Principal component analysis reveals gender-specific predictors of cardiometabolic risk in 6th graders.

BACKGROUND: The purpose of this study was to determine the sex-specific pattern of pediatric cardiometabolic risk with principal component analysis, using several biological, behavioral and parental variables in a large cohort (n = 2866) of 6th grade students. METHODS: Cardiometabolic risk components included waist circumference, fasting glucose, blood pressure, plasma triglycerides levels and HDL-cholesterol. Principal components analysis was used to determine the pattern of risk clustering and to derive a continuous aggregate score (MetScore). Stratified risk components and MetScore were analyzed for association with age, body mass index (BMI), cardiorespiratory fitness (CRF), physical activity (PA), and parental factors. RESULTS: In both boys and girls, BMI and CRF were associated with multiple risk components, and overall MetScore. Maternal smoking was associated with multiple risk components in girls and boys, as well as MetScore in boys, even after controlling for children's BMI. Paternal family history of early cardiovascular disease (CVD) and parental age were associated with increased blood pressure and MetScore for girls. Children's PA levels, maternal history of early CVD, and paternal BMI were also indicative for various risk components, but not MetScore. CONCLUSIONS: Several biological and behavioral factors were independently associated with children's cardiometabolic disease risk, and thus represent a unique gender-specific risk profile. These data serve to bolster the independent contribution of CRF, PA, and family-oriented healthy lifestyles for improving children's health.

Variants of the ankyrin repeat domain 6 gene (ANKRD6) and muscle and physical activity phenotypes among European-derived American adults.

Ankyrin repeat domain 6 (ANKRD6) is a ubiquitous protein that associates with early development in mammals and is highly expressed in the brain, spinal cord, and heart of humans. We examined the role of 8 ANKRD6 single-nucleotide polymorphisms (SNPs) on muscle performance and habitual physical activity (PA). Single-nucleotide polymorphisms were 545 T>A (rs9362667), 485 M>L (rs61736690), 233 T>M (rs2273238), 128 I>L (rs3748085), 631 P>L (rs61739327), 122 Q>E (rs16881983), 197805 G>A (rs9344950), and 710 L>X (NOVEL). This study consisted of 922 healthy, untrained, European-derived American men (n = 376, 23.6 ± 0.3 years, 25.0 ± 0.2 kg·m(-2)) and women (n = 546, 23.2 ± 0.2 years, 24.0 ± 0.2 kg·m(-2)). Muscle strength (maximum voluntary contraction [MVC] and 1 repetition maximum [1RM]) and size (cross-sectional area [CSA]) were assessed before and after 12 weeks of unilateral resistance training (RT). A subsample (n = 536, 23.4 ± 0.2 years, 24.6 ± 0.2 kg·m(-2)) completed the Paffenbarger Physical Activity Questionnaire. Associations among ANKRD6 genotypes and muscle phenotypes were tested with repeated measure analysis of covariance (ANCOVA) and PA phenotypes with multivariate ANCOVA, with age and body mass index as covariates. ANKRD6 122 Q>E was associated with increased baseline biceps CSA. ANKRD6 545 A>T and ANKRD6 710 L>X were associated with increased 1RM and MVC in response to RT, respectively. ANKRD6 631 P>L was associated with increased biceps CSA response to RT and time spent in moderate-intensity PA among the total sample and women. ANKRD6 genetic variants were associated with the muscle size and strength response to RT and habitual PA levels. Further research is needed to validate our results and explore mechanisms for the associations we observed.

AKT1 polymorphisms are associated with risk for metabolic syndrome.

