Accuracy of a non-exercise method using seismocardiography for the estimation of V̇O2peak in sub-elite football players.

A non-exercise method equation using seismocardiography for estimating V̇O2peak (SCG V̇O2peak) has previously been validated in healthy subjects. However, the performance of the SCG V̇O2peak within a trained population is unknown, and the ability of the model to detect changes over time is not well elucidated. Forty-seven sub-elite football players were tested at the start of pre-season (SPS) and 36 players completed a test after eight weeks at the end of the pre-season (EPS). Testing included an SCG V̇O2peak estimation at rest and a graded cardiopulmonary exercise test (CPET) on a treadmill for determination of V̇O2peak. Agreement between SCG V̇O2peak and CPET V̇O2peak showed a large underestimation at SPS (bias ± 95% CI: -9.9 ± 1.8, 95% Limits of Agreement: 2.2 to -22.0 mL·min-1 kg-1). At EPS no interaction (p = 0.3590) but a main effect of time (p < 0.0001) and methods (p < 0.0001) was observed between SCG and CPET V̇O2peak. No correlation in V̇O2peak changes was observed between SCG and CPET (r = -20.0, p = 0.2484) but a fair agreement in classifying the correct directional change in V̇O2peak with the SCG method was found (Cohen's κ coefficient = 0.28 ± 0.25). Overall, the SCG V̇O2peak method lacks accuracy and despite being able to estimate group changes, it was incapable of detecting individual changes in V̇O2peak following a pre-season period in sub-elite football players. The SCG algorithm needs to be further adjusted and the accuracy and precision improved for the method to be applicable for use within a trained population.

Prolonged Endurance Exercise Increases Macrophage Content and Mitochondrial Respiration in Adipose Tissue in Trained Men.

BACKGROUND: The aim of this study was to investigate the effect of prolonged endurance exercise on adipose tissue inflammation markers and mitochondrial respiration in younger and older men. METHODS: "Young" (aged 30 years, n = 7) and "old" (aged 65 years, n = 7) trained men were exposed to an exercise intervention of 15 consecutive days biking 7 to 9 hours/day at 63% and 65% of maximal heart rate (young and old, respectively), going from Copenhagen, Denmark to Palermo, Italy. Adipose tissue was sampled from both the gluteal and abdominal depot before and after the intervention. Mitochondrial respiration was measured by high-resolution respirometry, and adipose inflammation was assessed by immunohistochemical staining of paraffin embedded sections. RESULTS: An increased number of CD163+ macrophages was observed in both the gluteal and abdominal depot (P < .01). In addition, an increased mitochondrial respiration was observed in the abdominal adipose tissue from men in the young group with complex I (CIp) stimulated respiration, complex I + II (CI+IIp) stimulated respiration and the capacity of the electron transport system (ETS) (P < .05), and in the older group an increase in CIp and CI+IIp stimulated respiration (P < .05) was found. CONCLUSION: Overall, we found a positive effect of prolonged endurance exercise on adipose tissue inflammation markers and mitochondrial respiration in both young and old trained men, and no sign of attenuated function in adipose tissue with age.

Effects of Aerobic Training and Semaglutide Treatment on Pancreatic ß-Cell Secretory Function in Patients With Type 2 Diabetes.

CONTEXT: Prior to this study, it is known that type 2 diabetes is linked to obesity and a sedentary lifestyle, leading to inadequate ß-cell function and insulin resistance. Limited research has explored the metabolic effects of combining exercise training with antidiabetic medications, particularly focusing on insulin secretion in patients with type 2 diabetes and moderately preserved ß-cell function. OBJECTIVE: The effect of the interaction of semaglutide and physical training on pancreatic ß-cell secretory function is unknown in patients with type 2 diabetes. METHODS: Thirty-one patients with type 2 diabetes underwent 12 weeks of aerobic training alone or concurrent to treatment with semaglutide. Patients randomly allocated to concurrent semaglutide and training were treated with semaglutide for 20 weeks before the training and evaluated at inclusion and again before and after the training intervention. Patients randomized to training were evaluated before and after training. The primary outcome was a change in insulin secretory capacity with training, evaluated by a 2-stepped hyperglycemic (20 and 30 mM) clamp. RESULTS: Training increased the incremental area under the curve for insulin from 21 to 27 nM × 2 hours (ratio 1.28, 95% CI 1.02-1.60) during clamp step 1 and from 40 to 64 nM × 2 hours (ratio 1.61, 95% CI 1.25-2.07) during step 2. Semaglutide treatment increased insulin secretion from 16 to 111 nM × 2 hours (ratio 7.10, 95% CI 3.68-13.71), and from 35 to 447 nM × 2 hours (ratio 12.74, 95% CI 5.65-28.71), correspondingly. Semaglutide and training increased insulin secretion from 130 to 171 nM × 2 hours (ratio 1.31, 95% CI 1.06-1.63), and from 525 to 697 nM × 2 hours (ratio 1.33, 95% CI 1.02-1.72), correspondingly. The median increase in total insulin secretion with the combination was 134 nM × 2 hours greater (95% CI 108-232) than with training. CONCLUSION: The combination of aerobic training and semaglutide treatment synergistically improved ß-cell secretory function. (ClinicalTrials.gov number, ID NCT04383197).

