ACTN3 Genotype Research Articles

ACTN3 Gene R577X Polymorphism Associated with High-Density Lipoprotein Cholesterol and Adiponectin in Rugby Players

To determine the relationship between the R577X polymorphism of the α-actinin-3 (ACTN3), which may play a role in the individual differences observed in the effects of exercise on health benefits and antiatherogenic markers (i.e., high-density lipoprotein cholesterol [HDL-C] and adiponectin) in athletes. Seventy-six male rugby players (mean age 19.8 years) were enrolled in this study. Genomic DNA was extracted from peripheral blood samples, and restriction fragment length polymorphism-polymerase chain reactions were conducted to assess ACTN3 genotypes. Body mass index (BMI), waist circumference, serum lipids including HDL-C, and adiponectin levels were measured. Current smoking and alcohol intake habits were evaluated with a questionnaire. All of the parameters were compared between 2 groups displaying frequently observed genotypes: one group consisting of patients having either the R/R or R/X genotype and a second group with the X/X genotype. The frequency of the X allele was 0.55 and the distribution of the genotypes was 35.5% (n = 27) for X/X, 39.5% (n = 30) for R/X, and 25.0% (n = 19) for R/R. Serum HDL-C and adiponectin levels were significantly higher in X/X genotype compared to the R/R or R/X genotype (HDL-C 1.6 ± 0.3 [SD] vs. 1.4 ± 0.2 mmol/L; P<.01, adiponectin 8.8 ± 2.6 vs. 6.9 ± 2.3 μg/mL; P<.01), even after adjustments for confounders (P<.01). There may be a relationship between the ACTN3 genotype and HDL-C and adiponectin levels in rugby players. This may be useful information when determining the individual responses of antiatherogenic markers to exercise. ACTN3 = α-actinin-3 BMI = body mass index CVD = cardiovascular disease HDL-C = high-density lipoprotein cholesterol LDL-C = low-density lipoprotein cholesterol R = arginine (R) at amino acid position 577 of the ACTN3 protein TC = total cholesterol TG = triglyceride X = truncation at amino acid position 577 of the ACTN3 protein.

ACTN3 Genotype Association with Motoric Performance of Roma Children

ACTN3 Genotype Association with Motoric Performance of Roma Children

ACTN3 Genotype Affects Change in Muscle Fiber Cross-Sectional Area from Adolescence to Adulthood

INTRODUCTION: Alpha-actinin-3 is a Z-disc protein that is expressed only in type II muscle fibers. Common null polymorphism in the ACTN3 gene (R577X) results in lack of this protein in XX-genotypes. In sprint/power oriented elite athletes the prevalence of the X-allele is much lower than in control populations. That implies that lack of alpha-actinin-3 is detrimental for these athletes but a mechanistic link is not fully established. We have previously shown that ACTN3 genotype modulates skeletal muscle hypertrophy signaling in response to sprint exercise in moderately trained subjects. PURPOSE: To examine the impact of ACTN3 genotype on changes in fiber dimensions from adolescence to adulthood. METHODS: 63 male and female subjects (13 XX, 29 RX, 21 RR) from the general Swedish population were studied at 16 and 27 years of age. Their physical activity level was estimated by a questionnaire. Muscle samples were obtained from vastus lateralis muscle by needle biopsy technique. The samples were analyzed histochemically for fiber types (I, IIA, IIB). Cross-sectional area (CSA) of the different fiber types was measured from histological sections by planimetry. DNA was extracted from muscle samples and the genotyping was performed by allelic discrimination. Statistical analyses of the effect of ACTN3 and sex on changes in CSA with age were performed by ANOVA and multiple regression analysis. RESULTS: A significant difference in the relative change of CSA with age, across ACTN3 genotypes was observed in type IIA fibers (ANOVA P=0.02) but not in type I fibers and type IIB fibers. The change, expressed as 27-16 years/16-years value, was in type IIA fibers -4.2%, -2.5% and 7.7% in XX, RX and RR respectively and in type IIB -3.0%, -3.4%, and 9.9% in XX, RX and RR respectively. Multiple regression analysis showed that the change in CSA of type IIA fibers was dependent on ACTN3 genotype, while the change in CSA of type IIB was equally dependent on ACTN3 genotype and sex. No ACTN3 genotype effect was observed for the CSA change in type I fibers where alpha-actinin-3 is not expressed. No significant differences in CSA were detected across ACTN3 genotypes either at 16 or 27 years. CONCLUSION: ACTN3 genotype is strongly suggested to be a determinant of dimensions of type II skeletal muscle fibers in humans which supports the findings in ACNT3 knock out mice.

