Influence of promoter region variants of insulin-like growth factor pathway genes on the strength-training response of muscle phenotypes in older adults.

To examine the influence of insulin-like growth factor (IGF) pathway gene polymorphisms on muscle mass and strength responses to strength training (ST), we studied 128 White and Black men and women before and after a 10-wk single-leg knee extension ST program. One-repetition maximum strength, muscle volume (MV) via computed tomography, and muscle quality (MQ) were assessed at baseline and after 10 wk of ST. There was a significant combined IGF1 cytosine adenine (CA) repeat gene effect, which included both the IGF1 CA repeat main effect and IGF1 CA repeat x PPP3R1 insertion-deletion (I/D) gene x gene interaction effect, on the changes in strength (P < 0.01) and MQ (P < 0.05) with ST. There was a trend for a significant gene x gene interaction between IGF1 CA repeat and PPP3R1 I/D for changes in strength (P = 0.07) and MQ (P = 0.06) with ST. The influence of the PPP3R1 A-202C gene polymorphism on change in MV with ST approached significance (P = 0.06). The IGF1 CA repeat polymorphism had a significant influence on the change in strength and MV combined with ST (P < 0.05), whereas the influence of the PPP3R1 I/D polymorphism approached significance (P = 0.08). There were no associations between the IGFBP3 A-202C gene polymorphism and the muscle phenotypic responses to ST. These data suggest that two of the three IGF pathway gene polymorphisms identified in this study influence muscle phenotypic responses to ST in both black and white older men and women.     

IGF-II gene region polymorphisms related to exertional muscle damage.

We examined the association of a novel single-nucleotide polymorphism (SNP) in IGF-I (IGF-I -C1245T located in the promoter) and eight SNPs in the IGF-II gene region with indicators of muscle damage [strength loss, muscle soreness, and increases in circulating levels of creatine kinase (CK) and myoglobin] after eccentric exercise. We also examined two SNPs in the IGF binding protein-3 (IGFBP-3). The age, height, and body mass of the 151 subjects studied were 24.1 +/- 5.2 yr, 170.8 +/- 9.9 cm, and 73.3 +/- 17.0 kg, respectively. There were no significant associations of phenotypes with IGF-I. IGF-II SNP (G12655A, rs3213216) and IGFBP-3 SNP (A8618T, rs6670) were not significantly associated with any variable. The most significant finding in this study was that for men, IGF-II (C13790G, rs3213221), IGF-II (ApaI, G17200A, rs680), IGF-II antisense (IGF2AS) (G11711T, rs7924316), and IGFBP-3 (-C1592A, rs2132570) were significantly associated with muscle damage indicators. We found that men who were 1) homozygous for the rare IGF-II C13790G allele and rare allele for the ApaI (G17200A) SNP demonstrated the greatest strength loss immediately after exercise, greatest soreness, and highest postexercise serum CK activity; 2) homozygous wild type for IGF2AS (G11711T, rs7924316) had the greatest strength loss and most muscle soreness; and 3) homozygous wild type for the IGF2AS G11711T SNP showed the greatest strength loss, highest muscle soreness, and greater CK and myoglobin response to exercise. In women, fewer significant associations appeared.     

Polymorphisms in the CNTF and CNTF receptor genes are associated with muscle strength in men and women.

Genotypic associations between polymorphisms in the ciliary neurotrophic factor (CNTF) and CNTF receptor (CNTFR) genes and muscular strength phenotypes in 154 middle-aged men (45-49 yr) and 138 women (38-44 yr) and 99 older men (60-78 yr) and 102 older women (60-80 yr) were tested to validate earlier association studies. Allelic interaction effects were hypothesized between alleles of CNTF and CNTFR. We performed analysis of covariance with age, height, and fat-free mass (FFM) as covariates. FFM was anthropometrically estimated by the equation of Durnin-Womersley. Isometric, concentric, and eccentric torques for the knee flexors (KF) and extensors (KE) were measured using Biodex dynamometry. In the older male group, T-allele carriers of the C-1703T polymorphism in CNTFR performed significantly better on all noncorrected KF torques, whereas only noncorrected KE isometric torque at 120 degrees and concentric torque at 240 degrees/s were higher than the C/C homozygotes (P < 0.05). When age, height, and FFM were used as covariates, T-allele carriers performed only better on KE and KF isometric torque at 120 degrees (P < 0.05). Concentric KF torque at 180 degrees/s was lower in middle-aged female A-allele carriers compared with the T/T subjects for the T1069A polymorphism in CNTFR. After correction for age, height, and FFM, middle-aged female A-allele carriers exhibited lower values on all concentric KF strength measures and isometric torque at 120 degrees . There was a lack of association with the CNTF G-6A polymorphism in men, with inconclusive results for a limited number of phenotypes in women. No significant CNTF/CNTFR allele interaction effects were found. Results indicate that CNTFR C-1703T and T1069A polymorphisms are significantly associated with muscle strength in humans.     