A randomized double-blind single center study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention).

INTRODUCTION: Elevated luteinizing hormone (LH) in combination with low-normal testosterone (mild Leydig cell insufficiency) is common in testicular cancer (TC) survivors and is associated with impaired insulin sensitivity and metabolic syndrome. The aim was to evaluate if testosterone replacement therapy (TRT) improves metabolic health in this subgroup of TC survivors. PATIENTS AND METHODS: This was a single-center, double-blind, randomized, controlled trial. The main eligibility criterion was LH above the age-adjusted upper limit of normal in combination with free testosterone in the lower half of the age-adjusted normal range (mild Leydig cell insufficiency) >1 year after TC treatment. Eligible patients were randomly assigned (1:1) to 12 months transdermal TRT (Tostran, gel, 2%) or placebo with a maximum daily dose of 40 mg. The primary outcome was difference in Δ2 hour glucose measured with oral glucose tolerance test between groups assessed at 12 months. Outcomes were assessed after 6-, 12- and 3 months post-treatment. The study was registered at www. CLINICALTRIAL: gov (NCT02991209) and ended June 2019. RESULTS: Between October 2016 and February 2018, 140 patients were screened for eligibility and 69 were randomized to testosterone (n = 35, 51%) or placebo (n = 34, 49%). TRT was not associated with a statistically significant difference in Δ2 hour glucose compared to placebo after 12 months of treatment (0.04 mmol/L (95% CI: -0.53, 0.60)). There was no statistically significant difference in Δ2 hour insulin between the groups after 12 months of treatment (28.23 pmol/L (95% CI: -34.40, 90.86)). Similarly, TRT was not associated with significant improvement in components of metabolic syndrome. TRT was associated with a decrease in fat mass after 12 months compared to placebo (-1.35 kg, (95% CI: -2.53, -0.18)). CONCLUSION: In TC survivors with mild Leydig cell insufficiency, TRT was not associated with improvement of metabolic health. These findings do no not support routine use of TRT in these patients.

Extreme duration exercise affects old and younger men differently.

AIM & METHODS: Extreme endurance exercise provides a valuable research model for understanding the adaptive metabolic response of older and younger individuals to intense physical activity. Here, we compare a wide range of metabolic and physiologic parameters in two cohorts of seven trained men, age 30 ± 5 years or age 65 ± 6 years, before and after the participants travelled ≈3000 km by bicycle over 15 days. RESULTS: Over the 15-day exercise intervention, participants lost 2-3 kg fat mass with no significant change in body weight. V̇O2 max did not change in younger cyclists, but decreased (p = 0.06) in the older cohort. The resting plasma FFA concentration decreased markedly in both groups, and plasma glucose increased in the younger group. In the older cohort, plasma LDL-cholesterol and plasma triglyceride decreased. In skeletal muscle, fat transporters CD36 and FABPm remained unchanged. The glucose handling proteins GLUT4 and SNAP23 increased in both groups. Mitochondrial ROS production decreased in both groups, and ADP sensitivity increased in skeletal muscle in the older but not in the younger cohort. CONCLUSION: In summary, these data suggest that older but not younger individuals experience a negative adaptive response affecting cardiovascular function in response to extreme endurance exercise, while a positive response to the same exercise intervention is observed in peripheral tissues in younger and older men. The results also suggest that the adaptive thresholds differ in younger and old men, and this difference primarily affects central cardiovascular functions in older men after extreme endurance exercise.

Reliability and variation in mitochondrial respiration in human adipose tissue.