Converging lines of evidence suggest that AKT1 is a major mediator of the responses to insulin,insulin-like growth factor 1 (IGF1), and glucose. AKT1 also plays a key role in the regulation of both muscle cell hypertrophy and atrophy. We hypothesized that AKT1 variants may play a role in the endophenotypes that makeup metabolic syndrome. We studied a 12-kb region including the first exon of the AKT1 gene for association with metabolic syndrome-related phenotypes in four study populations [FAMUSS cohort (n = 574; age 23.7 ± 5.7 years), Strong Heart Study (SHS) (n = 2,134; age 55.5 ± 7.9 years), Dynamics of Health, Aging and Body Composition (Health ABC) (n = 3,075; age 73.6 ± 2.9 years), and Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE)(n = 175; age 40­65 years)]. We identified a three SNP haplotype that we call H1, which represents the ancestral alleles eles at the three loci and H2, which represents the derived alleles at the three loci. In young adult European Americans (FAMUSS), H1 was associated with higher fasting glucose levels in females. In middle age Native Americans (SHS), H1 carriers showed higher fasting insulin and HOMA in males, and higher BMI in females. Inolder African-American and European American subjects(Health ABC) H1 carriers showed a higher incidence of metabolic syndrome. Homozygotes for the H1 haplotype showed about twice the risk of metabolic syndrome in both males and females (p < 0.001). In middle-aged European Americans with insulin resistance (STRRIDE) studied by intravenous glucose tolerance test (IVGTT), H1 carriers showed increased insulin resistance due to the Sg component (p = 0.021). The 12-kb haplotype is a risk factor for metabolic syndrome and insulin resistance that needs to be explored in further populations.

The 1p13.3 LDL (C)-associated locus shows large effect sizes in young populations.

Genome-wide association studies (GWASs) have identified polymorphic loci associated with coronary artery disease (CAD) risk factors (i.e. serum lipids) in adult populations (42-69 y). We hypothesized that younger populations would show a greater relative genetic component due to fewer confounding variables. We examined the influence of 20 GWAS loci associated with serum lipids and insulin metabolism, in a university student cohort (n = 548; mean age = 24 y), and replicated statistically associated results in a second study cohort of primary school students (n = 810, mean age = 11.5 y). Nineteen loci showed no relationship with studied risk factors in young adults. However, the ancestral allele of the rs646776 (SORT1) locus was strongly associated with increased LDL (C) in young adults [TT: 97.6 ± 1.0 mg/dL (n = 345) versus CT/CC: 87.3 ± 1.0 mg/dL (n = 203); p = 3 × 10(x6)] and children [TT: 94.0 ± 1.3 mg/dL (n = 551) versus CT/CC: 84.7 ± 1.4 mg/dL (n = 259); p = 4 × 10(x6)]. This locus is responsible for 3.6% of population variance in young adults and 2.5% of population variance in children. The effect size of the SORT1 locus is considerably higher in young populations (2.5-4.1%) compared with older subjects (1%).

Blunted circadian cortisol in children is associated with poor cardiovascular health and may reflect circadian misalignment.

OBJECTIVES: Circadian cues in children (sunlight, exercise, diet patterns) may be associated with health outcomes. The primary objective was to assess associations of daily cortisol fluctuations (morning, night) with cardiovascular health outcomes. A secondary objective was to determine if 1-year longitudinal changes in circadian cortisol levels are associated with longitudinal changes in health outcomes. STUDY DESIGN: The Cardiovascular Health Intervention Program (CHIP) was a cross-sectional and longitudinal study of cardiovascular risk profiles in public elementary school children in Southern Maine. Participants were 689 students in 4th grade (baseline; age = 9.20 ± 0.41 years), and 647 students in 5th grade (age = 10.53 ± 0.52 years). Longitudinal data (4th and 5th grade) was available for 347 participants. Clinical outcomes were blood pressure, hip/waist ratios, body mass index, percent fat. Laboratory measures were fasting glucose, lipids, and salivary cortisol measures (morning and evening). RESULTS: Lower first-in-morning diurnal cortisol levels were associated with increased blood pressure (ß -0.23 ± 0.05; p < 0.001), increased body fat (ß -0.22 ± 0.05; p < 0.001), and poor lipid profiles (ß -0.15 ± 0.07; p < 0.05). Inclusion of night cortisol in the model (stress-related) improved associations of the model with bodyfat composition (morning ß -0.27 ± 0.05; p < 0.001; night ß +0.16 ± 0.06; p < 0.01). Adjustments for potential confounding variables improved associations of morning cortisol with lipids (ß -0.19 ± 0.07; p < 0.01). Longitudinal analysis showed that lower morning diurnal cortisol in 4th grade was associated with increases in blood pressure a year later (ß -0.18 ± 0.08; p = 0.017) after adjusting for confounding variables. CONCLUSION: Data presented suggest adding circadian misalignment (lower amplitude of first-in-morning cortisol) to existing models of metabolic syndrome in children. Further, circadian misalignment may be a factor contributing to high blood pressure.

