Brown adipose tissue metabolism in women is dependent on ovarian status.

In rodents, loss of estradiol (E2) reduces brown adipose tissue (BAT) metabolic activity. Whether E2 impacts BAT activity in women is not known. BAT oxidative metabolism was measured in premenopausal (n = 27; 35 ± 9 yr; body mass index = 26.0 ± 5.3 kg/m2) and postmenopausal (n = 25; 51 ± 8 yr; body mass index = 28.0 ± 5.0 kg/m2) women at room temperature and during acute cold exposure using [11C]acetate with positron emission tomography coupled with computed tomograph. BAT glucose uptake was also measured during acute cold exposure using 2-deoxy-2-[18F]fluoro-d-glucose. To isolate the effects of ovarian hormones from biological aging, measurements were repeated in a subset of premenopausal women (n = 8; 40 ± 4 yr; BMI = 28.0 ± 7.2 kg/m2) after 6 mo of gonadotropin-releasing hormone agonist therapy to suppress ovarian hormones. At room temperature, there was no difference in BAT oxidative metabolism between premenopausal (0.56 ± 0.31 min-1) and postmenopausal women (0.63 ± 0.28 min-1). During cold exposure, BAT oxidative metabolism (1.28 ± 0.85 vs. 0.91 ± 0.63 min-1, P = 0.03) and net BAT glucose uptake (84.4 ± 82.5 vs. 29.7 ± 31.4 nmol·g-1·min-1, P < 0.01) were higher in premenopausal than postmenopausal women. In premenopausal women who underwent gonadotropin-releasing hormone agonist, cold-stimulated BAT oxidative metabolism was reduced to a similar level (from 1.36 ± 0.66 min-1 to 0.91 ± 0.41 min-1) to that observed in postmenopausal women (0.91 ± 0.63 min-1). These results provide the first evidence in humans that reproductive hormones are associated with BAT oxidative metabolism and suggest that BAT may be a target to attenuate age-related reduction in energy expenditure and maintain metabolic health in postmenopausal women.NEW & NOTEWORTHY In rodents, loss of estrogen reduces brown adipose tissue (BAT) activity. Whether this is true in humans is not known. We found that BAT oxidative metabolism and glucose uptake were lower in postmenopausal compared to premenopausal women. In premenopausal women who underwent ovarian suppression to reduce circulating estrogen, BAT oxidative metabolism was reduced to postmenopausal levels. Thus the loss of ovarian function in women leads to a reduction in BAT metabolic activity independent of age.

Effects of follicle-stimulating hormone on energy balance and tissue metabolic health after loss of ovarian function.

Loss of ovarian function imparts increased susceptibility to obesity and metabolic disease. These effects are largely attributed to decreased estradiol (E2), but the role of increased follicle-stimulating hormone (FSH) in modulating energy balance has not been fully investigated. Previous work that blocked FSH binding to its receptor in mice suggested this hormone may play a part in modulating body weight and energy expenditure after ovariectomy (OVX). We used an alternate approach to isolate the individual and combined contributions of FSH and E2 in mediating energy imbalance and changes in tissue-level metabolic health. Female Wistar rats were ovariectomized and given the gonadotropin releasing hormone (GnRH) antagonist degarelix to suppress FSH production. E2 and FSH were then added back individually and in combination for a period of 3 wk. Energy balance, body mass composition, and transcriptomic profiles of individual tissues were obtained. In contrast to previous studies, suppression and replacement of FSH in our paradigm had no effect on body weight, body composition, food intake, or energy expenditure. We did, however, observe organ-specific effects of FSH that produced unique transcriptomic signatures of FSH in retroperitoneal white adipose tissue. These included reductions in biological processes related to lipogenesis and carbohydrate transport. In addition, rats administered FSH had reduced liver triglyceride concentration (P < 0.001), which correlated with FSH-induced changes at the transcriptomic level. Although not appearing to modulate energy balance after loss of ovarian function in rats, FSH may still impart tissue-specific effects in the liver and white adipose tissue that might affect the metabolic health of those organs.NEW & NOTEWORTHY We find no effect of follicle-stimulating hormone (FSH) on energy balance using a novel model in which rats are ovariectomized, subjected to gonadotropin-releasing hormone antagonism, and systematically given back FSH by osmotic pump. However, tissue-specific effects of FSH on adipose tissue and liver were observed in this study. These include unique transcriptomic signatures induced by the hormone and a stark reduction in hepatic triglyceride accumulation.