Adipose tissue mitochondrial function is gaining increasing interest since it is a good marker of overall health. Methodological challenges and variability in assessing mitochondrial respiration in fresh adipose tissue with high-resolution respirometry are unknown and should be explored. Mitochondrial respiratory capacity (MRC) in human adipose tissue declines in a gradual manner when analyses are postponed 3 h and 24 h, with a statistically significant decline 24 h after obtaining the biopsy. This decline in MRC is associated with a reduced integrity of the outer mitochondrial membrane at both time points. This study suggests that the optimal amount of tissue to be used is 20 mg and that different technicians handling the biopsy do not affect MRC.

High bone mineral density in lifelong trained female team handball players and young elite football players.

PURPOSE: Low bone mineral density (BMD) and fractures are a major concern in the female population and preventative strategies are needed. Whether team sports participation may reduce age-related bone loss in elderly women is still uncertain. METHODS: One hundred and thirty healthy, non-smoking women participated in this cross-sectional study, i.e., elderly (60-80 years) team handball players (EH, n = 35), elderly untrained controls (EC, n = 35), young (18-30 years) elite football players (YF, n = 30) and young untrained controls (YC, n = 30). A whole-body and two regional dual-energy X-ray absorptiometry (DXA) scans were performed to evaluate BMD and a blood sample was collected for measurement of bone turnover markers (BTMs). RESULTS: EH had higher BMD in all regions of the lumbar spine, except for L1, compared to EC (8-10%), and higher BMD in the femoral Ward's triangle (9%) and trochanter (7%) of the left leg. Furthermore, EH had higher mean leg BMD (8%) and whole-body BMD (5%) than EC. EH and YC had similar BMD in femoral trochanter, L1-L4 and mean leg despite an age difference of ~ 40 years. YF had higher BMD in all regions of the proximal femur (18-29%) and lumbar spine (12-16%) compared to YC, as well as higher mean leg BMD (20%) and whole-body BMD (13%). Sclerostin was 14% lower in EH compared to EC. YF showed higher PINP (98%), osteocalcin (57%), and CTX (83%) compared to YC. CONCLUSION: Lifelong team handball training and elite football training are associated with superior bone mineralization and changed bone turnover in elderly and young women.

Endotrophin is associated with chronic multimorbidity and all-cause mortality in a cohort of elderly women.

BACKGROUND: The signalling peptide endotrophin is derived through proteolytic cleavage of the carboxyl-terminal during formation of type VI collagen. It is expressed by most descendants of the mesenchymal stem cells lineage, including adipocytes and fibroblasts, and have been proposed to be a central extracellular matrix hormone associated with several age-related diseases. We aimed to assess the association of endotrophin with chronic disease incidence and death in older women. METHODS: 5,602 elderly Danish women from the observational, prospective cohort: The Prospective Epidemiological Risk Factor (PERF) study were included in the analysis which covered baseline (BL) and follow-up (FU) 14 years later. An elastic net was used to investigate the relative importance of 58 variables to serum endotrophin-levels. 20 chronic diseases were defined on the basis of clinical variables available along with diagnoses extracted from both the National Patient Register, the National Diabetes Register and the Danish Cancer Registry. The cross-sectional associations between endotrophin-levels and these 17 chronic age-related diseases were investigated using logistic regression and a set-analysis explored disease-combinations within multimorbidity. The association of endotrophin with mortality was assessed by Cox proportional hazard models. FINDINGS: Formation of type III collagen (PRO-C3), age and creatine-levels were the most influential variables of endotrophin-levels. Several chronic diseases were significantly associated with endotrophin-levels independent of age and BMI including chronic kidney disease (BL OR=3.7, p < 0.001; FU OR = 7.9 p < 0.001), diabetes (BL OR = 1.5, p = 0.0015, FU OR=1.6, p = 0.004) and peripheral arterial disease (BL OR = 1.3, p = 0.029; FU OR=2.4, p < 0.001). Lastly, endotrophin-levels were significantly rising with number of morbidities (p < 0.001) and a predictor of death after adjusting for age and BMI (BL HR=1.95; FU HR = 2.00). INTERPRETATION: Endotrophin was associated with death and increased with number of morbidities. Endotrophin may be a central hormone of fibroblast that warrant investigation and possible targeted intervention in several chronic diseases. FUNDING: The funder of the PERF study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

One year of Football Fitness improves L1-L4 BMD, postural balance, and muscle strength in women treated for breast cancer.

