Cervical angle as a possible predictor of abnormal placental position in women with endometriosis.

BACKGROUND: We aimed to examine the effects of endometriosis on the rate of abnormal placentation by comparing the data of pregnant women with and without endometriosis. METHODS: A case-control study was conducted to compare the perinatal outcomes between women with and without endometriosis. In the subgroup analysis, magnetic resonance imaging (MRI) scans of pregnant women with placenta previa were used to measure the cervical angle and its relationship with endometriosis. The cervical angle was measured as the angle between the cervical glands and the line perpendicular to the spinal column in each sagittal MRI section. RESULTS: We retrospectively analyzed data from 3453 cases of singleton deliveries between 2015 and 2019 at two study facilities. Among them, 159 had clinically or surgically confirmed endometriosis. The odds ratio (OR) for abnormal placental position was significantly higher in pregnant women with endometriosis (OR. 2.82; 95% confidence interval [CI], 1.58-5.04). The OR was 3.21 (95% CI, 1.57-6.55) in the endometriosis-surgery group (91 patients) and 2.32 (95% CI, 0.91-5.88) in the non-surgery group (68 patients). Furthermore, 44 women who underwent pelvic MRI after 30 weeks of gestation were included to examine the cervical angle. Then, we compared the date of pregnant women with (n = 6) and without endometriosis (n = 38). Regardless of placental attachment position, the cervical angle was significantly lower in the group with than in the group without a history of endometriosis. CONCLUSION: Pregnant women with a history of endometriosis may have stronger uterine retroversion, which could potentially contribute to abnormal placental positioning.

Significance of the association between early embryonic development and endocytosis.

Fertilization triggers a process called maternal-to-zygotic transition, in which the oocyte undergoes oocyte-to-embryo transition, leading to massive intracellular remodeling toward early embryogenesis. This transition requires the degradation of oocyte-derived components; however, the significance and mechanism of degradation of cell surface components remain unknown. In this review, we focused on the dynamics of plasma membrane proteins and investigated the relationship between embryonic development and endocytosis. Our survey of the extant literature on the topic led to the conclusion that clathrin-mediated endocytosis is essential for the progression of early embryogenesis and selective degradation of oocyte-derived plasma membrane proteins in mouse embryos, as reported by studies analyzing maternal cellular surface proteins, including a glycine transporter, GlyT1a. Evaluation of such endocytic activity in individual embryos may allow the selection of embryos with higher viability in assisted reproductive technologies, and it is important to select viable embryos to increase the rates of successful pregnancy and live birth. Although the early embryonic developmental abnormalities are mainly accompanied with chromosomal aneuploidy, other causes and mechanisms remain unclear. This review summarizes molecular biological approaches to early embryonic developmental abnormalities and their future prospects.

The Steroidal Alkaloid Tomatidine and Tomatidine-Rich Tomato Leaf Extract Suppress the Human Gastric Cancer-Derived 85As2 Cells In Vitro and In Vivo via Modulation of Interferon-Stimulated Genes.

The steroidal alkaloid tomatidine is an aglycone of α-tomatine, which is abundant in tomato leaves and has several biological activities. Tomatidine has been reported to inhibit the growth of cultured cancer cells in vitro, but its anti-cancer activity in vivo and inhibitory effect against gastric cancer cells remain unknown. We investigated the efficacy of tomatidine using human gastric cancer-derived 85As2 cells and its tumor-bearing mouse model and evaluated the effect of tomatidine-rich tomato leaf extract (TRTLE) obtained from tomato leaves. In the tumor-bearing mouse model, tumor growth was significantly inhibited by feeding a diet containing tomatidine and TRTLE for 3 weeks. Tomatidine and TRTLE also inhibited the proliferation of cultured 85As2 cells. Microarray data of gene expression analysis in mouse tumors revealed that the expression levels of mRNAs belonging to the type I interferon signaling pathway were altered in the mice fed the diet containing tomatidine and TRTLE. Moreover, the knockdown of one of the type I interferon-stimulated genes (ISGs), interferon α-inducible protein 27 (IFI27), inhibited the proliferation of cultured 85As2 cells. This study demonstrates that tomatidine and TRTLE inhibit the tumor growth in vivo and the proliferation of human gastric cancer-derived 85As2 cells in vitro, which could be due to the downregulation of ISG expression.

