Association of bradykinin receptor 2 (BDKRB2) variants with physical performance and muscle mass: Findings from the LACE sarcopenia trial.

INTRODUCTION: Understanding genetic contributors to sarcopenia (age-related loss of muscle strength and mass) is key to finding effective therapies. Variants of the bradykinin receptor 2 (BDKRB2) have been linked to athletic and muscle performance. The rs1799722-9 and rs5810761 T alleles have been shown to be overrepresented in endurance athletes, possibly due to increased transcriptional rates of the receptor. These variants have been rarely studied in older people or people with sarcopenia. METHODS: We performed a post hoc sub-study of the Leucine and ACE (LACE) inhibitor trial, which enrolled 145 participants aged ≥70 years with low grip strength and low gait speed. Participants' blood samples were genotyped for rs179972 using TaqMan and rs5810761 by amplification through Hotstar Taq. Genotypes were compared with outcomes of physical performance and body composition measures. RESULTS: Data from 136 individuals were included in the analysis. For rs1799722 the genotype frequency (TT: 17, CC: 48, CT: 71) remained in Hardy-Weinberg Equilibrium (HWE p = 0.248). There was no difference between the genotypes for six-Minute Walk Distance (6MWD) or Short Physical Performance Battery (SPPB). Men with the TT genotype had a significantly greater 6MWD than other genotypes (TT 400m vs CT 310m vs CC 314m, p = 0.027), and greater leg muscle mass (TT 17.59kg vs CT 15.04kg vs CC 15.65kg, p = 0.007). For rs5810761, the genotype frequency (-9-9: 31, +9+9: 43, -9+9: 60) remained in HWE (p = 0.269). The +9+9 genotype was associated with a significant change in SPPB score at 12 months (-9-9 0 vs -9+9 0 vs +9+9-1, p<0.001), suggesting an improvement. In men, the -9-9 genotype was associated with lower arm fat (-9-9 2.39kg vs -9+9 2.72kg vs +9+9 2.76kg, p = 0.019). CONCLUSION: In men, the rs1799722 TT genotype was associated with longer 6MWD and greater leg muscle mass, while the rs5810761 -9-9 genotype was associated with lower arm fat mass.

Study on the Polymorphic Loci of Explosive Strength-Related Genes in Elite Wrestlers.

This investigation aimed to explore the relationship between Chinese elite wrestlers and the polymorphic loci of explosive strength genes, and to further explore the feasibility of its application to athlete selection. The snapshot technique was used to resolve the polymorphic loci of explosive power genes in the wrestler group (59 elite wrestlers) and the control group (180 ordinary college students), and to analyze the genotype frequencies and allele frequencies of each group. A chi-square test was performed on the genotype and allele distribution data of each group to analyze the loci of explosive power genes that were associated with elite wrestlers. The loci that had an association with elite wrestlers were combined with the genotyping data, and the dominance ratios of the genotypes were calculated using the chi-square test to determine the dominant genotypes associated with elite wrestlers. The VDR gene rs2228570 locus exhibited statistically significant differences in genotype and allele distributions between elite wrestlers and the general population (p < 0.01). At the rs2228570 locus of the VDR gene, the difference between the CC genotype and other genotypes was statistically significant (p < 0.05). The rs2228570 locus of the VDR gene was identified as the locus associated with Chinese elite wrestlers. The polymorphism of the VDR gene can be used as a biomarker for Chinese wrestlers, and the CC genotype can be used as a molecular marker for the selection of Chinese elite athletes in this sport. However, expanding the sample size of elite athletes is necessary to further validate the scientific validity and feasibility of these findings.

Genetic Regulation of Physical Fitness in Children: A Twin Study of 15 Tests from Eurofit and Fitnessgram Test Batteries.