PURPOSE: To examine efficacy of 12 months Football Fitness offered twice per week on bone mineral density (BMD), bone turnover markers (BTM), postural balance, muscle strength, and body composition in women treated for early-stage breast cancer (BC). METHODS: Women treated for early-stage BC were randomized to Football Fitness (FFG, n = 46) or control (CON, n = 22) in a 2:1 ratio for 12 months, with assessments performed at baseline, 6 months and 12 months. Outcomes were total body-, lumbar spine- and proximal femur BMD, total body lean and fat mass, leg muscle strength, postural balance, and plasma amino-terminal propeptide of type 1 procollagen (P1NP), osteocalcin, and C-terminal telopeptide of type 1 collagen (CTX). Intention-to-treat (ITT) analyses and per-protocol analyses (≥50% attendance in FFG) were performed using linear mixed models. RESULTS: Participants in FFG completing the 12-month intervention (n = 33) attended 0.8 (SD = 0.4) sessions per week. Intention to treat analysis of mean changes over 12 months showed significant differences (p<.05) in L1-L4 BMD (0.029 g/cm2 , 95%CI: 0.001 to 0.057), leg press strength (7.2 kg, 95%CI: 0.1 to 14.3), and postural balance (-4.3 n need of support, 95%CI: -8.0 to -0.7) favoring FFG compared to CON. In the per-protocol analyses, L1-L4 and trochanter major BMD were improved (p = .012 and .030, respectively) in FFG compared with CON. No differences were observed between groups in BTMs in the ITT or per protocol analyses. CONCLUSION: One year of Football Fitness training may improve L1-L4 BMD, leg muscle strength, and postural balance in women treated for early-stage breast cancer.

Effects of football fitness training on lymphedema and upper-extremity function in women after treatment for breast cancer: a randomized trial.

BACKGROUND: Breast cancer survivors are encouraged to be physically active. A recent review suggests that football training is an effective exercise modality for women across the lifespan, positively influencing health variables such as strength, fitness and social well-being. However, football is a contact sport, potentially posing an increased risk of trauma-related injury. Against this backdrop, breast cancer survivors are advised to avoid trauma or injury to the affected or at-risk arm in order to protect against lymphedema onset or exacerbation. The aim of this study was therefore to evaluate the feasibility and safety of Football Fitness training in relation to lymphedema and upper-extremity function after treatment for breast cancer. MATERIAL AND METHODS: Sixty-eight women aged 18-75 years, who had received surgery for stage I-III breast cancer and completed (neo) adjuvant chemotherapy and/or radiotherapy within five years, were randomized (2:1) to a Football Fitness group (FFG, n = 46) or a control group (CON, n = 22) for twelve months. Secondary analyses using linear mixed models were performed to assess changes in upper-body morbidity, specifically arm lymphedema (inter-arm volume % difference, dual energy X-ray absorptiometry; extracellular fluid (L-Dex), bioimpedance spectroscopy), self-reported breast and arm symptoms (EORTC breast cancer-specific questionnaire (BR23) and upper-extremity function (DASH questionnaire) at baseline, six- and twelve-month follow-up. RESULTS: We observed similar point prevalent cases of lymphedema between groups at all time points, irrespective of measurement method. At the six-month post-baseline assessment, reductions in L-Dex (extracellular fluid) were found in FFG versus CON. These significant findings were not maintained at the twelve-month assessment. No difference between groups was observed for inter-limb volume difference %, nor any of the remaining outcomes. CONCLUSION: While superiority of Football Fitness was not observed, the results support that participation in Football Fitness training is feasible and suggests no negative effects on breast cancer-specific upper-body morbidity, including lymphedema. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov. NCT03284567.

Exercise intensity and cardiovascular health outcomes after 12 months of football fitness training in women treated for stage I-III breast cancer: Results from the football fitness After Breast Cancer (ABC) randomized controlled trial.

