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Alpha-Actinin-3 (ACTN3) R577X Polymorphism Influences Knee Extensor Peak Power Response to Strength Training in Older Men and Women

¹ Department of Kinesiology, College of Health and Human Performance, University of Maryland, College Park.
² Department of Epidemiology, University of Pittsburgh, Pennsylvania.
³ Research Center for Genetic Medicine, Children's National Medical Center, Washington, D.C.
⁴ USDA, ARS, BHNRC, Diet and Human Performance Laboratory, Beltsville, Maryland.
⁵ Department of Aerospace Engineering, Space Systems Laboratory, University of Maryland, College Park.

Address correspondence to Ben F. Hurley, PhD, Department of Kinesiology, University of Maryland, College Park, MD 20742. E-mail: benhur{at}umd.edu.

	Abstract

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Background. The alpha-actinin-3 (ACTN3) R577X polymorphism has been associated with muscle power performance in cross-sectional studies.

Methods. We examined baseline knee extensor concentric peak power (PP) and PP change with 10 weeks of unilateral knee extensor strength training (ST) using air-powered resistance machines in 71 older men (65 [standard deviation = 8] years) and 86 older women (64 [standard deviation = 9] years).

Results. At baseline in women, the XX genotype group had an absolute (same resistance) PP that was higher than the RR (p =.005) and RX genotype groups (p =.02). The women XX group also had a relative (70% of one-repetition maximum [1-RM]) PP that was higher than that in the RR (p =.002) and RX groups (p =.008). No differences in baseline absolute or relative PP were observed between ACTN3 genotype groups in men. In men, absolute PP change with ST in the RR (n = 16) group approached a significantly higher value than in the XX group (n = 9; p =.07). In women, relative PP change with ST in the RR group (n = 16) was higher than in the XX group (n = 17; p =.02).

Conclusions. The results indicate that the ACTN3 R577X polymorphism influences the response of quadriceps muscle power to ST in older adults.

These large inter-individual differences, along with the high heritability values for skeletal muscle phenotypes (15–18), suggest that genetic factors may explain at least a portion of muscle responses to ST. However, polymorphisms within specific gene loci that could potentially explain the genetic differences between responders and nonresponders to ST have not been clearly identified.

Recent cross-sectional data suggest that an alpha-actinin-3 (ACTN3) deficiency is compatible with elite athletic performance (19). A single nucleotide polymorphism (SNP) of the ACTN3 gene may be associated with muscle power and may at least partially explain the inter-individual variability in power (20). A C-to-T transition at position 1747 in exon 16 results in a premature stop codon in place of arginine at codon 577 (R577X) (21). Homozygosity of the X-allele results in an absence of ACTN3 expression, with no apparent association with muscle disease phenotypes (22). Approximately 19% of Caucasians are ACTN3 deficient, indicating that this SNP is a common polymorphism among this racial group, and the X-allele frequency is greater than 15% in several of the world's populations (23).

Elite power athletes appear to have a significantly lower X-allele frequency than endurance athletes or controls (20,24), suggesting an influence of the X-allele on certain types of muscle performance. Recent data with young adults showed that women who are X homozygotes have lower baseline arm strength compared to heterozygotes, but have significantly greater increases in strength with ST compared to heterozygotes (25). This finding was in contrast to what would be expected for muscle power given the known function of ACTN in aiding force transmission across the Z-line.

Thus, the primary purpose of this study was to determine the influence of the ACTN3 R577X polymorphism on peak muscle power at baseline and in response to ST in older adults. A secondary purpose was to compare the influence of this polymorphism to that reported previously for muscle strength and mass at baseline and in response to ST.

	METHODS

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Participants
One hundred fifty-seven relatively healthy, sedentary, Caucasian men and women aged 50–85 years served as participants in this study. They were nonsmokers and were free of significant cardiovascular, metabolic, or musculoskeletal disorders. Those who were already taking medications for >3 weeks prior to the start of the study were permitted entry into the study as long as medications and dosages were not changed. After all procedures were explained, participants read and signed a consent form, which was approved by the Institutional Review Board of the University of Maryland, College Park. All participants maintained stable body weight and were asked to maintain their regular physical activity levels and dietary habits.