A polymorphism near IGF1 is associated with body composition and muscle function in women from the Health, Aging, and Body Composition Study.

Previous studies have reported associations of polymorphisms in the IGF1 gene with phenotypes of body composition (BC). The purpose of this study was to identify phenotypes of BC and physical function that were associated with the IGF1 promoter polymorphism (rs35767, -C1245T). Subjects from the Health, Aging, and Body Composition Study, white males and females (n = 925/836) and black males and females (533/705) aged 70-79 years were genotyped for the polymorphism. Phenotypes of muscle size and function, bone mineral density, and BC were analyzed for associations with this polymorphism. To validate and compare these findings, a cohort of young (mean age = 24.6, SD = 5.9) white men and women (n = 173/296) with similar phenotypic measurements were genotyped. An association with BC was identified in elderly females when significant covariates (physical activity, age, smoking status, body mass index) were included. White women with C/C genotype had 3% more trunk fat and 2% more total fat than those with C/T (P < 0.05). Black women with C/C genotype had 3% less total lean mass and 3% less muscle mass than their T/T counterparts (P < 0.05). Associations were identified with muscle strength in white women (P < 0.01) that were in agreement with the C/C genotype having lower muscle function. Thus, in an elderly population but not a young population, a polymorphism in the IGF1 gene may be predictive of differences in body composition, primarily in black females.

Differences in fat and muscle mass associated with a functional human polymorphism in a post-transcriptional BMP2 gene regulatory element.

A classic morphogen, bone morphogenetic protein 2 (BMP2) regulates the differentiation of pluripotent mesenchymal cells. High BMP2 levels promote osteogenesis or chondrogenesis and low levels promote adipogenesis. BMP2 inhibits myogenesis. Thus, BMP2 synthesis is tightly controlled. Several hundred nucleotides within the 3' untranslated regions of BMP2 genes are conserved from mammals to fishes indicating that the region is under stringent selective pressure. Our analyses indicate that this region controls BMP2 synthesis by post-transcriptional mechanisms. A common A to C single nucleotide polymorphism (SNP) in the BMP2 gene (rs15705, +A1123C) disrupts a putative post-transcriptional regulatory motif within the human ultra-conserved sequence. In vitro studies indicate that RNAs bearing the A or C alleles have different protein binding characteristics in extracts from mesenchymal cells. Reporter genes with the C allele of the ultra-conserved sequence were differentially expressed in mesenchymal cells. Finally, we analyzed MRI data from the upper arm of 517 healthy individuals aged 18-41 years. Individuals with the C/C genotype were associated with lower baseline subcutaneous fat volumes (P = 0.0030) and an increased gain in skeletal muscle volume (P = 0.0060) following resistance training in a cohort of young males. The rs15705 SNP explained 2-4% of inter-individual variability in the measured parameters. The rs15705 variant is one of the first genetic markers that may be exploited to facilitate early diagnosis, treatment, and/or prevention of diseases associated with poor fitness. Furthermore, understanding the mechanisms by which regulatory polymorphisms influence BMP2 synthesis will reveal novel pharmaceutical targets for these disabling conditions.

Association of age with muscle size and strength before and after short-term resistance training in young adults.

The purpose of this study was to assess the association of age with muscle mass and strength in a group of young adults before and after 12 weeks of progressive resistance training. Eight hundred twenty-six young males and females (age 24.34 +/- 5.69 yr, range 18-39 yr) completed a strictly supervised 12-week unilateral resistance training program of the nondominant arm. Isometric (maximal voluntary contraction [MVC]) and dynamic strength (1 repetition maximum [1RM]) of the elbow flexors and cross-sectional area (CSA) of the biceps-brachii using magnetic resonance imaging (MRI) scans were measured before and after training. Pearson correlation coefficients were calculated for size and strength variables and age. In addition, the cohort was divided into groups according to decade of life and differences assessed by analysis of variance. Age correlated significantly and positively with all pretraining measures of muscle size and strength (CSA: r = 0.191, p < 0.001; MVC: r = 0.109, p = 0.002; 1RM: r = 0.109, p = 0.002). Age was not related to the training-induced changes in CSA or MVC but was negatively associated with the change in 1RM (r = -0.217, p < 0.001). The study indicates that age does have a significant positive relationship with muscle size and strength in untrained young adults. Although age was negatively associated with improvements in 1RM, the effect of age was small relative to the improvements induced through resistance training, thus suggesting age does not limit response to training in any practical way during early adulthood.