Associação de polimorfismos genéticos com capacidades físicas e composição corporal em idosas

DOI: http://dx.doi.org/10.5007/1980-0037.2016v18n1p11 The elderly population has grown substantially, and the decline in physical capacities and increase in the body fat percentage are important characteristics of aging. Genetic factors may explain these declines and studies related to this issue are justified because they predict what physical capacities present larger declines in different individuals and enable the adoption of strategies to slow them. Thus, the aim of this study was to evaluate the effect of ACE I / D and ACTN3 R / X genetic polymorphisms on body fat, muscle strength and power levels, aerobic capacity, flexibility and agility in older women. Sixty-six older women were genotyped with respect to ACTN3 and ACE polymorphisms for the division of groups and submitted to anthropometric measurements, physical tests in the AAHPERD and RIKLI and JONES test batteries and IPAQ to determine the level of physical activity and the Food Consumption Marker Form. Older women with XX genotype in relation to ACTN3 genotype had lower levels of flexibility of upper and lower limbs and lower cardiorespiratory fitness. Moreover, in relation to the ACE genotype, ID individuals exhibited higher cardiorespiratory fitness and lower body fat percentages. In relation to the other variables, there was no statistical difference among groups. It was concluded that the genetic variants under study play a role in some of the physical capacities and body composition in elderly women. In the future, data of this nature will enable each individual to have specific health interventions directed to the variables showing higher genetic potential for decline.

The Effect of Heterozygosity for the ACTN3 Null Allele on Human Muscle Performance.

α-Actinin-3 is primarily expressed in fast (Type II) fibers in the human skeletal muscle. Over 70% of the global population has at least one copy of a loss of function allele because of a premature stop codon in the ACTN3 gene (R577X). Homozygosity for this variant (577XX) occurs in approximately 16% of humans worldwide and results in complete α-actinin-3 deficiency, which is detrimental to sprint/power performance and alters adaptation to changing physical demands. The functional implications of α-actinin-3 deficiency have been the subject of over 90 studies; however, the effect of heterozygosity for the ACTN3 null allele is not well documented or understood. We reviewed the literature to focus on the most common ACTN3 genotype (577RX) and its effect on human muscle performance. Specifically, we aimed to determine whether the ACTN3 X allele exerts its effect on human performance only when two copies are present (i.e., in an autosomal recessive fashion). Across a spectrum of conditions, three genotype models (additive, dominant, and recessive) were reported. Most studies assessing healthy adults demonstrated that 577RX heterozygotes performed intermediately (additive model) and/or similarly to the RR genotypes (recessive model). Other studies, (aging, disease/injury, elite sprint performance) showed no definitive genetic model. Assessment of the biological link between dosage, regulation, and function for each ACTN3 genotype is required to improve our understanding of its functional effect and biological penetrance in healthy, aging, and disease populations.

Association of ACTN3 polymorphisms with BMD, and physical fitness of elderly women.

