Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% for TBLH-BMD, and 39% for TB-LM, with a shared genetic component of 43%. We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: _WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5_. Variants in the _TOM1L2/SREBF1_ locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that _SREBF1_ is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass

A randomized controlled trial on the effectiveness of strength training on clinical and muscle cellular outcomes in patients with prostate cancer during androgen deprivation therapy: rationale and design

Background Studies indicate that strength training has beneficial effects on clinical health outcomes in prostate cancer patients during androgen deprivation therapy. However, randomized controlled trials are needed to scientifically determine the effectiveness of strength training on the muscle cell level. Furthermore, close examination of the feasibility of a high-load strength training program is warranted. The Physical Exercise and Prostate Cancer (PEPC) trial is designed to determine the effectiveness of strength training on clinical and muscle cellular outcomes in non-metastatic prostate cancer patients after high-dose radiotherapy and during ongoing androgen deprivation therapy. Methods/design Patients receiving androgen deprivation therapy for 9-36 months combined with external high-dose radiotherapy for locally advanced prostate cancer are randomized to an exercise intervention group that receives a 16 week high-load strength training program or a control group that is encouraged to maintain their habitual activity level. In both arms, androgen deprivation therapy is continued until the end of the intervention period. Clinical outcomes are body composition (lean body mass, bone mineral density and fat mass) measured by Dual-energy X-ray Absorptiometry, serological outcomes, physical functioning (muscle strength and cardio-respiratory fitness) assessed with physical tests and psycho-social functioning (mental health, fatigue and health-related quality of life) assessed by questionnaires. Muscle cellular outcomes are a) muscle fiber size b) regulators of muscle fiber size (number of myonuclei per muscle fiber, number of satellite cells per muscle fiber, number of satellite cells and myonuclei positive for androgen receptors and proteins involved in muscle protein degradation and muscle hypertrophy) and c) regulators of muscle fiber function such as proteins involved in cellular stress and mitochondrial function. Muscle cellular outcomes are measured on muscle cross sections and muscle homogenate from muscle biopsies obtained from muscle vastus lateralis. Discussion The findings from the PEPC trial will provide new knowledge on the effects of high-load strength training on clinical and muscle cellular outcomes in prostate cancer patients during androgen deprivation therapy. Trial registration ClinicalTrials.gov: NCT0065822

Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% for TBLH-BMD, and 39% for TB-LM, with a shared genetic component of 43%. We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: _WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5_. Variants in the _TOM1L2/SREBF1_ locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that _SREBF1_ is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass

Design of a randomized controlled trial of physical training and cancer (Phys-Can) – the impact of exercise intensity on cancer related fatigue, quality of life and disease outcome

Background: Cancer-related fatigue is a common problem in persons with cancer, influencing health-related quality of life and causing a considerable challenge to society. Current evidence supports the beneficial effects of physical exercise in reducing fatigue, but the results across studies are not consistent, especially in terms of exercise intensity. It is also unclear whether use of behaviour change techniques can further increase exercise adherence and maintain physical activity behaviour. This study will investigate whether exercise intensity affects fatigue and health related quality of life in persons undergoing adjuvant cancer treatment. In addition, to examine effects of exercise intensity on mood disturbance, adherence to oncological treatment, adverse effects from treatment, activities of daily living after treatment completion and return to work, and behaviour change techniques effect on exercise adherence. We will also investigate whether exercise intensity influences inflammatory markers and cytokines, and whether gene expressions following training serve as mediators for the effects of exercise on fatigue and health related quality of life. Methods/design: Six hundred newly diagnosed persons with breast, colorectal or prostate cancer undergoing adjuvant therapy will be randomized in a 2 × 2 factorial design to following conditions; A) individually tailored low-to-moderate intensity exercise with or without behaviour change techniques or B) individually tailored high intensity exercise with or without behaviour change techniques. The training consists of both resistance and endurance exercise sessions under the guidance of trained coaches. The primary outcomes, fatigue and health related quality of life, are measured by self-reports. Secondary outcomes include fitness, mood disturbance, adherence to the cancer treatment, adverse effects, return to activities of daily living after completed treatment, return to work as well as inflammatory markers, cytokines and gene expression. Discussion: The study will contribute to our understanding of the value of exercise and exercise intensity in reducing fatigue and improving health related quality of life and, potentially, clinical outcomes. The value of behaviour change techniques in terms of adherence to and maintenance of physical exercise behaviour in persons with cancer will be evaluated

Comparaison de deux protocoles d'entraînement de force par occlusion vasculaire (à l'épuisement versus sous-maximal) sur la réponse des protéines de stress