Genotyping
Genomic DNA was prepared from EDTA-anticoagulated whole blood samples by standard salting-out procedures (Puregene DNA Extraction kit, Gentra Systems, Inc., Minneapolis, MN). Genotyping for the ACTN3 R577X polymorphism was carried out using standard techniques following the procedures described by Mills and colleagues (23), using the DdeI restriction enzyme. The accuracy of the genotyping assay was verified by direct sequencing of a random selection of 16 samples, with positive control samples used in all subsequent assays.

Body Composition Assessment
Body composition was estimated by dual-energy X-ray absorptiometry (DXA) using fan-beam technology (model QDR 4500A; Hologic, Waltham, MA) using procedures we described previously (7).

Muscular Strength
One-repetition maximum (1-RM) strength tests were assessed for the knee extensors before and after the ST program using air-powered resistance knee extension machines (Keiser Co. Inc., Fresno, CA) as we described previously using standardized procedures (7). At least two familiarization sessions were performed prior to 1-RM testing, power testing, and the ST program, in which the training program exercises were performed with little or no resistance. These low-resistance training sessions were conducted to familiarize the participants with the equipment, to help control for the large 1-RM strength gains that commonly result from skill (motor learning) acquisition during the initial stages of training, and to help prevent injuries during strength testing.

Muscle Volume
To quantify quadriceps muscle volume (MV), computed tomography (CT) imaging of the trained and untrained thighs was performed (GE Lightspeed Qxi; Milwaukee, WI) at baseline and at the end of the ST program as described previously (7). Briefly, axial sections of both thighs were obtained starting at the most distal point of the ischial tuberosity down to the most proximal part of the patella, while participants were in a supine position. The quadriceps cross-sectional area (CSA) was manually outlined in every 10-mm image, and MV was calculated using the truncated cone formula as reported previously by Tracy and colleagues (26) and described by Ross and colleagues (27). Muscle quality was calculated by dividing muscle strength (1-RM) by MV.

Peak Muscle Power
Determination of knee extensor peak power (PP) and peak movement velocity (PV) were performed at baseline and following ST on a Keiser air-powered resistance knee extension machine designed for muscle power assessment using methods we described previously (7). Participants performed three power tests on each leg at 50%, 60%, and 70% of their 1-RM. The highest PP value of the three trials for each percentage of 1-RM and the PV attained during this same trial were selected as the PP and PV, respectively, used for analyses. Muscle power quality (MPQ) and PV quality were calculated by dividing PP or PV by MV. The entire procedure at baseline was repeated 48–72 hours later, and the peak power values at each resistance level for both baseline tests were averaged in an effort to establish a more stable baseline assessment.

Training Program
The ST program was performed on Keiser A-300 air-powered leg extension machines and consisted of unilateral (one-legged) ST of the knee extensors of the right leg, three times per week, for 10 weeks using methods we described previously (7). Briefly, the individualized ST protocol consisted of five sets of knee extension exercise for participants <75 years old and four sets for participants 75 years old, specifically designed to elicit near maximal effort in an individualized manner on all repetitions following warm-up, while maintaining a high training volume. Participants who were 75 years old did not perform the last set because a total of 50 repetitions performed at near maximal effort were required when performing all sets, and we believed that this might have caused overtraining for this age group. Overtraining has been shown to result in a reduction in strength gains (28). The untrained control leg was kept in a relaxed position during all ST sessions.

Statistical Analyses
The ACTN3 genotype distribution was evaluated for conformity with Hardy–Weinberg equilibrium by using a chi-square test with two degrees of freedom. Differences in physical characteristics for men and women were tested by paired t tests. Because a previous report suggested that the influence of ACTN3 R577X genotype on muscle function may depend on what sex group is studied (25), and because there was little overlap between men and women with respect to strength and fat-free mass (FFM), separate analyses were performed for each sex group by ACTN3 genotype. Differences in means among genotype groups (using the R and X alleles) were determined using three level (RR, RX, and XX genotype groups) two-way analysis of covariance (ANCOVA), covarying for age, body mass index (BMI), % fat, FFM, baseline values, change or drift in the control leg, and medication use by using backward regression (p <.10 to remain in the model). Medication use was classified into four categories: diuretics, angiotensin-converting enzyme (ACE) inhibitors, hormone replacement therapy, and antiinflammatories/pain reducers. To reduce experiment-wise error rate, pairwise comparisons that were not preplanned (RR/RX vs XX) were reported only when a significant global F (p <.05) was found. Contrasts were used to determine if there was a dominant, recessive, or additive effect of the X-allele on PP. To estimate the proportion of the variance explained by the ACTN3 R577X polymorphism for an observed association, the R² of the full model with ACTN3 genotype and all covariates was compared to the R² of the constrained model without ACTN3 genotype in the model.