[Purpose] Association of ACTN3 polymorphism with bone mineral density and the physical fitness of elderly women is still unclear. Therefore, this study investigated the association between ACTN3 genotype and bone mineral density, and the physical fitness of elderly women. [Subjects and Methods] Sixty-eight elderly women (67.38 ± 3.68 years) were recruited at a Seongbuk-Gu (Seoul, Korea) Medical Service Public Health Center. Measurements of physical fitness included muscle strength, muscle endurance, flexibility, agility, balance and VO2max. Bone mineral density (BMD), upper limb muscle mass, lower limb muscle mass, percent body fat and body fat mass for the entire body were measured by dual-energy X-ray absorptiometry and an analyzer. Genotyping for the ACTN3 R577X (rs1815739) polymorphism was performed using the TaqMan approach. [Results] ACTN3 gene distribution of subjects were in the Hardy-Weinberg equilibrium (p=0.694). The relative bone mineral density trunk, pelvis and spine differed significantly among the ACTN3 genotypes. There were no significant differences among bone mineral densities of the head, arms, legs, ribs and total, but the RR genotype tended to be higher than other genotypes. Physical fitness was not significantly different among the ACTN3 genotypes. [Conclusion] These results suggest that ACTN3 gene polymorphisms could be used as one of the genetic determinants of bone mass in elderly women, and in particular, they indicate that individuals with the RR genotype have higher BMD and bone mineral composition.

Genetic ACE I/D and ACTN3 R577X polymorphisms and adolescent idiopathic scoliosis.

The etiology of adolescent idiopathic scoliosis remains unknown. Angiotensin-converting enzyme and α-actinin-3 polymorphisms influence the characteristics of muscle fibers. The aim of this study was to examine the association between idiopathic scoliosis and genetic polymorphism of angiotensin-converting enzyme and α-actinin-3. Ninety-seven females with scoliosis, and 137 healthy, age-matched control females were studied. The presence of polymorphisms was determined by PCR. A χ2 test was used to analyze differences, and odds ratios were estimated. The frequencies of ACE genotypes in the scoliotic group were 46.4% DD, 45.4% ID, and 8.2% II, while in the control group they were 40.1% DD, 43.8% ID, and 16.1% II (P = 0.197). The D allele had a frequency of 69.1% in patients with idiopathic scoliosis and 62% in the control group (P = 0.116). The frequencies of ACTN3 genotypes in females with scoliosis were 31.8% RR, 49.4% RX, and 18.8% XX, while in the control group they were 35% RR, 49% RX, and 16% XX (P = 0.810). The frequency of the R allele was 56.4% in the scoliotic group and 59.6% in the control group (P = 0.518). There was no statistically significant association between angiotensin-converting enzyme or α-actinin-3 polymorphisms and the presence of adolescent idiopathic scoliosis in females.

Analysis of the ACTN3 heterozygous genotype suggests that α-actinin-3 controls sarcomeric composition and muscle function in a dose-dependent fashion.

A common null polymorphism (R577X) in ACTN3 causes α-actinin-3 deficiency in ∼ 18% of the global population. There is no associated disease phenotype, but α-actinin-3 deficiency is detrimental to sprint and power performance in both elite athletes and the general population. However, despite considerable investigation to date, the functional consequences of heterozygosity for ACTN3 are unclear. A subset of studies have shown an intermediate phenotype in 577RX individuals, suggesting dose-dependency of α-actinin-3, while others have shown no difference between 577RR and RX genotypes. Here, we investigate the effects of α-actinin-3 expression level by comparing the muscle phenotypes of Actn3(+/-) (HET) mice to Actn3(+/+) [wild-type (WT)] and Actn3(-/-) [knockout (KO)] littermates. We show reduction in α-actinin-3 mRNA and protein in HET muscle compared with WT, which is associated with dose-dependent up-regulation of α-actinin-2, z-band alternatively spliced PDZ-motif and myotilin at the Z-line, and an incremental shift towards oxidative metabolism. While there is no difference in force generation, HET mice have an intermediate endurance capacity compared with WT and KO. The R577X polymorphism is associated with changes in ACTN3 expression consistent with an additive model in the human genotype-tissue expression cohort, but does not influence any other muscle transcripts, including ACTN2. Overall, ACTN3 influences sarcomeric composition in a dose-dependent fashion in mouse skeletal muscle, which translates directly to function. Variance in fibre type between biopsies likely masks this phenomenon in human skeletal muscle, but we suggest that an additive model is the most appropriate for use in testing ACTN3 genotype associations.