INTRODUCTION: The stress imposed to muscle fibers during blood flow restricted resistance exercise (BFRRE) is poorly investigated. Therefore, we aimed to compare the effect of a failure (FA) vs submaximal (SU) BFRRE protocol on heat-shock protein responses in the exercising muscles. METHODS: Sixteen untrained men (18-45 yrs) completed 14 BFRRE sessions divided into 2 blocks of 7 sessions in 5 days, interspersed by 10 days of rest. Legs were randomly assigned to either FA (4 sets to voluntary failure) or SU protocol (30-, 15-, 15-, 15 reps) using unilateral knee extensions at 20% of 1 repetition maximum with 30s rest between sets. BFRRE was conducted with partial blood flow restriction (100 mmHg) induced by a 15 cm wide pressure cuff. Biopsies from the m. vastus lateralis were collected before, during and post intervention. The HSP response investigated was changes in αB-crystallin staining intensity on muscle cross sections analyzed by immunofluorescence. RESULTS: Relative to pre-exercise, a significant increase in αB-crystallin staining intensity (reflecting cytoskeletal bound proteins) was observed 2h after the first session in both legs (129 ± 18%, p<0.001 and 77 ± 10%, p<0.05; FA and SU, respectively). There were no significant difference between protocols at any time point, but these changes tended to be larger in FA legs than SU legs. During the rest period and 10 days post intervention, αB-crystallin staining intensity gradually decreased to baseline values. CONCLUSION: The αB-crystallin immunostaining analyses suggest that cytoskeletal proteins are highly stressed after the first session of both FA and SU BFRRE protocols

Delayed leukocytosis after hard strength and endurance exercise: Aspects of regulatory mechanisms

Background During infections, polymorphonuclear neutrophilic granulocytes (PMN) are mobilized from their bone marrow stores, travel with blood to the affected tissue, and kill invading microbes there. The signal(s) from the inflammatory site to the marrow are unknown, even though a number of humoral factors that can mobilize PMN, are well known. We have employed a standardized, non-infectious human model to elucidate relevant PMN mobilizers. Well-trained athletes performed a 60-min strenuous strength workout of leg muscles. Blood samples were drawn before, during and just after exercise, and then repeatedly during the following day. Cortisol, GH, ACTH, complement factors, high-sensitive CRP (muCRP), IL-6, G-CSF, IL-8 (CXCL8) and MIP-1β (CCL4) were measured in blood samples. PMN chemotaxins in test plasma was assessed with a micropore membrane technique. Results About 5 hr after the workout, blood granulocytosis peaked to about 150% of baseline. Plasma levels of GH increased significantly 30 min into and 5 min after the exercise, but no increase was recorded for the other hormones. No significant correlation was found between concentrations of stress hormones and the subjects' later occurring PMN increases above their individual baselines. Plasma G-CSF increased significantly – but within the normal range – 65 min after the workout. IL-6 increased very slightly within the normal range, and the chemokines IL-8 and MIP-1β did not increase consistently. However, we found a significant increase of hitherto non-identified PMN-chemotactic activity in plasma 35, 50, and 60 min after the exercise. No systemic complement activation was detected, and (mu)CRP was within the reference range at rest, 5 h and 23 h after the exercise. After endurance exercise, similar findings were made, except for a cortisol response, especially from non-elite runners. Conclusion Apparently, a multitude of humoral factors can – directly or indirectly – mobilize PMN from marrow to blood; some of the factors are, others are not known to be, chemotactic. Under different conditions, different selections of these mobilizers may be used. In the late granulocytosis after heavy, long-lasting exercise a number of factors thought capable of mimicking the granulocytosis of infectious diseases were apparently irrelevant. © 2003 Risøy et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL

Functional and Structural Adaptations of Skeletal Muscle in Long-Term Juvenile Dermatomyositis; a Controlled Cross-Sectional Study

Objective To compare muscle strength and endurance of the knee extensors between patients with long‐term juvenile dermatomyositis (DM) and controls and between patients with active disease and those with inactive disease, and to explore associations between strength/endurance and 1) clinical parameters, 2) physical activity, and 3) humoral/structural adaptation in the skeletal muscle of patients. Methods In a cross‐sectional study (44 patients and 44 age‐ and sex‐matched controls), we tested isometric muscle strength (peak torque, in Nm) and dynamic muscle endurance (total work, in Joules) of the knee extensors, physical activity (measured by accelerometer), and serum myokine levels (by enzyme‐linked immunosorbent assay). Patients were examined with validated tools (clinical muscle tests and measures of disease activity/damage and inactive disease) and using magnetic resonance imaging of the thigh muscles, which included evaluation of the quadriceps cross‐sectional area (CSA). Needle biopsy samples of the vastus lateralis muscle (obtained from 12 patients ages ≥18 years) were assessed by histochemistry. Results After a mean ± SD disease duration of 21.8 ± 11.8 years, peak torque was lower in patients with juvenile DM compared to controls (mean difference 29 Nm, 95% confidence interval 13–46; P = 0.001). Similarly, total work of the knee extensors was lower in patients compared to controls (median 738J [interquartile range 565–1,155] versus 1,249J [interquartile range 815–1,665]; P < 0.001). Both peak torque and total work were lower in patients with active juvenile DM compared to those with inactive disease (both P < 0.019); in analyses controlled for quadriceps CSA, only total work remained lower in patients with active disease. Moreover, peak torque and total work correlated with findings from clinical muscle tests in patients with active disease (r = 0.57–0.84). Muscle biopsy results indicated that the fiber type composition was different, but capillary density was similar, between patients with active disease and those with inactive disease. Conclusion In patients with long‐term juvenile DM, both muscle strength and endurance of the knee extensors were lower when compared to matched controls, and also lower in patients with active disease compared to those with inactive disease. Our results indicate a need for more sensitive muscle tests in this clinical setting. We hypothesize that impaired muscle endurance in patients with active juvenile DM may be influenced by structural/functional adaptations of muscle tissue independent of muscle size