	RESULTS

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Participant characteristics and muscle function measures at baseline and after ST for men (n = 71) and women (n = 86) are shown in Table 1. There was a significant increase in 1-RM in both men (n = 61) and women (n = 64) with ST (both p <.001), but men had a significantly greater increase than did women (p =.006) when baseline differences, age, and FFM were covaried. MV also increased significantly in men (9.0 ± 1%) and women (8.8 ± 1%; both p <.001). There were no significant changes in BMI, body weight, % body fat, or total body FFM in men or women with ST.

Table 2 shows the differences in baseline muscle function measures by ACTN3 genotype in women. X-homozygotes had significantly higher baseline absolute (p =.005) and relative PP values than did the RR and RX groups (p =.002) when age and baseline FFM were covaried. Partial R² analysis indicated that the ACTN3 R577X polymorphism explained 8.2% of the variation in baseline relative PP in women. Contrasts indicate a significant additive effect of the X-allele on baseline absolute (p =.005) and relative PP in women (p =.002). Furthermore, women X-homozygotes had a significantly greater absolute MPQ than the RX group had (p =.02) and greater relative MPQ than both the RR (p =.03) and RX groups had (p =.005), when age and baseline FFM were covaried. Finally, women X-homozygotes had a significantly greater absolute PV than the RX group had (p =.04) and a greater relative PV than the RR (p =.02) and RX groups had (p =.03). There were no differences by ACTN3 genotype in men for any of the baseline muscle function measures shown in Table 2 (Table 3).

View larger version (19K): [in this window] [in a new window]   Figure 1. Changes in knee extensor absolute (same absolute resistance before and after strength training [ST]) peak power (PP) with ST by alpha-actinin-3 (ACTN3) R577X genotype in men and women. When covarying for age and changes in the untrained leg, there was a tendency toward a significantly greater increase in absolute PP in the RR group than in the XX group with ST in men (p =.07). There were no significant differences in absolute PP change among genotype groups in women. Values are least-square means ± standard error of the mean

View larger version (18K): [in this window] [in a new window]   Figure 2. Changes in knee extensor relative (70% of one-repetition maximum [1-RM] to baseline and after strength training [ST]) peak power (PP) with ST by alpha-actinin-3 (ACTN3) R577X genotype in men and women. When covarying for age and changes in the untrained leg, there was a significantly greater increase in relative PP in the RR group than in the XX group with ST in women (p =.02). There were no significant differences in relative PP change among genotype groups in men. Values are least-square means ± standard error of the mean

	DISCUSSION

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The ACTN3 protein may allow for skeletal muscle to have a greater capacity for the conduction of force at the Z-line during a rapid contraction (30,31). Because ACTN3 expression is limited to type II fibers (those most involved in maximal force, contractile speed, and power production), the measurement of PP might be a preferred phenotype for testing the influence of the ACTN3 polymorphism over typical strength measures. Based on the apparent physiological role of ACTN3 in force transmission, we hypothesized that participants who were ACTN3 deficient (XX) would not be as strong or produce as much instantaneous power, or show similar strength and power responses to ST as would R-allele carriers. Although the strength portion of this hypothesis was not supported by Clarkson and colleagues (25), the physiological role of the ACTN3 protein provided a biologically plausible rationale for ACTN3 enhancing PP and therefore support for our finding of an advantage for R-homozygotes in PP responses to ST. However, the higher baseline PP observed in the women X-homozygotes was unexpected.

In a cross-sectional study by Yang and colleagues (20), few X-homozygotic men and no X-homozygotic women were found in a group of elite power athletes, suggesting an advantage for R-allele carriers in muscle power performance. Those individuals were highly trained young athletes, whose muscle function values may not correspond to those observed in the older, sedentary adults who were studied in the current investigation. Nevertheless, our data showing greater improvements in RR men and women in response to ST are consistent with the findings of Yang and colleagues (20), which suggest a Gene x Environment interaction with training necessary to elicit performance differences among ACTN3 genotype groups.