The Difference of Anaerobic Power Based on Muslce Power Sports Athletes in ACTN3 Genotype

The Difference of Anaerobic Power Based on Muslce Power Sports Athletes in ACTN3 Genotype

ACE and ACTN3 Genes Polymorphisms and Endurance Performance

ACE I/D and ACTN3 R577X polymorphisms are the most extensively studied genes in recent years in association with human physical performance. VO2max is recognized as one of the major quantitative traits in sports physiology and the most common method to demonstrate cardiorespiratory endurance. The heritability for the VO2max in several studies has been observed up to 51%. PURPOSE: (1) To assess ACE gene ACTN3 genotype frequencies in young male skiers compared to the control group and (2) to analyze the relationships between VO2peak and ACE I/D and ACTN3 R577X polymorphisms in young male skiers. METHODS: Male skiers (n=56; 14 to 21 yrs), 52% of them are current or former junior national team members of Estonia. A standardized exercise test on a treadmill with determination VO2peak was performed. Anthropometric measurements and training characteristics were obtained. The male control group (n=145, 20 to 37 yrs) consisted of healthy sedentary subjects without previous athletic status. Venous blood samples for DNA extraction were collected. Genotyping of rs4343 (ACE, C_11942562_20) and rs1815739 (ACTN3, C_590093_1) was carried out by using the TaqMan SNP 5’ allelic discrimination assay. For statistical analysis, descriptive analysis, χ2-test was used. RESULTS: Frequency of ACE ID and ACTN3 RR genotypes in male skiers was statistically higher (p<0.05) and frequency of RX genotype of ACTN3 was lower (p<0.05) compared with controls. There were no significant differences in distribution of ACE I/D and ACTN3 R577X polymorphisms between the groups with different competing levels. We did not observe significant differences in mean VO2peak between ACE I/D, as well between ACTN3 R577X genotypes in male skiers. CONCLUSIONS: Our study results revealed a statistically higher prevalence of ACE ID and ACTN3 RR genotypes in young male skiers (64% and 40%, respectively) compared with male controls (47% and 18%, respectively). Mean VO2peak did not show significant differences between ACE I/D as well between ACTN3 R577X genotypes in male young skiers.

Overrepresentation of the ACTN3 XX genotype in elite canoe and kayak paddlers.

The aim of the study was to examine the association between the ACTN3 R577X polymorphism in canoe sprint athletes (canoe and kayak paddlers) and their results at 200- or 1000-m distance. Eighty-six European white male athletes divided into 2 groups-successful, who were outstanding at national championships, and nonsuccessful in these competitions-and 354 nonathletic controls were included in this study. The R577X polymorphism of ACTN3 was typed using PCR-RFLP. ACTN3 genotype distribution among all tested athletes and controls was in Hardy-Weinberg equilibrium. The odds ratio (OR) for successful 1000-m athletes harboring the XX genotype compared with sedentary controls was 2.95 (95% confidence interval [CI]: 1.37-6.35), but the OR for nonsuccessful 200-m athletes having the XX genotype compared with controls was 2.64 (95% CI: 1.30-5.36). These results suggest that factors associated with the ACTN3 XX genotype in canoe and kayak paddlers might provide some competitive advantage in performance at 1000 m, but it seems to limit at 200 m. Further studies aimed at development of training strategies based on genetic factors are needed.

History-dependent force, angular velocity and muscular endurance in ACTN3 genotypes.