PURPOSE: This study aimed to analyze the shared genetic background of physical fitness tests in children. METHODS: Physical fitness was assessed in 198 Portuguese twin pairs (6-18 yr old, 40% monozygotic) through 15 tests from the Eurofit and Fitnessgram test batteries. Genetic twin modeling was used to estimate the heritability of each test and the genetic correlations between them. RESULTS: Girls performed better than boys in flexibility, whereas boys performed better than girls in cardiorespiratory endurance and muscular strength. No sex differences were found in the influence of genetic factors on the physical fitness tests or their mutual correlations. Genetic factors explained 52% (standing long jump) to 79% (sit and reach) of the individual variation in motor performance, whereas individual-specific environmental factors explained the remaining variation. Most of the tests showed modest to moderate genetic correlations. Out of all 105 genetic correlations, 65% ranged from 0.2 to 0.6 indicating that they shared from 4% to 36% of genetic variation. The correlations between individual-specific environmental factors were mostly negligible. CONCLUSIONS: Tests measuring the strength of different muscle groups showed only modest correlations, but moderate correlations were found between tests measuring explosive strength, running speed/agility, and cardiorespiratory endurance. Genetic factors explained a major portion of the variation in tests included in the Eurofit and Fitnessgram test batteries and explained the correlations between them. The modest to moderate genetic correlations indicated that there is little redundancy of tests in either Eurofit or Fitnessgram test batteries.

Pleiotropic effects on Sarcopenia subphenotypes point to potential molecular markers for the disease.

Sarcopenia is a progressive age-related muscle disease characterized by low muscle strength, quantity and quality, and low physical performance. The clinical overlap between these subphenotypes (reduction in muscle strength, quantity and quality, and physical performance) was evidenced, but the genetic overlap is still poorly investigated. Herein, we investigated whether there is a genetic overlap amongst sarcopenia subphenotypes in the search for more effective molecular markers for this disease. For that, a Bioinformatics approach was used to identify and characterize pleiotropic effects at the genome, loci and gene levels using Genome-wide association study results. As a result, a high genetic correlation was identified between gait speed and muscle strength (rG=0.5358, p=3.39 × 10-8). Using a Pleiotropy-informed conditional and conjunctional false discovery rate method we identified two pleiotropic loci for muscle strength and gait speed, one of them was nearby the gene PHACTR1. Moreover, 11 pleiotropic loci and 25 genes were identified for muscle mass and muscle strength. Lastly, using a gene-based GWAS approach three candidate genes were identified in the overlap of the three Sarcopenia subphenotypes: FTO, RPS10 and CALCR. The current study provides evidence of genetic overlap and pleiotropy among sarcopenia subphenotypes and highlights novel candidate genes and molecular markers associated with the risk of sarcopenia.

Identification of Genomic Predictors of Muscle Fiber Size.

The greater muscle fiber cross-sectional area (CSA) is associated with greater skeletal muscle mass and strength, whereas muscle fiber atrophy is considered a major feature of sarcopenia. Muscle fiber size is a polygenic trait influenced by both environmental and genetic factors. However, the genetic variants underlying inter-individual differences in muscle fiber size remain largely unknown. The aim of our study was to determine whether 1535 genetic variants previously identified in a genome-wide association study of appendicular lean mass are associated with the CSA of fast-twitch muscle fibers (which better predict muscle strength) in the m. vastus lateralis of 148 physically active individuals (19 power-trained and 28 endurance-trained females, age 28.0 ± 1.1; 28 power-trained and 73 endurance-trained males, age 31.1 ± 0.8). Fifty-seven single-nucleotide polymorphisms (SNPs) were identified as having an association with muscle fiber size (p < 0.05). Of these 57 SNPs, 31 variants were also associated with handgrip strength in the UK Biobank cohort (n = 359,729). Furthermore, using East Asian and East European athletic (n = 731) and non-athletic (n = 515) cohorts, we identified 16 SNPs associated with athlete statuses (sprinter, wrestler, strength, and speed-strength athlete) and weightlifting performance. All SNPs had the same direction of association, i.e., the lean mass-increasing allele was positively associated with the CSA of muscle fibers, handgrip strength, weightlifting performance, and power athlete status. In conclusion, we identified 57 genetic variants associated with both appendicular lean mass and fast-twitch muscle fiber size of m. vastus lateralis that may, in part, contribute to a greater predisposition to power sports.

Dual FKRP/FST gene therapy normalizes ambulation, increases strength, decreases pathology, and amplifies gene expression in LGMDR9 mice.