Why baseline muscle power values were higher in X-homozygotes than in the RR and RX genotype groups in women but not in men is unclear. Data from a previous investigation by Clarkson and colleagues (25) found that young (25 years) women X-homozygotes had lower arm flexor isometric strength at baseline than RX-heterozygotes had, consistent with expectations for the X-allele. We did not observe baseline strength differences among genotype groups in either men or women. Contrary to their expectations, Clarkson and colleagues (25) reported that women X-homozygotes have a greater strength response than RX-heterozygotes have in response to ST. In contrast, we report here an 14% training-induced increase in relative peak power in women R-homozygotes, but no significant increase in women X-homozygotes, and greater increases in absolute peak power in men R-homozygotes than in X-homozygotes. Substantial differences in age, muscle groups studied (knee extensors vs biceps), and muscle phenotypes prevent clear comparisons between the two investigations. A recent report suggests that the ACTN3 R577X polymorphism influences baseline serum creatine kinase (CK) levels, which are associated with skeletal muscle damage (32). In this regard, muscle damage is thought to be a stimulus for ST-induced muscle hypertrophy (32) and, therefore, muscle strength, based on the high correlation between strength and muscle mass. It could be argued that the force component of muscle power could then be associated with muscle damage and therefore CK levels, but the association between CK and muscle power has not been established, particularly as it applies to ST effects.

Finally, it is unclear how to explain sex differences in the influence of ACTN3 on PP responses to ST observed in the present study. Clarkson and colleagues (25) suggested that sex differences in this regard may be associated with sex steroid hormone differences.

The finding of a greater increase in absolute MPQ in men R-homozygotes than in X-homozygotes with ST further demonstrates that there are factors other than muscle hypertrophy that are responsible for genotype differences in peak power. Further evidence for this comes from the finding that there were no significant differences in MV change among genotype groups. Earlier reports estimate that 60% of the increase in muscular strength with ST is due to factors other than muscle hypertrophy (33). Although we are not aware of any data to support these genotype differences, there is support for the conclusion that increases in power and strength with ST in older adults can be influenced substantially by neural adaptations (33). Nevertheless, the specific mechanisms responsible for these findings will require further investigation.

Our finding of a genotype difference in absolute PP responses in men when using relatively low loads (50% of 1-RM after training vs 70% of 1-RM for relative PP) may have important consequences for functional ability performance. This conclusion is based on recent data, which suggest that certain functional performance tasks in older adults may be more dependent on movement velocity at lower external loads than at higher loads (34).

There are several limitations to the current investigation. For example, muscle power is a complex phenotype, which is likely influenced by numerous genes and polymorphisms, as well as other environmental factors that may be interacting with these genes in unknown ways. The limited sample size in the current investigation, especially when stratifying by sex, does not allow for the analysis of the interaction of multiple loci. Additionally, participants in this investigation were trained using a moderate-velocity training protocol. A higher velocity training protocol would likely produce greater gains in power (10). We chose an ST protocol that is more commonly used for the improvement of strength and mass, with a track record for being safe and effective in older adults for producing substantial improvements in all the major components of sarcopenia (7,14,33,35–38). It is still not well-established whether a high-velocity training program is well tolerated by older persons (39). Another limitation was that there was a relatively wide range of ages. Age might be an effect modifier with regard to the influence of this polymorphism, as there are significant structural changes (e.g., motor unit denervation, muscle fiber loss, fiber type grouping) that occur in the skeletal muscle of older adults (40). It is conceivable that the youngest participants in the study may have slightly different training responses than the older ones, but age was included as a covariate in our analyses and there were no significant age differences between genotype groups.

Future studies will need to not only use much larger homogeneous sample sizes, but will need to carefully develop research designs to accommodate the limitations of this study and the ones highlighted by Clarkson and colleagues (25). Establishing the influence of the ACTN3 R577X SNP on functional abilities, likely an even more complex phenotype, in elderly populations is necessary to determine if this genotype is of importance for targeting individuals who may be more susceptible to the effects of sarcopenia and who may need specific interventions.

	Acknowledgments

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This study was supported by research contract 1-AG-4-2148 and grants AG-1620501, AG-022791, and AG-021500 from the National Institute on Aging.

We thank our research participants for their participation in this study. We also thank Jade Clark and Katie Voss for their genotyping assistance and Dr. Larry Douglass for his statistical guidance.

	Footnotes

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Decision Editor: Luigi Ferrucci, MD, PhD

Received March 20, 2006

Accepted May 17, 2006

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