Association of Genetically Predicted BCAA Levels with Muscle Fiber Size in Athletes Consuming Protein.

Branched-chain amino acid (BCAA) levels are associated with skeletal muscle cross-sectional area (CSA). Serum BCAA levels are enhanced by whey protein supplementation (WPS), and evidence in clinical populations suggests an association of single nucleotide polymorphisms (SNPs) with BCAA metabolite levels. It is not known whether the same SNPs are associated with the ability to catabolise BCAAs from exogenous sources, such as WPS. The present study investigated whether possessing a higher number of alleles associated with increased BCAA metabolites correlates with muscle fiber CSA of m. vastus lateralis in physically active participants, and whether any relationship is enhanced by WPS. Endurance-trained participants (n = 75) were grouped by self-reported habitual WPS consumption and genotyped for five SNPs (PPM1K rs1440580, APOA5 rs2072560, CBLN1 rs1420601, DDX19B rs12325419, and TRMT61A rs58101275). Body mass, BMI, and fat percentage were significantly lower and muscle mass higher in the WPS group compared to Non-WPS. The number of BCAA-increasing alleles was correlated with fiber CSA in the WPS group (r = 0.75, p < 0.0001) and was stronger for fast-twitch fibers (p = 0.001) than slow-twitch fibers (p = 0.048). Similar results remained when corrected for multiple covariates (age, physical activity, and meat and dairy intake). No correlation was found in the Non-WPS group. This study presents novel evidence of a positive relationship between BCAA-increasing alleles and muscle fiber CSA in athletes habitually consuming WPS. We suggest that a high number of BCAA-increasing alleles improves the efficiency of WPS by stimulation of muscle protein synthesis, and contributes to greater fiber CSA

The ADORA2A TT Genotype Is Associated with Anti-Inflammatory Effects of Caffeine in Response to Resistance Exercise and Habitual Coffee Intake

Caffeine is an adenosine A2A receptor (ADORA2A) antagonist with ergogenic and anti-inflammatory effects. Previous studies have reported that the ADORA2A gene regulates glutamate metabolism and immune responses, with the ADORA2A rs5751876 TT genotype (with high sensitivity to caffeine) showing larger ergogenic effect following caffeine ingestion. We therefore hypothesized that the TT genotype would be associated with greater anti-inflammatory effects of caffeine in response to exercise, and with higher coffee intake in physically active individuals. The aim of the present study was twofold: (1) to investigate the association of the ADORA2A variant with the anti-inflammatory effects of caffeine in response to intense resistance exercise (RE), and (2) to analyze the association of the rs5751876 with coffee intake in physically active individuals (n = 134). Fifteen resistance-trained athletes participated in a randomized, double-blind, placebo-controlled cross-over study, where they consumed 6 mg/kg of caffeine or placebo one hour prior to performing an RE protocol. Blood samples were taken immediately from the arterial vein before, immediately after, and 15 min after RE for the analysis of inflammatory markers myeloperoxidase (MPO) and acetylcholinesterase (AChE). We found that the ADORA2A TT genotype carriers experienced lower exercise-induced inflammatory responses (p < 0.05 for AchE) when compared to the C allele carriers (i.e., CC/CT) one hour following the ingestion of caffeine. Furthermore, the ADORA2A TT genotype was positively associated with coffee intake (p = 0.0143; irrespective of CYP1A2 rs762551 polymorphism). In conclusion, we found that the ADORA2A gene polymorphism is associated with anti-inflammatory effects of caffeine in response to resistance exercise, as well as with habitual coffee intake in physically active individuals

CKM Gene rs8111989 Polymorphism and Power Athlete Status.