Recent clinical studies of single gene replacement therapy for neuromuscular disorders have shown they can slow or stop disease progression, but such therapies have had little impact on reversing muscle disease that was already present. To reverse disease in patients with muscular dystrophy, new muscle mass and strength must be rebuilt at the same time that gene replacement prevents subsequent disease. Here, we show that treatment of FKRPP448L mice with a dual FKRP/FST gene therapy packaged into a single adeno-associated virus (AAV) vector can build muscle strength and mass that exceed levels found in wild-type mice and can induce normal ambulation endurance in a 1-h walk test. Dual FKRP/FST therapy also showed more even increases in muscle mass and amplified muscle expression of both genes relative to either single gene therapy alone. These data suggest that treatment with single AAV-bearing dual FKRP/FST gene therapies can overcome loss of ambulation by improving muscle strength at the same time it prevents subsequent muscle damage. This design platform could be used to create therapies for other forms of muscular dystrophy that may improve patient outcomes.

A genome-wide association study identifies a locus associated with knee extension strength in older Japanese individuals.

Sarcopenia is a common skeletal muscle disease in older people. Lower limb muscle strength is a good predictive value for sarcopenia; however, little is known about its genetic components. Here, we conducted a genome-wide association study (GWAS) for knee extension strength in a total of 3452 Japanese aged 60 years or older from two independent cohorts. We identified a significant locus, rs10749438 which is an intronic variant in TACC2 (transforming acidic coiled-coil-containing 2) (P = 4.2 × 10-8). TACC2, encoding a cytoskeleton-related protein, is highly expressed in skeletal muscle, and is reported as a target of myotonic dystrophy 1-associated splicing alterations. These suggest that changes in TACC2 expression are associated with variations in muscle strength in older people. The association was consistently observed in young and middle-aged subjects. Our findings would shed light on genetic components of lower limb muscle strength and indicate TACC2 as a potential therapeutic target for sarcopenia.

Acute responses of strength-related gene expressions to maximum strength and force sense acuity.

Background/aim: Although high muscle strength worsens the sense of force, it is unknown whether there is a relationship between this deterioration and the underlying molecular mechanisms. This study examined the relationship between decreased force sense (FS) acuity and strength-related gene expressions. Materials and methods: Maximal voluntary isometric contraction (MVIC) and FS (50% MVIC) tests were performed on the knee joints of twenty-two subjects. The expression analyses were evaluated by qRT-PCR in blood samples taken before, after MVIC, after 50% MVIC, and 15 min after the test. Results: MVIC and FS error values were significantly correlated with each other (r = .659, p = .001). The qRT-PCR analyses demonstrated that the expressed mRNAs of the interleukin 6 (IL-6), alpha-actinin 3 (ACTN3), angiotensin-converting enzyme (ACE), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor receptor (CNTFR) genes dramatically increased until 50% MVIC and subsequently decreased 15 min after the exercise (p < .05). The muscle-specific creatine kinase (CKMM), myosin light chain kinase (MLCK), and G-protein ß3 subunit (GNB3) genes reached their peak expression levels 30 min after MVIC (p < .05). ACE and ACTN3 gene expression increased significantly in parallel with the increased FS error (p < .05). These gene expression fluctuations observed at 50% MVIC and after the rest could be related to changes in cellular metabolism leading to fatigue. Conclusion: The time points of gene expression levels during exercise need to be considered. The force acuity of those whose maximal force develops too much may deteriorate.

Whole Genome Linkage and Association Analyses Identify DLG Associated Protein-1 as a Novel Positional and Biological Candidate Gene for Muscle Strength: The Long Life Family Study.

BACKGROUND: Grip strength is a robust indicator of overall health, is moderately heritable, and predicts longevity in older adults. METHODS: Using genome-wide linkage analysis, we identified a novel locus on chromosome 18p (mega-basepair region: 3.4-4.0) linked to grip strength in 3 755 individuals from 582 families aged 64 ±â€…12 years (range 30-110 years; 55% women). There were 26 families that contributed to the linkage peak (cumulative logarithm of the odds [LOD] score = 10.94), with 6 families (119 individuals) accounting for most of the linkage signal (LOD = 6.4). In these 6 families, using whole genome sequencing data, we performed association analyses between the 7 312 single nucleotide (SNVs) and insertion deletion (INDELs) variants in the linkage region and grip strength. Models were adjusted for age, age2, sex, height, field center, and population substructure. RESULTS: We found significant associations between genetic variants (8 SNVs and 4 INDELs, p < 5 × 10-5) in the Disks Large-associated Protein 1 (DLGAP1) gene and grip strength. Haplotypes constructed using these variants explained up to 98.1% of the LOD score. Finally, RNAseq data showed that these variants were significantly associated with the expression of nearby Myosin Light Chain 12A (MYL12A), Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1), Erythrocyte Membrane Protein Band 4.1 Like 3 (EPB41L3) genes (p < .0004). CONCLUSIONS: The DLGAP1 gene plays an important role in the postsynaptic density of neurons; thus, it is both a novel positional and biological candidate gene for follow-up studies aimed at uncovering genetic determinants of muscle strength.

