Sarcopenia is the age-induced, progressive loss of skeletal muscle mass and function. To better understand changes in skeletal muscle during sarcopenia, we performed a metabolomic analysis of skeletal muscle in young (8-week-old) and aged (28-month-old) mice by using capillary electrophoresis with electrospray ionization time-of-flight mass spectrometry. Principal component analysis showed clear changes in metabolites between young and aged mice. Glucose metabolism products were decreased in aged mice, specifically fructose 1,6-diphosphate (0.4-fold) and dihydroxyacetone phosphate (0.6-fold), possibly from decreased glycolytic muscle fibers. Multiple metabolic products associated with phospholipid metabolism were significantly changed in aged mice, which may reflect changes in cell membrane phospholipids of skeletal muscle. Products of polyamine metabolism, which are known to increase nucleic acid and protein synthesis, decreased in spermine (0.5-fold) and spermidine (0.6-fold) levels. By contrast, neurotransmitter levels were increased in skeletal muscle of aged mice, including acetylcholine (1.8-fold), histamine (2.6-fold), and serotonin (1.7-fold). The increase in acetylcholine might compensate for age-associated dropout of neuromuscular junctions, whereas the increases in histamine and serotonin might be due to muscle injury associated with aging. Further analysis focusing on the altered metabolites observed in this study will provide essential data for understanding aging muscles.
Malignant tumors usually involve a relatively hypoxic state, which induces overexpression of hypoxia-inducible factor-1alpha (HIF-1alpha) to satisfactorily enable the tumor to survive. Thus, inhibition of the mammalian target of rapamycin (mTOR) pathway including HIF-1alpha is expected to play a major role in suppression of tumor cell growth, having recently drawn much attention as an anti-cancer therapeutic strategy for various malignant tumors. In the present study, which compared clear cell adenocarcinoma (CLA) of the ovary with serous adenocarcinoma (SEA), the immunohistochemical expression of mTOR, phosphorylated-mTOR (p-mTOR), HIF-1alpha, and vascular endothelial growth factor (VEGF) was examined in surgically resected specimens of 29 SEA and 47 CLA. There were no significant differences in expression of mTOR, HIF-1alpha and VEGF between SEA and CLA, but it was noted that p-mTOR expression was more prominent in CLA than SEA. Then, using the cell lines of CLA (RMG-1 and W3uF), an experimental study was designed to clarify whether tumor suppression due to downregulation of mTOR activity could represent a promising therapeutic strategy for CLA. After treatment of an analogue of rapamycin (everolimus), expression of mTOR, p-mTOR, HIF-1alpha and VEGF was examined on western blot. As a result, although mTOR expression remained unchangeable, expression of p-mTOR, HIF-1alpha and VEGF was shown to be sharply depressed. The same expression alterations were demonstrated in the xenograft model treated with everolimus. In conclusion, mTOR-targeted therapy through usage of drugs such as everolimus may be more effective for CLA of the ovary because of its significant expression of p-mTOR.
Over the past few decades, the prevalence of overweight and obesity has increased markedly worldwide, along with the adoption of westernized lifestyles characterized by excessive energy intake and a lack of physical activity. Consequently, obesity and a cluster of obesity-related comorbidities often referred to as the metabolic syndrome have become a serious public health problem and a major risk factor for the development of severe diseases such as cardiovascular disease. 1) Obesity is strongly associated with insulin resistance, in which elevation of circulating fatty acids results in increased fatty acid availability that exceeds the fat disposal capacity of cells, which decreases insulin-stimulated glucose oxidation in muscles and subsequently leads to contractile dysfunction of the heart. 2) The precise mechanisms underlying these "lipotoxic" consequences remain incompletely defined, but it is currently accepted that excessive fatty acid uptake into cells leads to the accumulation of proinflammatory lipid metabolites such as fatty acyl-CoA, diacylglycerol and ceramide. These metabolites stimulate stress-activated kinases, which interfere with insulin signaling. 2,3) It is also becoming clear that fatty acid beta-oxidation is increased in the insulin-resistant heart and oxidative skeletal muscle, and that mitochondrial overload and incomplete oxidation of fatty acids contribute to the impairment of insulin sensitivity. 2,4) Under these conditions, enhanced beta-oxidation, which is not accompanied by appropriate upregulation of the tricarboxylic acid (TCA) cycle or electron transport chain (ETC) activity, fails to oxidize fatty acids completely to CO 2 and deposits incomplete fat catabolites along with diminished levels of TCA cycle intermediates. These stressful environments created within mitochondria are thought to exacerbate cellular insulin resistance by enhanced oxidative stress, for example. 4) However, acyl-CoA thioesterase (ACOT) exists within the mitochondrial matrix of mammalian cells 5) and its expression is expected to be upregulated in response to fatty acid overload, as demonstrated in diabetic and fasted animals. 6,7) ACOT comprises a group of enzymes that are localized in multiple compartments in cells and catalyze the hydrolysis of long-chain acyl-CoA thioesters to free fatty acids and CoA-SH. For example, ACOT1 (formerly known as CTE-I or ACH2) and ACOT7a (CTE-II, BACH or ACT) are localized in the cytosol while ACOT2 (MTE-I or ARTISt) and ACOT7b (MTE-II or LACH1) are present in mitochondria. [8][9][10] These catalytic properties of ACOT mean that it is capable of lowering the increased levels of acyl-CoA imported by carnitine palmitoyltransferase (CPT) across the mitochondrial membranes from the cytosol. Accordingly, ACOT could counteract the enhanced beta-oxidation and reduce the mitochondrial stress caused by the imbalance between beta-oxidation and TCA cycle/ETC activity during fatty acid overload. Moreover, the ACOT isoforms present in the cytosol could scavenge surplus acyl-CoA to prev...
