Extracellular matrix remodeling and its contribution to protective adaptation following lengthening contractions in human muscle.

This study determined the contribution of extracellular matrix (ECM) remodeling to the protective adaptation of human skeletal muscle known as the repeated-bout effect (RBE). Muscle biopsies were obtained 3 hours, 2 days, and 27 days following an initial bout (B1) of lengthening contractions (LCs) and 2 days following a repeated bout (B2) in 2 separate studies. Biopsies from the nonexercised legs served as controls. In the first study, global transcriptomic analysis indicated widespread changes in ECM structural, deadhesive, and signaling transcripts, 3 hours following LC. To determine if ECM remodeling is involved in the RBE, we conducted a second study by use of a repeated-bout paradigm. TNC immunoreactivity increased 10.8-fold following B1, was attenuated following B2, and positively correlated with LC-induced strength loss (r(2) = 0.45; P = 0.009). Expression of collagen I, III, and IV (COL1A1, COL3A1, COL4A1) transcripts was unchanged early but increased 5.7 ± 2.5-, 3.2 ± 0.9-, and 2.1 ± 0.4-fold (P < 0.05), respectively, 27 days post-B1 and were unaffected by B2. Likewise, TGF-ß signaling demonstrated a delayed response following LC. Satellite cell content increased 80% (P < 0.05) 2 days post-B1 (P < 0.05), remained elevated 27 days post-B1, and was unaffected by B2. Collectively, the data suggest sequential ECM remodeling characterized by early deadhesion and delayed reconstructive activity that appear to contribute to the RBE.

Effect of statins on skeletal muscle function.

BACKGROUND: Many clinicians believe that statins cause muscle pain, but this has not been observed in clinical trials, and the effect of statins on muscle performance has not been carefully studied. METHODS AND RESULTS: The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study assessed symptoms and measured creatine kinase, exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo was administered for 6 months to 420 healthy, statin-naive subjects. No individual creatine kinase value exceeded 10 times normal, but average creatine kinase increased 20.8±141.1 U/L (P<0.0001) with atorvastatin. There were no significant changes in several measures of muscle strength or exercise capacity with atorvastatin, but more atorvastatin than placebo subjects developed myalgia (19 versus 10; P=0.05). Myalgic subjects on atorvastatin or placebo had decreased muscle strength in 5 of 14 and 4 of 14 variables, respectively (P=0.69). CONCLUSIONS: These results indicate that high-dose atorvastatin for 6 months does not decrease average muscle strength or exercise performance in healthy, previously untreated subjects. Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins increase muscle complaints. Atorvastatin also increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects. This increase in creatine kinase should prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular performance. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00609063.

NF-KB activity functions in primary pericytes in a cell- and non-cell-autonomous manner to affect myotube formation.

INTRODUCTION: Skeletal muscle regeneration following damage relies on proliferation and differentiation of muscle precursor cells (MPCs). We recently observed increased NF-kB activity in vascular-associated muscle resident pericytes following muscle damage in humans. We determined how altered NF-kB activity in human primary pericytes (HPPs) affects their myogenic differentiation (cell-autonomous effects), as well as proliferation and differentiation of co-cultured MPCs (non-cell-autonomous effects). METHODS: HPPs were transfected with vectors that increased or decreased NF-kB activity. Transfected HPPs were co-cultured with C2 C12 myoblasts under differentiation conditions, and HPP fusion to myotubes was measured. We also co-cultured HPPs with C2 C12 myoblasts and measured proliferation and myotube formation. RESULTS: Inhibition of NF-kB activity increased HPP fusion to C2 C12 myotubes. Moreover, enhanced NF-kB activity in HPPs suppressed differentiation and enhanced proliferation of co-cultured myoblasts. CONCLUSIONS: NF-kB activity acts cell-autonomously to inhibit HPP myogenic differentiation and non-cell-autonomously to promote MPC proliferation and suppress MPC differentiation in vitro.

Activation of nuclear factor-κB following muscle eccentric contractions in humans is localized primarily to skeletal muscle-residing pericytes.