Differences in Muscle Strength Performance According to the Genotypes of the rs4646994 Polymorphism of the ACE Gene in a Sedentary Population / Diferencias en el Rendimiento de la Fuerza Muscular Según los Genotipos del Polimorfismo rs4646994 del Gen ACE en una Población Sedentaria

SUMMARY: The angiotensin converting enzyme gene (ACE) has been associated with endurance and strength performance through its I/D polymorphism. Nevertheless, contradictory results exist between different populations. In this context, the purpose of this research was to determine the influence of the I/D polymorphism of the ACE gene on muscle strength in a sedentary Chilean sample. In this study 102 healthy male students (21.3 ± 2.2 years) completed the assessment. I/D genotyping, cardiovascular, anthropometric, grip strength and knee extensor peak strength were evaluated. The ACE polymorphism frequency was: II, 33.3 %; ID, 46.1 %; DD, 20.6 %. The results showed significant differences and large effect size in maximum (p = 0.004; d = 0.85) and relative handgrip strength (p = 0.004; d = 0.9) between genotype II vs DD. No difference was found for maximal or relative knee extensor strength between groups (p = 0.74), showing a low effect size (d = 0.20). In conclusion, this study provides insights into the role of the ACE gene in muscle strength and highlights the importance of investigating genetic variants in sedentary populations to better understand strength performance.

El gen de la enzima convertidora de angiotensina (ACE) se ha asociado con el rendimiento de resistencia y fuerza a través de su polimorfismo I/D. Sin embargo, existen resultados contradictorios entre diferentes poblaciones. En este contexto, el propósito de esta investigación fue determinar la influencia del polimorfismo I/D del gen ACE sobre la fuerza muscular en una muestra chilena sedentaria. En este estudio, fueron evaluados 102 estudiantes varones sanos (21,3 ± 2,2 años). Se realizaron aplicaron las siguientes evaluaciones: genotipado del polimorfismo I/D, cardiovascular, antropométrica, fuerza de prensión y fuerza máxima de extensión de rodilla. La frecuencia del polimorfismo I/D de ACE fue: II, 33,3 %; DNI, 46,1 %; DD, 20,6 %. Los resultados mostraron diferencias significativas y un gran tamaño del efecto en la fuerza máxima (p = 0,004; d = 0,85) y relativa de prensión manual (p = 0,004; d = 0,9) entre el genotipo II y el DD. No se encontraron diferencias en la fuerza máxima o relativa de los extensores de rodilla entre los grupos (p = 0,74), lo que muestra un tamaño de efecto bajo (d = 0,20). En conclusión, este estudio proporciona información sobre el papel del gen ACE en la fuerza muscular y destaca la importancia de investigar variantes genéticas en poblaciones sedentarias para comprender mejor el rendimiento de la fuerza.

Genome-Wide Polygenic Score for Muscle Strength Predicts Risk for Common Diseases and Lifespan: A Prospective Cohort Study.

BACKGROUND: We used a polygenic score for hand grip strength (PGS HGS) to investigate whether genetic predisposition for higher muscle strength predicts age-related noncommunicable diseases, survival from acute adverse health events, and mortality. METHODS: This study consisted of 342 443 Finnish biobank participants from FinnGen Data Freeze 10 (53% women) aged 40-108 with combined genotype and health registry data. Associations between PGS HGS and a total of 27 clinical endpoints were explored with linear or Cox regression models. RESULTS: A higher PGS HGS was associated with a reduced risk of selected common noncommunicable diseases and mortality by 2%-10%. The risk for these medical conditions decreased by 5%-23% for participants in the highest PGS HGS quintile compared to those in the lowest PGS HGS quintile. A 1 standard deviation (SD) increase in the PGS HGS predicted a lower body mass index (ß = -0.112 kg/m2, standard error [SE] = 0.017, p = 1.69E-11) in women but not in men (ß = 0.004 kg/m2, p = .768). PGS HGS was not associated with better survival after acute adverse health events compared to the nondiseased period. CONCLUSIONS: The genotype that supports higher muscle strength appears to protect against future health adversities, albeit with modest effect sizes. Further research is needed to investigate whether or how a favorable lifestyle modifies this intrinsic capacity to resist diseases, and if the impacts of lifestyle behavior on health differs due to genetic predisposition for muscle strength.

