Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice.

Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and found that Notch3 inactivation alters regulation of calcium and contractile function and promotes a notable increase in extracellular matrix. These alterations adversely impact vascular reactivity, manifesting as dilation, tortuosity, microaneurysms, and decreased cerebral blood flow, as observed by MRI. Combined, these vascular impairments hinder glymphatic flow and result in buildup of glycosaminoglycans within the brain parenchyma. Remarkably, this phenomenon mirrors a key pathological feature found in brains of patients with CADASIL, a hereditary vascular dementia associated with NOTCH3 missense mutations. Additionally, single-cell RNA sequencing of the neuronal compartment in aging Notch3-null mice unveiled patterns reminiscent of those observed in neurodegenerative diseases. These findings offer direct evidence that age-related NOTCH3 deficiencies trigger a progressive decline in vascular function, subsequently affecting glymphatic flow and culminating in neurodegeneration.

Non-traditional HIIT-style ROTC training elicits positive bone quality and performance adaptations.

Military personnel experience elevated bone injury incidence, partly due to arduous and repetitive training. Non-traditional High-Intensity Interval Training-style (HIIT) may benefit pre-enlisted Reserve Officer Training Corps (ROTC) cadet's musculoskeletal health and performance prior to military service. This study investigated 16 ROTC (n = 12 males; n = 4 females) and 15 physically active sex-, age-, and body mass-matched Controls' musculoskeletal health and performance from November to April. Total body, lumbar spine, and dual- hip dual-energy X-ray absorptiometry scans and 4%, 38%, 66% tibial peripheral quantitative computed tomography scans, blood draws (serum sclerostin and parathyroid hormone), and maximal muscle strength and aerobic capacity testing were completed. From November to April, ROTC improved bone density (DXA) of the dominant total hip and greater trochanter and non-dominant greater trochanter and 38% and 66% tibial total volumetric and cortical bone density (pQCT) similarly or more than Controls (all p ≤ 0.049). From November to April, ROTC also improved bench and leg press, and peak aerobic capacity (all p ≤ 0.013). From November to January, serum sclerostin increased (p ≤ 0.007) and remained elevated through April, while parathyroid hormone was unchanged. HIIT-style training induced positive musculoskeletal adaptations, suggesting it may be an excellent pre-service training modality for this injury prone group.

Circulating microRNA responses to acute whole-body vibration and resistance exercise in postmenopausal women.

Evaluating alterations in circulating microRNA (c-miRNA) expression may provide deeper insight into the role of exercise in the attenuation of the negative effects of aging on musculoskeletal health. Currently, there are sparse data on c-miRNA responses to acute exercise in postmenopausal women. The purpose of this study was to characterize the effects of acute bouts of resistance exercise and whole-body vibration on expression of selected c-miRNAs in postmenopausal women aged 65-76 years (n=10). We also examined relationships between c-miRNAs and muscle strength and bone characteristics. This randomized crossover design study compared c-miRNA responses to a bout of resistance exercise (RE) (3 sets 10 reps 70% 1 repetition maximum (1RM), 5 exercises) and a bout of whole-body vibration (WBV) (5 sets 1 min bouts 20Hz 3.38mm peak to peak displacement, Vibraflex vibration platform). DXA was used to measure body composition and areal bone mineral density (aBMD) of the total body, AP lumbar spine, and dual proximal femur. pQCT was used to measure tibia bone characteristics (4%, 38%, 66% sites). Blood samples were collected before exercise (Pre), immediately-post (IP), 60 minutes post (60P), 24 hours (24H), and 48 hours (48H) after exercise to measure serum miR-21-5p, -23a-3p, -133a-3p, -148a-3p (qPCR) and TRAP5b (ELISA). There was a significant modality × time interaction for c-miR-21-5p expression (p=0.019), which decreased from 60P to 24H after WBV only. TRAP5b serum concentrations significantly increased IP then decreased below Pre at 24H for both WBV and RE (p<0.01). Absolute changes in TRAP5b were negatively correlated with c-miR-21-5p fold changes (r= -0.642 to -0.724, p<0.05) for both exercise modalities. There were significant negative correlations between baseline c-miRNAs and bone status variables (r= -0.639 to -0.877, p<0.05). Our findings suggest that whole-body vibration is a sufficient mechanical stimulus for altering c-miR-21-5p expression, whereas a high intensity resistance exercise protocol did not elicit any c-miRNA responses in postmenopausal women. Increases in the bone resorption marker, TRAP5b, were associated with greater downregulation of c-miR-21-5p expression.

