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      Factors mediating spaceflight-induced skeletal muscle atrophy

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          Abstract

          Skeletal muscle atrophy is a well-known consequence of spaceflight. Because of the potential significant impact of muscle atrophy and muscle dysfunction on astronauts and their mission, a thorough understanding of the mechanisms of this atrophy and the development of effective countermeasures is critical. Spaceflight-induced muscle atrophy is similar to atrophy seen in many terrestrial conditions, and therefore our understanding of this form of atrophy may also contribute to the treatment of atrophy in humans on Earth. The unique environmental features humans encounter in space include the weightlessness of microgravity, space radiation, and the distinctive aspects of living in a spacecraft. The disuse and unloading of muscles in microgravity are likely the most significant factors that mediate spaceflight-induced muscle atrophy and have been extensively studied and reviewed. However, there are numerous other direct and indirect effects on skeletal muscle that may be contributing factors to the muscle atrophy and dysfunction seen as a result of spaceflight. This review offers a novel perspective on the issue of muscle atrophy in space by providing a comprehensive overview of the unique aspects of the spaceflight environment and the various ways in which they can lead to muscle atrophy. We systematically review the potential contributions of these different mechanisms of spaceflight-induced atrophy and include findings from both actual spaceflight and ground-based models of spaceflight in humans, animals, and in vitro studies.

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          Most cited references143

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          Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects.

          Skeletal muscle mitochondrial content varies extensively between human subjects. Biochemical measures of mitochondrial proteins, enzyme activities and lipids are often used as markers of mitochondrial content and muscle oxidative capacity (OXPHOS). The purpose of this study was to determine how closely associated these commonly used biochemical measures are to muscle mitochondrial content and OXPHOS. Sixteen young healthy male subjects were recruited for this study. Subjects completed a graded exercise test to determine maximal oxygen uptake (VO2peak) and muscle biopsies were obtained from the vastus lateralis. Mitochondrial content was determined using transmission electron microscopy imaging and OXPHOS was determined as the maximal coupled respiration in permeabilized fibres. Biomarkers of interest were citrate synthase (CS) activity, cardiolipin content, mitochondrial DNA content (mtDNA), complex I–V protein content, and complex I–IV activity. Spearman correlation coefficient tests and Lin's concordance tests were applied to assess the absolute and relative association between the markers and mitochondrial content or OXPHOS. Subjects had a large range of VO2peak (range 29.9–71.6ml min−1 kg−1) and mitochondrial content (4–15% of cell volume).Cardiolipin content showed the strongest association with mitochondrial content followed by CS and complex I activities. mtDNA was not related to mitochondrial content. Complex IV activity showed the strongest association with muscle oxidative capacity followed by complex II activity.We conclude that cardiolipin content, and CS and complex I activities are the biomarkers that exhibit the strongest association with mitochondrial content, while complex IV activity is strongly associated with OXPHOS capacity in human skeletal muscle.
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            Overview of general physiologic features and functions of vitamin D.

            Vitamin D3 is a prohormone produced in skin through ultraviolet irradiation of 7-dehydrocholesterol. It is biologically inert and must be metabolized to 25-hydroxyvitamin D3 in the liver and then to 1alpha,25-dihydroxyvitamin D3 in the kidney before function. The hormonal form of vitamin D3, ie, 1alpha,25-dihydroxyvitamin D3, acts through a nuclear receptor to carry out its many functions, including calcium absorption, phosphate absorption in the intestine, calcium mobilization in bone, and calcium reabsorption in the kidney. It also has several noncalcemic functions in the body. This overview provides a brief description of the physiologic, endocrinologic, and molecular biologic characteristics of vitamin D. It also provides information on new selective analogs of 1alpha,25-dihydroyvitamin D3 for therapy.
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              One week of bed rest leads to substantial muscle atrophy and induces whole-body insulin resistance in the absence of skeletal muscle lipid accumulation.

              Short (<10 days) periods of muscle disuse, often necessary for recovery from illness or injury, lead to various negative health consequences. The present study investigated mechanisms underlying disuse-induced insulin resistance, taking into account muscle atrophy. Ten healthy, young males (age: 23±1 y, BMI: 23.0±0.9 kg·m(-2)) were subjected to one week of strict bed rest. Prior to and after bed rest, lean body mass (DXA) and quadriceps cross-sectional area (CSA; CT) were assessed, and VO2peak and leg strength were determined. Whole-body insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Additionally, muscle biopsies were collected to assess muscle lipid (fraction) content and various markers of mitochondrial and vascular content. Bed rest resulted in 1.4±0.2 kg lean tissue loss and a 3.2±0.9% decline in quadriceps CSA (both P<0.01). VO2peak and 1RM declined by 6.4±2.3 (P<0.05) and 6.9±1.4% (P<0.01), respectively. Bed rest induced a 29±5% decrease in whole-body insulin sensitivity (P<0.01). This was accompanied by a decline in muscle oxidative capacity, without alterations in skeletal muscle lipid content or saturation level, markers of oxidative stress, or capillary density. In conclusion, one week of bed rest substantially reduces skeletal muscle mass and lowers whole-body insulin sensitivity, without affecting mechanisms implicated in high-fat diet-induced insulin resistance.
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                Author and article information

                Contributors
                Journal
                American Journal of Physiology-Cell Physiology
                American Journal of Physiology-Cell Physiology
                American Physiological Society
                0363-6143
                1522-1563
                March 01 2022
                March 01 2022
                : 322
                : 3
                : C567-C580
                Affiliations
                [1 ]Department of Cardiothoracic Surgery, Southcoast Health, Fall River, Massachusetts
                [2 ]Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
                [3 ]Spiritus Medical, Inc., Columbus, Ohio
                [4 ]Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland
                [5 ]Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
                Article
                10.1152/ajpcell.00203.2021
                35171699
                69fa1e33-5775-4fbc-9602-5994d1572999
                © 2022
                History

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