Medicine (Western Health) - Research Publications
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ItemThe effect of dietary supplementation with blueberry, cyanidin-3-O-β-glucoside, yoghurt and its peptides on gene expression associated with glucose metabolism in skeletal muscle obtained from a high-fat-high-carbohydrate diet induced obesity model.(Public Library of Science (PLoS), 2022)Obesity is a leading global health problem contributing to various chronic diseases, including type II diabetes mellitus (T2DM). The aim of this study was to investigate whether blueberries, yoghurt, and their respective bioactive components, Cyanidin-3-O-β-glucoside (C3G) and peptides alone or in combinations, alter the expression of genes related to glucose metabolism in skeletal muscles from diet-induced obese mice. In extensor digitorum longus (EDL), yoghurt up-regulated the expression of activation of 5'adenosine monophosphate-activated protein kinase (AMPK), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-3 kinase (PI3K) and glucose transporter 4 (GLUT4), and down-regulated the expression of angiotensin II receptor type 1 (AGTR-1). The combination of blueberries and yoghurt down-regulated the mRNA expression of AGTR-1 and Forkhead box protein O1 (FoxO1) in the EDL. Whereas the combination of C3G and peptides down-regulated AGTR-1 and up-regulated GLUT4 mRNA expression in the EDL. In the soleus, blueberries and yoghurt alone, and their combination down-regulated AGTR-1 and up-regulated GLUT4 mRNA expression. In summary blueberries and yoghurt, regulated multiple genes associated with glucose metabolism in skeletal muscles, and therefore may play a role in the management and prevention of T2DM.
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ItemTransforming growth factor β1 impairs the transcriptomic response to contraction in myotubes from women with polycystic ovary syndrome.(Wiley, 2022-07)Polycystic ovary syndrome (PCOS) is characterised by a hormonal imbalance affecting the reproductive and metabolic health of reproductive-aged women. Exercise is recommended as a first-line therapy for women with PCOS to improve their overall health; however, women with PCOS are resistant to the metabolic benefits of exercise training. Here, we aimed to gain insight into the mechanisms responsible for such resistance to exercise in PCOS. We employed an in vitro approach with electrical pulse stimulation (EPS) of cultured skeletal muscle cells to explore whether myotubes from women with PCOS have an altered gene expression signature in response to contraction. Following EPS, 4719 genes were differentially expressed (false discovery rate <0.05) in myotubes from women with PCOS compared to 173 in healthy women. Both groups included genes involved in skeletal muscle contraction. We also determined the effect of two transforming growth factor β (TGFβ) ligands that are elevated in plasma of women with PCOS, TGFβ1 and anti-Müllerian hormone (AMH), alone and on the EPS-induced response. While AMH (30 ng/ml) had no effect, TGFβ1 (5 ng/ml) induced the expression of extracellular matrix genes and impaired the exercise-like transcriptional signature in myotubes from women with and without PCOS in response to EPS by interfering with key processes related to muscle contraction, calcium transport and actin filament. Our findings suggest that while the fundamental gene expression responses of skeletal muscle to contraction is intact in PCOS, circulating factors like TGFβ1 may be responsible for the impaired adaptation to exercise in women with PCOS. KEY POINTS: Gene expression responses to in vitro contraction (electrical pulse stimulation, EPS) are altered in myotubes from women with polycystic ovary syndrome (PCOS) compared to healthy controls, with an increased expression of genes related to pro-inflammatory pathways. Transforming growth factor β1 (TGFβ1) upregulates genes related to extracellular matrix remodelling and reduces the expression of contractile genes in myotubes, regardless of the donor's health status. TGFβ1 alters the gene expression response to EPS, providing a possible mechanism for the impaired exercise adaptations in women with PCOS.