Chronotropic Incompetence During Exercise Testing as a Marker of Autonomic Dysfunction in Individuals with Early Parkinson's Disease.

BACKGROUND: An attenuated heart rate response to exercise, termed chronotropic incompetence, has been reported in Parkinson's disease (PD). Chronotropic incompetence may be a marker of autonomic dysfunction and a cause of exercise intolerance in early stages of PD. OBJECTIVE: To investigate the relationship between chronotropic incompetence, orthostatic blood pressure change (supine - standing), and exercise performance (maximal oxygen consumption, VO2peak) in individuals with early PD within 5 years of diagnosis not on dopaminergic medications. METHODS: We performed secondary analyses of heart rate and blood pressure data from the Study in Parkinson's Disease of Exercise (SPARX). RESULTS: 128 individuals were enrolled into SPARX (63.7±9.3 years; 57.0% male, 0.4 years since diagnosis [median]). 103 individuals were not taking chronotropic medications, of which 90 had a normal maximal heart rate response to exercise testing (155.3±14.0 bpm; PDnon-chrono) and 13 showed evidence of chronotropic incompetence (121.3±11.3 bpm; PDchrono, p < 0.05). PDchrono had decreased VO2peak compared to PDnon-chrono (19.7±4.5 mL/kg/min and 24.3±5.8 mL/kg/min, respectively, p = 0.027). There was a positive correlation between peak heart rate during exercise and the change in systolic blood pressure from supine to standing (r = 0.365, p < 0.001). CONCLUSIONS: A subgroup of individuals with early PD not on dopaminergic medication had chronotropic incompetence and decreased VO2peak, which may be related to autonomic dysfunction. Evaluation of both heart rate responses to incremental exercise and orthostatic vital signs may serve as biomarkers of early autonomic impairment and guide treatment. Further studies should investigate whether cardiovascular autonomic dysfunction affects the ability to exercise and whether exercise training improves autonomic dysfunction.

Cardiopulmonary Performance Among Heart Failure Patients Before and After Left Ventricular Assist Device Implantation.

BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) have persistent impairments in functional capacity after continuous-flow left ventricular assist device (CF-LVAD) implantation. OBJECTIVES: This study aims to characterize longitudinal changes in exercise hemodynamics and functional capacity among patients with HFrEF before and after CF-LVAD implantation. METHODS: Ten patients underwent 3 invasive cardiopulmonary exercise tests on upright cycle ergometry with pulmonary artery catheterization: 1) Visit 1 before CF-LVAD implantation; 2) Visit 2 after device implantation with CF-LVAD pump speed held constant at baseline speed; and 3) Visit 3 with increases in pump speed during exercise (median: 1,050 rpm [IQR: 750-1,150 rpm] and 220 rpm [IQR: 120-220 rpm] for HeartMate 3 and HeartWare VAD, respectively). Hemodynamics and direct Fick cardiac output were monitored using pulmonary artery catheterization. Gas exchange metrics were determined using indirect calorimetry. RESULTS: Maximal oxygen uptake (Visits 1, 2, and 3: 10.8 ± 2.5 mL/kg/min, 10.7 ± 2.2 mL/kg/min, and 11.5 ± 1.7 mL/kg/min; P = 0.92) did not improve after device implantation. Mean pulmonary arterial and pulmonary capillary wedge pressures increased significantly during submaximal and peak exercise on preimplantation testing (P < 0.01 for rest vs peak exercise) and remained elevated, with minimal change on Visits 2 and 3 regardless of whether pump speed was fixed or increased. CONCLUSIONS: Among patients with HFrEF, cardiovascular hemodynamics and exercise capacity were similar after CF-LVAD implantation, regardless of whether patients exercised at fixed or adjusted pump speeds during exercise. Further research is needed to determine methods by which LVADs may alleviate the HFrEF syndrome after device implantation. (Effect of mechanIcal circulatoRy support ON exercise capacity aMong pAtieNts with heart failure [IRONMAN]; NCT03078972).

Bone Structure and Turnover in Postmenopausal Women With Long-Standing Type 1 Diabetes.