Pregnancy in hereditary sensory and autonomic neuropathy type V: A case report and literature review.

OBJECTIVE: Hereditary sensory and autonomic neuropathies (HSANs) are a clinical heterogenous group of inherited neuropathies featuring prominent sensory and autonomic involvement. We report on the management of pregnancy and delivery in a woman with HSAN type V (HSAN-V) that is a rare inherited disease characterized by pain insensitivity, and partial anhidrosis. CASE REPORT: A 25-year-old woman with HSAN-V at six weeks of gestation was referred to our hospital. She decided to continue her pregnancy after the genetic counseling. A multidisciplinary team including her decided to undergo cesarean section due to her short stature and the risk of an emergency in normal delivery. She successfully gave birth at 38 weeks of gestation by cesarean section under general anesthesia following an uneventful pregnancy course. CONCLUSION: Cesarean section seems favorable to vaginal delivery in women with HSANs.

Clathrin-mediated endocytosis is essential for the selective degradation of maternal membrane proteins and preimplantation development.

Fertilization triggers significant cellular remodeling through the oocyte-to-embryo transition. In this transition, the ubiquitin-proteasome system and autophagy are essential for the degradation of maternal components; however, the significance of degradation of cell surface components remains unknown. In this study, we show that multiple maternal plasma membrane proteins, such as the glycine transporter GlyT1a, are selectively internalized from the plasma membrane to endosomes in mouse embryos by the late two-cell stage and then transported to lysosomes for degradation at the later stages. During this process, large amounts of ubiquitylated proteins accumulated on endosomes. Furthermore, the degradation of GlyT1a with mutations in potential ubiquitylation sites was delayed, suggesting that ubiquitylation may be involved in GlyT1a degradation. The clathrin inhibitor blocked GlyT1a internalization. Strikingly, the protein kinase C (PKC) activator triggered the heterochronic internalization of GlyT1a; the PKC inhibitor markedly blocked GlyT1a endocytosis. Lastly, clathrin inhibition completely blocked embryogenesis at the two-cell stage and inhibited cell division after the four-cell stage. These findings demonstrate that PKC-dependent clathrin-mediated endocytosis is essential for the selective degradation of maternal membrane proteins during oocyte-to-embryo transition and early embryogenesis.

Fasting increases 18:2-containing phosphatidylcholines to complement the decrease in 22:6-containing phosphatidylcholines in mouse skeletal muscle.

Fasting stimulates catabolic reactions in skeletal muscle to survive nutrient deprivation. Cellular phospholipids have large structural diversity due to various polar-heads and acyl-chains that affect many cellular functions. Skeletal muscle phospholipid profiles have been suggested to be associated with muscle adaptations to nutritional and environmental status. However, the effect of fasting on skeletal muscle phospholipid profiles remains unknown. Here, we analyzed phospholipids using liquid chromatography mass spectrometry. We determined that fasting resulted in a decrease in 22:6-containing phosphatidylcholines (PCs) (22:6-PCs) and an increase in 18:2-containing PCs (18:2-PCs). The fasting-induced increase in 18:2-PCs was sufficient to complement 22:6-PCs loss, resulting in the maintenance of the total amount of polyunsaturated fatty acid (PUFA)-containing PCs. Similar phospholipid alterations occurred in insulin-deficient mice, which indicate that these observed phospholipid perturbations were characteristic of catabolic skeletal muscle. In lysophosphatidic acid acyltransferase 3-knockout muscles that mostly lack 22:6-PCs, other PUFA-containing PCs, mainly 18:2-PCs, accumulated. This suggests a compensatory mechanism for skeletal muscles to maintain PUFA-containing PCs.

Differences in phosphatidylcholine profiles and identification of characteristic phosphatidylcholine molecules in meat animal species and meat cut locations.