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ItemCB1 Ligand AM251 Induces Weight Loss and Fat Reduction in Addition to Increased Systemic Inflammation in Diet-Induced Obesity.(MDPI AG, 2022-09-28)Diet-induced obesity (DIO) reduces fatty acid oxidation in skeletal muscle and decreases circulating levels of adiponectin. Endocannabinoid signaling is overactive in obesity, with some effects abated by antagonism of cannabinoid receptor 1 (CB1). This research aimed to determine if treatment with the global CB1 antagonist/inverse agonist, AM251, in high-fat diet (HFD) fed rats influenced adiponectin signaling in skeletal muscle and a "browning" of white adipose tissue (WAT) defined by UCP1 expression levels. Male Sprague Dawley rats consumed an HFD (21% fat) for 9 weeks before receiving daily intraperitoneal injections with vehicle or AM251 (3 mg/kg) for 6 weeks. mRNA expression of genes involved in metabolic functions were measured in skeletal muscle and adipose tissue, and blood was harvested for the measurement of hormones and cytokines. Muscle citrate synthase activity was also measured. AM251 treatment decreased fat pad weight (epididymal, peri-renal, brown), and plasma levels of leptin, glucagon, ghrelin, and GLP-1, and increased PAI-1 along with a range of pro-inflammatory and anti-inflammatory cytokines; however, AM251 did not alter plasma adiponectin levels, skeletal muscle citrate synthase activity or mRNA expression of the genes measured in muscle. AM251 treatment had no effect on white fat UCP1 expression levels. AM251 decreased fat pad mass, altered plasma hormone levels, but did not induce browning of WAT defined by UCP1 mRNA levels or alter gene expression in muscle treated acutely with adiponectin, demonstrating the complexity of the endocannabinoid system and metabolism. The CB1 ligand AM251 increased systemic inflammation suggesting limitations on its use in metabolic disorders.
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ItemThe effect of malting on phenolic compounds and radical scavenging activity in grains and breakfast cereals.(Wiley, 2022-09)Breakfast cereals are popular grain foods and sources of polyphenols. Malting alters polyphenol content and activity; however, effects are varied. The total polyphenol content (TPC), radical scavenging activity (RSA), and polyphenol profile were analyzed in unmalted and malted grains (wheat, barley, and sorghum) and breakfast cereals (wheat, barley) by Folin Ciocalteu Reagent (FCR), % inhibition of the free radical 2,2-diphenyl-1-picryl-hydrazyl, and high performance liquid chromatography. Higher TPC was observed in all malted grains and breakfast cereals compared with unmalted samples (p < 0.05). Higher RSA was also observed in all malted samples compared to unmalted samples (p < 0.05) except for wheat grain to malted wheat grain. In this study, malting induced additional polyphenols and antioxidant activity in grains and cereal products. Malted grain breakfast cereals may be practical sources of polyphenol antioxidants. PRACTICAL APPLICATION: This study utilized malting in a unique way to investigate potential health benefits of polyphenols and antioxidant activity in grains (wheat, barley, and sorghum) and ready-to-eat breakfast cereals (wheat and barley). This study found that grains and breakfast cereals are important sources of antioxidant polyphenols, and these were significantly increased in malted varieties. Understanding this is important as grains and breakfast cereals are widely consumed staple foods. Consuming healthier grain products may be a practical strategy in reducing the risk of noncommunicable diseases such as colorectal cancer and type-2 diabetes, where wholegrain consumption may be important in prevention.
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ItemNo Preview AvailableMaternal diet high in linoleic acid alters offspring fatty acids and cardiovascular function in a rat model.(Cambridge University Press (CUP), 2022-02-28)Linoleic acid (LA), an essential n-6 fatty acid (FA), is critical for fetal development. We investigated the effects of maternal high LA (HLA) diet on offspring cardiac development and its relationship to circulating FA and cardiovascular function in adolescent offspring, and the ability of the postnatal diet to reverse any adverse effects. Female Wistar Kyoto rats were fed low LA (LLA; 1·44 % energy from LA) or high LA (HLA; 6·21 % energy from LA) diets for 10 weeks before pregnancy and during gestation/lactation. Offspring, weaned at postnatal day 25, were fed LLA or HLA diets and euthanised at postnatal day 40 (n 6-8). Maternal HLA diet decreased circulating total cholesterol and HDL-cholesterol in females and decreased total plasma n-3 FA in males, while maternal and postnatal HLA diets decreased total plasma n-3 FA in females. α-Linolenic acid (ALA) and EPA were decreased by postnatal but not maternal HLA diets in both sexes. Maternal and postnatal HLA diets increased total plasma n-6 and LA, and a maternal HLA diet increased circulating leptin, in both male and female offspring. Maternal HLA decreased slopes of systolic and diastolic pressure-volume relationship (PVR), and increased cardiac Col1a1, Col3a1, Atp2a1 and Notch1 in males. Maternal and postnatal HLA diets left-shifted the diastolic PVR in female offspring. Coronary reactivity was altered in females, with differential effects on flow repayment after occlusion. Thus, maternal HLA diets impact lipids, FA and cardiac function in offspring, with postnatal diet modifying FA and cardiac function in the female offspring.