Compromised bone structural and mechanical properties are implicated in the increased fracture risk in type 1 diabetes (T1D). We investigated bone structure and turnover by histomorphometry in postmenopausal women with T1D and controls without diabetes using tetracycline double-labeled transiliac bone biopsy. After in vivo tetracycline double labeling, postmenopausal women with T1D of at least 10 years and without diabetes underwent transiliac bone biopsy. An expert blinded to the study group performed histomorphometry. Static and dynamic histomorphometry measurements were performed and compared between the two groups. The analysis included 9 postmenopausal women with T1D (mean age 58.4 ± 7.1 years with 37.9 ± 10.9 years of diabetes and HbA1c 7.1% ± 0.4%) and 7 postmenopausal women without diabetes (mean age 60.9 ± 3.3 years and HbA1c 5.4% ± 0.2%). There were no significant differences in serum PTH (38.6 ± 8.1 versus 51.9 ± 23.9 pg/mL), CTX (0.4 ± 0.2 versus 0.51 ± 0.34 ng/mL), or P1NP (64.5 ± 26.2 versus 87.3 ± 45.3 ng/mL). Serum 25-hydroxyvitamin D levels were higher in T1D than in controls (53.1 ± 20.8 versus 30.9 ± 8.2 ng/mL, p < 0.05). Bone structure metrics (bone volume, trabecular thickness, trabecular number, and cortical thickness) were similar between the groups. Indices of bone formation (osteoid volume, osteoid surface, and bone formation rate) were 40% lower in T1D and associated with lower activation frequency. However, the differences in bone formation were not statistically significant. Long-standing T1D may affect bone turnover, mainly bone formation, without significantly affecting bone structure. Further research is needed to understand bone turnover and factors affecting bone turnover in people with T1D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Study in Parkinson's disease of exercise phase 3 (SPARX3): study protocol for a randomized controlled trial.

BACKGROUND: To date, no medication has slowed the progression of Parkinson's disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline. METHODS: This is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60-65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80-85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity. DISCUSSION: SPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health. TRIAL REGISTRATION: ClinicalTrials.gov NCT04284436 . Registered on February 25, 2020.

The Bone Biomarker Response to an Acute Bout of Exercise: A Systematic Review with Meta-Analysis.

BACKGROUND: Circulating biomarkers are often used to investigate the bone response to an acute bout of exercise, but heterogeneity in factors such as study design, quality, selected biomarkers, and exercise and participant characteristics render it difficult to synthesize and evaluate available evidence. OBJECTIVE: The aim of this study was to quantify the effects of an acute exercise bout on bone biomarkers, along with the influence of potential moderators such as participant, exercise, and design characteristics, using a systematic review and meta-analytic approach. METHODS: The protocol was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines and prospectively published. Seven databases were systematically searched in accordance with predefined eligibility criteria. Bayesian three-level hierarchical meta-analysis models were used to explore the main effects of acute exercise on bone biomarkers, as well as potential moderating factors. Modelled effect sizes were interpreted according to three metrics, namely (1) evidence of an effect (defined by whether, or how much of, the credible interval [CrI] included zero); (b) the size of that effect (threshold values of 0.01, 0.2, 0.5 and 0.8 were used to describe effect sizes as very small, small, medium and large, respectively); and (c) the level of certainty in the estimated effect (defined using the GRADE framework). RESULTS: Pooling of outcomes across all designs and categories indicated that an acute bout of exercise increased bone resorption (ES0.5 0.10, 95% CrI 0.00-0.20) and formation (ES0.5 0.05, 95% CrI 0.01-0.08) markers but the effects were very small and highly variable. Furthermore, moderator analyses revealed the source of some of this variability and indicated that exercise type and impact loading influenced the bone resorptive response. A moderate increase in C-terminal telopeptide of type 1 collagen (CTX-1) was observed in response to cycling (ES0.5 0.65, 95% CrI 0.20-0.99), with greater durations and more work leading to larger CTX-1 increases. CTX-1 response peaked within 15 min and 2 h after the exercise bout. Other exercise types did not influence CTX-1. Changes to all bone formation markers were very small and transient, with the very small increases returning to baseline within 15 min of exercise cessation. No major trends for bone formation markers were identified across any of the moderating categories investigated. Certainty of evidence in most outcomes was deemed to be low or very low. CONCLUSION: The large influence of an acute bout of prolonged cycling on the bone resorption marker CTX-1, alongside the lack of a response of any biomarker to resistance or high-impact exercise types, indicate that these biomarkers may be more useful at investigating potentially osteolytic aspects of exercise, and raises questions about their suitability to investigate the osteogenic potential of different exercise types, at least in the short term and in response to a single exercise bout. Certainty in all outcomes was low or very low, due to factors including risk of bias, lack of non-exercise controls, inconsistency, imprecision and small-study effects. PROTOCOL REGISTRATION AND PUBLICATION: This investigation was prospectively registered on the Open Science Framework Registry ( https://osf.io/6f8dz ) and the full protocol underwent peer review prior to conducting the investigation.