Phosphatidylcholine (PC) is an essential component of the plasma membrane. Its profile varies with species and tissues. However, the PC profiles in meat have not been explored in depth. This study aimed to investigate the differences in PC profiles between various meat animal species and meat cut sites, along with the identification of characteristic PC molecules. The results demonstrated that the PC profiles of chicken meat differed from those of other species. Significant differences were also observed between the PC profiles of pork meat and the meat obtained from other species. The amount of PCs containing ether bonds was high in pork meat. PCs containing an odd number of carbon atoms were characteristic of beef and lamb meats. Furthermore, PC profiles differed based on the muscle location in chicken and pork. These results suggest that the PC profiles of skeletal muscles are indicators of animal species and muscle location.

Citrus hassaku Extract Powder Increases Mitochondrial Content and Oxidative Muscle Fibers by Upregulation of PGC-1α in Skeletal Muscle.

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is expressed in skeletal muscles and regulates systemic metabolism. Thus, nutraceuticals targeting skeletal muscle PGC-1α have attracted attention to modulate systemic metabolism. As auraptene contained in citrus fruits promotes lipid metabolism and improves mitochondrial respiration, it could increase mitochondrial function through PGC-1α. Therefore, we hypothesized that PGC-1α is activated by auraptene and investigated its effect using Citrus hassaku extract powder (CHEP) containing >80% of auraptene. C2C12 myotubes were incubated with vehicle or CHEP for 24 h; C57BL/6J mice were fed a control diet or a 0.25% (w/w) CHEP-containing diet for 5 weeks. PGC-1α protein level and mitochondrial content increased following CHEP treatment in cultured myotubes and skeletal muscles. In addition, the number of oxidative fibers increased in CHEP-fed mice. These findings suggest that CHEP-mediated PGC-1α upregulation induced mitochondrial biogenesis and fiber transformation to oxidative fibers. Furthermore, as CHEP increased the expression of the protein sirtuin 3 and of phosphorylated AMP-activated protein kinase (AMPK) and the transcriptional activity of PGC-1α, these molecules might be involved in CHEP-induced effects in skeletal muscles. Collectively, our findings indicate that CHEP mediates PGC-1α expression in skeletal muscles and may serve as a dietary supplement to prevent metabolic disorders.

Effects of fenofibrate and its combination with lovastatin on the expression of genes involved in skeletal muscle atrophy, including FoxO1 and its targets.

Fibrates and statins have been widely used to reduce triglyceride and cholesterol levels, respectively. Besides its lipid-lowering effect, the side effect of muscle atrophy after fibrate administration to humans has been demonstrated in some studies. Combination therapy with fibrates and statins also increases the risk of rhabdomyolysis. FoxO1, a member of the FoxO forkhead type transcription factor family, is markedly upregulated in skeletal muscle in energy-deprived states and induces muscle atrophy via the expression of E3-ubiquitine ligases. In this study, we investigated the changes in FoxO1 and its targets in murine skeletal muscle with fenofibrate treatment. High doses of fenofibrate (greater than 0.5% (wt/wt)) over one week increased the expression of FoxO1 and its targets in the skeletal muscles of mice and decreased skeletal muscle weight. These fenofibrate-induced changes were diminished in the PPARα knockout mice. When the effect of combination treatment with fenofibrate and lovastatin was investigated, a significant increase in FoxO1 protein levels was observed despite the lack of deterioration of muscle atrophy. Collectively, our findings suggest that a high dose of fenofibrate over one week causes skeletal muscle atrophy via enhancement of FoxO1, and combination treatment with fenofibrate and lovastatin may further increase FoxO1 protein level.

Skeletal muscle-specific forkhead box protein-O1 overexpression suppresses atherosclerosis progression in apolipoprotein E-knockout mice.