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ItemThe mitochondrial profile in women with polycystic ovary syndrome: impact of exercise(BIOSCIENTIFICA LTD, 2022-04-01)Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting pre-menopausal women and involves metabolic dysregulation. Despite the high prevalence of insulin resistance, the existence of mitochondrial dysregulation and its role in the pathogenesis of PCOS is not clear. Exercise is recommended as the first-line therapy for women with PCOS. In particular, high-intensity interval training (HIIT) is known to improve metabolic health and enhance mitochondrial characteristics. In this narrative review, the existing knowledge of mitochondrial characteristics in skeletal muscle and adipose tissue of women with PCOS and the effect of exercise interventions in ameliorating metabolic and mitochondrial health in these women are discussed. Even though the evidence on mitochondrial dysfunction in PCOS is limited, some studies point to aberrant mitochondrial functions mostly in skeletal muscle, while there is very little research in adipose tissue. Although most exercise intervention studies in PCOS report improvements in metabolic health, they show diverse and inconclusive findings in relation to mitochondrial characteristics. A limitation of the current study is the lack of comprehensive mitochondrial analyses and the diversity in exercise modalities, with only one study investigating the impact of HIIT alone. Therefore, further comprehensive large-scale exercise intervention studies are required to understand the association between metabolic dysfunction and aberrant mitochondrial profile, and the molecular mechanisms underlying the exercise-induced metabolic adaptations in women with PCOS.
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ItemFour weeks of electrical stimulation improves glucose tolerance in a sedentary overweight or obese Hispanic population.(Bioscientifica, 2022-02-04)INTRODUCTION/PURPOSE: Most US adults (54%) do not meet the minimum exercise recommendations by the American College of Sports Medicine. Neuromuscular electrical stimulation (NMES) is a novel alternate strategy to induce muscle contraction. However, the effectiveness of NMES to improve insulin sensitivity and energy expenditure is unclear. The purpose of this study was to investigate the effects of 4 weeks of NMES on glucose tolerance in a sedentary overweight or obese population. METHODS: Participants (n = 10; age: 36.8 ± 3.8 years; BMI = 32 ± 1.3 kg/m2) were randomized into either control or NMES group. All participants received bilateral quadriceps stimulation (12 sessions; 30 min/session; three times/week at 50 Hz and 300 µs pulse width) altering pulse amplitude to either provide low-intensity sensory level (control; tingling sensation) or at high-intensity neuromuscular level (NMES; maximum tolerable levels with visible muscle contraction). Glucose tolerance was assessed by a 3-h oral glucose tolerance test (OGTT), and substrate utilization was measured by indirect calorimetry and body composition via dual X-ray absorptiometry at baseline and after 4 weeks of NMES intervention. RESULTS: Control and NMES groups had comparable fasting blood glucose, glucose tolerance, substrate utilization, and muscle mass at baseline. Four weeks of NMES resulted in a significant improvement in glucose tolerance measured by OGTT, whereas no change was observed in the control group. There was no change in substrate utilization and muscle mass in both control and NMES groups. CONCLUSION: NMES is a novel and effective strategy to improve glucose tolerance in an at-risk overweight or obese sedentary population.