PURPOSE: To examine the exercise intensity and impact of 12 months of twice-weekly recreational football training on cardiorespiratory fitness (CRF), blood pressure (BP), resting heart rate (HRrest), body fat mass, blood lipids, inflammation, and health-related quality of life in women treated for early-stage breast cancer (BC). METHODS: Sixty-eight women who had received surgery for stage I-III BC and completed adjuvant chemo- and/or radiation therapy within 5 years were randomized in a 2:1 ratio to a Football Fitness group (FFG, n = 46) or a control group (CON, n = 22). Football Fitness sessions comprised a warm-up, drills and 3-4 × 7 min of small-sided games (SSG). Assessments were performed at baseline, 6 months and 12 months. Outcomes were peak oxygen uptake (VO2peak), blood pressure (BP), HRrest, total body fat mass, and circulating plasma lipids and hs-CRP, and the 36-Item Short Form Health Survey (SF36). Intention-to-treat (ITT) analyses were performed using linear mixed models. Data are means with SD or 95% confidence intervals. RESULTS: Adherence to training in participants completing the 12-months follow-up (n = 33) was 47.1% (22.7), and HR during SSG was ≥80% of HRmax for 69.8% (26.5) of total playing time. At baseline, VO2peak was 28.5 (6.4) and 25.6 (5.9) ml O2/kg/min in FFG and CON, respectively, and no significant changes were observed at 6- or 12 months follow-up. Systolic BP (SBP) was 117.1 (16.4) and 116.9 (14.8) mmHg, and diastolic BP (DBP) was 72.0 (11.2) and 72.4 (8.5) mmHg in FFG and CON, respectively, at baseline, and a 9.4 mmHg decrease in SBP in CON at 12 months resulted in a between-group difference at 12 months of 8.7 mmHg (p = .012). Blood lipids and hs-CRP were within the normal range at baseline, and there were no differences in changes between groups over the 12 months. Similarly, no differences between groups were observed in HRrest and body fat mass at 6- and12-months follow-up. A between-group difference in mean changes of 23.5 (0.95-46.11) points in the role-physical domain of the SF36 survey favored FFG at 6 months. CONCLUSION: Football Fitness training is an intense exercise form for women treated for breast cancer, and self-perceived health-related limitations on daily activities were improved after 6 months. However, 1 year of Football Fitness training comprising 1 weekly training session on average did not improve CRF, BP, blood lipids, fat mass, or HRrest. TRIAL REGISTRATION NUMBER: The trial was registered at ClinicalTrials.gov with identifier NCT03284567.

Mitochondrial adaptations to high intensity interval training in older females and males.

Introduction: High intensity interval training (HIIT) has shown to be as effective as moderate intensity endurance training to improve metabolic health. However, the current knowledge on the effect of HIIT in older individuals is limited and it is uncertain whether the adaptations are sex specific. The aim was to investigate effects of HIIT on mitochondrial respiratory capacity and mitochondrial content in older females and males. Methods: Twenty-two older sedentary males (n = 11) and females (n = 11) completed 6 weeks of supervised HIIT 3 days per week. The training consisted of 5 × 1 min cycling (124 ± 3% of max power output at session 2-6 and 135 ± 3% of max power output at session 7-20) interspersed by 1½ min recovery. Before the intervention and 72 h after last training session a muscle biopsy was obtained and mitochondrial respiratory capacity, citrate synthase activity and proteins involved in mitochondria metabolism were assessed. Furthermore, body composition and ⩒O2max were measured. Results: ⩒O2max increased and body fat percentage decreased after HIIT in both sexes (p < 0.05). In addition, CS activity and protein content of MnSOD and complex I-V increased in both sexes. Coupled and uncoupled mitochondrial respiratory capacity increased only in males. Mitochondrial respiratory capacity normalised to CS activity (intrinsic mitochondrial respiratory capacity) did not change following HIIT. Conclusion: HIIT induces favourable adaptions in skeletal muscle in older subjects by increasing mitochondrial content, which may help to maintain muscle oxidative capacity and slow down the process of sarcopenia associated with ageing.

Determination and validation of peak fat oxidation in endurance-trained men using an upper body graded exercise test.

Peak fat oxidation rate (PFO) and the intensity that elicits PFO (Fatmax ) are commonly determined by a validated graded exercise test (GE) on a cycling ergometer with indirect calorimetry. However, for upper body exercise fat oxidation rates are not well elucidated and no protocol has been validated. Thus, our aim was to test validity and inter-method reliability for determination of PFO and Fatmax in trained men using a GE protocol applying double poling on a ski-ergometer. PFO and Fatmax were assessed during two identical GE tests (GE1 and GE2) and validated against separated short continuous exercise bouts (SCE) at 35%, 50%, and 65% of V̇O2peak on the ski-ergometer in 10 endurance-trained men (V̇O2peak : 65.1 ± 1.0 mL·min-1 ·kg-1 , mean ± SEM). Between GE tests no differences were found in PFO (GE1: 0.42 ± 0.03; GE2: 0.45 ± 0.03 g·min-1 , P = .256) or Fatmax (GE1: 41 ± 2%; GE2: 43 ± 3% of V̇O2peak , P = .457) and the intra-individual coefficient of variation (CV) was 8 ± 2% and 11 ± 2% for PFO and Fatmax , respectively. Between GE and SCE tests, PFO (GEavg : 0.44 ± 0.03; SCE; 0.47 ± 0.06 g·min-1 , P = .510) was not different, whereas a difference in Fatmax (GEavg : 42 ± 2%; SCE: 52 ± 4% of V̇O2peak , P = .030) was observed with a CV of 17 ± 4% and 15 ± 4% for PFO and Fatmax , respectively. In conclusion, GE has a high day-to-day reliability in determination of PFO and Fatmax in trained men, whereas it is unclear if PFO and Fatmax determined by GE reflect continuous exercise in general.