INSIG2 gene polymorphism is associated with increased subcutaneous fat in women and poor response to resistance training in men.

BACKGROUND: A common SNP upstream of the INSIG2 gene, rs7566605 (g.-10,1025G>C, Chr2:118,552,255, NT_022135.15), was reported to be associated with obesity (Body Mass Index, [BMI]) in a genome-wide association scan using the Framingham Heart Study but has not been reproduced in other cohorts. As BMI is a relatively insensitive measure of adiposity that is subject to many confounding variables, we sought to determine the relationship between the INSIG2 SNP and subcutaneous fat volumes measured by MRI in a young adult population. METHODS: We genotyped the INSIG2 SNP rs7566605 in college-aged population enrolled in a controlled resistance-training program, (the Functional Polymorphism Associated with Human Muscle Size and Strength, FAMuSS cohort, n = 752 volunteers 18-40 yrs). In this longitudinal study, we examined the effect of the INSIG2 polymorphism on subcutaneous fat and muscle volumes of the upper arm measured by magnetic resonance imaging (MRI) before and after 12 wks of resistance training. Gene/phenotype associations were tested using an analysis of covariance model with age and weight as covariates. Further, the % variation in each phenotype attributable to genotype was determined using hierarchical models and tested with a likelihood ratio test. RESULTS: Women with a copy of the C allele had higher levels of baseline subcutaneous fat (GG: n = 139; 243473 +/- 5713 mm3 vs. GC/CC: n = 181; 268521 +/- 5003 mm3; p = 0.0011); but men did not show any such association. Men homozygous for the G ancestral allele showed a loss of subcutaneous fat, while those with one or two copies of the C allele gained a greater percentage of subcutaneous fat with resistance training (GG: n = 103; 1.02% +/- 1.74% vs. GC/CC: n = 93; 6.39% +/- 1.82%; p = 0.035). CONCLUSION: Our results show that the INSIG2 rs7566605 polymorphism underlies variation in subcutaneous adiposity in young adult women and suppresses the positive effects of resistance training on men. This supports and extends the original finding that there is an association between measures of obesity and INSIG2 rs7566605 and further implicates this polymorphism in fat regulation.

Interleukin-15 and interleukin-15R alpha SNPs and associations with muscle, bone, and predictors of the metabolic syndrome.

The aims of this study were to examine associations between two SNPs in the human IL-15 gene and three SNPs in the IL-15Ralpha gene with predictors of metabolic syndrome and phenotypes in muscle, strength, and bone at baseline and in response to resistance training (RT). Subjects were Caucasians who had not performed RT in the previous year and consisted of a strength cohort (n=748), volumetric cohort (n=722), and serum cohort (n=544). Subjects completed 12 weeks of unilateral RT of the non-dominant arm, using their dominant arm as an untrained control. ANCOVA analyses revealed gender-specific associations with: (1) IL-15 SNP (rs1589241) and cholesterol (p=0.04), LDL (p=0.02), the homeostasis model assessment (HOMA; p=0.03), and BMI (p=0.002); (2) IL-15 SNP (rs1057972) and the pre- to post-training absolute difference in 1RM strength (p=0.02), BMI (p=0.008), and fasting glucose (p=0.03); (3) IL-15Ralpha SNP (rs2296135) and baseline total bone volume (p=0.04) and the pre- to post-training absolute difference in isometric strength (p=0.01); and 4) IL-15Ralpha SNP (rs2228059) and serum triglycerides (p=0.04), baseline whole muscle volume (p=0.04), baseline cortical bone volume (p=0.04), and baseline muscle quality (p=0.04). All associations were consistent in showing a potential involvement of the IL-15 pathway with muscle and bone phenotypes and predictors of metabolic syndrome.

PPARalpha L162V underlies variation in serum triglycerides and subcutaneous fat volume in young males.