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ItemNon-cell autonomous mechanisms control mitochondrial gene dysregulation in polycystic ovary syndrome.(Bioscientifica, 2021-12-03)Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with insulin resistance and impaired energy metabolism in skeletal muscle, the aetiology of which is currently unclear. Here, we mapped the gene expression profile of skeletal muscle from women with PCOS and determined if cultured primary myotubes retain the gene expression signature of PCOS in vivo. Transcriptomic analysis of vastus lateralis biopsies collected from PCOS women showed lower expression of genes associated with mitochondrial function, while the expression of genes associated with the extracellular matrix was higher compared to controls. Altered skeletal muscle mRNA expression of mitochondrial-associated genes in PCOS was associated with lower protein expression of mitochondrial complex II-V, but not complex I, with no difference in mitochondrial DNA content. Transcriptomic analysis of primary myotube cultures established from biopsies did not display any differentially expressed genes between controls and PCOS. Comparison of gene expression profiles in skeletal muscle biopsies and primary myotube cultures showed lower expression of mitochondrial and energy metabolism-related genes in vitro, irrespective of the group. Together, our results show that the altered mitochondrial-associated gene expression in skeletal muscle in PCOS is not preserved in cultured myotubes, indicating that the in vivo extracellular milieu, rather than genetic or epigenetic factors, may drive this alteration. Dysregulation of mitochondrial-associated genes in skeletal muscle by extracellular factors may contribute to the impaired energy metabolism associated with PCOS.
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ItemSex-Specific Differences in Lysine, 3-Hydroxybutyric Acid and Acetic Acid in Offspring Exposed to Maternal and Postnatal High Linoleic Acid Diet, Independent of Diet.(MDPI AG, 2021-09-23)BACKGROUND: Linoleic acid (LA) is an essential polyunsaturated fatty acid (PUFA) that is required for foetal growth and development. Excess intake of LA can be detrimental for metabolic health due to its pro-inflammatory properties; however, the effect of a diet high in LA on offspring metabolites is unknown. In this study, we aimed to determine the role of maternal or postnatal high linoleic acid (HLA) diet on plasma metabolites in adult offspring. METHODS: Female Wistar Kyoto (WKY) rats were fed with either low LA (LLA) or HLA diet for 10 weeks prior to conception and during gestation/lactation. Offspring were weaned at postnatal day 25 (PN25), treated with either LLA or HLA diets and sacrificed at PN180. Metabolite analysis was performed in plasma samples using Nuclear Magnetic Resonance. RESULTS: Maternal and postnatal HLA diet did not alter plasma metabolites in male and female adult offspring. There was no specific clustering among different treatment groups as demonstrated by principal component analysis. Interestingly, there was clustering among male and female offspring independent of maternal and postnatal dietary intervention. Lysine was higher in female offspring, while 3-hydroxybutyric acid and acetic acid were significantly higher in male offspring. CONCLUSION: In summary, maternal or postnatal HLA diet did not alter the plasma metabolites in the adult rat offspring; however, differences in metabolites between male and female offspring occurred independently of dietary intervention.
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ItemTransforming Growth Factor Beta 1 Alters Glucose Uptake but Not Insulin Signalling in Human Primary Myotubes From Women With and Without Polycystic Ovary Syndrome.(Frontiers Media SA, 2021)Women with polycystic ovary syndrome (PCOS), commonly have profound skeletal muscle insulin resistance which can worsen other clinical features. The heterogeneity of the condition has made it challenging to identify the precise mechanisms that cause this insulin resistance. A possible explanation for the underlying insulin resistance may be the dysregulation of Transforming Growth Factor-beta (TGFβ) signalling. TGFβ signalling contributes to the remodelling of reproductive and hepatic tissues in women with PCOS. Given the systemic nature of TGFβ signalling and its role in skeletal muscle homeostasis, it may be possible that these adverse effects extend to other peripheral tissues. We aimed to determine if TGFβ1 could negatively regulate glucose uptake and insulin signalling in skeletal muscle of women with PCOS. We show that both myotubes from women with PCOS and healthy women displayed an increase in glucose uptake, independent of changes in insulin signalling, following short term (16 hr) TGFβ1 treatment. This increase occurred despite pro-fibrotic signalling increasing via SMAD3 and connective tissue growth factor in both groups following treatment with TGFβ1. Collectively, our findings show that short-term treatment with TGFβ1 does not appear to influence insulin signalling or promote insulin resistance in myotubes. These findings suggest that aberrant TGFβ signalling is unlikely to directly contribute to skeletal muscle insulin resistance in women with PCOS in the short term but does not rule out indirect or longer-term effects.