Abstract. The expression of hypoxia inducible factor-1α (HIF-1α) and glucose transporter-1 (GLUT-1) was immunohistochemically analyzed in ovarian adenocarcinomas with the aim of elucidating whether hypoxic status is associated with histological type or structural character. The following ovarian adenocarcinomas were used: serous adenocarcinoma (SEA), 21 cases; mucinous adenocarcinoma (MUA), 19 cases; endometrioid adenocarcinoma (ENA), 16 cases; clear cell adenocarcinoma (CLA), 19 cases. High-level expression (3+) of HIF-1α was observed in 100% of SEAs, 58% of MUAs, 100% of ENAs and 89% of CLAs, and high-level expression of GLUT-1 in 76% of SEAs, 26% of MUAs, 50% of ENAs and 67% of CLAs. Heterogeneous or localized staining was relatively evident for GLUT-1. Immunohistochemical profiles were in accord with the immunoblotting and mRNA levels of both markers. ELISA for the detection of active HIF-1 demonstrated that HIF-1 is strongly activated in SEAs, ENAs and CLAs as compared to MUAs. Our results show that GLUT-1 overexpression is to some extent regulated by HIF-1α and is also strongly associated with histological features, i.e., papillary or stratified structure accompanied by little or no vascular stroma. In conclusion, hypoxic status differs according to the histological type of ovarian adenocarcinoma and the micro-environmental conditions of each type. IntroductionMalignant tumors are considered to be in a more or less hypoxic state, with highly malignant tumors being especially hypoxia-resistant (1). Hypoxia inducible factor-1 (HIF-1), which is a heterodimer made up of an α and ß subunit, is one of the interesting recently discovered factors involved in tumor development and histogenesis (1). The heterodimer of HIF-1 in the nucleus is biologically functional when it is bound to hypoxia response elements (HREs). It is known that pathophysiological phenomena, including glucose transport, glycolysis, angiogenesis, erythropoiesis and the inhibition of apoptosis, are usually regulated by transcription factors such as HIF-1α (2). In this regulation, the expression level of the HIF-1α subunit is a determinant of HIF-1 transcription activity (2) and the loss of the von Hippel-Lindau tumor suppressor gene results in constitutive high-level expression of HIF-1α (3). In general, when compared to non-malignant tumor cells or normal tissue cells the glucose utilization rate is increased in malignant tumor cells (4). One or more members of the glucose transporter (GLUT) gene family are expressed in all mammalian cells. GLUTs are integral membrane glycoproteins that play a key role in facilitating glucose transport (5). GLUT-1 is a representative member of the family and is widely distributed in normal tissues such as erythrocytes and endothelial cells at the blood-brain barrier (6-8). Various studies have shown a close relationship between GLUT-1 expression and carcinogenesis, tumor development or the unfavorable prognosis of various malignancies (9-12).We have observed a progressive increase in HIF-1α and GLUT-1 expressio...
Organic solute carrier protein 1 (OSCP1) is a recently described human gene that facilitates the transport of various organic solutes into the cell, when expressed in frog eggs. In this study, we cloned a mouse ortholog of OSCP1 encoding 379 amino acid protein, with 94% homology to the human counterpart. The mouse OSCP1 mRNA was predominantly expressed in the testis, in which it was attributed to the spermatogenic cells, except the spermatogonia. Immunohistochemistry confirmed that OSCP1 protein is continuously expressed during spermatogenesis in a stage- and cell type-specific manner, in the leptotene spermatocytes at stage IX through step 15 spermatids. Subcellular fractionation of mouse testis homogenates indicated that OSCP1 is a 45-kDa cytosolic protein. Moreover, when green fluorescent protein-OSCP1 fusion constructs were transfected into cultured cells, the fluorescence localized evenly in the cytoplasm. These results suggest that mouse testis OSCP1 may indirectly mediate substrate uptake into meiotic and spermiogenic germ cells, within the cytosol.
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