This study aimed at determining the influence of the ACTN3 R577X polymorphism on muscle strength and muscle endurance in non-athletic young men. 266 healthy young men were included in this study. Each subject performed maximal isometric, concentric and eccentric contractions of the knee extensor muscles on an isokinetic dynamometer. Force depression, force enhancement and the fatigue index were derived from these data. In addition, handgrip strength, squat jump (SJ) and counter movement jump (CMJ) height were obtained. Our group included 83 RR (31 %), 131 RX (49 %) and 52 XX (20 %) individuals. The muscle bone cross-sectional area of the thigh was 5 % higher in RR compared to XX individuals (P = 0.033). RR genotypes showed 6 % higher handgrip strength compared to the XX group (P = 0.047). They also jumped 5 % higher in both the SJ and CMJ tests (P = 0.029; P = 0.031). No differences were found in force depression, force enhancement, isometric or eccentric strength. The relative concentric knee torque at 200°/s and at 300°/s was 7 and 8 % higher in RR compared to XX genotypes, respectively (P = 0.049; P = 0.048). Also, the fatigue index was found to be 4 % lower in XX genotypes (P = 0.037). Our findings are in agreement with the higher prevalence of the RR genotype in power-oriented activities. The better fatigue index of XX genotypes may be beneficial in endurance-type activities.

ACTN3 and AMPD1 Polymorphism and Genotype Combinations in Bulgarian Athletes Performing Wingate Test

ACTN3 and AMPD1 Polymorphism and Genotype Combinations in Bulgarian Athletes Performing Wingate Test

1000 Norms Project: protocol of a cross-sectional study cataloging human variation

BackgroundClinical decision-making regarding diagnosis and management largely depends on comparison with healthy or ‘normal’ values. Physiotherapists and researchers therefore need access to robust patient-centred outcome measures and appropriate reference values. However there is a lack of high-quality reference data for many clinical measures. The aim of the 1000 Norms Project is to generate a freely accessible database of musculoskeletal and neurological reference values representative of the healthy population across the lifespan. Methods/designIn 2012 the 1000 Norms Project Consortium defined the concept of ‘normal’, established a sampling strategy and selected measures based on clinical significance, psychometric properties and the need for reference data. Musculoskeletal and neurological items tapping the constructs of dexterity, balance, ambulation, joint range of motion, strength and power, endurance and motor planning will be collected in this cross-sectional study. Standardised questionnaires will evaluate quality of life, physical activity, and musculoskeletal health. Saliva DNA will be analysed for the ACTN3 genotype (‘gene for speed’). A volunteer cohort of 1000 participants aged 3 to 100 years will be recruited according to a set of self-reported health criteria. Descriptive statistics will be generated, creating tables of mean values and standard deviations stratified for age and gender. Quantile regression equations will be used to generate age charts and age-specific centile values. DiscussionThis project will be a powerful resource to assist physiotherapists and clinicians across all areas of healthcare to diagnose pathology, track disease progression and evaluate treatment response. This reference dataset will also contribute to the development of robust patient-centred clinical trial outcome measures.

The ACTN3 R577X variant in sprint and strength performance.

[Purpose]The aim of this study is to examine the association between the distribution of ACTN3 genotypes and alleles in power, speed, and strength-oriented athletics.[Methods]ACTN3 genotyping was carried out for a total of 975 Korean participants: top-level sprinters (n = 58), top-level strength athletes (n = 63), and healthy controls (n = 854).[Results]Genetic associations were evaluated by chi-squire test or Fisher’s exact test. In the power-oriented group composed of sprinters and strength athletes, the frequency of the XX genotype was significantly underrepresented (11.6%) in comparison to its representation in the control group (11.6% versus 19.1%, P < 0.05). When the power-oriented group was divided into strength-oriented and speed-oriented groups, no significant difference in the ACTN3 XX genotype was found between the strength-oriented athletes and the controls (15.9% versus 19.1%, P < 0.262). Only the speed-oriented athletes showed significant differences in the frequency distributions of the ACTN3 XX genotype (6.9% versus 19.1%, P < 0.05) from that of the controls.[Conclusion]The ACTN3 genotype seems to mainly affect sports performance and especially speed.