A Genotype-Phenotype Model for Predicting Resistance Training Effects on Leg Press Performance.

This study develops a comprehensive genotype-phenotype model for predicting the effects of resistance training on leg press performance. A cohort of physically inactive adults (N=193) underwent 12 weeks of resistance training, and measurements of maximum isokinetic leg press peak force, muscle mass, and thickness were taken before and after the intervention. Whole-genome genotyping was performed, and genome-wide association analysis identified 85 novel SNPs significantly associated with changes in leg press strength after training. A prediction model was constructed using stepwise linear regression, incorporating seven lead SNPs that explained 40.4% of the training effect variance. The polygenic score showed a significant positive correlation with changes in leg press strength. By integrating genomic markers and phenotypic indicators, the comprehensive prediction model explained 75.4% of the variance in the training effect. Additionally, five SNPs were found to potentially impact muscle contraction, metabolism, growth, and development through their association with REACTOME pathways. Individual responses to resistance training varied, with changes in leg press strength ranging from -55.83% to 151.20%. The study highlights the importance of genetic factors in predicting training outcomes and provides insights into the potential biological functions underlying resistance training effects. The comprehensive model offers valuable guidance for personalized fitness programs based on individual genetic profiles and phenotypic characteristics.

Association of MMP3 gene polymorphism and sex on recovery of muscle strength after eccentric exercise.

Individual differences in recovery of muscle strength after eccentric exercise may be influenced by sex and genotype. A candidate genetic polymorphism associated with response during muscle recovery is the MMP3 gene rs522616 polymorphism, encoding matrix metalloproteinase (MMP-3). Here, we investigated the effect of the MMP3 gene rs522616 polymorphism and sex on recovery of muscle strength after eccentric exercise. A total of 95 healthy subjects (50 men and 45 women) performed five sets of six maximal eccentric elbow flexion exercises. Maximal voluntary contraction (MVC) torque, range of motion (ROM), and muscle soreness, as well as blood parameters [creatine kinase (CK) and interleukin-6 (IL-6)], were assessed immediately before and after and 1, 2, 3, and 5 days after eccentric exercise. No significant time × group interaction in MVC torque after exercise was observed between groups in both sexes. Furthermore, sex differences were identified in the area under the curves (AUC) of CK and IL-6, both of which were higher in men than those in women. A significant genotype-sex interaction was identified in the recovery of MVC, calculated by subtracting the MVC immediately after exercise from the MVC on day 5 after eccentric exercise. The G allele showed a significantly lower recovery of MVC than the AA genotype in men. However, no significant differences were observed in women. This study demonstrated the interaction between the MMP3 rs522616 polymorphism and sex in recovery of muscle strength after eccentric exercise.NEW & NOTEWORTHY Sex differences were identified in the AUC of creatin kinase (CK) and interleukin 6 (IL-6) after eccentric exercise, both of which were greater in men. A genotype-sex interaction was identified in recovery of maximal voluntary contraction (MVC). The G allele showed a significantly lower recovery of MVC than AA genotype in men. To our knowledge, this is the first study to report the interaction between MMP3 gene rs522616 polymorphism and sex difference on recovery of muscle strength after eccentric exercise.

Association of Gene Variants with Seasonal Variation in Muscle Strength and Aerobic Capacity in Elite Skiers.