Multiple genetic variants are known to influence athletic performance. These include polymorphisms of the muscle-specific creatine kinase (CKM) gene, which have been associated with endurance and/or power phenotypes. However, independent replication is required to support those findings. The aim of the present study was to determine whether the CKM (rs8111989, c.*800A>G) polymorphism is associated with power athlete status in professional Russian and Lithuanian competitors. Genomic DNA was collected from 693 national and international standard athletes from Russia (n = 458) and Lithuania (n = 235), and 500 healthy non-athlete subjects from Russia (n = 291) and Lithuania (n = 209). Genotyping for the CKM rs8111989 (A/G) polymorphism was performed using PCR or micro-array analysis. Genotype and allele frequencies were compared between all athletes and non-athletes, and between non-athletes and athletes, segregated according to population and sporting discipline (from anaerobic-type events). No statistically significant differences in genotype or allele frequencies were observed between non-athletes and power athletes (strength-, sprint- and speed/strength-oriented) athletes. The present study reports the non-association of the CKM rs8111989 with elite status in athletes from sports in which anaerobic energy pathways determine success

The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity: novel findings and a meta-analysis.

PURPOSE: Iron is an important component of the oxygen-binding proteins and may be critical to optimal athletic performance. Previous studies have suggested that the G allele of C/G rare variant (rs1799945), which causes H63D amino acid replacement, in the HFE is associated with elevated iron indexes and may give some advantage in endurance-oriented sports. The aim of the present study was to investigate the association between the HFE H63D polymorphism and elite endurance athlete status in Japanese and Russian populations, aerobic capacity and to perform a meta-analysis using current findings and three previous studies. METHODS: The study involved 315 international-level endurance athletes (255 Russian and 60 Japanese) and 809 healthy controls (405 Russian and 404 Japanese). Genotyping was performed using micro-array analysis or by PCR. VO2max in 46 male Russian endurance athletes was determined using gas analysis system. RESULTS: The frequency of the iron-increasing CG/GG genotypes was significantly higher in Russian (38.0 vs 24.9%; OR 1.85, P = 0.0003) and Japanese (13.3 vs 5.0%; OR 2.95, P = 0.011) endurance athletes compared to ethnically matched controls. The meta-analysis using five cohorts (two French, Japanese, Spanish, and Russian; 586 athletes and 1416 controls) showed significant prevalence of the CG/GG genotypes in endurance athletes compared to controls (OR 1.96, 95% CI 1.58-2.45; P = 1.7 × 10-9). Furthermore, the HFE G allele was associated with high V̇O2max in male athletes [CC: 61.8 (6.1), CG/GG: 66.3 (7.8) ml/min/kg; P = 0.036]. CONCLUSIONS: We have shown that the HFE H63D polymorphism is strongly associated with elite endurance athlete status, regardless ethnicities and aerobic capacity in Russian athletes

UBR5 is a Novel E3 Ubiquitin Ligase involved in Skeletal Muscle Hypertrophy and Recovery from Atrophy

We have recently identified that a HECT domain E3 ubiquitin ligase, named UBR5, was epigenetically altered (via DNA methylation) after human skeletal muscle hypertrophy, where its gene expression was positively correlated with increased lean leg mass in humans [1]. This was counterintuitive given the well-defined role of other E3 ligase family members, MuRF1 and MAFbx in muscle atrophy. Therefore, in the present study we aimed to investigate this relatively uncharacterised E3 ubiquitin ligase using multiple in-vivo and in-vitro models of skeletal muscle atrophy, injury, recovery from atrophy as well as anabolism and hypertrophy. We report for the first time, that during atrophy evoked by tetrodotoxin (TTX) nerve silencing in rats, the UBR5 promoter was significantly hypomethylated with a concomitant increase in gene expression early (3 & 7 days) after the induction of atrophy. However, at these timepoints larger increases in MuRF1/MAFbx were observed, and UBR5 expression had returned to baseline levels during later atrophy (14 days) where muscle mass loss was greatest. We confirmed an alternate gene expression profile for UBR5 versus MuRF1/MAFbx in a secondary model of atrophy induced by 7 days continuous low frequency electrical stimulation, where UBR5 demonstrated no significant increase, whereas MuRF1/MAFbx were elevated. Further, after partial (52%) recovery of muscle mass following 7 days TTX-cessation, UBR5 was hypomethylated and increased at the gene expression level, while alternately, reductions in gene expression of MuRF1 and MAFbx were observed. To substantiate these gene expression findings, we observed a significant increase in UBR5 protein abundance after full recovery (14 days) of muscle mass from hindlimb unloading (HU) in rats. Aged rats also demonstrated a similar temporal increase in UBR5 protein abundance after recovery from HU. Further, we confirmed significant increases in UBR5 protein during recovery from nerve crush injury in mice at 28 and 45 days, that related to a full recovery of muscle mass between 45-60 days. During anabolism and hypertrophy, UBR5 gene expression increased following an acute bout of mechanical loading in three-dimensional bioengineered mouse muscle in-vitro, and after chronic electrical stimulation-induced hypertrophy in rats in-vivo, without increases in MuRF1/MAFbx. Additionally, increased UBR5 protein abundance was identified following synergist ablation/functional overload (FO)-induced hypertrophy of the plantaris muscle in mice in-vivo, and finally over a 7-day time-course of regeneration in primary human muscle cells in-vitro. Finally, genetic association studies (> 700,000 SNPs) in human cohorts identified that the A alleles of rs10505025 and rs4734621 SNPs were strongly associated with larger cross-sectional area of fast-twitch muscle fibres and favoured strength/power versus endurance/untrained phenotypes. Overall, we suggest that UBR5 is a novel E3 ubiquitin ligase that is alternatively regulated compared to MuRF1/MAFbx, and is elevated during early atrophy (but not later atrophy), recovery, anabolism and hypertrophy in animals in-vivo as well as during human muscle cell regeneration in-vitro. In humans, genetic variations of the UBR5 gene are strongly associated with larger fast-twitch muscle fibres and strength/power performance