Hematopoietic Stem Cell-Derived Adipocytes Modulate Adipose Tissue Cellularity, Leptin Production and Insulin Responsiveness in Female Mice.

A subpopulation of adipocytes in the major adipose depots of mice is produced from hematopoietic stem cells rather than mesenchymal progenitors that are the source of conventional white and brown/beige adipocytes. To analyze the impact of hematopoietic stem cell-derived adipocytes (HSCDAs) in the adipose niche we transplanted HSCs in which expression of a diphtheria toxin gene was under the control of the adipocyte-specific adiponectin gene promoter into irradiated wild type recipients. Thus, only adipocytes produced from HSC would be ablated while conventional white and brown adipocytes produced from mesenchymal progenitor cells would be spared. Wild type mice transplanted with HSCs from mice containing a reporter gene, but not the diphtheria toxin gene, regulated by the adiponectin gene promoter served as controls. In mice in which HSCDA production was suppressed, adipocyte size declined while adipose depot weights were unchanged and the number of conventional adipocyte progenitors significantly increased. We also measured a paradoxical increase in circulating leptin levels while physical activity was significantly decreased in the HSCDA depleted mice. Finally, insulin sensitivity was significantly reduced in HSCDA depleted mice. In contrast, loss of HSCDA production had no effect on body weight, components of energy balance, or levels of several circulating adipokines and tissue-resident inflammatory cells. These data indicate that ablation of this low-abundance subpopulation of adipocytes is associated with changes in circulating leptin levels and leptin-regulated endpoints associated with adipose tissue function. How they do so remains a mystery, but our results highlight the need for additional studies to explore the role of HSCDAs in other physiologic contexts such as obesity, metabolic dysfunction or loss of sex hormone production.

Age-associated reductions in cardiovagal baroreflex sensitivity are exaggerated in middle-aged and older men with low testosterone.

Aging is associated with reductions in cardiovagal baroreflex sensitivity (cBRS), which increases cardiovascular disease risk. Preclinical data indicate that low testosterone reduces cBRS. We determined whether low testosterone is associated with greater age-associated reductions in cBRS in healthy men. Twenty-six men categorized as young (N = 6; age = 31 ± 4 yr; testosterone = 535 ± 60 ng/dL), middle-aged/older with normal (N = 10; aged 56 ± 3 yr; testosterone = 493 ± 85 ng/dL) or low (N = 10; age = 57 ± 6 yr; testosterone = 262 ± 31 ng/dL) testosterone underwent recordings of beat-by-beat blood pressure and R-R interval during rest and two Valsalva maneuvers, and measures of carotid artery compliance. IL-6, C-reactive protein (CRP), oxidized LDL cholesterol, and total antioxidant status (TAS) were also measured in blood. Middle-aged/older men had lower cBRS compared with young men (17.0 ± 6.5 ms/mmHg; P = 0.028); middle-age/older men with low testosterone had lower cBRS (5.5 ± 3.2 ms/mmHg; P = 0.039) compared with age-matched men with normal testosterone (10.7 ± 4.0 ms/mmHg). No differences existed between groups during Phase II of the Valsalva maneuver; middle-aged/older men with low testosterone had reduced cBRS (4.7 ± 2.6 ms/mmHg) compared with both young (12.8 ± 2.8 ms/mmHg; P < 0.001) and middle-aged/older men with normal testosterone (8.6 ± 4.4 ms/mmHg; P = 0.046). There were no differences in oxidized LDL (P = 0.882) or TAS across groups (P = 0.633). IL-6 was significantly higher in middle-aged/older men with low testosterone compared with the other groups (P < 0.05 for all) and inversely correlated with cBRS (r = -0.594, P = 0.007). Middle-aged/older men had reduced carotid artery compliance compared with young, regardless of testosterone status (P < 0.001). These observations indicate that low testosterone in middle-aged/older men may contribute to reductions in cBRS. These data suggest that increased inflammation may contribute to reductions in cBRS.NEW & NOTEWORTHY Middle-aged/older men with low testosterone have accelerated reductions in cardiovagal BRS compared with middle-aged/older men with normal testosterone. Increased concentrations of the proinflammatory cytokine IL-6 appear to contribute to the reductions in cardiovagal BRS in men with low testosterone.