Calorie restriction (CR) reportedly prevents atherosclerotic diseases. Furthermore, CR induces forkhead box protein-O1 (FOXO-1) expression in the skeletal muscle, altering the character of the skeletal muscle. We previously reported that the change in skeletal muscle character, induced by the overexpression of peroxisome proliferator-activated receptor γ coactivator-1α, suppresses atherosclerotic progression in an atherosclerotic apolipoprotein E-knockout (ApoE-KO) mouse model. Thus, we hypothesized that skeletal muscle alternation induced by FOXO-1 may also have an anti-atherosclerotic effect in ApoE-KO mice. In this study, we investigated whether skeletal muscle-specific FOXO-1 overexpression suppresses the progression of atherosclerosis in ApoE-KO mice. We generated ApoE-KO/FOXO-1 mice, in which an ApoE-KO mouse was crossbred with a mouse presenting skeletal muscle-specific FOXO-1 overexpression (FOXO-1Tg). The mice were sacrificed at 20 weeks of age, and atherosclerotic plaque area and protein expression in the plaque were measured. Additionally, we measured the tumor necrosis factor α (TNFα)- induced mRNA expression in human umbilical vein endothelial cells (HUVECs), using serum collected from the FOXO-1Tg mice. Accordingly, ApoE-KO/FOXO-1 mice showed a 65% reduced atherosclerotic plaque area when compared with the ApoE-KO mice, with concomitantly reduced vascular cell adhesion molecule-1 (VCAM-1) and macrophage infiltration. As compared to serum from wild-type mice, the serum collected from the FOXO-1Tg mice significantly suppressed the mRNA expression of VCAM-1, an atherosclerosis initiation factor, in TNFα-treated HUVECs. Therefore, these data suggest that skeletal muscle-specific FOXO-1 overexpression suppresses the progression of atherosclerosis in ApoE-KO mice. In part, the CR-induced anti-atherosclerotic effect could be attributed to FOXO-1 upregulation in the skeletal muscle.

The enhancement of fat oxidation during the active phase and suppression of body weight gain in glycerol-3-phosphate dehydrogenase 1 deficient mice.

We investigated whether the deletion of glycerol-3-phosphate dehydrogenase (GPD) 1 would affect carbohydrate oxidation, fat oxidation, and body weight by using the GPD1 null mice (BALB/cHeA (HeA)). We found that fat oxidation in HeA mice was significantly high during the early active phase than in BALB/cBy (By) mice used as a control under ad libitum conditions. Metabolic tracer experiment revealed that fatty acid oxidation in the skeletal muscle of HeA mice tended to be high. The energy expenditure and fat oxidation in HeA mice under fasting conditions were significantly higher than that in the By mice. Moreover, we monitored body weight gain in HeA mice under ad libitum feeding and found lower body weight gain. These data indicate that GPD1 deficiency induces enhancement of fat oxidation with suppression of weight gain. We propose that GPD1 deletion contributes to the reduction of body weight gain via enhancement of fat oxidation.

Glycerophospholipid profile alterations are associated with murine muscle-wasting phenotype.

INTRODUCTION: Phospholipids are essential components of cellular membranes and are closely associated with cellular functions, but relationships involving skeletal muscle phospholipid profiles and their physiological phenotypes have remained unclear. METHODS: We carried out comprehensive phospholipid analyses using liquid chromatography-tandem mass spectrometry to determine the phospholipid profiles of skeletal muscles derived from muscle-wasting mouse models, including denervated and Duchenne muscular dystrophy mouse models (mdx) as well as rescued mdx mice expressing truncated dystrophin. RESULTS: Consistent phosphatidylcholine and phosphatidylethanolamine alterations in skeletal muscles isolated from denervated and mdx mice were observed. Notably, the levels of these phospholipids binding polyunsaturated fatty acids were reduced in denervated and mdx muscles. Moreover, rescuing the mdx pathology by expressing truncated dystrophin led to the restoration of phospholipid profiles. DISCUSSION: Our findings support the hypothesis that phospholipid profiles of the skeletal muscle may be associated with skeletal muscle function.

ß-Aminoisobutyric Acid Suppresses Atherosclerosis in Apolipoprotein E-Knockout Mice.

