ORCID Profile
0000-0001-6953-106X
Current Organisation
Deakin University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: American Diabetes Association
Date: 15-05-2014
DOI: 10.2337/DB13-0967
Abstract: Induction of heat shock protein (HSP)72 protects against obesity-induced insulin resistance, but the underlying mechanisms are unknown. Here, we show that HSP72 plays a pivotal role in increasing skeletal muscle mitochondrial number and oxidative metabolism. Mice overexpressing HSP72 in skeletal muscle (HSP72Tg) and control wild-type (WT) mice were fed either a chow or high-fat diet (HFD). Despite a similar energy intake when HSP72Tg mice were compared with WT mice, the HFD increased body weight, intramuscular lipid accumulation (triacylglycerol and diacylglycerol but not ceramide), and severe glucose intolerance in WT mice alone. Whole-body VO2, fatty acid oxidation, and endurance running capacity were markedly increased in HSP72Tg mice. Moreover, HSP72Tg mice exhibited an increase in mitochondrial number. In addition, the HSP72 coinducer BGP-15, currently in human clinical trials for type 2 diabetes, also increased mitochondrial number and insulin sensitivity in a rat model of type 2 diabetes. Together, these data identify a novel role for activation of HSP72 in skeletal muscle. Thus, the increased oxidative metabolism associated with activation of HSP72 has potential clinical implications not only for type 2 diabetes but also for other disorders where mitochondrial function is compromised.
Publisher: Wiley
Date: 07-10-2011
DOI: 10.1111/J.1600-0838.2011.01395.X
Abstract: The influence of adenosine mono phosphate (AMP)-activated protein kinase (AMPK) vs Akt-mammalian target of rapamycin C1 (mTORC1) protein signaling mechanisms on converting differentiated exercise into training specific adaptations is not well-established. To investigate this, human subjects were ided into endurance, strength, and non-exercise control groups. Data were obtained before and during post-exercise recovery from single-bout exercise, conducted with an exercise mode to which the exercise subjects were accustomed through 10 weeks of prior training. Blood and muscle s les were analyzed for plasma substrates and hormones and for muscle markers of AMPK and Akt-mTORC1 protein signaling. Increases in plasma glucose, insulin, growth hormone (GH), and insulin-like growth factor (IGF)-1, and in phosphorylated muscle phospho-Akt substrate (PAS) of 160 kDa, mTOR, 70 kDa ribosomal protein S6 kinase, eukaryotic initiation factor 4E, and glycogen synthase kinase 3a were observed after strength exercise. Increased phosphorylation of AMPK, histone deacetylase5 (HDAC5), cAMP response element-binding protein, and acetyl-CoA carboxylase (ACC) was observed after endurance exercise, but not differently from after strength exercise. No changes in protein phosphorylation were observed in non-exercise controls. Endurance training produced an increase in maximal oxygen uptake and a decrease in submaximal exercise heart rate, while strength training produced increases in muscle cross-sectional area and strength. No changes in basal levels of signaling proteins were observed in response to training. The results support that in training-accustomed in iduals, mTORC1 signaling is preferentially activated after hypertrophy-inducing exercise, while AMPK signaling is less specific for differentiated exercise.
Publisher: IMR Press
Date: 2008
DOI: 10.2741/2907
Abstract: The AMP-activated protein kinase (AMPK) is an energy sensing enzyme that once activated, promotes energy production and limits energy utilisation to ensure cellular survival. In addition to targeting numerous metabolic enzymes for this purpose, it is becoming apparent that AMPK can also regulate a number of transcriptional processes. These processes ensure cell survival through the inhibition of cell cycle and growth mechanisms, and also prepare the cell for future perturbations in energy balance by increasing the capacity of the cell to produce ATP. While these adaptations might be inextricably linked through regulation of the proliferation-differentiation process, recent studies have identified a number of transcriptional regulators as AMPK substrates that give insights into the regulation of transcription by AMPK in a number of metabolically active tissues.
Publisher: Wiley
Date: 15-03-2008
Publisher: Wiley
Date: 17-04-2020
DOI: 10.1002/JOR.24686
Publisher: Wiley
Date: 23-07-2012
Publisher: American Physiological Society
Date: 02-2008
DOI: 10.1152/AJPENDO.00403.2007
Abstract: Women exhibit an enhanced capability for lipid metabolism during endurance exercise compared with men. The underlying regulatory mechanisms behind this sex-related difference are not well understood but may comprise signaling through a myocyte enhancer factor 2 (MEF2) regulatory pathway. The primary purpose of this study, therefore, was to investigate the protein signaling of MEF2 regulatory pathway components at rest and during 90 min of bicycling exercise at 60% V̇o 2peak in healthy, moderately trained men ( n = 8) and women ( n = 9) to elucidate the potential role of these proteins in substrate utilization during exercise. A secondary purpose was to screen for mRNA expression of MEF2 isoforms and myogenic regulatory factor (MRF) family members of transcription factors at rest and during exercise. Muscle biopsies were obtained before and immediately after exercise. Nuclear AMP-activated protein kinase-α (αAMPK) Thr 172 ( P 0.001), histone deacetylase 5 (HDAC5) Ser 498 ( P 0.001), and MEF2 Thr ( P 0.01) phosphorylation increased with exercise. No significant sex differences were observed at rest or during exercise. At rest, no significant sex differences were observed in mRNA expression of the measured transcription factors. mRNA for transcription factors MyoD, myogenin, MRF4, MEF2A, MEF2C, MEF2D, and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) were significantly upregulated by exercise. Of these, MEF2A mRNA increased 25% specifically in women ( P 0.05), whereas MEF2D mRNA tended to increase in men ( P = 0.11). Although minor sex differences in mRNA expression were observed, the main finding of the present study was the implication of a joint signaling action of AMPK, HDAC5, and PGC1α on MEF2 in the immediate regulatory response to endurance exercise. This signaling response was independent of sex.