Bone Turnover Markers After Six Nights of Insufficient Sleep and Subsequent Recovery Sleep in Healthy Men.

PURPOSE: The goal of this study was to determine the bone turnover marker (BTM) response to insufficient and subsequent recovery sleep, independent of changes in posture, body weight, and physical activity. METHODS: Healthy men (N = 12) who habitually slept 7-9 h/night were admitted to an inpatient sleep laboratory for a baseline 8 h/night sleep opportunity followed by six nights of insufficient sleep (5 h/night). Diet, physical activity, and posture were controlled. Serum markers of bone formation (osteocalcin, PINP) and resorption (ß-CTX) were obtained over 24 h at baseline and on the last night of sleep restriction, and on fasted samples obtained daily while inpatient and five times after discharge over 3 weeks. Maximum likelihood estimates in a repeated measures model were used to assess the effect of insufficient and subsequent recovery sleep on BTM levels. RESULTS: There was no statistically or clinically significant change in PINP (p = 0.53), osteocalcin (p = 0.66), or ß-CTX (p = 0.10) in response to six nights of insufficient sleep. There were no significant changes in BTMs from the inpatient stay through 3 weeks of recovery sleep (all p [Formula: see text] 0.63). On average, body weight was stable during the inpatient stay (Δweight = - 0.55 ± 0.91 kg, p = 0.06). CONCLUSION: No significant changes in serum BTMs were observed after six nights of insufficient or subsequent recovery sleep in young healthy men. Changes in weight and physical activity may be required to observe significant BTM change in response to sleep and circadian disruptions. Clinical Trials Registration Registered at ClinicalTrials.gov (NCT03733483) on November 7, 2018.

Oxidative Stress and Inflammation Are Associated With Age-Related Endothelial Dysfunction in Men With Low Testosterone.

CONTEXT: Vascular aging, including endothelial dysfunction secondary to oxidative stress and inflammation, increases the risk for age-associated cardiovascular disease (CVD). Low testosterone in middle-aged/older men is associated with increased CVD risk. OBJECTIVE: We hypothesized that low testosterone contributes to age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. METHODS: This cross-sectional study included 58 healthy, nonsmoking men categorized as young (N = 20; age 29 ± 4 years; testosterone 500 ± 58 ng/dL), middle-aged/older with higher testosterone (N = 20; age 60 ± 6 years; testosterone 512 ± 115 ng/dL), and middle-aged/older lower testosterone (N = 18; age 59 ± 8 years; testosterone 269 ± 48 ng/dL). Brachial artery flow-mediated dilation (FMDBA) was measured during acute infusion of saline (control) and vitamin C (antioxidant). Markers of oxidative stress (total antioxidant status and oxidized low-density lipoprotein cholesterol), inflammation (interleukin [IL]-6 and C-reactive protein [CRP]), and androgen deficiency symptoms were also examined. RESULTS: During saline, FMDBA was reduced in middle-aged/older compared with young, regardless of testosterone status (P < 0.001). FMDBA was reduced in middle-aged/older lower testosterone (3.7% ± 2.0%) compared with middle-aged/older higher testosterone (5.7% ± 2.2%; P = 0.021), independent of symptoms. Vitamin C increased FMDBA (to 5.3% ± 1.6%; P = 0.022) in middle-aged/older lower testosterone but had no effect in young (P = 0.992) or middle-aged/older higher testosterone (P = 0.250). FMDBA correlated with serum testosterone (r = 0.45; P < 0.001), IL-6 (r = -0.41; P = 0.002), and CRP (r = -0.28; P = 0.041). CONCLUSION: Healthy middle-aged/older men with low testosterone appear to have greater age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. These data suggest that low testosterone concentrations may contribute to accelerated vascular aging in men.