BACKGROUND: Of the five sub-phenotypes defining metabolic syndrome, all are known to have strong genetic components (typically 50-80% of population variation). Studies defining genetic predispositions have typically focused on older populations with metabolic syndrome and/or type 2 diabetes. We hypothesized that the study of younger populations would mitigate many confounding variables, and allow us to better define genetic predisposition loci for metabolic syndrome. METHODS: We studied 610 young adult volunteers (average age 24 yrs) for metabolic syndrome markers, and volumetric MRI of upper arm muscle, bone, and fat pre- and post-unilateral resistance training. RESULTS: We found the PPARalpha L162V polymorphism to be a strong determinant of serum triglyceride levels in young White males, where carriers of the V allele showed 78% increase in triglycerides relative to L homozygotes (LL = 116 +/- 11 mg/dL, LV = 208 +/- 30 mg/dL; p = 0.004). Men with the V allele showed lower HDL (LL = 42 +/- 1 mg/dL, LV = 34 +/- 2 mg/dL; p = 0.001), but women did not. Subcutaneous fat volume was higher in males carrying the V allele, however, exercise training increased fat volume of the untrained arm in V carriers, while LL genotypes significantly decreased in fat volume (LL = -1,707 +/- 21 mm3, LV = 17,617 +/- 58 mm3 ; p = 0.002), indicating a systemic effect of the V allele on adiposity after unilateral training. Our study suggests that the primary effect of PPARalpha L162V is on serum triglycerides, with downstream effects on adiposity and response to training. CONCLUSION: Our results on association of PPARalpha and triglycerides in males showed a much larger effect of the V allele than previously reported in older and less healthy populations. Specifically, we showed the V allele to increase triglycerides by 78% (p = 0.004), and this single polymorphism accounted for 3.8% of all variation in serum triglycerides in males (p = 0.0037).

Subcutaneous fat alterations resulting from an upper-body resistance training program.

PURPOSE: It is believed spot reduction, the exercise-induced localized loss of subcutaneous fat, does not occur as a result of an exercise program; however, evidence as a whole has been inconsistent. To reexamine this concept, we compared subcutaneous fat measurements before and after resistance training among 104 subjects (45 men, 59 women). METHODS: Subjects participated in 12 wk of supervised resistance training of their nondominant arm. Magnetic resonance imaging and skinfold calipers examined subcutaneous fat in the nondominant (trained) and dominant (untrained) arms before and after resistance training. Repeated-measures ANCOVA tested for subcutaneous fat differences within and between arms before, after, and from before to after resistance training by gender and measurement technique, with BMI and age as covariates. Simple linear regression compared subcutaneous fat changes before and after resistance training as assessed by MRI and skinfold. RESULTS: Subcutaneous fat, measured by skinfold, decreased in the trained arm and not the untrained arm in the men (P < 0.01); it was similar in the total sample and in the women (P > 0.05). MRI determinations of subcutaneous fat changes were not different between arms in the total sample and by gender (P > 0.05). CONCLUSION: Subcutaneous fat changes resulting from resistance training varied by gender and assessment technique. Skinfold findings indicate that spot reduction occurred in men but not in women. In contrast, MRI found a generalized subcutaneous fat loss independent of gender, supporting the notion that spot reduction does not occur as a result of resistance training. MRI, sensitive to changes along the entire upper arm, detected greater variation in resistance training responses, preventing significant differences between trained and untrained arms. Variation in upper-arm resistance training response was not evident from a single skinfold measurement at the belly of the muscle.

Comparison of Concussion Rates Between NCAA Division I and Division III Men's and Women's Ice Hockey Players.