Endurance exercise training has been shown to induce peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression in skeletal muscle. We recently reported that skeletal muscle-specific PGC-1α overexpression suppressed atherosclerosis in apolipoprotein E-knockout (ApoE-/-) mice. ß-Aminoisobutyric acid (BAIBA) is a PGC-1α-dependent myokine secreted from myocytes that affects multiple organs. We have also reported that BAIBA suppresses tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) gene expression in endothelial cells. In the present study, we hypothesized that BAIBA suppresses atherosclerosis progression, and tested that hypothesis with ApoE-/- mice. The mice were administered water containing BAIBA for 14 weeks, and were then sacrificed at 20 weeks of age. Atherosclerotic plaque area, plasma BAIBA concentration, and plasma lipoprotein profiles were assessed. Immunohistochemical analyses of the plaque were performed to assess VCAM-1 and MCP-1 protein expression levels and macrophage infiltration. The results showed that BAIBA administration decreased atherosclerosis plaque area by 30%, concomitant with the elevation of plasma BAIBA levels. On the other hand, plasma lipoprotein profiles were not changed by the administration. Immunohistochemical analyses indicated reductions in VCAM-1, MCP-1, and Mac-2 protein expression levels in the plaque. These results suggest that BAIBA administration suppresses atherosclerosis progression without changing plasma lipoprotein profiles. We propose that the mechanisms of this suppression are reductions in both VCAM-1 and MCP-1 expression as well as macrophage infiltration into the plaque.

Acute fructose intake suppresses fasting-induced hepatic gluconeogenesis through the AKT-FoxO1 pathway.

Excessive intake of fructose increases lipogenesis in the liver, leading to hepatic lipid accumulation and development of fatty liver disease. Metabolic alterations in the liver due to fructose intake have been reported in many studies, but the effect of fructose administration on hepatic gluconeogenesis is not fully understood. The aim of this study was to evaluate the acute effects of fructose administration on fasting-induced hepatic gluconeogenesis. C57BL/6J mice were administered fructose solution after 14 h of fasting and plasma insulin, glucose, free fatty acids, and ketone bodies were analysed. We also measured phosphorylated AKT and forkhead box O (FoxO) 1 protein levels and gene expression related to gluconeogenesis in the liver. Furthermore, we measured glucose production from pyruvate after fructose administration. Glucose-administered mice were used as controls. Fructose administration enhanced phosphorylation of AKT in the liver, without increase of blood insulin levels. Blood free fatty acids and ketone bodies concentrations were as high as those in the fasting group after fructose administration, suggesting that insulin-induced inhibition of lipolysis did not occur in mice administered with fructose. Fructose also enhanced phosphorylation of FoxO1 and suppressed gluconeogenic gene expression, glucose-6-phosphatase activity, and glucose production from pyruvate. The present study suggests that acute fructose administration suppresses fasting-induced hepatic gluconeogenesis in an insulin-independent manner.

Skeletal Muscle-specific PGC-1α Overexpression Suppresses Atherosclerosis in Apolipoprotein E-Knockout Mice.

Endurance exercise training prevents atherosclerosis. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) increases myokine secretion from the skeletal muscle, and these myokines have been shown to affect the function of multiple organs. Since endurance exercise training increases PGC-1α expression in skeletal muscles, we investigated whether skeletal muscle-specific PGC-1α overexpression suppresses atherosclerosis. Apolipoprotein E-knockout (ApoE-KO)/PGC-1α mice, which overexpress PGC-1α in the skeletal muscle of ApoE-KO mice, were sacrificed, and the atherosclerotic plaque area, spontaneous activity, plasma lipid profile, and aortic gene expression were measured. Immunohistochemical analyses were also performed. The atherosclerotic lesions in ApoE-KO/PGC-1α mice were 40% smaller than those in ApoE-KO mice, concomitant with the reduction in vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA and protein levels in the aorta. Spontaneous activity and plasma lipid profiles were not changed by the overexpression of PGC-1α in the skeletal muscle. In human umbilical vein endothelial cells, Irisin and ß-aminoisobutyric acid (BAIBA), PGC-1α-dependent myokines, inhibited the tumor necrosis factor α-induced VCAM-1 gene and protein expression. BAIBA also inhibited TNFα-induced MCP-1 gene expression. These results showed that the skeletal muscle-specific overexpression of PGC-1α suppresses atherosclerosis and that PGC-1α-dependent myokines may be involved in the preventive effects observed.