Acute and Chronic Bone Marker and Endocrine Responses to Resistance Exercise With and Without Blood Flow Restriction in Young Men.

In this study, we compared acute and chronic bone marker and hormone responses to 6 weeks of low intensity (20% 1RM) blood flow restriction (BFR20) resistance training to high intensity (70% 1RM) traditional resistance training (TR70) and moderate intensity (45% 1RM) traditional resistance training (TR45) in young men (18-35 years). Participants were randomized to one of the training groups or to a control group (CON). The following training programs were performed 3 days per week for 6 weeks for knee extension and knee flexion exercises: BFR20, 20%1RM, 4 sets (30, 15, 15, 15 reps) wearing blood flow restriction cuffs around the proximal thighs; TR70, 70% 1RM 3 sets 10 reps; and TR45, 45% 1RM 3 sets 15 reps. Muscle strength and thigh cross-sectional area were assessed at baseline, between week 3 and 6 of training. Acute bone marker (Bone ALP, CTX-I) and hormone (testosterone, IGF-1, IGFBP-3, cortisol) responses were assessed at weeks 1 and 6, with blood collection done in the morning after an overnight fast. The main findings were that the acute bone formation marker (Bone ALP) showed significant changes for TR70 and BFR20 but there was no difference between weeks 1 and 6. TR70 had acute increases in testosterone, IGF-1, and IGFBP-3 (weeks 1 and 6). BFR20 had significant acute increases in testosterone (weeks 1 and 6) and in IGF-1 at week 6, while TR45 had significant acute increases in testosterone (week 1), IGF-1 (week 6), and IGFBP-3 (week 6). Strength and muscle size gains were similar for the training groups. In conclusion, low intensity BFR resistance training was effective for stimulating acute bone formation marker and hormone responses, although TR70 showed the more consistent hormone responses than the other training groups.

Associations of serum IL-6 with muscle, bone, and adipose tissue in women.

This cross-sectional study examined the associations between serum interleukin-6 (IL-6) and muscle, bone, and fat parameters in recreationally active women. One-hundred forty-five women (48.7 ± 17.8 years; 164.4 ± 7.1 cm; 66.8 ± 10.7 kg; and 24.7 ± 3.9 kg/m2) underwent dual energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) assessments to determine total and regional muscle, bone, and fat parameters. Muscle performance of the knee extensors was examined via isometric, isotonic, and isokinetic dynamometry assessments, and serum IL-6 was measured via enzyme linked immunosorbent assay. Serum IL-6 was inversely associated with thigh muscle cross-sectional area (mCSA, r = -0.28, p < 0.01); isometric strength (r = -0.19, p < 0.05); hip areal bone mineral density [aBMD] (r = -0.18, p < 0.05); trochanter aBMD (r = -0.23, p < 0.01); total body aBMD (r = -0.20, p < 0.05); cortical volumetric bone density at 38 and 66% tibia (r = -0.18 and r = -0.19, respectively, both p < 0.05), and 66% cortical thickness (r = -0.17, p < 0.05). These associations were present after adjusting for age, BMI, and physical activity. Thigh mCSA was significantly lower in the tertile possessing the greatest IL-6 compared to the lowest tertile (p < 0.01); after adjusting for age, body mass index, and physical activity. Collectively, these observations indicate that IL-6 is inversely associated with skeletal muscle and bone parameters independent of relevant confounders. These observations bolster the prognostic value of serum IL-6.

Skeletal Health and Associated Injury Risk in Collegiate Female Rowers.