Evidence of LPL gene-exercise interaction for body fat and LPL activity: the HERITAGE Family Study.

Evidence of a gene-exercise interaction for traits related to body composition is limited. Here, the association between the lipoprotein lipase (LPL) S447X polymorphism and changes in body mass index, fat mass, percent body fat, abdominal visceral fat measured by computed tomography, and post-heparin plasma LPL activity in response to 20 wk of endurance training was investigated in 741 adult white and black subjects. Changes were compared between carriers and noncarriers of the X447 allele after adjustment for the effects of age and pretraining values. No evidence of association was observed in men. However, white women carrying the X447 allele exhibited greater reductions of body mass index (P = 0.01), fat mass (P = 0.01), and percent body fat (P = 0.03); in black women, the carriers exhibited a greater reduction of abdominal visceral fat (P = 0.05) and a greater increase in post-heparin LPL activity (P = 0.02). These results suggest that the LPL S447X polymorphism influences the training-induced changes in body fat and post-heparin LPL activity in women but not in men.     

Muscle quality. II. Effects of strength training in 65-to 75-yr-old men and women

To determine theeffects of strength training (ST) on muscle quality (MQ,strength/muscle volume of the trained muscle group), 12 healthy oldermen (69 ± 3 yr, range 65-75 yr) and 11 healthy older women (68 ± 3 yr, range 65-73 yr) were studied before and after aunilateral leg ST program. After a warm-up set, four sets ofheavy-resistance knee extensor ST exercise were performed 3 days/wk for9 wk on the Keiser K-300 leg extension machine. The men exhibitedgreater absolute increases in the knee extension one-repetition maximum(1-RM) strength test (75 ± 2 and 94 ± 3 kg before andafter training, respectively) and in quadriceps muscle volume measuredby magnetic resonance imaging (1,753 ± 44 and 1,955 ± 43 cm³) than the women (42 ± 2 and 55 ± 3 kg for the 1-RM test and 1,125 ± 53 vs.1,261 ± 65 cm³ forquadriceps muscle volume before and after training, respectively, inwomen; both P < 0.05). However,percent increases were similar for men and women in the 1-RM test (27 and 29% for men and women, respectively), muscle volume (12% forboth), and MQ (14 and 16% for men and women, respectively).Significant increases in MQ were observed in both groups in the trainedleg (both P < 0.05) and in the 1-RMtest for the untrained leg (both P < 0.05), but no significant differences were observed between groups,suggesting neuromuscular adaptations in both gender groups. Thus,although older men appear to have a greater capacity for absolutestrength and muscle mass gains than older women in response to ST, the relative contribution of neuromuscular and hypertrophic factors to theincrease in strength appears to be similar between genders.

     

Muscle size and strength are increased following walk training with restricted venous blood flow from the leg muscle, Kaatsu-walk training.