Publisher: Cold Spring Harbor Laboratory
Date: 17-10-2022
DOI: 10.1101/2022.10.17.512492
Abstract: Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle, resulting in increased non-oxidative glucose metabolism. This metabolic reprogramming was also associated with impaired apoptosis and ferroptosis responses, and preserved muscle cell viability in response to lipotoxicity. Mechanistically, increased HDAC4 and 5 decreased acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis. Redox drivers of ferroptosis derived from oxidative metabolism were also reduced. The relevance of this pathway was demonstrated by overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice, which enhanced oxidative metabolic capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of skeletal muscle oxidative metabolism, which is linked to inhibition of cell death pathways and preservation of muscle integrity in response to lipotoxicity.
Publisher: Public Library of Science (PLoS)
Date: 14-06-2013
Publisher: Wiley
Date: 27-08-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2008
Publisher: American Physiological Society
Date: 10-2005
DOI: 10.1152/JAPPLPHYSIOL.00197.2005
Abstract: Skeletal muscle possesses a high degree of plasticity and can adapt to both the physical and metabolic challenges that it faces. An acute bout of exercise is sufficient to induce the expression of a variety of metabolic genes, such as GLUT4, pyruvate dehydrogenase kinase 4 (PDK-4), uncoupling protein-3 (UCP3), and peroxisome proliferator-activated receptor-γ coactivator 1 (PGC-1). Reducing muscle glycogen levels before exercise potentiates the effect of exercise on many genes. Similarly, altered substrate availability induces transcription of many of these genes. The purpose of this study was to determine whether glucose ingestion attenuates the exercise-induced increase in a variety of exercise-responsive genes. Six male subjects (28 ± 7 yr 83 ± 3 kg peak pulmonary oxygen uptake = 46 ± 6 ml·kg −1 ·min −1 ) performed 60 min of cycling at 74 ± 2% of peak pulmonary oxygen uptake on two separate occasions. On one occasion, subjects ingested a 6% carbohydrate drink. On the other occasion, subjects ingested an equal volume of a sweet placebo. Muscle s les were obtained from vastus lateralis at rest, immediately after exercise, and 3 h after exercise. PDK-4, UCP3, PGC-1, and GLUT4 mRNA levels were measured on these s les using real-time RT-PCR. Glucose ingestion attenuated ( P 0.05) the exercise-induced increase in PDK-4 and UCP3 mRNA. A similar trend ( P = 0.09) was observed for GLUT4 mRNA. In contrast, PGC-1 mRNA increased following exercise to the same extent in both conditions. These data suggest that glucose availability can modulate the effect of exercise on metabolic gene expression.
Publisher: American Chemical Society (ACS)
Date: 30-01-2014
DOI: 10.1021/JM401945K
Abstract: An improved synthesis and structural reassignment of the class IIa selective histone deacetylase (HDAC) inhibitor MC1568 are described.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2008
DOI: 10.1007/S00125-008-1108-7
Abstract: The 5'-AMP-activated protein kinase (AMPK) pathway is intact in type 2 diabetic patients and is seen as a target for diabetes treatment. In this study, we aimed to assess the impact of the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) on both glucose and fatty acid metabolism in vivo in type 2 diabetic patients. Stable isotope methodology and blood and muscle biopsy s ling were applied to assess blood glucose and fatty acid kinetics following continuous i.v. infusion of AICAR (0.75 mg kg(-1) min(-1)) and/or NaCl (0.9%) in ten male type 2 diabetic patients (age 64 +/- 2 years BMI 28 +/- 1 kg/m(2)). Plasma glucose rate of appearance (R (a)) was reduced following AICAR administration, while plasma glucose rate of disappearance (R (d)) was similar in the AICAR and control test. Consequently, blood glucose disposal (R (d) expressed as a percentage of R (a)) was increased following AICAR infusion (p < 0.001). Accordingly, a greater decline in plasma glucose concentration was observed following AICAR infusion (p < 0.001). Plasma NEFA R (a) and R (d) were both significantly reduced in response to AICAR infusion, and were accompanied by a significant decline in plasma NEFA concentration. Although AMPK phosphorylation in skeletal muscle was not increased, we observed a significant increase in acetyl-CoA carboxylase phosphorylation (p < 0.001). The i.v. administration of AICAR reduces hepatic glucose output, thereby lowering blood glucose concentrations in vivo in type 2 diabetic patients. Furthermore, AICAR administration stimulates hepatic fatty acid oxidation and/or inhibits whole body lipolysis, thereby reducing plasma NEFA concentration.