Background: The training of elite skiers follows a systematic seasonal periodization with a preparation period, when anaerobic muscle strength, aerobic capacity, and cardio-metabolic recovery are specifically conditioned to provide extra capacity for developing ski-specific physical fitness in the subsequent competition period. We hypothesized that periodization-induced alterations in muscle and metabolic performance demonstrate important variability, which in part is explained by gene-associated factors in association with sex and age. Methods: A total of 34 elite skiers (20.4 ± 3.1 years, 19 women, 15 men) underwent exhaustive cardiopulmonary exercise and isokinetic strength testing before and after the preparation and subsequent competition periods of the World Cup skiing seasons 2015-2018. Biometric data were recorded, and frequent polymorphisms in five fitness genes, ACE-I/D (rs1799752), TNC (rs2104772), ACTN3 (rs1815739), and PTK2 (rs7460, rs7843014), were determined with specific PCR reactions on collected DNA. Relative percentage changes of cardio-pulmonary and skeletal muscle metabolism and performance over the two seasonal periods were calculated for 160 data points and subjected to analysis of variance (ANOVA) to identify hypothesized and novel associations between performance alterations and the five respective genotypes and determine the influence of age × sex. A threshold of 0.1 for the effect size (h2) was deemed appropriate to identify relevant associations and motivate a post hoc test to localize effects. Results: The preparation and competition periods produced antidromic functional changes, the extent of which varied with increasing importance for anaerobic strength, aerobic performance, cardio-metabolic efficiency, and cardio-metabolic/muscle recovery. Only peak RER (-14%), but not anaerobic strength and peak aerobic performance, and parameters characterizing cardio-metabolic efficiency, differed between the first and last studied skiing seasons because improvements over the preparation period were mostly lost over the competition period. A number of functional parameters demonstrated associations of variability in periodic changes with a given genotype, and this was considerably influenced by athlete "age", but not "sex". This concerned age-dependent associations between periodic changes in muscle-related parameters, such as anaerobic strength for low and high angular velocities of extension and flexion and blood lactate concentration, with rs1799752 and rs2104772, whose gene products relate to sarcopenia. By contrast, the variance in period-dependent changes in body mass and peak VO2 with rs1799752 and rs2104772, respectively, was independent of age. Likely, the variance in periodic changes in the reliance of aerobic performance on lactate, oxygen uptake, and heart rate was associated with rs1815739 independent of age. These associations manifested at the post hoc level in genotype-associated differences in critical performance parameters. ACTN3 T-allele carriers demonstrated, compared to non-carriers, largely different periodic changes in the muscle-associated parameters of aerobic metabolism during exhaustive exercise, including blood lactate and respiration exchange ratio. The homozygous T-allele carriers of rs2104772 demonstrated the largest changes in extension strength at low angular velocity during the preparation period. Conclusions: Physiological characteristics of performance in skiing athletes undergo training period-dependent seasonal alterations the extent of which is largest for muscle metabolism-related parameters. Genotype associations for the variability in changes of aerobic metabolism-associated power output during exhaustive exercise and anaerobic peak power over the preparation and competition period motivate personalized training regimes. This may help to predict and maximize the benefit of physical conditioning of elite skiers based on chronological characteristics and the polymorphisms of the ACTN3, ACE, and TNC genes investigated here.

Rare genetic variants impact muscle strength.

Muscle strength is highly heritable and predictive for multiple adverse health outcomes including mortality. Here, we present a rare protein-coding variant association study in 340,319 individuals for hand grip strength, a proxy measure of muscle strength. We show that the exome-wide burden of rare protein-truncating and damaging missense variants is associated with a reduction in hand grip strength. We identify six significant hand grip strength genes, KDM5B, OBSCN, GIGYF1, TTN, RB1CC1, and EIF3J. In the example of the titin (TTN) locus we demonstrate a convergence of rare with common variant association signals and uncover genetic relationships between reduced hand grip strength and disease. Finally, we identify shared mechanisms between brain and muscle function and uncover additive effects between rare and common genetic variation on muscle strength.

Genetic risk, muscle strength and risk of incident major depressive disorder: results from the UK Biobank.

BACKGROUND: Genetic factors and muscle strength both contribute to the risk of major depressive disorder (MDD), but whether high muscle strength can offset the risk of MDD with different genetic risk is unknown. This study aims to examine whether a higher muscle strength is associated with lower risk of MDD regardless of genetic risk among middle-aged and older adults. METHODS: This cohort study obtained data from the UK Biobank, which includes 345,621 individuals aged 40-69 years (mean (standard deviation): 56.7 (7.99) years) without baseline MDD. Polygenic risk score for MDD was categorised as low, intermediate or high. The mean of the right- and left-hand grip strength values was used in the analysis and was divided into three categories. RESULTS: 9,753 individuals developed MDD within 2,752,461 person-years of follow-up. The multivariable adjusted hazard ratios (HRs) (95% confidence intervals (CIs)) of MDD across increased grip strength categories were 1.00, 0.72 (0.68-0.75) and 0.56 (0.53-0.59) (P for trend <0.0001). The HRs (95% CIs) of incident MDD across the genetic risk categories were 1.00, 1.11 (1.05-1.17) and 1.20 (1.13-1.28) (P for trend <0.0001); 4.07% of individuals with a high genetic risk and low grip strength developed MDD, and 1.72% of individuals with a low genetic risk and high grip strength developed MDD, with an HR (95% CI) of 0.44 (0.39-0.50). CONCLUSIONS: Both muscle strength and genetic risk were significantly associated with incident MDD. A higher muscle strength was associated with a lower MDD risk among individuals with a high genetic risk. Improving muscle strength should be encouraged for all individuals, including individuals with high genetic risk for MDD.