Previous studies have shown that low-intensity resistance training with restricted muscular venous blood flow (Kaatsu) causes muscle hypertrophy and strength gain. To investigate the effects of daily physical activity combined with Kaatsu, we examined the acute and chronic effects of walk training with and without Kaatsu on MRI-measured muscle size and maximum dynamic (one repetition maximum) and isometric strength, along with blood hormonal parameters. Nine men performed Kaatsu-walk training, and nine men performed walk training alone (control-walk). Training was conducted two times a day, 6 days/wk, for 3 wk using five sets of 2-min bouts (treadmill speed at 50 m/min), with a 1-min rest between bouts. Mean oxygen uptake during Kaatsu-walk and control-walk exercise was 19.5 (SD 3.6) and 17.2 % (SD 3.1) of treadmill-determined maximum oxygen uptake, respectively. Serum growth hormone was elevated (P < 0.01) after acute Kaatsu-walk exercise but not in control-walk exercise. MRI-measured thigh muscle cross-sectional area and muscle volume increased by 4-7%, and one repetition maximum and maximum isometric strength increased by 8-10% in the Kaatsu-walk group. There was no change in muscle size and dynamic and isometric strength in the control-walk group. Indicators of muscle damage (creatine kinase and myoglobin) and resting anabolic hormones did not change in both groups. The results suggest that the combination of leg muscle blood flow restriction with slow-walk training induces muscle hypertrophy and strength gain, despite the minimal level of exercise intensity. Kaatsu-walk training may be a potentially useful method for promoting muscle hypertrophy, covering a wide range of the population, including the frail and elderly.     

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.     

Training-induced changes in muscle CSA, muscle strength, EMG, and rate of force development in elderly subjects after long-term unilateral disuse.

The ability to develop muscle force rapidly may be a very important factor to prevent a fall and to perform other tasks of daily life. However, information is still lacking on the range of training-induced neuromuscular adaptations in elderly humans recovering from a period of disuse. Therefore, the present study examined the effect of three types of training regimes after unilateral prolonged disuse and subsequent hip-replacement surgery on maximal muscle strength, rapid muscle force [rate of force development (RFD)], muscle activation, and muscle size. Thirty-six subjects (60-86 yr) were randomized to a 12-wk rehabilitation program consisting of either 1) strength training (3 times/wk for 12 wk), 2) electrical muscle stimulation (1 h/day for 12 wk), or 3) standard rehabilitation (1 h/day for 12 wk). The nonoperated side did not receive any intervention and thereby served as a within-subject control. Thirty subjects completed the trial. In the strength-training group, significant increases were observed in maximal isometric muscle strength (24%, P < 0.01), contractile RFD (26-45%, P < 0.05), and contractile impulse (27-32%, P < 0.05). No significant changes were seen in the two other training groups or in the nontrained legs of all three groups. Mean electromyogram signal amplitude of vastus lateralis was larger in the strength-training than in the standard-rehabilitation group at 5 and 12 wk (P < 0.05). In contrast to traditional physiotherapy and electrical stimulation, strength training increased muscle mass, maximal isometric strength, RFD, and muscle activation in elderly men and women recovering from long-term muscle disuse and subsequent hip surgery. The improvement in both muscle mass and neural function is likely to have important functional implications for elderly individuals.     

NADPH oxidase p22phox gene variants are associated with systemic oxidative stress biomarker responses to exercise training.

Systemic oxidative stress plays a role in many degenerative diseases. Although regular physical activity has been known as the most effective nonpharmacological intervention to alleviate the oxidative stress, the beneficial effect varies between individuals. We investigated whether NADPH oxidase p22phox gene C242T and A640G polymorphisms are associated with systemic oxidative stress level response to exercise training (ExTr). Fifty-nine sedentary middle-aged to older Caucasians with relatively high cardiovascular disease risk factors underwent a 6-mo standardized ExTr program. Body mass index, plasma lipoprotein-lipid profiles, cardiovascular fitness, and plasma thiobarbituric acid reactive substances (TBARS) were measured before and after ExTr. Demographic and initial levels of cardiovascular disease risk factors were similar among genotype groups for both polymorphisms. Overall, TBARS was decreased by 16% with ExTr in the entire group (P < 0.001). There was no significant difference in TBARS changes with ExTr among the C242T genotype groups. However, A allele carriers showed greater reduction in TBARS than noncarriers at the A640G locus (P = 0.05). There was a significant interaction (P = 0.05) between ExTr and A640G polymorphism in TBARS changes with ExTr. This interaction remained after accounting for age and baseline TBARS level. Furthermore, diplotype analysis showed that TBARS was decreased to a greater extent in the C242/A640 haplotype carriers compared with the noncarriers (P < 0.05). We found that p22phox polymorphisms, especially A640G, were associated with differential changes in systemic oxidative stress with aerobic exercise training.     

Ultrastructural muscle damage in young vs. older men after high-volume, heavy-resistance strength training.