Is testosterone responsible for athletic success in female athletes?

BACKGROUND: The aim of this study was to determine the interrelationship between the resting serum testosterone (T) levels of female athletes from different types of sporting events and their athletic success. METHODS: The study involved 599 Russian international-level female athletes (95 highly elite, 190 elite, and 314 sub-elite; age: 16-35 years) and 298 age-matched female controls. The athlete cohort was stratified into four groups according to event duration, distance, and type of activity: 1) endurance athletes; 2) athletes with mixed activity; 3) speed/strength athletes; 4) sprinters. Athletic success was measured by determining the level of achievement of each athlete. RESULTS: The mean T levels of athletes and controls were 1.65±0.87 and 1.76±0.6 nmol/L (P=0.057 for difference between groups) with ranges of 0.08-5.82 and 0.38-2.83 nmol/L in athletes and controls, respectively. T levels were positively associated with athletic success in sprinters (P=0.0002 adjusted for age) only. Moreover, none of the sub-elite sprinters had T>1.9 nmol/L, while 50% of elite and highly elite sprinters had T>1.9 nmol/L (OR=47.0; P<0.0001). CONCLUSIONS: Our data suggest that the measurement of the serum T levels significantly correlates with athletic success in sprinters but not other types of athletes and in the future may be useful in the prediction of sprinting ability

DNA methylation across the genome in aged human skeletal muscle tissue and muscle-derived cells: the role of HOX genes and physical activity.