Coenzyme Q10 does not improve peripheral insulin sensitivity in statin-treated men and women: the LIFESTAT study.

Simvastatin is a cholesterol-lowering drug that is prescribed to lower the risk of cardiovascular disease following high levels of blood cholesterol. There is a possible risk of new-onset diabetes mellitus with statin treatment but the mechanisms behind are unknown. Coenzyme Q10 (CoQ10) supplementation has been found to improve glucose homeostasis in various patient populations and may increase muscle glucose transporter type 4 content. Our aim was to investigate if 8 weeks of CoQ10 supplementation can improve glucose homeostasis in simvastatin-treated subjects. Thirty-five men and women in treatment with a minimum of 40 mg of simvastatin daily were randomized to receive either 2 × 200 mg/day of CoQ10 supplementation or placebo for 8 weeks. Glucose homeostasis was investigated with fasting blood samples, oral glucose tolerance test (OGTT) and intravenous glucose tolerance test. Insulin sensitivity was assessed with the hyperinsulinemic-euglycemic clamp. Different indices were calculated from fasting samples and OGTT as secondary measures of insulin sensitivity. A muscle biopsy was obtained from the vastus lateralis muscle for muscle protein analyzes. There were no changes in body composition, fasting plasma insulin, fasting plasma glucose, or 3-h glucose with intervention, but glycated hemoglobin decreased with time. Glucose homeostasis measured as the area under the curve for glucose, insulin, and C-peptide during OGTT was unchanged after intervention. Insulin secretory capacity was also unaltered after CoQ10 supplementation. Insulin sensitivity was unchanged but hepatic insulin sensitivity increased. No changes in muscle GLUT4 content was observed after intervention. CoQ10 supplementation does not change muscle GLUT4 content, insulin sensitivity, or secretory capacity, but hepatic insulin sensitivity may improve.

The Influence of Age and Cardiorespiratory Fitness on Bioactive Lipids in Muscle.

Reduced insulin sensitivity is observed with aging and often explained by decreased physical activity. The mechanisms involved are not clarified, but bioactive lipids may play a role. We aimed to evaluate the influence of age and cardiorespiratory fitness on ceramide and diacylglycerol content in muscle and key proteins in lipid metabolism and insulin signaling. Healthy males were stratified by age into trained and untrained groups including 27 young (23.2 ± 0.3 years) and 33 aged (65.2 ± 0.6 years). Maximal oxygen uptake and body composition were measured and fasting blood samples and muscle biopsies obtained. Muscle ceramide and diacylglycerol were determined by thin-layer and gas-liquid chromatography and proteins by western blotting. We show that HOMA-IR was higher and VO2 peak lower in aged compared with young. Total, saturated, C16:0 and C18:0 ceramide content were lower in muscle from aged compared with young. Intramuscular C18:1n9 and C20:4n6 content were higher in trained versus untrained. Content of total unsaturated and C16:1n7 diacylglycerol fatty acids were higher and C24:0 lower in muscle of aged versus young. Cardiorespiratory fitness had no impact on total diacylglycerol content. In conclusion, these data argue against intramuscular ceramide or diacylglycerol accumulation as driver of age-related insulin resistance in lean individuals.

Simvastatin-Induced Insulin Resistance May Be Linked to Decreased Lipid Uptake and Lipid Synthesis in Human Skeletal Muscle: the LIFESTAT Study.