ABSTRACT: Baker, BS, Buchanan, SR, and Bemben, DA. Skeletal health and associated injury risk in collegiate female rowers. J Strength Cond Res 36(4): 1125-1133, 2022-Rowing has been associated with low bone mass and stress fractures. The aim of this study was to compare bone density, geometry, and skeletal asymmetries between competitive female rowers and matched controls and within rowers based on reported injury status, allowing for the calculation of practical injury risk prediction equations. Rowers (n = 24) and controls (n = 24) completed total body, lumbar spine, and and dual femur and radii dual energy x-ray absorptiometry and peripheral quantitative computed tomography scans. One-way analyses of covariance were performed between rowers and controls, and one-way analyses of variance were performed between rowers based on reported rib injury status (injured [n = 11]; injury-free [n = 13]). Logistic regression was used to create prediction models of rowers' injury status. Significance was set at p ≤ 0.05. Rowers were taller, had greater lean mass, less fat mass, and mostly equivalent skeletal measures compared to controls, which were within normal ranges (p < 0.048). Injury-free rowers consumed over 500 mg·d-1 more calcium and were less symmetrical at the 4% tibiae and hips (p < 0.015). The strongest predictive regression model of reported rib injury in rowers comprised calcium intake and the symmetry index of hip strength index (R2 = 0.833; p < 0.001). A more practical model including daily calcium intake and total bone specific physical activity (PA) scores can be used to correctly predict injury status 75% of the time (R2 = 0.750; p = 0.022). This is the first study to provide practitioners an injury prediction model for competitive rowers, reiterating the importance of proper nutrition and auxiliary PA focusing on balanced movement patterns.

Sclerostin and Dickkopf-1 Characteristics According to Age and Physical Activity Levels in Premenopausal Women.

We aimed to compare serum concentrations of sclerostin and DKK-1 in young (20-30 yrs, n = 25) and middle-aged (35-45 yrs, n = 25) premenopausal women and based on physical activity (PA) status. PA status was assessed by the International Physical Activity Questionnaire (low-moderate (≤ 2999 MET-min/week) and high (≥ 3000 MET-min/week). Serum sclerostin and DKK-1 levels were measured in fasting morning blood samples by ELISA. Areal bone mineral density (aBMD) was measured by DXA, and non-dominant tibia bone characteristics were assessed by pQCT. After adjusting for total body aBMD, middle-aged women had significantly (p < 0.001) higher (0.54 ± 0.01 ng/mL) serum sclerostin than young women (0.41 ± 0.01 ng/mL), and sclerostin was positively correlated with age (rs = 0.065, p ≤ 0.001) and total PA score (rs = 0.33, p = 0.021). Young women had higher left trochanter aBMD (p = 0.036) than middle-aged women and aBMD variables were higher (all p ≤ 0.043) in the high active group. Middle-aged women had higher 38% cortical vBMD than young women (p = 0.021), otherwise young women had higher values for pQCT variables (all p ≤ 0.036). Sclerostin showed significant correlations (r = 0.32 to 0.58, all p ≤ 0.026) with spine aBMD for the entire cohort and for each age group. Middle-aged women had significant correlations between sclerostin and hip aBMD sites (r = 0.043 to 0.56, all p ≤ 0.031). Sclerostin and cortical vBMD were positively correlated in the entire cohort (r = 0.35 to 0.50; both p < 0.013); split by age group, middle-aged women had positive correlations (r = 0.45 to 0.61 age and, all p ≤ 0.021) between sclerostin and pQCT variables. No significant differences for physical activity were observed for serum DKK-1 concentrations. Serum sclerostin concentrations were positively associated with age and bone characteristics in premenopausal women; however, these findings were not evident for circulating DKK-1. Further research is needed to elucidate the mechanisms for the discordant results in these Wnt inhibitors.

Bone, Biomarker, Body Composition, and Performance Responses to 8 Weeks of Reserve Officers' Training Corps Training.