BACKGROUND: Examinations related to divisional differences in the incidence of sports-related concussions (SRC) in collegiate ice hockey are limited. PURPOSE: To compare the epidemiologic patterns of concussion in National Collegiate Athletic Association (NCAA) ice hockey by sex and division. STUDY DESIGN: Descriptive epidemiology study. METHODS: A convenience sample of men's and women's ice hockey teams in Divisions I and III provided SRC data via the NCAA Injury Surveillance Program during the 2009-2010 to 2014-2015 academic years. Concussion counts, rates, and distributions were examined by factors including injury activity and position. Injury rate ratios (IRRs) and injury proportion ratios (IPRs) with 95% confidence intervals (CIs) were used to compare concussion rates and distributions, respectively. RESULTS: Overall, 415 concussions were reported for men's and women's ice hockey combined. The highest concussion rate was found in Division I men (0.83 per 1000 athlete-exposures [AEs]), followed by Division III women (0.78/1000 AEs), Division I women (0.65/1000 AEs), and Division III men (0.64/1000 AEs). However, the only significant IRR was that the concussion rate was higher in Division I men than Division III men (IRR = 1.29; 95% CI, 1.02-1.65). The proportion of concussions from checking was higher in men than women (28.5% vs 9.4%; IPR = 3.02; 95% CI, 1.63-5.59); however, this proportion was higher in Division I women than Division III women (18.4% vs 1.8%; IPR = 10.47; 95% CI, 1.37-79.75). The proportion of concussions sustained by goalkeepers was higher in women than men (14.2% vs 2.9%; IPR = 4.86; 95% CI, 2.19-10.77), with findings consistent within each division. CONCLUSION: Concussion rates did not vary by sex but differed by division among men. Checking-related concussions were less common in women than men overall but more common in Division I women than Division III women. Findings highlight the need to better understand the reasons underlying divisional differences within men's and women's ice hockey and the need to develop concussion prevention strategies specific to each athlete population.

ACE ID genotype and the muscle strength and size response to unilateral resistance training.

PURPOSE: To examine associations among the angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism and the response to a 12-wk (2 d.wk) unilateral, upper-arm resistance training (RT) program in the trained (T, nondominant) and untrained (UT, dominant) arms. METHODS: Subjects were 631 (mean+/-SEM, 24.2+/-0.2 yr) white (80%) men (42%) and women (58%). The ACE ID genotype was in Hardy-Weinberg equilibrium with frequencies of 23.1, 46.1, and 30.8% for ACE II, ID, and DD, respectively (chi=1.688, P=0.430). Maximum voluntary contraction (MVC) and one-repetition maximum (1RM) assessed peak elbow flexor muscle strength. Magnetic resonance imaging measured biceps muscle cross-sectional area (CSA). Multiple variable and repeated-measures ANCOVA tested whether muscle strength and size differed at baseline and pre- to post-RT among T and UT and ACE ID genotype. RESULTS: Baseline muscle strength and size were greater in UT than T (P<0.001) and did not differ among ACE ID genotype in either arm (P >or= 0.05). In T, MVC increases were greater for ACE II/ID (22%) than DD (17%) (P<0.05), whereas 1RM (51%) and CSA (19%) gains were not different among ACE ID genotype pre- to post-RT (P >or= 0.05). In UT, MVC increased among ACE II/ID (7%) (P<0.001) but was similar among ACE DD (2%) pre- to post-RT (P >or= 0.05). In UT, 1RM (11%) and CSA (2%) increases were greater for ACE DD/ID than ACE II (1RM, 7%; CSA, -0.1%) (P<0.05). ACE ID genotype explained approximately 1% of the MVC response to RT in T and approximately 2% of MVC, 2% of 1RM, and 4% of CSA response in UT (P<0.05). CONCLUSION: ACE ID genotype is associated with the contralateral effects of unilateral RT, perhaps more so than with the muscle strength and size adaptations that result from RT.

Low Muscle Strength Thresholds for the Detection of Cardiometabolic Risk in Adolescents.

INTRODUCTION: There is an association between strength and health among adolescents, yet, what remains to be determined is sex-specific cut points for low strength in the detection of risk in this population. The purpose of this study was to determine thresholds of low grip strength in a large cohort (N=1,326) of adolescents. METHODS: All data were collected between 2005 and 2008, and analyzed in 2014-2015. A cardiometabolic risk score (MetScore) was computed from the following components: percent body fat, fasting glucose, blood pressure, plasma triglyceride levels, and high-density lipoprotein cholesterol. A high-risk cardiometabolic phenotype was characterized as ≥75th percentile of the MetScore. Conditional inference tree analyses were used to identify sex-specific, low normalized strength (grip strength/body mass) thresholds and risk categories. RESULTS: Lower strength was independently associated with increased odds of the high-risk cardiometabolic phenotype, such that for every 5% decrement of normalized strength, there were 1.48 and 1.45 increased odds (p<0.001) for boys and girls, even after adjusting for cardiorespiratory fitness and physical activity. Conditional tree analysis revealed a high-risk threshold for boys (≤0.33) and girls (≤0.28), as well as an intermediate threshold (boys, >0.33 and ≤0.45; girls, >0.28 and ≤0.36). CONCLUSIONS: These sex-specific thresholds of low strength can be incorporated into a clinical setting for identifying adolescents that would benefit from lifestyle interventions to improve muscular fitness and reduce cardiometabolic risk.