ACTN3 R577X genotypes associate with Class II and deepbite malocclusions

α-Actinins are myofibril anchor proteins that influence the contractile properties of skeletal muscles. ACTN2 is expressed in slow type I and fast type II fibers, whereas ACTN3 is expressed only in fast fibers. ACTN3 homozygosity for the 577X stop codon (ie, changing 577RR to 577XX, the R577X polymorphism) results in the absence of α-actinin-3 in about 18% of Europeans, diminishes fast contractile ability, enhances endurance performance, and reduces bone mass or bone mineral density. We have examined ACTN3 expression and genetic variation in the masseter muscle of orthognathic surgery patients to determine the genotype associations with malocclusion. Clinical information, masseter muscle biopsies, and saliva samples were obtained from 60 subjects. Genotyping for ACTN3 single nucleotide polymorphisms, real-time polymerase chain reaction quantitation of muscle gene message, and muscle morphometric fiber type properties were compared to determine statistical differences between genotype and phenotype. Muscle mRNA expression level was significantly different for ACTN3 single nucleotide polymorphism genotypes (P<0.01). The frequency of ACTN3 genotypes was significantly different for the sagittal and vertical classifications of malocclusion, with the clearest association being elevated 577XX genotype in skeletal Class II malocclusion (P=0.003). This genotype also resulted in significantly smaller diameters of fast type II fibers in masseter muscles (P=0.002). ACTN3 577XX is overrepresented in subjects with skeletal Class II malocclusion, suggesting a biologic influence during bone growth. ACTN3 577XX is underrepresented in subjects with deepbite malocclusion, suggesting that muscle differences contribute to variations in vertical facial dimensions.

ACTN3 genotype predicts metabolic, anthropometric and cardiovascular phenotypes in a young, healthy population (711.8)

Exercise‐related polymorphisms have played an important role in shaping human evolution. One such polymorphism, ACTN3 R577X, is overrepresented in endurance athletes and centenarians suggesting an association with favorable metabolic health. As such, we examined the influence of ACTN3 genotype on health‐related phenotypes in young subjects (age 18‐35) from the Assessing Inherent Markers for Metabolic syndrome in the Young (AIMMY) study (n=188). Cardiovascular, anthropometric, metabolic and body composition characteristics were assessed. ACTN3 genotype was associated with BMI in a sex specific manner, with null (XX) females having higher scores, while male positive (RR/RX) allele carriers had greater scores compared to XX males (p&lt;0.05). Similarly, body fat percentage and waist circumference measurements were higher in females of the XX genotype compared to RR/RX allele carriers (p&lt;0.05). In males, body circumferences and waist:hip ratio were higher in RR/RX allele carriers compared to XX individuals. Interestingly, Male RR/RX allele carriers had higher blood glucose and diastolic blood pressure than XX males. It was also found that female RR/RX carriers had higher VO2 peak scores than XX females (p&lt;0.05). Metabolic and cardiovascular associations with ACTN3 genotype may offer novel insight into predicted athletic performance and disease risk.

Actn3 genotype is associated with testosterone levels of athletes.