Effects of the dietary carbohydrate-fat ratio on plasma phosphatidylcholine profiles in human and mouse.

Phosphatidylcholines (PCs), a major class of human plasma phospholipids, are composed of highly diverse fatty acids. Because the dietary carbohydrate-fat ratio alters the hepatic fatty acid metabolism, plasma fatty acids that bind PCs, which are secreted as lipoproteins from the liver, may be affected by long-term consumption of a high-carbohydrate diet or a high-fat diet. Therefore, in this study, we profiled the plasma PC species comprehensively in formulated dieting conditions to identify those phospholipid molecules that reflect the dietary carbohydrate-fat ratio. C57BL6J mice were fed diets containing different amounts of fat for 8 weeks, and plasma PC species were analyzed under fasting conditions using liquid chromatography-mass spectrometry. In addition, a cross-sectional study of 78 middle-aged Japanese men, who participated in health checkups, was conducted. Nutrient intakes were estimated by a brief self-administered diet-history questionnaire. The plasma PC profiles changed depending on the dietary carbohydrate-fat ratio. Especially, PC (16:0/16:1) and PC (16:0/18:1) levels increased as the dietary carbohydrate-fat ratio increased in human and mouse, suggesting that these PC species reflected the increase in de novo lipogenesis and might become useful biomarkers of the dietary carbohydrate-fat ratio. Since these PCs act as ligands for peroxisome proliferator-activated receptor α, PC species reflecting the dietary carbohydrate-fat ratio may influence metabolism of glucose and lipids.

Glycerol-3-phosphate dehydrogenase 1 deficiency induces compensatory amino acid metabolism during fasting in mice.

BACKGROUND: Glucose is used as an energy source in many organs and obtained from dietary carbohydrates. However, when the external energy supply is interrupted, e.g., during fasting, carbohydrates preserved in the liver and glycogenic precursors derived from other organs are used to maintain blood glucose levels. Glycerol and glycogenic amino acids derived from adipocytes and skeletal muscles are utilized as glycogenic precursors. Glycerol-3-phosphate dehydrogenase 1 (GPD1), an NAD+/NADH-dependent enzyme present in the cytosol, catalyzes the reversible conversion of glycerol-3-phosphate (G3P) to dihydroxyacetone phosphate (DHAP). Since G3P is one of the substrates utilized for gluconeogenesis in the liver, the conversion of G3P to DHAP by GPD1 is essential for maintaining blood glucose levels during fasting. We focused on GPD1 and examined its roles in gluconeogenesis during fasting. METHODS: Using GPD1 null model BALB/cHeA mice (HeA mice), we measured gluconeogenesis from glycerol and the change of blood glucose levels under fasting conditions. We also measured gene expression related to gluconeogenesis in the liver and protein metabolism in skeletal muscle. BALB/cBy mice (By mice) were used as a control. RESULTS: The blood glucose levels in the HeA mice were lower than that in the By mice after glycerol administration. Although lack of GPD1 inhibited gluconeogenesis from glycerol, blood glucose levels in the HeA mice after 1-4h of fasting were significantly higher than that in the By mice. Muscle protein synthesis in HeA mice was significantly lower than that in the By mice. Moreover, blood alanine levels and usage of alanine for gluconeogenesis in the liver were significantly higher in the HeA mice than that in the By mice. CONCLUSIONS: Although these data indicate that a lack of GPD1 inhibits gluconeogenesis from glycerol, chronic GPD1 deficiency may induce an adaptation that enhances gluconeogenesis from glycogenic amino acids.

PGC-1α-mediated changes in phospholipid profiles of exercise-trained skeletal muscle.

