The results of this study demonstrate that muscle function progressively declines in the Cy/+ rat model of CKD. Because whole muscle mass and architecture do not vary between CKD and NL, but CKD muscles show reduction in individual fiber CSA, our data suggest that the functional decline is related to increased muscle fiber atrophy.
The objective of this study was to evaluate the effects of varying light doses on the viability and cellular activity of osteoblasts, osteocytes, and osteoclasts. A light application device was developed to apply 940-nm wavelength light from light-emitting diodes on three cultured cells, MC3T3-E1, MLO-A5, and RANKL-treated RAW264.7 cells. The doses (energy density) on cells were 0, 1, 5, and 7.5 J / cm2. The corresponding light power densities at the cell site were 0, 1.67, 8.33, and 12.5 mW / cm2, respectively, and the duration was 10 min. The results showed that the three cell types respond differently to light and their responses were dose dependent. Low-dose treatment (1 J / cm2) enhanced osteoblast proliferation, osteoclast differentiation, and osteoclastic bone resorption activity. Osteocyte proliferation was not affected by both low- and high-dose (5 J / cm2) treatments. While 1 J / cm2 did not affect viability of all three cell types, 5 J / cm2 significantly decreased viability of osteocytes and osteoclasts. Osteoblast viability was negatively impacted by the higher dose (7.5 J / cm2). The findings suggest that optimal doses exist for osteoblast and osteoclast, which can stimulate cell activities, and there is a safe dose range for each type of cell tested.
Calcific aortic valve disease (CAVD) is a deadly disease that is rising in prevalence due to population aging. While the disease is complex and poorly understood, one well-documented driver of valvulopathy is serotonin agonism. Both serotonin overexpression, as seen with carcinoid tumors and drug-related agonism, such as with Fenfluramine use, are linked with various diseases of the valves. Thus, the objective of this study was to determine if genetic ablation or pharmacological antagonism of the 5-HT2B serotonin receptor (gene: Htr2b) could improve the hemodynamic and histological progression of calcific aortic valve disease. Htr2b mutant mice were crossed with Notch1+/- mice, an established small animal model of CAVD, to determine if genetic ablation affects CAVD progression. To assess the effect of pharmacological inhibition on CAVD progression, Notch1+/- mice were treated with the 5-HT2B receptor antagonist SB204741. Mice were analyzed using echocardiography, histology, immunofluorescence, and real-time quantitative polymerase chain reaction. Htr2b mutant mice showed lower aortic valve peak velocity and mean pressure gradient–classical hemodynamic indicators of aortic valve stenosis–without concurrent left ventricle change. 5-HT2B receptor antagonism, however, did not affect hemodynamic progression. Leaflet thickness, collagen density, and CAVD-associated transcriptional markers were not significantly different in any group. This study reveals that genetic ablation of Htr2b attenuates hemodynamic development of CAVD in the Notch1+/- mice, but pharmacological antagonism may require high doses or long-term treatment to slow progression.
The musculoskeletal system is remarkably plastic during growth. The purpose of this study was to examine the muscular plasticity in functional and structural properties in a model known to result in significant developmental plasticity of the postcranial skeleton. Fifteen weanling C57BL/6 mice were raised to 16 weeks of age in one of two enclosures: a climbing enclosure that simulates a fine branch arboreal habitat and is traversed by steel wires crossing at 45° relative to horizontal at multiple intersections, and a control enclosure that resembles a parking deck with no wires but the same volume of habitable space. At killing, ex vivo contractility properties of the soleus (SOL) and extensor digitorum longus (EDL) muscles were examined. Our results demonstrate that EDL muscles of climbing mice contracted with higher specific forces and were comprised of muscle fibers with slower myosin heavy chain isoforms. EDL muscles also fatigued at a higher rate in climbing mice compared to controls. SOL muscle function is not affected by the climbing environment. Likewise, mass and architecture of both EDL and SOL muscles were not different between climbing and control mice. Our data demonstrate that functional adaptation does not require concomitant architectural adaptation in order to increase contractile force. Anat Rec, 301:434-440, 2018. © 2018 Wiley Periodicals, Inc.
Post-menopausal women tend to have worse cardiovascular outcomes in a manner that is associated with osteoporosis severity. In this study we performed the first evaluation of the left ventricle and aortic valve phenotype of ovariectomized mice aged on Western diet to one year. Disease was monitored in vivo using echocardiography and dual x-ray absorptiometry imaging and ex vivo using quantitative histological and immunostaining analysis. Mice had decreased bone mineral density in response to ovariectomy and increased fat mass in response to Western diet. Ovariectomized mice had a significantly increased left ventricle mass compared to control animals, absent of fibrosis. There was a slight increase in aortic valve peak velocity but no change in mean pressure gradient across the valve in the ovariectomy group. There was no evidence of leaflet hypertrophy, fibrosis, calcification, or protein markers of dystrophic or osteogenic calcification. This model of ovariectomy may present a novel method of studying left ventricle hypertrophy in female populations but does not have a phenotype for study of aortic stenosis. This is particularly useful as it does not require genetic manipulation or drug treatment and more faithfully mimics the aging, high-cholesterol diet, and post-menopausal osteoporosis many female patients experience potentially resulting in a more translatable disease model.
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