RE in young persons, and highlights the novelty of the atrogin-1 induction in OW. Although we found a robust induction of MuRF-1 in our YW, Jones and colleagues (26) found no change in MuRF-1 24 hours after RE. The differences in results may, in part, be due to a difference in biopsy timing because gene expression is transient in the first few hours (14,30) after RE.

Although protein measurements were not included in the current study, the robust increases in atrogin-1 and MuRF-1 mRNA levels point to a possible increase in their respective protein levels. However, it cannot be assumed that there is a 1:1 ratio between mRNA and a fully functioning protein, given the complexity of posttranscriptional events (35). Future aging investigations are warranted examining the protein levels of these important E3 ligases.

FOXO3A mRNA levels were unchanged 4 hours after the RE bout. We expected that, based on the aforementioned regulation of FOXO3A through the anabolic PI3K/Akt pathway (23,24), the women would have decreased FOXO3A mRNA levels with exercise to aid in the anabolic response (36) to RE. However, the regulation of this transcription factor is multifaceted (23,24) and may be more involved in the atrophy process in the absence of an anabolic stimulus such as RE. In support of the latter, and as highlighted earlier, the higher levels of FOXO3A at rest in the OW are consistent with the potential role of FOXO3A in muscle atrophy (20,22–24,37) given the smaller muscle mass profile of these individuals.

TNF- gene expression was not affected by age or exercise. This finding is in contrast to those of Greiwe and colleagues (38), who reported increased levels of mRNA in aging human skeletal muscle using an in situ hybridization technique. The TNF- mRNA levels in the current study were very low, and it is possible that the contradictory findings are due to methodological differences. TNF- gene expression has been found to increase in skeletal muscle after vigorous resistance training (39) in young men. The lack of change in TNF- in the current study is consistent with our recent study in young men (30), and it may suggest that our exercise protocol was not strenuous enough to elicit an increase in TNF-.

Summary
These data show that women older than 80 years who are experiencing a large degree of sarcopenia express select proteolytic (FOXO3A and MuRF-1) genes at higher levels compared to young adults. After an acute bout of RE, both YW and OW had a robust induction in MuRF-1, suggesting that this marker is involved in the protein breakdown and muscle-remodeling process associated with RE. Perhaps most noteworthy was the pronounced upregulation of atrogin-1 with RE in the OW, suggesting a greater proteolytic response to a known hypertrophic stimulus. Future research should focus on signaling pathways regulating proteolytic transcription, as well as protein levels of selected markers. Fiber type–specific gene expression is also warranted, given the greater degree of fast-twitch fiber atrophy present in old individuals (40,41). The higher mRNA levels of FOXO3A and MuRF-1 at rest and the response of atrogin-1 in the OW after RE may be significant attributes to the sarcopenia process and provide potential targets for therapeutic interventions.

	Acknowledgments

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This investigation was supported by National Institute on Aging Grant AG-18409 (S. Trappe).

	Footnotes

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Decision Editor: Luigi Ferrucci, MD, PhD

Received February 22, 2007

Accepted March 25, 2007

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