BACKGROUND: A prevalent side-effect of simvastatin is attenuated glucose homeostasis. The underlying mechanism is unknown, but impaired lipid metabolism may provide the link. The aim of this study was to investigate whether simvastatin-treated patients had a lower capacity to oxidize lipids and reduced expression of the major proteins regulating lipid uptake, synthesis, lipolysis, and storage in skeletal muscle than matched controls. MATERIALS AND METHODS: Ten men were treated with simvastatin (HbA1c: 5.7 ± 0.1%), and 10 healthy men (HbA1c: 5.2 ± 0.1%) underwent an oral glucose tolerance test and a muscle biopsy was obtained. Fat oxidation rates were measured at rest and during exercise. Western blotting was used to assess protein content. RESULTS: Patients treated with simvastatin had impaired glucose tolerance compared with control subjects, but fat oxidation at rest and during exercise was compatible. Skeletal muscle protein content of CD36, lipoprotein lipase (LPL), and diacylglycerol acyltransferase (DGAT) 1 were lower, and DGAT 2 tended to be lower in patients treated with simvastatin. CONCLUSIONS: Patients treated with simvastatin had a reduced capacity to synthesize FA and diacylglycerol (DAG) into triacylglycerol in skeletal muscle compared to matched controls. Decreased lipid synthesis capacity may lead to accumulation of lipotoxic intermediates (FA and DAG) and hence impair glucose tolerance.

Bone mineral density in lifelong trained male football players compared with young and elderly untrained men.

PURPOSE: The purpose of the present controlled cross-sectional study was to investigate proximal femur and whole-body bone mineral density (BMD), as well as bone turnover profile, in lifelong trained elderly male football players and young elite football players compared with untrained age-matched men. METHODS: One hundred and forty healthy, non-smoking men participated in the study, including lifelong trained football players (FTE, n = 35) aged 65-80 years, elite football players (FTY, n = 35) aged 18-30 years, as well as untrained age-matched elderly (UE, n = 35) and young (UY, n = 35) men. All participants underwent a regional dual-energy X-ray Absorptiometry (DXA) scan of the proximal femur and a whole-body DXA scan to determine BMD. From a resting blood sample, the bone turnover markers (BTMs) osteocalcin, carboxy-terminal type-1 collagen crosslinks (CTX-1), procollagen type-1 amino-terminal propeptide (P1NP), and sclerostin were measured. RESULTS: FTE had 7.3%-12.9% higher (p < 0.05) BMD of the femoral neck, wards, shaft, and total proximal femur in both legs compared to UE, and 9.3%-9.7% higher (p < 0.05) BMD in femoral trochanter in both legs compared to UY. FTY had 24.3%-37.4% higher (p < 0.001) BMD in all femoral regions and total proximal femur in both legs compared to UY. The whole-body DXA scan confirmed these results, with FTE showing similar whole-body BMD and 7.9% higher (p < 0.05) leg BMD compared to UY, and with FTY having 9.6% higher (p < 0.001) whole-body BMD and 18.2% higher (p < 0.001) leg BMD compared to UY. The plasma concentration of osteocalcin, CTX-1, and P1NP were 29%, 53%, and 52% higher (p < 0.01), respectively, in FTY compared to UY. CONCLUSION: BMD of the proximal femur and whole-body BMD are markedly higher in lifelong trained male football players aged 65-80 years and young elite football players aged 18-30 years compared to age-matched untrained men. Elderly football players even show higher BMD in femoral trochanter and leg BMD than untrained young despite an age difference of 47 years.

Variation in mitochondrial respiratory capacity and myosin heavy chain composition in repeated muscle biopsies.

Skeletal muscle is a heterogeneous tissue and it is essential to know the methodological variation and reliability when measuring aspects of muscle function. We assessed the methodological and biological variation when measuring mitochondrial respiratory capacity (MRC), citrate synthase (CS) activity and myosin heavy chain (MHC) composition in muscle biopsies from nine healthy male participants, and in addition we assessed variation in MRC in isolated mitochondria and yeast suspension. We analysed MRC, CS activity and MHC composition in duplicates (intra-biopsy variation) to quantify the methodological variation, as well as the biological variation from multiple muscle biopsies (inter-biopsy variation) obtained at different sites of the same muscle. Three muscle biopsies (B1, B2 and B3) were obtained from each subject in m. vastus lateralis. Two of the biopsies were from the same leg and one from the other leg. For MRC, intra-biopsy coefficient of variation (CV) was 8.4% and inter-biopsy CV was 13.3%. For MHC type I, IIa and IIx intra-biopsy CV was 8.3, 6.0 and 22.3%, respectively. Inter-biopsy CV for these MHC types were 21.5, 15.4 and 42.0%, respectively. For CS activity intra-biopsy CV was 0.6% and inter-biopsy CV was 15.3%. No differences between B1, B2 and B3 were detected for MRC, CS activity or MHC composition.