Glucocorticoid Receptor (NR3C1) Variants Associate with the Muscle Strength and Size Response to Resistance Training.

Glucocorticoid receptor (NR3C1) polymorphisms associate with obesity, muscle strength, and cortisol sensitivity. We examined associations among four NR3C1 polymorphisms and the muscle response to resistance training (RT). European-American adults (n = 602, 23.8±0.4yr) completed a 12 week unilateral arm RT program. Maximum voluntary contraction (MVC) assessed isometric strength (kg) and MRI assessed biceps size (cm2) pre- and post-resistance training. Subjects were genotyped for NR3C1 -2722G>A, -1887G>A, -1017T>C, and +363A>G. Men carrying the -2722G allele gained less relative MVC (17.3±1.2vs33.5±6.1%) (p = 0.010) than AA homozygotes; men with -1887GG gained greater relative MVC than A allele carriers (19.6±1.4vs13.2±2.3%) (p = 0.016). Women carrying the -1017T allele gained greater relative size (18.7±0.5vs16.1±0.9%) (p = 0.016) than CC homozygotes. We found sex-specific NR3C1 associations with the muscle strength and size response to RT. Future studies should investigate whether these associations are partially explained by cortisol's actions in muscle tissue as they interact with sex differences in cortisol production.

ACTN3 genotype is associated with increases in muscle strength in response to resistance training in women.

The alpha-actinin 3 (ACTN3) gene encodes a protein of the Z disk of myofibers, and a polymorphism of ACTN3 results in complete loss of the protein. The ACTN3 genotype (R577X) has been found to be associated with performance in Australian elite athletes (Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, Easteal S, and North K. Am J Hum Genet 73: 627-631, 2003). We studied associations between ACTN3 genotype and muscle size [cross-sectional area of the biceps brachii via magnetic resonance imaging (MRI)] and elbow flexor isometric (MVC) and dynamic [1-repetition maximum (1-RM)] strength in a large group of men (N = 247) and women (N = 355) enrolled in a 12-wk standardized elbow flexor/extensor resistance training program of the nondominant arm at one of eight study centers. We found no association between ACTN3 R577X genotype and muscle phenotype in men. However, women homozygous for the ACTN3 577X allele (XX) had lower baseline MVC compared with heterozygotes (P < 0.05) when adjusted for body mass and age. Women homozygous for the mutant allele (577X) demonstrated greater absolute and relative 1-RM gains compared with the homozygous wild type (RR) after resistance training when adjusted for body mass and age (P < 0.05). There was a trend for a dose-response with genotype such that gains were greatest for XX and least for RR. Significant associations were validated in at least one ethnic subpopulation (Caucasians, Asians) and were independent of training volume. About 2% of baseline MVC and of 1-RM strength gain after training were attributable to ACTN3 genotype (likelihood-ratio test P value, P = 0.01), suggesting that ACTN3 is one of many genes contributing to genetic variation in muscle performance and adaptation to exercise.

Variability in muscle size and strength gain after unilateral resistance training.

PURPOSE: This study assessed variability in muscle size and strength changes in a large cohort of men and women after a unilateral resistance training program in the elbow flexors. A secondary purpose was to assess sex differences in size and strength changes after training. METHODS: Five hundred eighty-five subjects (342 women, 243 men) were tested at one of eight study centers. Isometric (MVC) and dynamic strength (one-repetition maximum (1RM)) of the elbow flexor muscles of each arm and magnetic resonance imaging (MRI) of the biceps brachii (to determine cross-sectional area (CSA)) were assessed before and after 12 wk of progressive dynamic resistance training of the nondominant arm. RESULTS: Size changes ranged from -2 to +59% (-0.4 to +13.6 cm), 1RM strength gains ranged from 0 to +250% (0 to +10.2 kg), and MVC changes ranged from -32 to +149% (-15.9 to +52.6 kg). Coefficients of variation were 0.48 and 0.51 for changes in CSA (P = 0.44), 1.07 and 0.89 for changes in MVC (P < 0.01), and 0.55 and 0.59 for changes in CSA (P < 0.01) in men and women, respectively. Men experienced 2.5% greater gains for CSA (P < 0.01) compared with women. Despite greater absolute gains in men, relative increases in strength measures were greater in women versus men (P < 0.05). CONCLUSION: Men and women exhibit wide ranges of response to resistance training, with some subjects showing little to no gain, and others showing profound changes, increasing size by over 10 cm and doubling their strength. Men had only a slight advantage in relative size gains compared with women, whereas women outpaced men considerably in relative gains in strength.