CONTEXT: Military personnel engage in vigorous exercise, often resulting in higher bone mineral density; however, leg bone injuries occur frequently in this population. Predictors of change in tibial bone quality and strength need to be characterized in this high-risk population. OBJECTIVES: To examine the effects of an 8-week military training intervention on total body and site-specific bone density and tibial bone quality, serum biomarkers (parathyroid hormone and sclerostin), body composition, and physical performance and to investigate which outcome variables (biomarkers, body composition, and physical performance) predict estimated tibial bone strength in college-aged Reserve Officers' Training Corps (ROTC) participants. DESIGN: Prospective cohort study. SETTING: University of Oklahoma. PATIENTS OR OTHER PARTICIPANTS: The ROTC participants (14 males, 4 females) were matched for sex, age, and mass to physically active control participants (14 males, 4 females). The ROTC participants engaged in an 8-week training intervention, while the physically active control group made no changes to their exercise routines. MAIN OUTCOME MEASURE(S): Preintervention general health questionnaires were completed. Pre-, mid-, and postintervention bone scans (dual-energy x-ray absorptiometry and peripheral quantitative computed tomography); serum blood draws (parathyroid hormone and sclerostin); and physical performance measures (muscle strength and aerobic capacity) were obtained. RESULTS: The ROTC participants exhibited increased hip bone density mineral and content (both P values ≤ .02) after the 8-week intervention. Sclerostin, but not parathyroid hormone, was a positive correlate and predictor in all ROTC models for estimated bone strength at the fracture-prone 38% tibial site (ie, 38% of the tibial length proximal to the distal end of the tibia). Both groups displayed decreased total body and regional fat mass, and ROTC participants' aerobic capacity increased (all P values ≤ .05). CONCLUSIONS: All bone, body composition, and performance measures either improved or were maintained in response to ROTC training. Sclerostin should be further investigated as a potential early indicator of changes in estimated tibial bone strength in military cohorts.

Muscle Performance Changes with Age in Active Women.

The purpose of this study was to examine age-related differences in muscle performance in women divided into young (YW, 20-39 years, n = 29) middle-aged (MAW, 40-59 years, n = 33), and older (OW, ≥60 years, n = 40) age groups. METHODS: Hand grip strength, vertical jump performance, and knee extensor (KE) strength (0 deg/s, 60 deg/s, and 240 deg/s), speed of movement (SoM; at 1 Nm, 20%, 40%, and 60% isometric strength), and endurance (30-repetition test at 60 degs/s and 240 deg/s) were assessed. Computed tomography-acquired muscle cross-sectional area (mCSA) was measured and included to determine specific strength (KE strength/mCSA). RESULTS: Hand grip strength was similar across groups, while jump performance declined with age (YW and MAW > OW, p < 0.001). KE strength declined significantly with age (all conditions p < 0.01), while specific strength was similar across groups. SoM was significantly higher for YW and MAW compared to OW (both p < 0.01). An age × velocity interaction revealed YW KE endurance was similar between conditions, whereas MAW and OW displayed significantly better endurance during the 60 deg/s condition. OW displayed impaired KE endurance at 240 deg/s (vs. YW and MAW, p < 0.01) but improved at 60 deg/s (vs. YW, p < 0.01). Dynamic torque decline increased with age (YW < OW, p = 0.03) and was associated with intramuscular adipose tissue (r = 0.21, p = 0.04). CONCLUSIONS: Performance declines were most evident among OW, but few performance deficits had emerged in MAW. Interestingly, strength declines disappeared after normalizing to mCSA and endurance appears to be velocity-dependent.

Muscle-Bone Interactions in Chinese Men and Women Aged 18-35 Years.