The Association between ACTN3 R577X Polymorphism and Range of Motion: A Systematic Review and Meta-analysis.

The R577X polymorphism in the α-actinin-3 gene (ACTN3) is associated with muscle strength and power; there is an association between ACTN3 R577X polymorphism and range of motion (ROM). We examined the effect of the ACTN3 R577X polymorphism on ROM through meta-analysis and systematic review. Relevant studies published before April 14, 2022 were identified from the PubMed database using the following keywords and Boolean operators: ("flexibility" or "Joint Range of Motion" or "Joint Flexibility" or "Range of motion") and ("ACTN3" or "alpha-actinin 3"). Studies that met the following criteria were included: (1) published in English, (2) included human subjects, (3) provided ROM measurements, and (4) analyzed the ACTN3 R577X genotype. A total of 2908 participants from seven studies were included in the meta-analysis. The additive genetic model was assessed using a meta-regression model, and dominant and recessive models were analyzed using a random effects model. The ROM in the XX+RX genotype was significantly higher than that in the RR genotype (recessive model: p<0.001), and it increased additively in the order XX>RX>RR (additive model: p=0.029). However, no significant association was observed in the dominant model. These findings further elucidate the association between flexibility and the ACTN3 R577X genotype.

Loss of FoxOs in muscle increases strength and mitochondrial function during aging.

BACKGROUND: Muscle mitochondrial decline is associated with aging-related muscle weakness and insulin resistance. FoxO transcription factors are targets of insulin action and deletion of FoxOs improves mitochondrial function in diabetes. However, disruptions in proteostasis and autophagy are hallmarks of aging and the effect of chronic inhibition of FoxOs in aged muscle is unknown. This study investigated the role of FoxOs in regulating muscle strength and mitochondrial function with age. METHODS: We measured muscle strength, cross-sectional area, muscle fibre-type, markers of protein synthesis/degradation, central nuclei, glucose/insulin tolerance, and mitochondrial bioenergetics in 4.5-month (Young) and 22-24-month-old (Aged) muscle-specific FoxO1/3/4 triple KO (TKO) and littermate control (Ctrl) mice. RESULTS: Lean mass was increased in Aged TKO compared with both Aged Ctrl and younger groups by 26-33% (P < 0.01). Muscle strength, measured by max force of tibialis anterior (TA) contraction, was 20% lower in Aged Ctrl compared with Young Ctrls (P < 0.01) but was not decreased in Aged TKOs. Increased muscle strength in Young and Aged TKO was associated with 18-48% increased muscle weights compared with Ctrls (P < 0.01). Muscle cross-sectional analysis of TA, soleus, and plantaris revealed increases in fibre size distribution and a 2.5-10-fold increase in central nuclei in Young and Aged TKO mice, without histologic signs of muscle damage. Age-dependent increases in Gadd45a and Ube4a expression as well accumulation of K48 polyubiquitinated proteins were observed in quad and TA but were prevented by FoxO deletion. Young and Aged TKO muscle showed minimal changes in autophagy flux and no accumulation of autophagosomes compared with Ctrl groups. Increased strength in Young and Aged TKO was associated with a 10-20% increase in muscle mitochondrial respiration using glutamate/malate/succinate compared with controls (P < 0.05). OXPHOS subunit expression and complex I activity were decreased 16-34% in Aged Ctrl compared with Young Ctrl but were prevented in Aged TKO. Both Aged Ctrl and Aged TKO showed impaired glucose tolerance by 33% compared to young groups (P < 0.05) indicating improved strength and mitochondrial respiration are not due to improved glycemia. CONCLUSIONS: FoxO deletion increases muscle strength even during aging. Deletion of FoxOs maintains muscle strength in part by mild suppression of atrophic pathways, including inhibition of Gadd45a and Ube4a expression, without accumulation of autophagosomes in muscle. Deletion of FoxOs also improved mitochondrial function by maintenance of OXPHOS in both young and aged TKO.