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.BBR.2012.12.033
Abstract: Several animal models are currently utilised in the investigation of major depressive disorder however, each is validated by its response to antidepressant pharmacotherapy. Few animal models consider the notion of antidepressant treatment resistance. Chronic daily administration of adrenocorticotropic hormone (ACTH) or corticosterone can alter behavioural responses to antidepressants, effectively blocking antidepressant efficacy. Herein, we demonstrate that ACTH-(1-24) (100μg/day 14 days) blocks the immobility-reducing 'antidepressant' effects of a single dose of imipramine (10mg/kg) in the forced swim test. This finding was accompanied by altered monoamine tissue levels in the prefrontal cortex (PFC) 1h after exposure to the acute stress of the forced swim test. PFC tissue from ACTH pre-treated animals contained significantly higher serotonin, noradrenaline and adrenaline concentrations relative to saline pre-treated controls. Conversely, dopamine levels were significantly decreased. Altered plasma corticosterone responses to ACTH injections were observed over the treatment course. Measures were taken on treatment days 1, 4, 8, 11, 14 and 15. ACTH administration initially enhanced plasma corticosterone levels, however, these normalised to levels consistent with control animals by day 14. No differences in corticosterone levels were observed across the treatment time course in saline-treated animals. Taken together these results indicate that pre-treatment with ACTH (100μg/day 14 days) blocks the antidepressant effects of imipramine (10mg/kg), significantly alters key PFC monoamine responses to stress and downregulates glucocorticoid responses. These results suggest that chronic ACTH treatment is a promising paradigm for elucidation of mechanisms mediating antidepressant treatment resistance.
Publisher: Wiley
Date: 14-09-2020
DOI: 10.1111/OBR.13145
Publisher: American Diabetes Association
Date: 04-2003
DOI: 10.2337/DIABETES.52.4.926
Abstract: An acute bout of exercise increases skeletal muscle glucose uptake, improves glucose homeostasis and insulin sensitivity, and enhances muscle oxidative capacity. Recent studies have shown an association between these adaptations and the energy-sensing 5′ AMP-activated protein kinase (AMPK), the activity of which is increased in response to exercise. Activation of AMPK has been associated with enhanced expression of key metabolic proteins such as GLUT-4, hexokinase II (HKII), and mitochondrial enzymes, similar to exercise. It has been hypothesized that AMPK might regulate gene and protein expression through direct interaction with the nucleus. The purpose of this study was to determine if nuclear AMPK α2 content in human skeletal muscle was increased by exercise. Following 60 min of cycling at 72 ± 1% of Vo2peak in six male volunteers (20.6 ± 2.1 years 72.9 ± 2.1 kg Vo2peak = 3.62 ± 0.18 l/min), nuclear AMPK α2 content was increased 1.9 ± 0.4-fold (P = 0.024). There was no change in whole-cell AMPK α2 content or AMPK α2 mRNA abundance. These results suggest that nuclear translocation of AMPK might mediate the effects of exercise on skeletal muscle gene and protein expression.
Publisher: American Physiological Society
Date: 2011
DOI: 10.1152/JAPPLPHYSIOL.00979.2010
Abstract: The spatial association between genomic DNA and histone proteins within chromatin plays a key role in the regulation of gene expression and is largely governed by post-translational modifications to histone proteins, particularly H3 and H4. These modifications include phosphorylation, acetylation, and mono-, di-, and tri-methylation, and while some are associated with transcriptional repression, acetylation of lysine residues within H3 generally correlates with transcriptional activation. Histone acetylation is regulated by the balance between the activities of histone acetyl transferase (HAT) and histone deacetylase (HDAC). In skeletal muscle, the class II HDACs 4, 5, 7, and 9 play a key role in muscle development and adaptation and have been implicated in exercise adaptations. As just one ex le, exercise results in the nuclear export of HDACs 4 and 5, secondary to their phosphorylation by CaMKII and AMPK, two kinases that are activated during exercise in response to changes in sarcoplasmic Ca 2+ levels and energy status, in association with increased GLUT4 expression in human skeletal muscle. Unraveling the complexities of the so-called “histone code” before and after exercise is likely to lead to a greater understanding of the regulation of exercise/activity-induced alterations in skeletal muscle gene expression and reinforce the importance of skeletal muscle plasticity in health and disease.
Publisher: Wiley
Date: 03-03-2027
DOI: 10.1111/DOM.12896
Abstract: To determine the effect of Scriptaid, a compound that can replicate aspects of the exercise adaptive response through disruption of the class IIa histone deacetylase (HDAC) corepressor complex, on muscle insulin action in obesity. Diet-induced obese mice were administered Scriptaid (1 mg/kg) via daily intraperitoneal injection for 4 weeks. Whole-body and skeletal muscle metabolic phenotyping of mice was performed, in addition to echocardiography, to assess cardiac morphology and function. Scriptaid treatment had no effect on body weight or composition, but did increase energy expenditure, supported by increased lipid oxidation, while food intake was also increased. Scriptaid enhanced the expression of oxidative genes and proteins, increased fatty acid oxidation and reduced triglycerides and diacylglycerides in skeletal muscle. Furthermore, ex vivo insulin-stimulated glucose uptake by skeletal muscle was enhanced. Surprisingly, heart weight was reduced in Scriptaid-treated mice and was associated with enhanced expression of genes involved in oxidative metabolism in the heart. Scriptaid also improved indices of both diastolic and systolic cardiac function. These data show that pharmacological targeting of the class IIa HDAC corepressor complex with Scriptaid could be used to enhance muscle insulin action and cardiac function in obesity.
