Female mice may have exacerbated catabolic signalling response compared to male mice during development and progression of disuse atrophy

Background: Muscle atrophy is a common pathology associated with disuse, such as prolonged bed rest or spaceflight, and is associated with detrimental health outcomes. There is emerging evidence that disuse atrophy may differentially affect males and females. Cellular mechanisms contributing to the development and progression of disuse remain elusive, particularly protein turnover cascades. The purpose of this study was to investigate the initial development and progression of disuse muscle atrophy in male and female mice using the well-established model of hindlimb unloading (HU). Methods: One hundred C57BL/6J mice (50 male and 50 female) were hindlimb suspended for 0 (control), 24, 48, 72, or 168 h to induce disuse atrophy (10 animals per group). At designated time points, animals were euthanized, and tissues (extensor digitorum longus, gastrocnemius, and soleus for mRNA analysis, gastrocnemius and extensor digitorum longus for protein synthesis rates, and tibialis anterior for histology) were collected for analysis of protein turnover mechanisms (protein anabolism and catabolism). Results: Both males and females lost ~30% of tibialis anterior cross-sectional area after 168 h of disuse. Males had no statistical difference in MHCIIB fibre area, whereas unloaded females had ~33% lower MHCIIB cross-sectional area by 168 h of unloading. Both males and females had lower fractional protein synthesis rates (FSRs) within 24-48 h of HU, and females appeared to have a greater reduction compared with males within 24 h of HU (~23% lower FSRs in males vs. 40% lower FSRs in females). Males and females exhibited differential patterns and responses in multiple markers of protein anabolism, catabolism, and myogenic capacity during the development and progression of disuse atrophy. Specifically, females had greater mRNA inductions of catabolic factors Ubc and Gadd45a (~4-fold greater content in females compared with ~2-fold greater content in males) and greater inductions of anabolic inhibitors Redd1 and Deptor with disuse across multiple muscle tissues exhibiting different fibre phenotypes. Conclusions: These results suggest that the aetiology of disuse muscle atrophy is more complicated and nuanced than previously thought, with different responses based on muscle phenotypes and between males and females, with females having greater inductions of atrophic markers early in the development of disuse atrophy

A Molecular Mechanism for DEPTOR in the Control of Cellular Metabolism and Disease

One of the main hubs of cellular metabolic integration is the mechanistic target of rapamycin, or mTOR. In normal, healthy cells, mTOR helps to regulate and balance cellular growth and proliferation against metabolic conservation and maintenance. However, when cellular conditions deteriorate due to environmental stressors or genetic mutations, mTOR’s contribution towards normal cellular metabolism can become dysregulated, leading to a number of disease states in different tissues, including type 2 diabetes, a large percentage of human cancers, Parkinson’s disease, Alzheimer’s disease, cancer cachexia, and many effects of ageing. One of the primary regulators of mTOR activation is DEPTOR, a potent endogenous inhibitor of mTOR. The purpose of this dissertation is to mechanistically define the role of DEPTOR protein expression in regulating cellular metabolism under various conditions. While the direct relationship between DEPTOR and mTOR has been explored under some steady state conditions, there are only a handful of studies that have explored the use of directed changes in DEPTOR protein content as a means to regulate mTOR activity. By taking advantage of recently developed precision gene editing technologies, we have shown that the chronic and constitutively active expression of DEPTOR protein can act as a potent regulator of cellular anabolism through mTOR in both the normal, healthy C2C12 murine myoblast, and in MCF7 human epithelial cancer cells. This approach offers a number of benefits over pharmacological inhibition of mTOR or of upstream signaling proteins, as those strategies often suffer from a lack of specificity, have inherent cytotoxic properties, or eventually become ineffective due to altered feedback mechanisms. The current experiments are the first to demonstrate a causative relationship between DEPTOR expression, the resultant mTOR activity, and eventual downstream anabolic function. In addition, the outcomes contained within this dissertation indicate the possibility that certain anabolically aggressive diseases may be treated through directed changes in DEPTOR protein content

OUTDOOR RECREATION IN THE UNITED STATES WITH SPECIAL REFERENCE TO RECREATION AT U.S. ARMY CORP OF ENGINEERS SITES

Resource /Energy Economics and Policy,

Argonne National Laboratory Reports

The abstracts are given of thirteen papers presented at a ''SQUID Symposium'' organized by the Division of Materials Sciences of the U.S. Department of Energy and held March 23-25, 1978, at the University of Virginia. Since SQUID systems have already been utilized in feasibility demonstration in geothermal reservoir exploration, it was recognized that these devices also hold great potential for many other important scientific measurements. Many of these are energy-related, and others include forefront investigations in a diverse group of scientific areas, from biomedical to earthquake monitoring. Research in SQUIDs has advanced so rapidly in recent years that it was felt that a symposium to review the current status and future prospects of the devices would be timely. The abstracts given present an overview of work in this area and hopefully provide an opportunity to increase awareness among basic and applied scientists of the inherent implications of the extreme measurement sensitivity in advanced SQUID systems