Skeletal muscle tissue demonstrates global hypermethylation with age. However, methylome changes across the time-course of differentiation in aged human muscle derived cells, and larger coverage arrays in aged muscle tissue have not been undertaken. Using 850K DNA methylation arrays we compared the methylomes of young (27 ± 4.4 years) and aged (83 ± 4 years) human skeletal muscle and that of young/aged heterogenous muscle-derived human primary cells (HDMCs) over several time points of differentiation (0, 72 h, 7, 10 days). Aged muscle tissue was hypermethylated compared with young tissue, enriched for; pathways-in-cancer (including; focal adhesion, MAPK signaling, PI3K-Akt-mTOR signaling, p53 signaling, Jak-STAT signaling, TGF-beta and notch signaling), rap1-signaling, axon-guidance and hippo-signalling. Aged cells also demonstrated a hypermethylated profile in pathways; axon-guidance, adherens-junction and calcium-signaling, particularly at later timepoints of myotube formation, corresponding with reduced morphological differentiation and reductions in MyoD/Myogenin gene expression compared with young cells. While young cells showed little alterations in DNA methylation during differentiation, aged cells demonstrated extensive and significantly altered DNA methylation, particularly at 7 days of differentiation and most notably in focal adhesion and PI3K-AKT signalling pathways. While the methylomes were vastly different between muscle tissue and HDMCs, we identified a small number of CpG sites showing a hypermethylated state with age, in both muscle tissue and cells on genes KIF15, DYRK2, FHL2, MRPS33, ABCA17P. Most notably, differential methylation analysis of chromosomal regions identified three locations containing enrichment of 6-8 CpGs in the HOX family of genes altered with age. With HOXD10, HOXD9, HOXD8, HOXA3, HOXC9, HOXB1, HOXB3, HOXC-AS2 and HOXC10 all hypermethylated in aged tissue. In aged cells the same HOX genes (and additionally HOXC-AS3) displayed the most variable methylation at 7 days of differentiation versus young cells, with HOXD8, HOXC9, HOXB1 and HOXC-AS3 hypermethylated and HOXC10 and HOXC-AS2 hypomethylated. We also determined that there was an inverse relationship between DNA methylation and gene expression for HOXB1, HOXA3 and HOXC-AS3. Finally, increased physical activity in young adults was associated with oppositely regulating HOXB1 and HOXA3 methylation compared with age. Overall, we demonstrate that a considerable number of HOX genes are differentially epigenetically regulated in aged human skeletal muscle and HDMCs and increased physical activity may help prevent age-related epigenetic changes in these HOX genes

Prediction of muscle fiber composition using multiple repetition testing

Direct determination of muscle fiber composition is invasive and expensive, with indirect methods also requiring specialist resources and expertise. Performing resistance exercises at 80% 1RM is suggested as a means of indirectly estimating muscle fiber composition, though this hypothesis has never been validated against a direct method. The aim of the study was to investigate the relationship between the number of completed repetitions at 80% 1RM of back squat exercise and muscle fiber composition. Thirty recreationally active participants’ (10 females, 20 males) 1RM back squat load was determined, before the number of consecutive repetitions at 80% 1RM was recorded. The relationship between the number of repetitions and the percentage of fast-twitch fibers from vastus lateralis was investigated. The number of completed repetitions ranged from 5 to 15 and was independent of sex, age, 1RM, training frequency, training type, training experience, BMI or muscle fiber cross-sectional area. The percentage of fast-twitch muscle fibers was inversely correlated with the number of repetitions completed (r = –0.38, P = 0.039). Participants achieving 5 to 8 repetitions (n = 10) had significantly more fast-twitch muscle fibers (57.5 ± 9.5 vs 44.4 ± 11.9%, P = 0.013) than those achieving 11–15 repetitions (n = 11). The remaining participants achieved 9 or 10 repetitions (n = 9) and on average had equal proportion of fast- and slow-twitch muscle fibers. In conclusion, the number of completed repetitions at 80% of 1RM is moderately correlated with muscle fiber composition

Association of ACTN3 R577X Polymorphism with Elite Basketball Player Status and Training Responses

The α-actinin-3 (ACTN3) gene rs1815739 (C/T, R577X) polymorphism is a variant frequently associated with athletic performance among different populations. However, there is limited research on the impact of this variant on athlete status and physical performance in basketball players. Therefore, the aim of this study was twofold: (1) to determine the association of ACTN3 rs1815739 polymorphism with changes in physical performance in response to six weeks of training in elite basketball players using 30 m sprint and Yo-Yo Intermittent Recovery Test Level 2 (IR 2) tests, and (2) to compare ACTN3 genotype and allelic frequencies between elite basketball players and controls. The study included a total of 363 individuals, comprising 101 elite basketball players and 262 sedentary individuals. Genomic DNA was isolated from oral epithelial cells or leukocytes, and genotyping was performed by real-time PCR using KASP genotyping method or by microarray analysis. We found that the frequency of the ACTN3 rs1815739 XX genotype was significantly lower in basketball players compared to controls (10.9 vs. 21.4%, p = 0.023), suggesting that RR/RX genotypes were more favorable for playing basketball. Statistically significant (p = 0.045) changes were observed in Yo-Yo IRT 2 performance measurement tests in basketball players with the RR genotype only. In conclusion, our findings suggest that the carriage of the ACTN3 rs1815739 R allele may confer an advantage in basketball