Limited data exist on the molecular mechanisms that govern skeletal muscle regeneration in humans. This study characterized the early molecular alterations in humans to eccentric contractions (ECs), a stimulus known to induce a muscle regenerative response. Thirty-five subjects completed 100 ECs of the knee extensors with 1 leg, and muscle biopsies were taken from both legs 3 h post-EC. The sample from the non-EC leg served as the control. We first conducted a well-powered transcriptomic screen and network analysis. Our screen identified significant changes in several transcripts with functions relating to inflammation, cell growth, and proliferation. Network analysis then identified the transcription factor NF-κB as a key molecular element affected by ECs. A transcription factor ELISA, using nuclear extracts from EC and control muscle samples, showed a 1.6-fold increase in NF-κB DNA binding activity following ECs. Immunohistochemical experiments localized the majority of NF-κB-positive nuclei to cells in the interstitium, which stained positive for the pericyte markers NG2 proteoglycan and alkaline phosphatase. Our results provide the first evidence of NF-κB activation in human muscle following ECs and suggest a novel role for muscle residing pericytes in the early adaptive response to ECs.

Effects of quercetin supplementation on markers of muscle damage and inflammation after eccentric exercise.

The flavonoid quercetin is purported to have potent antioxidant and anti-inflammatory properties. This study examined if quercetin supplementation attenuates indicators of exercise-induced muscle damage in a double-blind laboratory study. Thirty healthy subjects were randomized to quercetin (QU) or placebo (PL) supplementation and performed 2 separate sessions of 24 eccentric contractions of the elbow flexors. Muscle strength, soreness, resting arm angle, upper arm swelling, serum creatine kinase (CK) activity, plasma quercetin (PQ), interleukin-6 (IL-6), and C-reactive protein (CRP) were assessed before and for 5 d after exercise. Subjects then ingested nutrition bars containing 1,000 mg/d QU or PL for 7 d before and 5 d after the second exercise session, using the opposite arm. PQ reached 202 ± 52 ng/ml after 7 d of supplementation and remained elevated during the 5-d postexercise recovery period (p < .05). Subjects experienced strength loss (peak = 47%), muscle soreness (peak = 39 ± 6 mm), reduced arm angle (-7° ± 1°), CK elevations (peak = 3,307 ± 1,481 U/L), and arm swelling (peak = 11 ± 2 mm; p < .0001), indicating muscle damage and inflammation; however, differences between treatments were not detected. Eccentric exercise did not alter plasma IL-6 (peak = 1.9 pg/ml) or CRP (peak = 1.6 mg/L) relative to baseline or by treatment. QU supplementation had no effect on markers of muscle damage or inflammation after eccentric exercise of the elbow flexors.

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.

Transcriptional deficits in oxidative phosphorylation with statin myopathy.

INTRODUCTION: Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, are widely used drugs for hyperlipidemia and are generally well-tolerated, but the can produce skeletal muscle toxicity. The molecular mechanisms driving statin myopathy are unknown. We investigated the effects of statin treatment and eccentric (damaging) exercise on transcriptional patterns between statin myopathy (Sym; N = 9) and statin-tolerant subjects (Asym; N = 6). METHODS: Skeletal muscle biopsies were collected 6 h post-exercise at baseline and after statin treatment. Subjects performed concentric (non-damaging) exercise with one leg and concentric + eccentric exercise with the other leg using a cross-over design between time-points. RESULTS: Sym as compared with Asym demonstrated decreased skeletal muscle gene expression for oxidative phosphorylation-related and mitochondrial ribosomal protein genes before and after statin treatment with eccentric exercise. CONCLUSIONS: These results suggest that pre-existing deficiencies in energy production may contribute to the development of symptoms during statin therapy, especially when muscle is exposed to eccentric exercise.

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%).

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.

Rhabdomyolysis in a collegiate football player.

Rhabdomyolysis is a serious, potentially life threatening condition that can develop unexpectedly under supervised training conditions. Here we present a case of exertional rhabdomyolysis occurring in a healthy, fit 18-year-old placekicker following a supervised practice session led by the team's strength and conditioning coach. The day after this session, the player experienced extreme pain and dark urine and sought treatment at a local emergency department. Hospitalization resulted in a diagnosis of rhabdomyolysis based on myoglobinuria, muscle pain, and extremely elevated circulating creatine kinase values (>130,000 IU x L(-1)). Following eight days of hospitalization with intravenous fluids, the patient recovered without complications. This case illustrates that rhabdomyolysis can occur after strenuous exercise in the absence of dehydration in otherwise conditioned and healthy athletes.

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.

Sex differences in response to maximal eccentric exercise.