Exercise training influences phospholipid fatty acid composition in skeletal muscle and these changes are associated with physiological phenotypes; however, the molecular mechanism of this influence on compositional changes is poorly understood. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a nuclear receptor coactivator, promotes mitochondrial biogenesis, the fiber-type switch to oxidative fibers, and angiogenesis in skeletal muscle. Because exercise training induces these adaptations, together with increased PGC-1α, PGC-1α may contribute to the exercise-mediated change in phospholipid fatty acid composition. To determine the role of PGC-1α, we performed lipidomic analyses of skeletal muscle from genetically modified mice that overexpress PGC-1α in skeletal muscle or that carry KO alleles of PGC-1α. We found that PGC-1α affected lipid profiles in skeletal muscle and increased several phospholipid species in glycolytic muscle, namely phosphatidylcholine (PC) (18:0/22:6) and phosphatidylethanolamine (PE) (18:0/22:6). We also found that exercise training increased PC (18:0/22:6) and PE (18:0/22:6) in glycolytic muscle and that PGC-1α was required for these alterations. Because phospholipid fatty acid composition influences cell permeability and receptor stability at the cell membrane, these phospholipids may contribute to exercise training-mediated functional changes in the skeletal muscle.

Glycerol 3-phosphate dehydrogenase 1 deficiency enhances exercise capacity due to increased lipid oxidation during strenuous exercise.

A large percentage of energy produced during high-intensity exercise depends on the aerobic glycolytic pathway. Maintenance of a cytoplasmic redox balance ([NADH]/[NAD(+)] ratio) by the glycerophosphate shuttle involves sustained aerobic glycolysis. Glycerol 3-phosphate dehydrogenase 1 (GPD1) catalyzes an oxidation reaction in the glycerophosphate shuttle. In this study, we examined whether GPD1 deficiency decreases exercise capacity due to impairment of aerobic glycolysis by using the GPD1 null mouse model BALB/cHeA (HeA). Unexpectedly, we found that exercise endurance was significantly higher in HeA mice than in BALBc/By (By) mice used as controls. Furthermore, aerobic glycolysis in HeA mice was not impaired. During exercise, lipid oxidation was significantly higher in HeA mice than in By mice, concomitant with an increase in phosphorylation of AMP-activated protein kinase (AMPK). HeA mice also showed a delay in the onset of muscle glycogen usage and lactate production during exercise. These data suggest that contribution of lipid oxidation as a fuel source for exercise is increased in HeA mice, and GPD1 deficiency enhances exercise capacity by increasing lipid oxidation, probably due to activation of AMPK. We propose that GPD1 deficiency induces an adaptation that enhances lipid availability in the skeletal muscle during exercise.

PGC-1α-mediated branched-chain amino acid metabolism in the skeletal muscle.

Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α) is a coactivator of various nuclear receptors and other transcription factors, which is involved in the regulation of energy metabolism, thermogenesis, and other biological processes that control phenotypic characteristics of various organ systems including skeletal muscle. PGC-1α in skeletal muscle is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Branched-chain amino acid (BCAA) metabolism mainly occurs in skeletal muscle mitochondria, and enzymes related to BCAA metabolism are increased by exercise. Using murine skeletal muscle overexpressing PGC-1α and cultured cells, we investigated whether PGC-1α stimulates BCAA metabolism by increasing the expression of enzymes involved in BCAA metabolism. Transgenic mice overexpressing PGC-1α specifically in the skeletal muscle had increased the expression of branched-chain aminotransferase (BCAT) 2, branched-chain α-keto acid dehydrogenase (BCKDH), which catabolize BCAA. The expression of BCKDH kinase (BCKDK), which phosphorylates BCKDH and suppresses its enzymatic activity, was unchanged. The amount of BCAA in the skeletal muscle was significantly decreased in the transgenic mice compared with that in the wild-type mice. The amount of glutamic acid, a metabolite of BCAA catabolism, was increased in the transgenic mice, suggesting the activation of muscle BCAA metabolism by PGC-1α. In C2C12 cells, the overexpression of PGC-1α significantly increased the expression of BCAT2 and BCKDH but not BCKDK. Thus, PGC-1α in the skeletal muscle is considered to significantly contribute to BCAA metabolism.