VEGFA rs2010963 GG genotype is associated with superior adaptations to resistance versus endurance training in the same group of healthy, young men.

PURPOSE: We used a within-subject, cross-over study to determine the relationship between the intra-individual adaptations to four weeks' resistance (RT) versus four weeks' endurance (END) training, and we investigated whether three single nucleotide polymorphisms (SNPs) were associated with these adaptations. METHODS: Thirty untrained, healthy, young men completed a cycling test to exhaustion to determine peak oxygen uptake (V̇O2peak), and a knee extension (KE) maximum voluntary isometric contraction (MVIC) of the right leg before and after four weeks' supervised RT (four sets of 10 repetitions at 80% single repetition maximum unilateral KE exercise, three times weekly) and four weeks' supervised END (30 min combined continuous/interval cycling, three times weekly), separated by a three-week washout phase. Participants were genotyped for the ACTN3 rs1815739, NOS3 rs2070744 and VEGFA rs2010963 SNPs. RESULTS: The intra-individual adaptations regarding percentage changes in MVIC force and V̇O2peak following RT and END, respectively, were unrelated (r2 = 0.003; P = 0.79). However, a VEGFA genotype × training modality interaction (P = 0.007) demonstrated that VEGFA GG homozygotes increased their MVIC force after RT (+ 20.9 ± 13.2%) more than they increased their V̇O2peak after END (+ 8.4 ± 9.1%, P = 0.005), and more than VEGFA C-allele carriers increased their MVIC force after RT (+ 12.2 ± 8.1%, P = 0.04). There were no genotype × training modality interactions for the ACTN3 or NOS3 SNPs. CONCLUSION: High/low responders to RT were not consequently high/low responders to END or vice versa. However, preferential adaptation of VEGFA rs2010963 GG homozygotes to RT over END, and their greater adaptation to RT compared to VEGFA C-allele carriers, indicate a novel genetic predisposition for superior RT adaptation.

Genetic polymorphisms related to muscular strength and flexibility are associated with artistic gymnastic performance in the Japanese population.

This study aimed to examine how genetic polymorphisms related to muscular strength and flexibility influence artistic gymnastic performance in an attempt to identify a novel polymorphism associated with flexibility. In study 1, the passive straight-leg-raise (PSLR) score and aromatase gene CYP19A1 rs936306 polymorphism, a key enzyme for estrogen biosynthesis, were assessed in 278 individuals. In study 2, athletes (281 gymnasts and 1908 other athletes) were asked about their competition level, and gymnasts were assessed using the difficulty score (D-score) for each event. Muscular strength- (ACTN3 R577X rs1815739 and ACE I/D rs4341) and flexibility-related (ESR1 rs2234693 T/C and CYP19A1 rs936306 C/T) genetic polymorphisms were analyzed. In study 1, males with the CYP19A1 CT + TT genotype showed significantly higher PSLR scores than those with the CC genotype. In study 2, male gymnasts with the R allele of ACTN3 R577X showed a correlation with the floor, rings, vault, and total D-scores. In addition, male gymnasts with the C allele of ESR1 T/C and T allele of CYP19A1 C/T polymorphisms were correlated with the pommel horse, parallel bars, horizontal bar, and total D-scores. Furthermore, genotype scores of these three polymorphisms correlated with the total D-scores and competition levels in male gymnasts. In contrast, no such associations were observed in female gymnasts. Our findings suggest that muscular strength- and flexibility-related polymorphisms play important roles in achieving high performance in male artistic gymnastics by specifically influencing the performance of events that require muscular strength and flexibility, respectively.HighlightsEstrogen-related CYP19A1 polymorphism is a novel determinant of flexibility in males.Muscular strength- and flexibility-related polymorphisms play important roles in high performance in male artistic gymnastics.Genotypes of ACTN3 R577X, ESR1 rs2234693, and CYP19A1 rs936306 may contribute to training plan optimization and event selection in artistic gymnastics.