PURPOSE: This study examined sex differences in strength loss, muscle soreness, and serum creatine kinase (CK) and myoglobin (Mb) after high-intensity eccentric exercise of the elbow flexors in a large group of men and women. METHODS: One hundred participants (58 women, 42 men) performed 50 maximal eccentric contractions of the elbow flexor muscles of their nondominant arm. Maximum isometric voluntary contraction (MVC) was recorded at baseline, immediately after exercise, and at 0.5 (12-14 h), 3, 4, 7, and 10 d after exercise. Blood samples for serum CK activity and Mb were taken at baseline and at 4, 7, and 10 d after exercise. Soreness was evaluated at baseline and at 0.5, 3, 4, 7, and 10 d after exercise. RESULTS: Women experienced significantly greater relative strength loss immediately after exercise (-57.8% +/- 19.1) than men (-50.4% +/- 16.9%) (independent t-test; P < or = 0.05), and a greater percentage of women experienced more than 70% strength loss immediately after exercise compared with men (34.4% of women; 7.1% of men). Men exhibited a larger CK response compared with women (ANCOVA; P < or = 0.05), partly because there were more men who were high responders. There were no significant differences between the sexes for serum Mb or soreness measures. Generally, stronger relationships among CK, soreness, and strength-loss measures were found in men compared with women (r = 0.55-0.59 for men; r = 0.12-0.49 for women). CONCLUSION: In response to eccentric exercise, women experienced greater immediate strength loss than men and were more likely to be high responders for immediate strength loss; men experienced greater serum CK activity than women and were more likely to be high responders for increased serum CK. Although the explanation for high responders to eccentric exercise remains unknown, we have shown that there are sex-specific differences in CK and strength-loss response after eccentric exercise.

Muscle function in men and women during maximal eccentric exercise.

This study assessed muscle fatigue patterns of the elbow flexors in untrained men and women to determine if sex differences exist during acute maximal eccentric exercise. High-intensity eccentric exercise is often used by athletes to elicit gains in muscle strength and size gains. Development of fatigue during this type of exercise can increase risk of injury; therefore, it is important to understand fatigue patterns during eccentric exercise to minimize injury risk exposure while still promoting training effects. While many isometric exercise studies have demonstrated that women show less fatigue, the patterns of fatigue during purely eccentric exercise have not been assessed in men and women. Based on the lack of sex differences in overall strength loss immediately post-eccentric exercise, it was hypothesized that women and men would have similar relative fatigue pattern responses (i.e., change from baseline) during a single bout of maximal eccentric exercise. Forty-six subjects (24 women and 22 men) completed 5 sets of 10 maximal eccentric contractions on an isokinetic dynamometer. Maximal voluntary isometric contraction strength was assessed at baseline and immediately following each exercise set. Maximal eccentric torque and contractile properties (i.e., contraction time, work, half relaxation time, and maximal rate of torque development) were calculated for each contraction. Men and women demonstrated similar relative isometric (32% for men and 39% for women) and eccentric (32% for men and 39% for women) fatigue as well as similar deficits in work done and rates of torque development and relaxation during exercise (p > 0.05). Untrained men and women displayed similar relative responses in all measures of muscle function during a single bout of maximal eccentric exercise of the elbow flexors. Thus, there is no reason to suspect that women may be more vulnerable to fatigue-related injury.

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).

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.

Exertional rhabdomyolysis and acute renal failure in marathon runners.

Strenuous exercise, including marathon running, can result in damage to skeletal muscle cells, a process known as exertional rhabdomyolysis. In most cases, this damage is resolved without consequence. However, when the damage is profound, there is a release of muscle proteins into the blood; one of these proteins, myoglobin, in high concentrations and under certain conditions (such as dehydration and heat stress) can precipitate in the kidneys, thereby resulting in acute renal failure. Although the marathon is a gruelling physiological challenge, with races sometimes run in hot and humid weather, acute renal failure is relatively infrequent. From case reports, a high proportion of marathon runners who developed acute renal failure had taken analgesics, had a viral or bacterial infection, or a pre-existing condition. The rare cases of acute renal failure in marathon runners may be a situation of the 'perfect storm' where there are several factors (heat stress, dehydration, latent myopathy, non-steroidal anti-inflammatory or other drug/analgesic use, and viral/bacterial infection) that, in some combination, come together to result in acute renal failure.