A randomized double-blind study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention).

BACKGROUND: Elevated serum levels of luteinizing hormone and slightly decreased serum levels of testosterone (mild Leydig cell insufficiency) is a common hormonal disturbance in testicular cancer (TC) survivors. A number of studies have shown that low serum levels of testosterone is associated with low grade inflammation and increased risk of metabolic syndrome. However, so far, no studies have evaluated whether testosterone substitution improves metabolic dysfunction in TC survivors with mild Leydig cell insufficiency. METHODS/DESIGN: This is a single-center, randomized, double-blind, placebo-controlled study, designed to evaluate the effect of testosterone replacement therapy in TC survivors with mild Leydig cell insufficiency. Seventy subjects will be randomized to receive either testosterone replacement therapy or placebo. The subjects will be invited for an information meeting where informed consent will be obtained. Afterwards, a 52-weeks treatment period begins in which study participants will receive a daily dose of transdermal testosterone or placebo. Dose adjustment will be made three times during the initial 8 weeks of the study to a maximal daily dose of 40 mg of testosterone in the intervention arm. Evaluation of primary and secondary endpoints will be performed at baseline, 26 weeks post-randomization, at the end of treatment (52 weeks) and 3 months after completion of treatment (week 64). DISCUSSION: This study is the first to investigate the effect of testosterone substitution in testicular cancer survivors with mild Leydig cell insufficiency. If positive, it may change the clinical handling of testicular cancer survivors with borderline low levels of testosterone. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02991209 (November 25, 2016).

Influence of maximal fat oxidation on long-term weight loss maintenance in humans.

Impaired maximal fat oxidation has been linked to obesity and weight regain after weight loss. The aim was to investigate the relationship between maximal fat oxidation (MFO) and long-term weight loss maintenance. Eighty subjects [means (SD): age, 36(13) yrs; BMI, 38(1) kg/m2] were recruited from a total of 2,420 former participants of an 11- to 12-wk lifestyle intervention. Three groups were established based on percent weight loss at follow-up [5.3(3.3) yr]: clinical weight loss maintenance (CWL), >10% weight loss; moderate weight loss (MWL), 1-10% weight loss; and weight regain (WR). Body composition (dual X-ray absorptiometry) and fat oxidation (indirect calorimetry) during incremental exercise were measured at follow-up. Blood and a muscle biopsy were sampled. At follow-up, a U-shaped parabolic relationship between MFO and percent weight loss was observed (r = 0.448; P < 0.001). Overall differences between CWL, MWL, and WR were observed in MFO (mean [95% confidence interval], in g/min, respectively: 0.46 [0.41-0.52]; 0.32 [0.27-0.38]; 0.45 [0.38-0.51]; P = 0.002), maximal oxygen uptake (V̇o2max, in ml·min-1·FFM-1, respectively; 49 [46-51]; 43 [40-47]; 41 [39-44]; P = 0.007), HAD-activity (in µmol·g-1·min-1, respectively: 123 [113-133]; 104 [91-118]; 97 [88-105]; P < 0.001), muscle protein content of CD36 (in AU, respectively: 1.1 [1.0-1.2]; 0.9 [0.8-1.0]; 0.9 [0.8-0.9]; P = 0.008) and FABPpm (in AU, respectively, 1.0 [0.8-1.2]; 0.7 [0.5-0.8]; 0.7 [0.5-0.9]; P = 0.008), body fat (in %, respectively: 33 [29-38]; 42 [38-46]; 52 [49-55]; P < 0.001), and plasma triglycerides (in mM, respectively: 0.8 [0.7-1.0]; 1.3 [0.9-1.7]; 1.6 [1.0-2.1]; P = 0.013). CWL and WR both had higher MFO compared with MWL, but based on different mechanisms. CWL displayed higher V̇o2max and intramuscular capacity for fat oxidation, whereas abundance of lipids at whole-body level and in plasma was higher in WR.NEW & NOTEWORTHY Impaired maximal fat oxidation has been linked to obesity and weight regain after weight loss. Noteworthy, maximal fat oxidation was equally high after clinical weight loss maintenance and weight regain compared with moderate weight loss. A high maximal fat oxidation after clinical weight loss maintenance was related to higher maximal oxygen updake, content of key proteins involved in transport of lipids across the plasma membrane and ß-oxidation. In contrast, a high maximal fat oxidation after weight regain was related to higher availability of lipids, i.e., general adiposity and plasma concentration of triglycerides.