α-Actinin-3 (ACTN3) has been proposed to regulate skeletal muscle differentiation and hypertrophy through its interaction with the signalling protein calcineurin. Since the inhibition of calcineurin potentiates the production of testosterone, we hypothesized that α-actinin-3 deficiency (predicted from the ACTN3 XX genotype) may influence serum levels of testosterone of athletes. Objective: To investigate the association of ACTN3 gene R577X polymorphism with resting testosterone levels in athletes. Methods: A total of 209 elite Russian athletes from different sports (119 males, 90 females) were genotyped for ACTN3 gene R577X polymorphism by real-time PCR. Resting testosterone was examined in serum of athletes using enzyme immunoassay. Results: The mean testosterone levels were significantly higher in both males and females with the ACTN3 R allele than in XX homozygotes (males: RR: 24.9 (5.7), RX: 21.8 (5.5), XX: 18.6 (4.9) ng · mL-1, P = 0.0071; females: RR: 1.43 (0.6), RX: 1.21 (0.71), XX: 0.79 (0.66) ng · mL-1, P = 0.0167). Conclusions: We found that the ACTN3 R allele was associated with high levels of testosterone in athletes, and this may explain, in part, the association between the ACTN3 RR genotype, skeletal muscle hypertrophy and power athlete status.

ACTN3genotype and modulation of skeletal muscle response to exercise in human subjects

α-Actinin-3 is a Z-disc protein expressed only in type II muscle fibers. A polymorphism in the ACTN3 gene (R577X) results in lack of α-actinin-3 in XX genotype. The prevalence of the mutated X-allele is lower among power/sprint oriented athletes compared with controls, indicating that the lack of α-actinin-3 is detrimental in these sports, but a mechanistic link has not been established. Results from Actn3-knockout (KO) mouse model suggest that α-actinin-3 may affect muscle mass and muscle glycogen levels. In the present investigation we examined muscle fiber type composition, cross-sectional fiber area (CSA), and muscle glycogen levels at baseline in 143 human subjects with different ACTN3 genotypes. In addition, hypertrophy signaling and glycogen utilization in response to sprint exercise were studied in a subset of subjects. Glycogen utilization was analyzed in separate pools of type I and type II fibers. No differences in fiber type composition, CSA, or muscle glycogen levels were observed at baseline across the ACTN3 genotypes. However, the sprint exercise-induced increase in phosphorylation of mTOR and p70S6k was smaller in XX than in RR+RX (P = 0.03 and P = 0.01, respectively), indicating a less pronounced activation of hypertrophy signaling in XX. Glycogen utilization during sprint exercise varied across ACTN3 genotypes in type II fibers (P = 0.03) but not in type I fibers (P = 0.38). The present results are in accordance with findings from the KO mice and reinforce the hypothesis that ACTN3 genotype-associated differences in muscle mass and glycogen utilization provide a mechanistic explanation for the modulation of human performance by the ACTN3 genotype.

α-Actinin-3 deficiency alters muscle adaptation in response to denervation and immobilization

Homozygosity for a common null polymorphism (R577X) in the ACTN3 gene results in the absence of the fast fibre-specific protein, α-actinin-3 in ∼16% of humans worldwide. α-Actinin-3 deficiency is detrimental to optimal sprint performance and benefits endurance performance in elite athletes. In the general population, α-actinin-3 deficiency is associated with reduced muscle mass, strength and fast muscle fibre area, and poorer muscle function with age. The Actn3 knock-out (KO) mouse model mimics the human phenotype, with fast fibres showing a shift towards slow/oxidative metabolism without a change in myosin heavy chain (MyHC) isoform. We have recently shown that these changes are attributable to increased activity of the calcineurin-dependent signalling pathway in α-actinin-3 deficient muscle, resulting in enhanced response to exercise training. This led us to hypothesize that the Actn3 genotype influences muscle adaptation to disuse, irrespective of neural innervation. Separate cohorts of KO and wild-type mice underwent 2 weeks immobilization and 2 and 8 weeks of denervation. Absence of α-actinin-3 resulted in reduced atrophic response and altered adaptation to disuse, as measured by a change in MyHC isoform. KO mice had a lower threshold to switch from the predominantly fast to a slower muscle phenotype (in response to immobilization) and a higher threshold to switch to a faster muscle phenotype (in response to denervation). We propose that this change is mediated through baseline alterations in the calcineurin signalling pathway of Actn3 KO muscle. Our findings have important implications for understanding individual responses to muscle disuse/disease and training in the general population.