Publisher: Wiley
Date: 06-09-2011
DOI: 10.1111/J.1463-1326.2011.01426.X
Abstract: We investigated the effects of exercise training on adipose tissue and skeletal muscle GLUT4 expression in patients with type 2 diabetes (T2D). Muscle and adipose tissue s les were obtained before and after 4-weeks of exercise training in seven patients with T2D [47 ± 2 years, body mass index (BMI) 28 ± 2]. Seven control subjects (54 ± 4, BMI 30 ± 2) were recruited for baseline comparison. Adipose tissue GLUT4 protein expression was 43% lower (p < 0.05) in patients with T2D compared with control subjects and exercise training increased (p < 0.05) adipose tissue GLUT4 expression by 36%. Skeletal muscle GLUT4 protein expression was not different between control subjects and patients with T2D. Exercise training increased (p < 0.05) skeletal muscle GLUT4 protein expression by 20%. In conclusion, 4-weeks of exercise training increased GLUT4 expression in adipose tissue and skeletal muscle of patients with T2D, although the functional benefits of this adaptation appear to be dependent on an optimal β-cell function.
Publisher: Informa UK Limited
Date: 03-2008
Publisher: American Physiological Society
Date: 06-2007
DOI: 10.1152/AJPENDO.00702.2006
Abstract: As substrate for evaluation of metabolic diseases, we developed novel rat models that contrast for endurance exercise capacity. Through two-way artificial selection, we created rodent phenotypes of intrinsically low-capacity runners (LCR) and high-capacity runners (HCR) that also differed markedly for cardiovascular and metabolic disease risk factors. Here, we determined skeletal muscle proteins with putative roles in lipid and carbohydrate metabolism to better understand the mechanisms underlying differences in whole body substrate handling between phenotypes. Animals ( generation 16) differed for endurance running capacity by 295%. LCR animals had higher resting plasma glucose (6.58 ± 0.45 vs. 6.09 ± 0.45 mmol/l), insulin (0.48 ± 0.03 vs. 0.32 ± 0.02 ng/ml), nonesterified fatty acid (0.57 ± 0.14 v 0.35 ± 0.05 mM), and triglyceride (TG 0.47 ± 0.11 vs. 0.25 ± 0.08 mmol/l) concentrations (all P 0.05). Muscle TG (72.3 ± 14.7 vs. 38.9 ± 6.2 mmol/kg dry muscle wt P 0.05) and diacylglycerol (96 ± 28 vs. 42 ± 8 pmol/mg dry muscle wt P 0.05) contents were elevated in LCR vs. HCR rats. Accompanying the greater lipid accretion in LCR was increased fatty acid translocase/CD36 content (1,014 ± 80 vs. 781 ± 70 arbitrary units P 0.05) and reduced TG lipase activity (0.158 ± 0.0125 vs. 0.274 ± 0.018 mmol·min −1 ·kg dry muscle wt −1 P 0.05). Muscle glycogen, GLUT4 protein, and basal phosphorylation states of AMP-activated protein kinase-α 1 , AMP-activated protein kinase-α 2 , and acetyl-CoA carboxylase were similar in LCR and HCR. In conclusion, rats with low intrinsic aerobic capacity demonstrate abnormalities in lipid-handling capacity. These disruptions may, in part, be responsible for the increased risk of metabolic disorders observed in this phenotype.
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000331724
Abstract: Zinc accumulation may impair cellular bioenergetics, which is associated with neuronal apoptosis. We simultaneously assessed anaerobic and aerobic metabolism in live cells to characterise this effect and hypothesised that the omega 3 fatty acid docosahexaenoic acid (DHA) would protect against any zinc mediated alterations in bioenergetics. In this study we observed a decrease in cellular oxygen consumption, but not glycolytic rate, following chronic zinc exposure, which was specific for neuronal cells. This was due to impaired ATP turnover, without any other effects on mitochondrial function, and was restored by DHA. DHA had no further effects on bioenergetics. These data suggest that zinc disrupts bioenergetics at a point distal to the respiratory chain, which is restored by DHA.