The Effects of Exercise on Bone Mineral Density in Men: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

The aim of this systematic review and meta-analysis was to provide an updated analysis, including the use of more robust methods, on the effects of exercise on bone mineral density in men. Randomised Control Trials of > 24 weeks and published in English up to 01/05/20 were retrieved from 3 electronic databases, cross-referencing, and expert review. The primary outcome measures were changes in FN, LS, and lower limb BMD Standardised effect sizes were calculated from each study and pooled using the inverse heterogeneity model. A statistically significant benefit of exercise was observed on FN BMD [g = 0.21 (0.03, 0.40), Z = 2.23 p = 0.03], with no observed statistically significant benefit of exercise on LS BMD [g = 0.10 (- 0.07, 0.26), Z = 1.15 p = 0.25]. This analysis provided additional evidence to recommend ground- and/or joint-reaction force exercises for improving or maintaining FN, but not LS BMD. Additional well-designed RCTs are unlikely to alter this evidence, although interventions that include activities that directly load the lumbar spine are needed to ensure this is not a potential method of improving LS BMD.

Body composition and cardiometabolic health across the menopause transition.

Every year, 2 million women reach menopause in the United States, and they may spend 40% or more of their life in a postmenopausal state. In the years immediately preceding menopause-known as the menopause transition (or perimenopause)-changes in hormones and body composition increase a woman's overall cardiometabolic risk. In this narrative review, we summarize the changes in weight, body composition, and body fat distribution, as well as the changes in energy intake, energy expenditure, and other cardiometabolic risk factors (lipid profile, glucose metabolism, sleep health, and vascular function), that occur during the menopause transition. We also discuss the benefits of lifestyle interventions in women in the earlier stages of menopause before these detrimental changes occur. Finally, we discuss how to include perimenopausal women in research studies so that women across the life-span are adequately represented.

Acute catabolic bone metabolism response to exercise in young and older adults: A narrative review.

Exercise is recommended for cardiometabolic benefits and to preserve or improve bone health, especially for older adults at increased risk of fracture. However, exercise interventions have modest benefits on areal bone mineral density (aBMD), and exercise can lead to bone loss in young athletes under certain conditions. In this narrative review, we discuss evidence for a disruption in calcium homeostasis during exercise that may diminish the skeletal benefits of exercise. Topics include 1) a general overview of the effects of exercise on aBMD; 2) discussion of the exercise-induced disruption in calcium homeostasis; 3) factors that influence the magnitude of the exercise-induced disruption in calcium homeostasis, including age, sex, and exercise mode, intensity, and duration; 4) oral calcium supplementation to minimize the exercise-induced disruption in calcium homeostasis; and 5) potential for exercise-induced increase in parathyroid hormone to be both catabolic and anabolic to bone.

The Effects of Exercise Duration and Intensity on Breast Cancer-Related DNA Methylation: A Randomized Controlled Trial.

Emerging research suggests that one mechanism through which physical activity may decrease cancer risk is through its influence on the methylation of genes associated with cancer. The purpose of the current study was to prospectively test, using a rigorous experimental design, whether aerobic exercise affects DNA methylation in genes associated with breast cancer, as well as whether quantity of exercise completed affects change in DNA methylation in a dose-response manner. 276 women (M age = 37.25, SD = 4.64) were recruited from the Denver metro area for a randomized controlled trial in which participants were assigned to a supervised aerobic exercise program varying in a fully crossed design by intensity (55-65% versus 75-85% of VO2max) and duration (40 versus 20 min per session). DNA methylation was assessed via blood samples provided at baseline, after completing a 16-week supervised exercise intervention, and six months after the intervention. 137 participants completed the intervention, and 81 had viable pre-post methylation data. Contrary to our hypotheses, total exercise volume completed in kcal/kg/week was not associated with methylation from baseline to post-intervention for any of the genes of interest. An increase in VO2max over the course of the intervention, however, was associated with decreased post-intervention methylation of BRCA1, p = 0.01. Higher levels of self-reported exercise during the follow-up period were associated with lower levels of GALNT9 methylation at the six-month follow-up. This study provides hypothesis-generating evidence that increased exercise behavior and or increased fitness might affect methylation of some genes associated with breast cancer to reduce risk.