This study assessed ultrastructural muscle damage in young (20-30 yr old) vs. older (65-75 yr old) men after heavy-resistance strength training (HRST). Seven young and eight older subjects completed 9 wk of unilateral leg extension HRST. Five sets of 5-20 repetitions were performed 3 days/wk with variable resistance designed to subject the muscle to near-maximal loads during every repetition. Biopsies were taken from the vastus lateralis of both legs, and muscle damage was quantified via electron microscopy. Training resulted in a 27% strength increase in both groups (P < 0.05). In biopsies before training in the trained leg and in all biopsies from untrained leg, 0-3% of muscle fibers exhibited muscle damage in both groups (P = not significant). After HRST, 7 and 6% of fibers in the trained leg exhibited damage in the young and older men, respectively (P < 0.05, no significant group differences). Myofibrillar damage was primarily focal, confined to one to two sarcomeres. Young and older men appear to exhibit similar levels of muscle damage at baseline and after chronic HRST.     

Relations of APOE promoter polymorphisms to LDL cholesterol and markers of subclinical atherosclerosis in young adults

The common apolipoprotein E (apoE) gene (APOE) epsilon2/epsilon3/epsilon4 polymorphism explains part of serum lipid variation, and polymorphisms in the APOE promoter region have been proposed to participate in the regulation of serum lipid levels within the most common APOE epsilon3/epsilon3 genotype group. We determined APOE -219G/T and +113G/C promoter genotypes and estimated APOE haplotypes in 525 participants of the Cardiovascular Risk in Young Finns Study. We studied the associations of the APOE promoter polymorphisms and their haplotypes with cross-sectional and longitudinal serum lipid and apolipoprotein concentrations as well as with flow-mediated dilatation (FMD), carotid artery compliance (CAC), and intima-media thickness (IMT) within the APOE epsilon3/epsilon3 carriers. We found no significant association between the APOE promoter genotypes and serum lipids [low density lipoprotein-cholesterol (LDL-C), HDL-C, and triglycerides], apolipoproteins (apoA-I and apoB), or brachial artery FMD, CAC, or carotid IMT in either men or women. In longitudinal analyses in males, the carriers of heterozygous genotypes (-219G/T or +113G/C) and, furthermore, carriers of the -219T/+113C/epsilon3 haplotype had significantly higher LDL-C and total cholesterol concentrations throughout the 21 year follow-up period compared with homozygous G allele carriers or noncarriers of the -219T/+113C/epsilon3 haplotype. Such associations were not found in females. In summary, the APOE promoter polymorphisms -219G/T and +113G/C as well as their haplotype are associated with longitudinal changes in LDL-C and total cholesterol concentrations in young Finnish males but do not seem to be major determinants for FMD, CAC, or carotid IMT in males or females.     

DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease.

A common polymorphism at codon 192 in the human paraoxonase (PON) 1 gene has been shown to be associated with increased risk for coronary heart disease (CHD) in Caucasian populations. However, these findings have not been reported consistently in all Caucasian and non-Caucasian populations, suggesting that this is not a functional mutation but may mark a functional mutation present in either PON1 or a nearby gene. Recently, two other PON-like genes, designated "PON2" and "PON3," have been identified, and they are linked with the known PON1 gene on chromosome 7. Identification of additional polymorphisms in the PON-gene cluster may help to locate the functional polymorphism. In this report, we describe the existence of a common polymorphism at codon 311 (Cys-->Ser; PON2*S) in the PON2 gene, as well as its association with CHD alone and in combination with the PON1 codon 192 polymorphism in Asian Indians. The frequency of the PON2*S allele was significantly higher in cases than in controls (.71 vs. .61; P=.016). The age- and sex-adjusted odds ratio (OR) was 2.5 (95% confidence interval &sqbl0;95% CI&sqbr0;=1.8-3.1; P=.0090) for the PON2*S allele carriers. Further stratification of the PON2*S association, on the basis of the presence or absence of the PON1*B allele, showed that the CHD risk associated with the PON2*S allele was confined to PON1*B-allele carriers. Likewise, the PON1*B-allele risk was present only among PON2*S carriers. Age- and sex-adjusted ORs for the PON2*S and PON1*B were 3.6 (95% CI=2.6-4.6; P=.011) and 2.9 (95% CI=2.4-3.5; P=.0002) among the PON1*B and PON2*S carriers, respectively. Our data indicate that both polymorphisms synergistically contribute to the CHD risk in this sample and that this genetic risk is independent of the conventional plasma lipid profile.     