Publisher: Wiley
Date: 02-09-2004
Publisher: American Association for Cancer Research (AACR)
Date: 04-2014
DOI: 10.1158/2159-8290.CD-13-0440
Abstract: Deregulated glucose metabolism fulfills the energetic and biosynthetic requirements for tumor growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF-mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF-mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including hypoxia-inducible factor-1α, MYC, and MONDOA (MLXIP), drives glycolysis downstream of BRAFV600, is critical for responses to BRAF inhibition, and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor (BRAFi)–resistant melanoma cells. Thus, we provide a proof-of-principle for treatment of melanoma with combinations of BRAFis and glycolysis inhibitors. Significance: BRAFis suppress glycolysis and provide strong clinical benefit in BRAFV600 melanoma. We show that BRAF inhibition suppresses glycolysis via a network of transcription factors that are critical for complete BRAFi responses. Furthermore, we provide evidence for the clinical potential of therapies that combine BRAFis with glycolysis inhibitors. Cancer Discov 4(4) 423–33. ©2014 AACR. See related commentary by Haq, p. 390 This article is highlighted in the In This Issue feature, p. 377
Publisher: Wiley
Date: 14-01-2010
DOI: 10.1113/EXPPHYSIOL.2009.049353
Abstract: We have previously demonstrated that well-trained subjects who completed a 3 week training programme in which selected high-intensity interval training (HIT) sessions were commenced with low muscle glycogen content increased the maximal activities of several oxidative enzymes that promote endurance adaptations to a greater extent than subjects who began all training sessions with normal glycogen levels. The aim of the present study was to investigate acute skeletal muscle signalling responses to a single bout of HIT commenced with low or normal muscle glycogen stores in an attempt to elucidate potential mechanism(s) that might underlie our previous observations. Six endurance-trained cyclists/triathletes performed a 100 min ride at approximately 70% peak O(2) uptake (AT) on day 1 and HIT (8 x 5 min work bouts at maximal self-selected effort with 1 min rest) 24 h later (HIGH). Another six subjects, matched for fitness and training history, performed AT on day 1 then 1-2 h later, HIT (LOW). Muscle biopsies were taken before and after HIT. Muscle glycogen concentration was higher in HIGH versus LOW before the HIT (390 +/- 28 versus 256 +/- 67 micromol (g dry wt)(1)). After HIT, glycogen levels were reduced in both groups (P < 0.05) but HIGH was elevated compared with LOW (229 +/- 29 versus 124 +/- 41 micromol (g dry wt)(1) P < 0.05). Phosphorylation of 5 AMP-activated protein kinase (AMPK) increased after HIT, but the magnitude of increase was greater in LOW (P < 0.05). Despite the augmented AMPK response in LOW after HIT, selected downstream AMPK substrates were similar between groups. Phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was unchanged for both groups before and after the HIT training sessions. We conclude that despite a greater activation AMPK phosphorylation when HIT was commenced with low compared with normal muscle glycogen availability, the localization and phosphorylation state of selected downstream targets of AMPK were similar in response to the two interventions.
Publisher: MyJove Corporation
Date: 14-01-2013
DOI: 10.3791/4300
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.CELREP.2013.06.017
Abstract: Caveolae and caveolin-1 (CAV1) have been linked to several cellular functions. However, a model explaining their roles in mammalian tissues in vivo is lacking. Unbiased expression profiling in several tissues and cell types identified lipid metabolism as the main target affected by CAV1 deficiency. CAV1-/- mice exhibited impaired hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent oxidative fatty acid metabolism and ketogenesis. Similar results were recapitulated in CAV1-deficient AML12 hepatocytes, suggesting at least a partial cell-autonomous role of hepatocyte CAV1 in metabolic adaptation to fasting. Finally, our experiments suggest that the hepatic phenotypes observed in CAV1-/- mice involve impaired PPARα ligand signaling and attenuated bile acid and FXRα signaling. These results demonstrate the significance of CAV1 in (1) hepatic lipid homeostasis and (2) nuclear hormone receptor (PPARα, FXRα, and SHP) and bile acid signaling.
Publisher: American Diabetes Association
Date: 05-2004
DOI: 10.2337/DIABETES.53.5.1208
Abstract: Overexpression of GLUT4 in skeletal muscle enhances whole-body insulin action. Exercise increases GLUT4 gene and protein expression, and a binding site for the myocyte enhancer factor 2 (MEF-2) is required on the GLUT4 promoter for this response. However, the molecular mechanisms involved remain elusive. In various cell systems, MEF-2 regulation is a balance between transcriptional repression by histone deacetylases (HDACs) and transcriptional activation by the nuclear factor of activated T-cells (NFAT), peroxisome proliferator-activated receptor-γ coactivator 1 (PGC-1), and the p38 mitogen-activated protein kinase. The purpose of this study was to determine if these same mechanisms regulate MEF-2 in contracting human skeletal muscle. Seven subjects performed 60 min of cycling at ∼70% of Vo2peak. After exercise, HDAC5 was dissociated from MEF-2 and exported from the nucleus, whereas nuclear PGC-1 was associated with MEF-2. Exercise increased total and nuclear p38 phosphorylation and association with MEF-2, without changes in total or nuclear p38 protein abundance. This result was associated with p38 sequence-specific phosphorylation of MEF-2 and an increase in GLUT4 mRNA. Finally, we found no role for NFAT in MEF-2 regulation. From these data, it appears that HDAC5, PGC-1, and p38 regulate MEF-2 and could be potential targets for modulating GLUT4 expression.