Hematopoietic stem cells produce intermediate lineage adipocyte progenitors that simultaneously express both myeloid and mesenchymal lineage markers in adipose tissue.

Some adipocytes are produced from bone marrow hematopoietic stem cells. In vitro studies previously indicated that these bone marrow-derived adipocytes (BMDAs) were generated from adipose tissue macrophage (ATM) that lose their hematopoietic markers and acquire mesenchymal markers prior to terminal adipogenic differentiation. Here we interrogated whether this hematopoietic-to-mesenchymal transition drives BMDA production In vitro. We generated transgenic mice in which the lysozyme gene promoter (LysM) indelibly labeled ATM with green fluorescent protein (GFP). We discovered that adipose stroma contained a population of LysM-positive myeloid cells that simultaneously expressed hematopoietic/myeloid markers (CD45 and CD11b), and mesenchymal markers (CD29, PDGFRa and Sca-1) typically found on conventional adipocyte progenitors. These cells were capable of adipogenic differentiation In vitro and In vitro, while other stromal populations deficient in PDGFRa and Sca-1 were non-adipogenic. BMDAs and conventional adipocytes expressed common fat cell markers but exhibited little or no expression of hematopoietic and mesenchymal progenitor cell markers. The data indicate that BMDAs are produced from ATM simultaneously expressing hematopoietic and mesenchymal markers rather than via a stepwise hematopoietic-to-mesenchymal transition. Because BMDA production is stimulated by high fat feeding, their production from hematopoietic progenitors may maintain adipocyte production when conventional adipocyte precursors are diminished.

Maintaining serum ionized calcium during brisk walking attenuates the increase in bone resorption in older adults.

BACKGROUND: Endurance exercise can cause a decrease in serum ionized calcium (iCa) and increases in parathyroid hormone (PTH) and bone resorption, reflected by serum carboxy-terminal collagen crosslinks (CTX). We developed a calcium clamp to prevent the decrease in iCa during exercise, which attenuated increases in PTH and CTX during vigorous cycling in young men. The goal was to determine whether this occurs in older adults during brisk walking. METHODS: Twelve older adults (6 men, 6 women) performed two identical 60-min treadmill walking bouts with Ca gluconate or half-normal saline infusion. Blood sampling for iCa, total calcium (tCa), phosphate (P), PTH, and CTX, occurred before, during, and for 4 h after exercise. RESULTS: iCa decreased during exercise with the saline infusion (p = 0.04) and this provoked increases in PTH and CTX (both p < 0.01). The Ca clamp prevented the decrease in serum iCa during exercise and attenuated the PTH and CTX responses. CONCLUSIONS: Preventing the exercise-induced decrease in iCa markedly attenuated the increases in PTH and CTX. The cause of the decrease in iCa during exercise remains unclear, but the increases in PTH and CTX are likely counter-regulatory responses to defend serum iCa. This contention is supported by previous observations that the disruption of Ca homeostasis during exercise occurs regardless of training status. It will be important to establish whether this acute catabolic effect of exercise diminishes the potential chronic anabolic effects of exercise on bone.

Bone turnover marker responses to sleep restriction and weekend recovery sleep.

