Browsing by Subject "disuse"
Now showing 1 - 3 of 3
Results Per Page
Sort Options
Item Bone Canonical WNT/B-Catenin Signaling in Models of Reduced Microgravity(2012-10-25) Macias, Brandon 1979-Human exposure to reduced weightbearing results in bone loss. The rate of bone loss during microgravity exposure is similar to that of a post-menopausal women. In fact, the maintenance of bone mass is intimately dependent on exercise. Therefore, exercise associated mechanical loads to bone tissue are an important countermeasure to prevent disuse-induced bone loss. However, the types of exercise modalities required to prevent such bone loss are unclear. Moreover, how mechanical loading to bone translates into molecular osteogenic signals in bone cells is unknown. Radiation exposure is another potent inducer of bone loss, namely observed on Earth in the clinical setting following radiotherapy procedures. It is expected that long duration space missions outside the protection of Earth?s magnetosphere will result in significant galactic cosmic radiation exposure. However, the magnitude of bone loss resulting from this galactic cosmic radiation exposure is unclear. Moreover, it is unknown if radiation exposure will exacerbate disuse-induced bone loss. Therefore, a series of experiments were designed to determine: 1) Will simulated galactic cosmic radiation exacerbate reduced weightbearing-induced bone loss? 2) Will pharmacological activation of the putative mechanosensing Wnt pathway enhance exercise-induced bone mass gain? To address these questions the experimental study series employed two animal models of reduced weightbearing, hindlimb unloading and partial weightbearing. These model test-beds enabled the evaluation of two novel countermeasures (simulated resistance exercise and glycogen synthase kinase-3 (GSK-3) therapeutic) and simulated exposure to space radiation environments. To test the impact of simulated space radiation (28Si) one study of the series was conducted at Brookhaven National Laboratory. To quantify the impact of the abovementioned countermeasures and space radiation on bone, mechanical testing, peripheral quantitative computed tomography, micro-computed tomography, histomorphometry, and immunohistochemistry served as primary outcome measures. The primary findings are: 1) Low-dose high-LET radiation negativity impacts maintenance of bone mass by lowering bone formation and increasing bone resorption. This impaired bone formation response is in part due to sclerostin induced suppression of Wnt signaling. 2) Combining GSK-3 inhibition with high intensity exercise mitigates cancellous bone loss and restores cortical periosteal growth during disuse.Item Mechanisms of impaired osteoblast function during disuse(Texas A&M University, 2004-11-15) Allen, Matthew RobertProlonged periods of non-weightbearing activity result in a significant loss of bone mass which increases the risk of fracture with the initiation of mechanical loading. The loss of bone mass is partially driven by declines in bone formation yet the mechanisms responsible for this decline are unclear. To investigate the limitations of osteoblasts during disuse, marrow ablation was superimposed on hindlimb unloaded mice. Marrow ablation is a useful model to study osteoblast functionality as new cancellous bone is rapidly formed throughout the marrow of a long bone while hindlimb unloading is the most common method used to produce skeletal unloading. The specific hypotheses of this study were aimed at determining if changes in osteoblast functionality, differentiation, and/or proliferation were compromised in non-weightbearing bone in response to a bone formation stimulus. Additionally, the influence of having compromised osteoblast functionality at the time of stimulation was assessed in non-weightbearing bones. Key outcome measures used to address these hypotheses included static and dynamic cancellous bone histomorphometry, bone densitometry, and real-time polymerase chain reaction (PCR) analyses of gene expression. The results document similar ablation-induced increases of cancellous bone in both weightbearing and unloaded animals. Similarly, there was no influence of load on ablation-induced increases in cancellous bone forming surface or mineral apposition rate. Unloading did significantly attenuate the ablation-induced increase in bone formation rate, due to reduced levels of total surface mineralization. When osteoblast functionality was compromised prior to marrow ablation, bone formation rate increases were also attenuated in ablated animals due to reduced mineralization. Additionally, increases in forming surface were attenuated as compared to unloaded animals having normal osteoblast function at the time of ablation. Collectively, these data identify mineralization as the limiting step in new bone formation during periods of disuse. The caveat, however, is that when bone formation is stimulated after a period of unloading sufficient to compromise osteoblast functionality, increases in osteoblast recruitment to the bone surface are compromised.Item Simulated Microgravity and Radiation Exposure Effects on the Regulation of Skeletal Muscle Protein Synthesis(2012-10-19) Wiggs, MichaelLong duration spaceflight missions out of lower earth orbit, back to the lunar surface, or possibly to Mars highlight the importance of preserving muscle mass and function. Muscle atrophy occurs within days of exposure to microgravity and prevailing thought is that a primary mechanism for muscle atrophy is a reduction in skeletal muscle protein synthesis. This dissertation examines the ability of skeletal muscle to recover muscle protein synthesis with slight perturbation, such as ambulatory reloading during disuse as well as partial loading, similar to body mass seen on the moon or Mars. We use traditional precursor-product labeling to measure protein synthesis, but use a relatively novel tracer, deuterium oxide, in order to make cumulative measures of protein synthesis over 24 h. The overarching goal of this dissertation is to define the response of skeletal muscle protein synthesis to different loading parameters in order to better understand the contribution of protein synthesis to skeletal muscle mass during disuse. In the first study, we demonstrate that muscle atrophy during 5 days of hindlimb unloading is in part due to a decrease in protein synthesis. We also highlight the ability of skeletal muscle to adapt by allowing two 1 h ambulatory reloading sessions on days 2 and 4. Although this countermeasure is able to rescue protein synthesis in soleus and gastrocnemius, it is unable attenuate any losses in muscle mass. In the second study, we compare partial weight loading to traditional hindlimb unloading. Weight bearing of 1/3 or 1/6 body weight is able to attenuate losses in muscle mass seen with unloading. Protein synthesis is maintained after 21 days of the experimental protocol, suggesting that protein synthesis is responsive to load and is likely not the only mechanism for determining muscle mass. In the final study, the effects of < 1 Gy x-ray exposure and partial weight suspension are measured to better understand the complex space environment, which includes a wide variety of radiation. Surprisingly, we found no effects of radiation on muscle protein synthesis in 1 G or partial loading. Targeting only protein synthesis may not be enough of a stimulus as evidenced by the data in this dissertation. Future plans should use a multiple-systems approach to counteract atrophy by increasing protein synthesis to maintain/elevate muscle mass during periods when it is otherwise compromised.