To characterize bone mineral density (BMD), bone strength, muscle and fat mass, and muscle strength and power in Chinese women (n = 25) and men (n = 28) classified as in the bone accrual phase (18-25 years) or in the peak bone mass phase (26-35 years). Calcium intakes, physical activity levels, and serum vitamin D were measured. Dual-energy X-ray absorptiometry (DXA) assessed body composition, lumbar spine, and hip areal BMD (aBMD) variables and peripheral quantitative computed tomography (pQCT) assessed cortical and trabecular volumetric BMD (vBMD) and bone strength. Muscle strength and power were assessed by grip strength, leg press, and vertical jump tests. Calcium, serum vitamin D, and physical activity levels were similar across age and sex groups. Significant sex differences (p < 0.05) were found for most body composition variables, hip aBMD, tibia variables, and muscle strength and power. Adjusting for height and weight eliminated most of the significant sex differences. Women showed stronger positive correlations between body composition and bone variables (r = 0.44 to 0.78) than men. Also, correlations between muscle strength/power were stronger in women vs. men (r = 0.43 to 0.82). Bone traits were better related to body composition and muscle function in Chinese women compared to Chinese men aged 18 to 35 years, and peak bone mass seems to be achieved by 25 years of age in both Chinese men and women since there were no differences between the two age groups.

Low-grade and high-grade endometrial stromal sarcoma: A National Cancer Database study.

OBJECTIVE: To provide refined prognostic information from large cohorts of women with low-grade or high-grade endometrial stromal sarcoma (ESS). METHODS: We performed an observational retrospective cohort analysis of women diagnosed with low-grade or high-grade ESS from the 1998-2013 National Cancer Database. Kaplan-Meier and multivariable accelerated failure time survival analyses were performed to identify prognostic factors after multiple imputation of missing data. Recursive partitioning methods were used to rank prognostic factors in high-grade ESS. Matched cohort analyses were performed to hypothesis-test effects of adjuvant treatments. RESULTS: We identified 2414 and 1383 women with low-grade or high-grade ESS, respectively. Women with high-grade ESS had markedly decreased survival compared to women with low-grade ESS (five-year survival (95% CI): 32.6 (30.1-35.3%) versus 90.5% (89.3-91.8%), P<0.001). Among women with high-grade ESS, median survival (95% CI) was only 19.9 (17.1-22.1) months. Increased age and tumor size were associated with decreased survival in low-grade ESS. In high-grade ESS, additional negative prognostic factors were distant or nodal metastasis, omission of lymphadenectomy, and pathologically-positive surgical margins (all P<0.001). Use of adjuvant chemotherapy (time ratio (TR) (95% CI): 1.36 (1.17-1.58), P<0.001) and radiotherapy (TR (95% CI): 1.57 (1.32-1.87), P<0.001) were associated with increased survival for high-grade ESS. CONCLUSION: The contrasting excellent versus poor prognosis of low-grade versus high-grade ESS, respectively, was confirmed. The best treatment of high-grade ESS is early and complete surgical resection including lymphadenectomy. Adjuvant chemotherapy and radiotherapy may increase survival of women with high-grade ESS.

Knockout of ADAMTS5 does not eliminate cartilage aggrecanase activity but abrogates joint fibrosis and promotes cartilage aggrecan deposition in murine osteoarthritis models.

To investigate the role of ADAMTS5 in murine osteoarthritis (OA), resulting from destabilization of the medial meniscus (DMM model) or from TGFb1 injection and enforced uphill treadmill running (TTR model). Wild-type (WT) and ADAMTS5-/- mice were subjected to either DMM or TTR and joints were evaluated for meniscal damage, cartilage changes, and fibrotic ingrowths from the joint margins. Cartilage lesions were quantified on an 8-point scoring system. Cartilage chondroitin sulfate (CS) content was evaluated by SafraninO staining and by quantitative electrophoresis (FACE). The abundance of aggrecan, versican, and specific aggrecanase-generated products was determined by Western analysis. Joint changes were similar for WT mice taken through either the DMM or the TTR model. ADAMTS5 ablation essentially eliminated cartilage erosion and fibrous overgrowth in both models. In the TTR model, ADAMTS5 ablation did not eliminate aggrecanase activity from the articular cartilage but blocked fibrosis and resulted in the accumulation of aggrecan in the articular cartilage. The cartilage protection provided by ADAMTS5 ablation in the mouse does not result from prevention of aggrecanase activity per se, but it appears to be due to a blockade of joint tissue fibrosis and a concomitant increase in cartilage aggrecan content.