Publisher: Rockefeller University Press
Date: 21-10-2013
Abstract: Although the canonical transforming growth factor β signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling. In agreement, we observed that BMP signaling is augmented in models of muscle growth. Importantly, stimulation of BMP signaling is essential for conservation of muscle mass after disruption of the neuromuscular junction. Inhibiting the phosphorylation of Smad1/5 exacerbated denervation-induced muscle atrophy via an HDAC4-myogenin–dependent process, whereas increased BMP–Smad1/5 activity protected muscles from denervation-induced wasting. Our studies highlight a novel role for the BMP signaling pathway in promoting muscle growth and inhibiting muscle wasting, which may have significant implications for the development of therapeutics for neuromuscular disorders.
Publisher: Springer Science and Business Media LLC
Date: 26-03-2013
DOI: 10.1038/BJC.2013.120
Publisher: Canadian Science Publishing
Date: 06-2006
DOI: 10.1139/H06-003
Abstract: Glycogen availability can influence glucose transporter 4 (GLUT4) expression in skeletal muscle through unknown mechanisms. The multisubstrate enzyme AMP-activated protein kinase (AMPK) has also been shown to play an important role in the regulation of GLUT4 expression in skeletal muscle. During contraction, AMPK α2 translocates to the nucleus and the activity of this AMPK isoform is enhanced when skeletal muscle glycogen is low. In this study, we investigated if decreased pre-exercise muscle glycogen levels and increased AMPK α2 activity reduced the association of AMPK with glycogen and increased AMPK α2 translocation to the nucleus and GLUT4 mRNA expression following exercise. Seven males performed 60 min of exercise at ~70% VO 2 peak on 2 occasions: either with normal (control) or low (LG) carbohydrate pre-exercise muscle glycogen content. Muscle s les were obtained by needle biopsy before and after exercise. Low muscle glycogen was associated with elevated AMPK α2 activity and acetyl-CoA carboxylase β phosphorylation, increased translocation of AMPK α2 to the nucleus, and increased GLUT4 mRNA. Transfection of primary human myotubes with a constitutively active AMPK adenovirus also stimulated GLUT4 mRNA, providing direct evidence of a role of AMPK in regulating GLUT4 expression. We suggest that increased activation of AMPK α2 under conditions of low muscle glycogen enhances AMPK α2 nuclear translocation and increases GLUT4 mRNA expression in response to exercise in human skeletal muscle.Key words: exercise, subcellular localization, glycogen binding domain, AMP-activated protein kinase.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.CELL.2012.09.021
Abstract: Diabetes, obesity, and cancer affect upward of 15% of the world's population. Interestingly, all three diseases juxtapose dysregulated intracellular signaling with altered metabolic state. Exactly which genetic factors define stable metabolic set points in vivo remains poorly understood. Here, we show that hedgehog signaling rewires cellular metabolism. We identify a cilium-dependent Smo-Ca(2+)-Ampk axis that triggers rapid Warburg-like metabolic reprogramming within minutes of activation and is required for proper metabolic selectivity and flexibility. We show that Smo modulators can uncouple the Smo-Ampk axis from canonical signaling and identify cyclopamine as one of a new class of "selective partial agonists," capable of concomitant inhibition of canonical and activation of noncanonical hedgehog signaling. Intriguingly, activation of the Smo-Ampk axis in vivo drives robust insulin-independent glucose uptake in muscle and brown adipose tissue. These data identify multiple noncanonical endpoints that are pivotal for rational design of hedgehog modulators and provide a new therapeutic avenue for obesity and diabetes.
Publisher: American Physiological Society
Date: 03-2009
DOI: 10.1152/JAPPLPHYSIOL.90880.2008
Abstract: From a cell signaling perspective, short-duration intense muscular work is typically associated with resistance training and linked to pathways that stimulate growth. However, brief repeated sessions of sprint or high-intensity interval exercise induce rapid phenotypic changes that resemble traditional endurance training. We tested the hypothesis that an acute session of intense intermittent cycle exercise would activate signaling cascades linked to mitochondrial biogenesis in human skeletal muscle. Biopsies (vastus lateralis) were obtained from six young men who performed four 30-s “all out” exercise bouts interspersed with 4 min of rest ( kJ total work). Phosphorylation of AMP-activated protein kinase (AMPK subunits α1 and α2) and the p38 mitogen-activated protein kinase (MAPK) was higher ( P ≤ 0.05) immediately after bout 4 vs. preexercise. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA was increased approximately twofold above rest after 3 h of recovery ( P ≤ 0.05) however, PGC-1α protein content was unchanged. In contrast, phosphorylation of protein kinase B/Akt (Thr 308 and Ser 473 ) tended to decrease, and downstream targets linked to hypertrophy (p70 ribosomal S6 kinase and 4E binding protein 1) were unchanged after exercise and recovery. We conclude that signaling through AMPK and p38 MAPK to PGC-1α may explain in part the metabolic remodeling induced by low-volume intense interval exercise, including mitochondrial biogenesis and an increased capacity for glucose and fatty acid oxidation.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.IJBIOMAC.2009.08.006
Abstract: Glycogen is a cellular energy store that is crucial for whole body energy metabolism, metabolic regulation and exercise performance. To understand glycogen structure we have purified glycogen particles from rat liver and human skeletal muscle tissues and compared their biophysical properties with those found in commercial glycogen preparations. Ultrastructural analysis of commercial liver glycogens fails to reveal the classical alpha-rosette structure but small irregularly shaped particles. In contrast, commercial slipper limpet glycogen consists of beta-particles with similar branching and chain lengths to purified rat liver glycogen together with a tendency to form small alpha-particles, and suggest it should be used as a source of glycogen for all future studies requiring a substitute for mammalian liver glycogen.