Obesity-Related Genetic Variants and their Associations with Physical Activity.

BACKGROUND: Meta-analysis of genome-wide association studies identified obesity-related genetic variants. Due to the pleiotropic effects of related phenotypes, we tested six of these obesity-related genetic variants for their association with physical activity: fat mass and obesity-associated (FTO)(rs9939609)T>A, potassium channel tetramerization domain containing (KCTD15) (rs11084753)G>A, melanocortin receptor4 (MC4R)(rs17782313)T>C, neuronal growth regulator 1 (NEGR1)(rs2815752)A>G, SH2B adapter protein 1 (SH2B1)(rs7498665)A>G, and transmembrane protein18 (TMEM18)(rs6548238)C>T. METHOD: European-American women (n = 263) and men (n = 229) (23.5 ± 0.3 years, 24.6 ± 0.2 kg/m2) were genotyped and completed the Paffenbarger physical activity Questionnaire. Physical activity volume in metabolic energy equivalents [MET]-hour/week was derived from the summed time spent (hour/week) times the given MET value for vigorous, moderate, and light intensity physical activity, and sitting and sleeping, respectively. Multivariable adjusted [(age, sex, and body mass index (BMI)] linear regression tested associations among genotype (dominant/recessive model) and the log of physical activity volume. RESULT: MC4R (rs17782313)T>C explained 1.1 % (p = 0.02), TMEM18(rs6548238)C>T 1.2 % (p = 0.01), and SH2B1 (rs7498665)A>G 0.6 % (p = 0.08) of the variability in physical activity volume. Subjects with the MC4R C allele spent 3.5 % less MET-hour/week than those with the TT genotype (p = 0.02). Subjects with the TMEM18 T allele spent 4.1 % less MET-hour/week than those with the CC genotype (p = 0.01). Finally, subjects with the SH2B1 GG genotype spent 3.6 % less MET-hour/week than A allele carriers (p = 0.08). CONCLUSION: Our findings suggest a shared genetic influence among some obesity-related gene loci and physical activity phenotypes that should be explored further. Physical activity volume differences by genotype have public health importance equating to 11-13 lb weight difference annually.

Strength capacity and cardiometabolic risk clustering in adolescents.

OBJECTIVES: The purpose of this study was to determine the gender-specific independent association between muscular strength and cardiometabolic risk clustering in a large cohort (n = 1421) of children. METHODS: Principal component analysis was used to determine the pattern of risk clustering and to derive a continuous aggregate score (MetScore) from various cardiometabolic risk components: percent body fat (%BF), fasting glucose, blood pressure, plasma triglycerides levels, and HDL-cholesterol. Gender-stratified risk and MetScore were assessed by using general linear models and logistic regression for differences between strength tertiles, as well as independent associations with age, BMI, estimated cardiorespiratory fitness (CRF), physical activity, and muscular strength (normalized for body mass). RESULTS: In both boys (n = 670) and girls (n = 751), there were significant differences in cardiometabolic profiles across strength tertiles, such that stronger adolescents had lower overall risk. Age, BMI, cardiorespiratory fitness, physical activity participation, and strength were all individually correlated with multiple risk components, as well as the overall MetScore. However, in the adjusted model, only BMI (ß = 0.30), physical inactivity (ß = 0.30), and normalized strength capacity (ß = -1.5) emerged as significant (P < .05) predictors of MetScore. %BF was the strongest loading coefficient within the principal component analysis-derived MetScore outcome. CONCLUSIONS: Normalized strength is independently associated with lower cardiometabolic risk in boys and girls. Moreover, %BF was associated with all cardiometabolic risk factors and carried the strongest loading coefficient. These findings bolster the importance of early strength acquisition and healthy body composition in childhood.