BACKGROUND: Prior data demonstrated three weeks of sleep restriction and concurrent circadian disruption uncoupled bone turnover markers (BTMs), indicating decreased bone formation and no change or increased bone resorption. The effect of insufficient sleep with or without ad libitum weekend recovery sleep on BTMs is unknown. METHODS: BTMs were measured in stored serum from 20 healthy adults randomized to one of three study groups consisting of a control group (N = 3 men; 9 h/night) or one of two nocturnal sleep restriction groups in an inpatient laboratory environment. One Sleep Restriction group ("SR"; N = 9; 4 women) had 5 h sleep opportunity per night for nine nights. The other sleep restriction group had an opportunity for ad libitum Weekend Recovery sleep ("WR"; N = 8; 4 women) after four nights of 5 h sleep opportunity per night. Food intake was energy balanced at baseline and ad libitum thereafter. Fasted morning BTM levels and hourly 24 h melatonin levels were obtained on study days 3 (baseline), 5 (after 1 night of sleep restriction for WR and SR), and 11 (after a sleep restricted workweek with weekend recovery sleep in WR or 7 nights of sleep restriction in SR). Linear mixed-effects modeling was used to examine the effect of study duration (e.g., change over time), study condition, age, and sex on BTMs. Pearson correlations were used to determine associations between changes in BTMs and changes in weight and morning circadian misalignment (i.e., duration of high melatonin levels after wake time). RESULTS: There was no significant difference between the three study groups in change over time (p ≥ 0.4 for interaction between assigned group and time for all BTMs), adjusted for age and sex. There was no significant change in N-terminal propeptide of procollagen type I (P1NP), osteocalcin, or C-telopeptide of type I collagen (CTX) from baseline to day 11 (all p ≥ 0.3). In women <25 years old, there was a non-significant decline in P1NP from day 3 to day 5 (= -15.74 ± 7.80 ng/mL; p = 0.06). Change in weight and morning circadian misalignment from baseline to day 11 were correlated with statistically non-significant changes in BTMs (all p ≤ 0.05). CONCLUSION: In this small secondary analysis, we showed that nine nights of prescribed sleep restriction with or without weekend recovery sleep and ad libitum food intake did not alter BTMs. It is possible that age, sex, weight change and morning circadian misalignment modify the effects of sleep restriction on bone metabolism.

Effects of Estradiol on Immunoglobulin G Glycosylation: Mapping of the Downstream Signaling Mechanism.

Glycans attached to immunoglobulin G (IgG) directly affect this antibody effector functions and regulate inflammation at several levels. The composition of IgG glycome changes significantly with age. In women, the most notable change coincides with the perimenopausal period. Aiming to investigate the effect of estrogen on IgG glycosylation, we analysed IgG and total serum glycomes in 36 healthy premenopausal women enrolled in a randomized controlled trial of the gonadotropin-releasing hormone analogue (GnRHAG) leuprolide acetate to lower gonadal steroids to postmenopausal levels and then randomized to transdermal placebo or estradiol (E2) patch. The suppression of gonadal hormones induced significant changes in the IgG glycome, while E2 supplementation was sufficient to prevent changes. The observed glycan changes suggest that depletion of E2 primarily affects B cell glycosylation, while liver glycosylation stays mostly unchanged. To determine whether previously identified IgG GWAS hits RUNX1, RUNX3, SPINK4, and ELL2 are involved in downstream signaling mechanisms, linking E2 with IgG glycosylation, we used the FreeStyle 293-F transient system expressing IgG antibodies with stably integrated CRISPR/dCas9 expression cassettes for gene up- and downregulation. RUNX3 and SPINK4 upregulation using dCas9-VPR resulted in a decreased IgG galactosylation and, in the case of RUNX3, a concomitant increase in IgG agalactosylation.

Ibuprofen taken before exercise blunts the IL-6 response in older adults but does not alter bone alkaline phosphatase or c-telopeptide.

INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) taken before exercise have been shown to impair bone formation. NSAIDs also suppress inflammatory cytokines, such as interleukin-6 (IL-6), that can have pro-resorptive effects. It is unclear how taking NSAIDs timed around exercise influences inflammatory and bone biomarkers following an acute exercise bout in older adults. PURPOSE: To determine if timing of ibuprofen use relative to a single exercise bout has acute effects on serum IL-6, bone-specific alkaline phosphatase (BAP, marker of bone formation), and c-telopeptide of type I collagen (CTX, marker of bone resorption). METHODS: As part of a 36-week exercise intervention, participants aged 60 to 75 years were randomized to 3 groups: placebo before and after exercise (PP), ibuprofen before and placebo after exercise (IP), or placebo before and ibuprofen after exercise (PI). Acute responses were studied in a subset of participants (12 PP, 17 IP, 13 PI). Blood was sampled before and immediately, 30 min, and 60 min after exercise for IL-6, BAP, and CTX. RESULTS: The exercise-induced increase in IL-6 was blunted in response to IP when compared to PI 60-min after exercise (p < 0.001). There were no significant differences in the change in BAP or CTX between groups at any time points CONCLUSION: Ibuprofen taken before exercise dampened the inflammatory response to exercise but had no effects on bone biomarkers in older adults. It may be necessary to monitor changes for a longer time interval after an acute exercise bout to determine whether bone turnover is altered by ibuprofen or other NSAIDs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00462722; Posted 04/19/2007.