Deleterious Effects of Simulated Spaceflight on Bone and Microvasculature in Adult Mice

Long-term spaceflight leads to extensive changes in the musculoskeletal system attributable, in part, to unloading during microgravity exposure. Additionally, irradiation at doses similar to that of a solar flare or a round-trip sojourn to Mars may cause significant depletion of stem/progenitor cell pools throughout the body as well as inflammation associated with prompt skeletal-tissue degradation. Previously, we demonstrated that irradiation leads to rapid bone loss, which can be mitigated in the short term by injection of a potent antioxidant (-lipoic acid). Furthermore, simulated weightlessness in adult mice adversely affects skeletal responses to low linear energy transfer (LET) radiation (137Cs). Here, we hypothesized that simulated weightlessness exacerbates the adverse effects of simulated space radiation (including both protons and 56Fe ions) by adversely affecting skeletal structure and functions as well as associated vasculature. Furthermore, we hypothesized that an antioxidant cocktail, which has been shown to be protective in other tissues, mitigates space radiation induced bone loss

Exercise Training Augments Regional Bone and Marrow Blood Flow during Exercise

INTRODUCTION: The principal nutrient artery to the femur demonstrates an increase in nitric oxide mediated vasodilation in rats after treadmill exercise training. The present study sought to determine whether exercise training improves hindlimb bone and marrow blood flow distribution at rest and during exercise. METHODS: Six-eight month old male Sprague-Dawley rats were exercise trained (ET) with treadmill walking at 15 m/min up a 15° incline for 60 min/d over a 10–12 wk period. Sedentary (SED) control animals were acclimated to treadmill exercise for 5 min/d during the week preceding the blood flow measurements. Blood flow to nine distinct regions of the femur, tibia, and fibula were determined at rest and during low-intensity exercise (15 m/min walking, 0° incline) using the reference sample microsphere method. RESULTS: The results demonstrate an augmentation of exercise hyperemia above that observed in SED rats during exercise in only one region of bone, the femoral diaphysis of ET rats. However, while exercise hyperemia occurred in 3 of the 9 hindlimb bone regions measured in SED rats, exercise hyperemia occurred in 7 of 9 regions in ET rats. CONCLUSION: These data indicate an increase in generalized hindlimb bone and marrow blood flow during physical activity following a period of exercise training. Elevations in regional bone and marrow blood flow after training may augment medullary pressure and bone interstitial fluid flow, thus benefiting bone integrity

High resolution linkage and linkage disequilibrium analyses of chromosome 1p36 SNPs identify new positional candidate genes for low bone mineral density

A quantitative trait locus (QTL) for BMD maps to chromosome 1p36. We have analyzed a high density SNP panel from this region for linkage and association to BMD in 39 osteoporosis pedigrees. Our results support the presence of genes controlling BMD on 1p36 and indicate new candidates for further analyses. Low BMD is one of the major risk factors for osteoporosis. Following a genome scan in a sample of Caucasian families recruited through probands with low BMD, a region on 1p36 near marker D1S214 received support as a QTL for BMD from linkage (maximum lod-score = 2.87) and linkage disequilibrium (LD) analysis (p < 0.01). To better characterize the genetic risk factors for low BMD located in this genomic region, we have genotyped the same group of families for 1095 SNPs located across 11 Mb on 1p36. Linkage and LD analyses have been performed using the variance component approach. Multivariate linkage analysis indicated two QTLs for femoral neck BMD, lumbar spine BMD and trochanter BMD simultaneously on 1p36, with maximum lod-scores of 4.37 at 12 cM and 3.59 at 22 cM. LD analysis identified several SNPs potentially associated with BMD, including the RERE gene SNP rs11121179 (p = 0.000005 for lumbar spine BMD). Other candidate genes include G1P2, SSU72 and CCDC27 (each containing 1 SNP with p < 0.001 for at least one BMD trait). This study supports the presence in 1p36 of QTLs affecting BMD at multiple skeletal sites. Replication of our results in other independent cohorts is warranted

Effects of hindlimb unloading and ionizing radiation on skeletal muscle resistance artery vasodilation and its relation to cancellous bone in mice

Spaceflight has profound effects on vascular function as a result of weightlessness that may be further compounded by radiation exposure. The purpose of the present study was to assess the individual and combined effects of hindlimb unloading (HU) and radiation (Rad) on vasodilator responses in the skeletal muscle vasculature. Adult male C57BL/6J mice were randomized to one of four groups: control (Con), HU (tail suspension for 15 days), Rad (200 cGy of137Cs), and HU-Rad (15-day tail suspension and 200 cGy of137Cs). Endothelium-dependent vasodilation of gastrocnemius feed arteries was assessed in vitro using acetylcholine (ACh, 10−9–10−4M) and inhibitors of nitric oxide synthase (NOS) and cyclooxygenase (COX). Endothelium-independent vasodilation was assessed using Dea-NONOate (10−9–10−4M). Endothelium-dependent and -independent vasodilator responses were impaired relative to Con responses in all treatment groups; however, there was no further impairment from the combination of treatments (HU-Rad) relative to that in the HU and Rad groups. The NOS-mediated contribution to endothelium-dependent vasodilation was depressed with HU and Rad. This impairment in NOS signaling may have been partially compensated for by an enhancement of PGI2-mediated dilation. Changes in endothelium-dependent vasodilation were also associated with decrements in trabecular bone volume in the proximal tibia metaphysis. These data demonstrate that the simulated space environment (i.e., radiation exposure and unloading of muscle and bone) significantly impairs skeletal muscle artery vasodilation, mediated through endothelium-dependent reductions in NOS signaling and decrements in vascular smooth muscle cell responsiveness to NO.</jats:p