Selective muscle hypertrophy, changes in EMG and force, and serum hormones during strength training in older women.

Effects of strength training (ST) for 21 wk were examined in 10 older women (64 +/- 3 yr). Electromyogram, maximal isometric force, one-repetition maximum strength, and rate of force development of the leg extensors, muscle cross-sectional area (CSA) of the quadriceps femoris (QF) and of vastus lateralis (VL), medialis (VM), intermedius (VI) and rectus femoris (RF) throughout the lengths of 3/12--12/15 (Lf) of the femur, muscle fiber proportion and areas of types I, IIa, and IIb of the VL were evaluated. Serum hormone concentrations of testosterone, growth hormone (GH), cortisol, and IGF-I were analyzed for the resting, preexercise, and postexercise conditions. After the 21-wk ST, maximal force increased by 37% (P < 0.001) and 1-RM by 29% (P < 0.001), accompanied by an increase (P < 0.01) in rate of force development. The integrated electromyograms of the vastus muscles increased (P < 0.05). The CSA of the total QF increased (P < 0.05) throughout the length of the femur by 5--9%. The increases were significant (P < 0.05) at 7/15--12/15 Lf for VL and at 3/15--8/15 Lf for VM, at 5/15--9/15 for VI and at 9/15 (P < 0.05) for RF. The fiber areas of type I (P < 0.05), IIa (P < 0.001), and IIb (P < 0.001) increased by 22--36%. No changes occurred during ST in serum basal concentrations of the hormones examined, but the level of testosterone correlated with the changes in the CSA of the QF (r = 0.64, P < 0.05). An acute increase of GH (P < 0.05), remaining elevated up to 30 min (P < 0.05) postloading, was observed only at posttraining. Both neural adaptations and the capacity of skeletal muscle to undergo training-induced hypertrophy even in older women explain the strength gains. The increases in the CSA of the QF occurred throughout its length but differed selectively between the individual muscles. The serum concentrations of hormones remained unaltered, but a low level of testosterone may be a limiting factor in training-induced muscle hypertrophy. The magnitude and time duration of the acute GH response may be important physiological indicators of anabolic adaptations during strength training even in older women.     

Differential effects of strength training leading to failure versus not to failure on hormonal responses, strength, and muscle power gains.

The purpose of this study was to examine the efficacy of 11 wk of resistance training to failure vs. nonfailure, followed by an identical 5-wk peaking period of maximal strength and power training for both groups as well as to examine the underlying physiological changes in basal circulating anabolic and catabolic hormones. Forty-two physically active men were matched and then randomly assigned to either a training to failure (RF; n = 14), nonfailure (NRF; n = 15), or control groups (C; n = 13). Muscular and power testing and blood draws to determine basal hormonal concentrations were conducted before the initiation of training (T0), after 6 wk of training (T1), after 11 wk of training (T2), and after 16 wk of training (T3). Both RF and NRF resulted in similar gains in 1-repetition maximum bench press (23 and 23%) and parallel squat (22 and 23%), muscle power output of the arm (27 and 28%) and leg extensor muscles (26 and 29%), and maximal number of repetitions performed during parallel squat (66 and 69%). RF group experienced larger gains in the maximal number of repetitions performed during the bench press. The peaking phase (T2 to T3) after NRF resulted in larger gains in muscle power output of the lower extremities, whereas after RF it resulted in larger gains in the maximal number of repetitions performed during the bench press. Strength training leading to RF resulted in reductions in resting concentrations of IGF-1 and elevations in IGFBP-3, whereas NRF resulted in reduced resting cortisol concentrations and an elevation in resting serum total testosterone concentration. This investigation demonstrated a potential beneficial stimulus of NRF for improving strength and power, especially during the subsequent peaking training period, whereas performing sets to failure resulted in greater gains in local muscular endurance. Elevation in IGFBP-3 after resistance training may have been compensatory to accommodate the reduction in IGF-1 to preserve IGF availability.     

Physical capacity influences the response of insulin-like growth factor and its binding proteins to training.