Functional and Structural Adaptations of Skeletal Muscle in Long-Term Juvenile Dermatomyositis: a Controlled Cross-Sectional Study

Objective: To compare muscle strength and endurance of the knee extensors between patients with long‐term juvenile dermatomyositis (DM) and controls and between patients with active disease and those with inactive disease, and to explore associations between strength/endurance and 1) clinical parameters, 2) physical activity, and 3) humoral/structural adaptation in the skeletal muscle of patients. Methods: In a cross‐sectional study (44 patients and 44 age‐ and sex‐matched controls), we tested isometric muscle strength (peak torque, in Nm) and dynamic muscle endurance (total work, in Joules) of the knee extensors, physical activity (measured by accelerometer), and serum myokine levels (by enzyme‐linked immunosorbent assay). Patients were examined with validated tools (clinical muscle tests and measures of disease activity/damage and inactive disease) and using magnetic resonance imaging of the thigh muscles, which included evaluation of the quadriceps cross‐sectional area (CSA). Needle biopsy samples of the vastus lateralis muscle (obtained from 12 patients ages ≥18 years) were assessed by histochemistry. Results: After a mean ± SD disease duration of 21.8 ± 11.8 years, peak torque was lower in patients with juvenile DM compared to controls (mean difference 29 Nm, 95% confidence interval 13–46; P = 0.001). Similarly, total work of the knee extensors was lower in patients compared to controls (median 738J [interquartile range 565–1,155] versus 1,249J [interquartile range 815–1,665]; P < 0.001). Both peak torque and total work were lower in patients with active juvenile DM compared to those with inactive disease (both P < 0.019); in analyses controlled for quadriceps CSA, only total work remained lower in patients with active disease. Moreover, peak torque and total work correlated with findings from clinical muscle tests in patients with active disease (r = 0.57–0.84). Muscle biopsy results indicated that the fiber type composition was different, but capillary density was similar, between patients with active disease and those with inactive disease. Conclusion: In patients with long‐term juvenile DM, both muscle strength and endurance of the knee extensors were lower when compared to matched controls, and also lower in patients with active disease compared to those with inactive disease. Our results indicate a need for more sensitive muscle tests in this clinical setting. We hypothesize that impaired muscle endurance in patients with active juvenile DM may be influenced by structural/functional adaptations of muscle tissue independent of muscle size

Effects of training, detraining, and retraining on strength, hypertrophy, and myonuclear number in human skeletal muscle

Previously trained mouse muscles acquire strength and volume faster than naïve muscles; it has been suggested that this is related to increased myonuclear density. The present study aimed to determine whether a previously strength-trained leg (mem-leg) would respond better to a period of strength training than a previously untrained leg (con-leg). Nine men and 10 women performed unilateral strength training (T1) for 10 wk, followed by 20 wk of detraining (DT) and a 5-wk bilateral retraining period (T2). Muscle biopsies were taken before and after each training period and analyzed for myonuclear number, fiber volume, and cross-sectional area (CSA). Ultrasound and one repetition of maximum leg extension were performed to determine muscle thickness (MT) and strength. CSA (~17%), MT (~10%), and strength (~20%) increased during T1 in the mem-leg. However, the myonuclear number and fiber volume did not change. MT and CSA returned to baseline values during DT, but strength remained elevated (~60%), supporting previous findings of a long-lasting motor learning effect. MT and strength increased similarly in the mem-leg and con-leg during T2, whereas CSA, fiber volume, and myonuclear number remained unaffected. In conclusion, training response during T2 did not differ between the mem-leg and con-leg. However, this does not discount the existence of human muscle memory, since no increase in the number of myonuclei was detected during T1 and no clear detraining effect was observed for cell size during DT; thus, the present data did not allow for a rigorous test of the muscle memory hypothesis. NEW &amp; NOTEWORTHY If a long-lasting intramuscular memory exists in humans, this will affect strength-training advice for both athletes and the public. Based on animal experiments, we hypothesized that such a memory exists and that it is related to the myonuclear number. However, a period of unilateral strength training, followed by detraining, did not increase the myonuclear number. The training response, during a subsequent bilateral retraining period, was not enhanced in the previously trained leg.