Publisher: Wiley
Date: 16-03-2006
DOI: 10.1111/J.1440-1681.2006.04362.X
Abstract: 1. Skeletal muscle is a highly plastic tissue that has a remarkable ability to adapt to external demands, such as exercise. Many of these adaptations can be explained by changes in skeletal muscle gene expression. A single bout of exercise is sufficient to induce the expression of some metabolic genes. We have focused our attention on the regulation of glucose transporter isoform 4 (GLUT-4) expression in human skeletal muscle. 2. Glucose transporter isoform 4 gene expression is increased immediately following a single bout of exercise, and the GLUT-4 enhancer factor (GEF) and myocyte enhancer factor 2 (MEF2) transcription factors are required for this response. Glucose transporter isoform enhancer factor and MEF2 DNA binding activities are increased following exercise, and the molecular mechanisms regulating MEF2 in exercising human skeletal muscle have also been examined. 3. These studies find possible roles for histone deacetylase 5 (HDAC5), adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) and p38 mitogen-activated protein kinase (MAPK) in regulating MEF2 through a series of complex interactions potentially involving MEF2 repression, coactivation and phosphorylation. 4. Given that MEF2 is a transcription factor required for many exercise responsive genes, it is possible that these mechanisms are responsible for regulating the expression of a variety of metabolic genes during exercise. These mechanisms could also provide targets for the treatment and management of metabolic disease states, such as obesity and type 2 diabetes, which are characterized by mitochondrial dysfunction and insulin resistance in skeletal muscle.
Publisher: Informa UK Limited
Date: 29-04-2020
Publisher: Wiley
Date: 23-02-2010
DOI: 10.1111/J.1440-1681.2009.05311.X
Abstract: 1. Skeletal muscle oxidative function and metabolic gene expression are co-ordinately downregulated in metabolic diseases such as insulin resistance, obesity and Type 2 diabetes. Altering skeletal muscle metabolic gene expression to favour enhanced energy expenditure is considered a potential therapy to combat these diseases. 2. Histone deacetylases (HDACs) are chromatin-remodelling enzymes that repress gene expression. It has been shown that HDAC4 and 5 co-operatively regulate a number of genes involved in various aspects of metabolism. Understanding how HDACs are regulated provides insights into the mechanisms regulating skeletal muscle metabolic gene expression. 3. Multiple kinases control phosphorylation-dependent nuclear export of HDACs, rendering them unable to repress transcription. We have found a major role for the AMP-activated protein kinase (AMPK) in response to energetic stress, yet metabolic gene expression is maintained in the absence of AMPK activity. Preliminary evidence suggests a potential role for protein kinase D, also a Class IIa HDAC kinase, in this response. 4. The HDACs are also regulated by ubiquitin-mediated proteasomal degradation, although the exact mediators of this process have not been identified. 5. Because HDACs appear to be critical regulators of skeletal muscle metabolic gene expression, HDAC inhibition could be an effective therapy to treat metabolic diseases. 6. Together, these data show that HDAC4 and 5 are critical regulators of metabolic gene expression and that understanding their regulation could provide a number of points of intervention for therapies designed to treat metabolic diseases, such as insulin resistance, obesity and Type 2 diabetes.
Publisher: S. Karger AG
Date: 2013
DOI: 10.1159/000354433
Abstract: Beta-amyloid (Aβ) protein is a key factor in the pathogenesis of Alzheimer's disease (AD) and it has been reported that mitochondria is involved in the biochemical pathway by which Aβ can lead to neuronal dysfunction. Coenzyme Q10 (CoQ10) is an essential cofactor involved in the mitochondrial electron transport chain and has been suggested as a potential therapeutic agent in AD. Zinc toxicity also affects cellular energy production by decreasing oxygen consumption rate (OCR) and ATP turnover in human neuronal cells, which can be restored by the neuroprotective effect of docosahexaenoic acid (DHA). In the present study, using Seahorse XF-24 Metabolic Flux Analysis we investigated the effect of DHA and CoQ10 alone and in combination against Aβ- and zinc-mediated changes in the mitochondrial function of M17 neuroblastoma cell line. Here, we observed that DHA is specifically neuroprotective against zinc-triggered mitochondrial dysfunction, but does not directly affect Aβ neurotoxicity. CoQ10 has shown to be protective against both Aβ- and zinc-induced alterations in mitochondrial function. Our results indicate that DHA and CoQ10 may be useful for the prevention, treatment and management of neurodegenerative diseases such as AD.