The influence of initial training status on the response of circulating insulin-like growth factor (IGF) and its binding proteins (IGFBP) to prolonged physical training was studied in young men. It was hypothesized that highly standardized training would result in more extensive changes in the circulating IGF system in untrained subjects because of lower fitness level. Seven untrained (UT) and 12 well-trained (WT) individuals performed 11 wk of intense physical training (2-4 h daily). Fasting serum samples were analyzed for total and free IGF-I and -II, for IGFBP-1 to -4, as well as for IGFBP-3 proteolysis. Eleven weeks of physical training resulted in decreased levels of total IGF-I, free IGF-I, and IGFBP-4 in both the UT and WT groups. In the UT group, IGFBP-2 increased, IGFBP-3 decreased [from 4,255 +/- 410 (baseline) to 3,896 +/- 465 (SD) microg/l (week 4); P < 0.05], and IGFBP-3 proteolysis increased [from 28 +/- 8% (baseline) to 37 +/- 7% (week 4) and 39 +/- 12% (week 11); P < 0.05], whereas no significant changes were found in the WT group. In conclusion, intense physical training results in a marked influence on the IGF system and its binding proteins with generally more extensive changes seen in the untrained individuals. Also, prolonged physical training resulted in increased IGFBP-3 proteolysis in previously untrained individuals only, indicating that intense physical training affects trained and untrained individuals differently.     

Do PTK2 gene polymorphisms contribute to the interindividual variability in muscle strength and the response to resistance training? A preliminary report

The protein tyrosine kinase-2 (PTK2) gene encodes focal adhesion kinase, a structural protein involved in lateral transmission of muscle fiber force. We investigated whether single-nucleotide polymorphisms (SNPs) of the PTK2 gene were associated with various indexes of human skeletal muscle strength and the interindividual variability in the strength responses to resistance training. We determined unilateral knee extension single repetition maximum (1-RM), maximum isometric voluntary contraction (MVC) knee joint torque, and quadriceps femoris muscle specific force (maximum force per unit physiological cross-sectional area) before and after 9 wk of knee extension resistance training in 51 untrained young men. All participants were genotyped for the PTK2 intronic rs7843014 A/C and 3'-untranslated region (UTR) rs7460 A/T SNPs. There were no genotype associations with baseline measures or posttraining changes in 1-RM or MVC. Although the training-induced increase in specific force was similar for all PTK2 genotypes, baseline specific force was higher in PTK2 rs7843014 AA and rs7460 TT homozygotes than in the respective rs7843014 C- (P = 0.016) and rs7460 A-allele (P = 0.009) carriers. These associations between muscle specific force and PTK2 SNPs suggest that interindividual differences exist in the way force is transmitted from the muscle fibers to the tendon. Therefore, our results demonstrate for the first time the impact of genetic variation on the intrinsic strength of human skeletal muscle.     

C174T polymorphism in the CNTF receptor gene is associated with fat-free mass in men and women.

We performed gene screening of the ciliary neurotrophic factor receptor (CNTFR) gene and genotyped three newly identified polymorphisms: C-1703T in the 5' promoter region, T1069A in intron 5, and C174T in exon 9. We studied the association of these CNTFR variants with muscle strength, mass, and body composition in 465 men and women (20-90 yr) from the Baltimore Longitudinal Study of Aging. Only the C174T variant was significantly associated with muscle-related phenotypes. In the entire cohort, when corrected for age, sex, race, physical activity, and height, homozygotes for the common C allele at C174T (CC) exhibited lower total body mass and body mass index than carriers of the rare T allele, which appeared to be due to significant differences in total nonosseous fat-free mass (FFM) (48.0 +/- 0.4 vs. 50.0 +/- 0.7 kg; P = 0.011) and lower limb FFM (16.5 +/- 0.1 vs. 17.2 +/- 0.2 kg; P = 0.002). The CC group also exhibited significantly lower quadriceps concentric and eccentric isokinetic strength values at both 30 and 180 degrees /s than the T allele carriers (all P < 0.04), but these differences were no longer significant after adjustment for lower limb FFM. There were no significant sex-by-genotype interactions. The results indicate that the C174T polymorphism in exon 9 of CNTFR is significantly associated with FFM in men and women, with concomitant differences in muscular strength.