Publisher: Wiley
Date: 15-12-2009
Publisher: American Diabetes Association
Date: 04-2008
DOI: 10.2337/DB07-0843
Abstract: OBJECTIVE—Insulin resistance associated with obesity and diabetes is ameliorated by specific overexpression of GLUT4 in skeletal muscle. The molecular mechanisms regulating skeletal muscle GLUT4 expression remain to be elucidated. The purpose of this study was to examine these mechanisms. RESEARCH DESIGN AND METHODS AND RESULTS—Here, we report that AMP-activated protein kinase (AMPK) regulates GLUT4 transcription through the histone deacetylase (HDAC)5 transcriptional repressor. Overexpression of HDAC5 represses GLUT4 reporter gene expression, and HDAC inhibition in human primary myotubes increases endogenous GLUT4 gene expression. In vitro kinase assays, site-directed mutagenesis, and site-specific phospho-antibodies establish AMPK as an HDAC5 kinase that targets S259 and S498. Constitutively active but not dominant-negative AMPK and 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR) treatment in human primary myotubes results in HDAC5 phosphorylation at S259 and S498, association with 14-3-3 isoforms, and H3 acetylation. This reduces HDAC5 association with the GLUT4 promoter, as assessed through chromatin immunoprecipitation assays and HDAC5 nuclear export, concomitant with increases in GLUT4 gene expression. Gene reporter assays also confirm that the HDAC5 S259 and S498 sites are required for AICAR induction of GLUT4 transcription. CONCLUSIONS—These data reveal a signal transduction pathway linking cellular energy charge to gene transcription directed at restoring cellular and whole-body energy balance and provide new therapeutic targets for the treatment and management of insulin resistance and type 2 diabetes.
Publisher: Bioscientifica
Date: 18-09-2012
DOI: 10.1530/JME-12-0095
Abstract: The class IIa histone deacetylases (HDACs) act as transcriptional repressors by altering chromatin structure through histone deacetylation. This family of enzymes regulates muscle development and phenotype, through regulation of muscle-specific genes including myogenin and MyoD ( MYOD1 ). More recently, class IIa HDACs have been implicated in regulation of genes involved in glucose metabolism. However, the effects of HDAC5 on glucose metabolism and insulin action have not been directly assessed. Knockdown of HDAC5 in human primary muscle cells increased glucose uptake and was associated with increased GLUT4 ( SLC2A4 ) expression and promoter activity but was associated with reduced GLUT1 ( SLC2A1 ) expression. There was no change in PGC-1 α ( PPARGC1A ) expression. The effects of HDAC5 knockdown on glucose metabolism were not due to alterations in the initiation of differentiation, as knockdown of HDAC5 after the onset of differentiation also resulted in increased glucose uptake and insulin-stimulated glycogen synthesis. These data show that inhibition of HDAC5 enhances metabolism and insulin action in muscle cells. As these processes in muscle are dysregulated in metabolic disease, HDAC inhibition could be an effective therapeutic strategy to improve muscle metabolism in these diseases. Therefore, we also examined the effects of the pan HDAC inhibitor, Scriptaid, on muscle cell metabolism. In myotubes, Scriptaid increased histone 3 acetylation, GLUT4 expression, glucose uptake and both oxidative and non-oxidative metabolic flux. Together, these data suggest that HDAC5 regulates muscle glucose metabolism and insulin action and that HDAC inhibitors can be used to modulate these parameters in muscle cells.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-04-2012
DOI: 10.1002/HEP.24810
Abstract: Caveolin-1 (CAV1) is a structural protein of caveolae involved in lipid homeostasis and endocytosis. Using newly generated pure Balb/C CAV1 null ((Balb/C)CAV1-/-) mice, CAV1-/- mice from Jackson Laboratories ((JAX)CAV1-/-), and CAV1-/- mice developed in the Kurzchalia Laboratory ((K)CAV1-/-), we show that under physiological conditions CAV1 expression in mouse tissues is necessary to guarantee an efficient progression of liver regeneration and mouse survival after partial hepatectomy. Absence of CAV1 in mouse tissues is compensated by the development of a carbohydrate-dependent anabolic adaptation. These results were supported by extracellular flux analysis of cellular glycolytic metabolism in CAV1-knockdown AML12 hepatocytes, suggesting cell autonomous effects of CAV1 loss in hepatic glycolysis. Unlike in (K)CAV1-/- livers, in (JAX)CAV1-/- livers CAV1 deficiency is compensated by activation of anabolic metabolism (pentose phosphate pathway and lipogenesis) allowing liver regeneration. Administration of 2-deoxy-glucose in (JAX)CAV1-/- mice indicated that liver regeneration in (JAX)CAV1-/- mice is strictly dependent on hepatic carbohydrate metabolism. Moreover, with the exception of regenerating (JAX)CAV1-/- livers, expression of CAV1 in mice is required for efficient hepatic lipid storage during fasting, liver regeneration, and diet-induced steatosis in the three CAV1-/- mouse strains. Furthermore, under these conditions CAV1 accumulates in the lipid droplet fraction in wildtype mouse hepatocytes. Our data demonstrate that lack of CAV1 alters hepatocyte energy metabolism homeostasis under physiological and pathological conditions.
Publisher: Canadian Science Publishing
Date: 10-2007
DOI: 10.1139/H07-082
Abstract: Exercise increases the metabolic capacity of skeletal muscle, which improves whole-body energy homeostasis and contributes to the positive health benefits of exercise. This is, in part, mediated by increases in the expression of a number of metabolic enzymes, regulated largely at the level of transcription. At a molecular level, many of these genes are regulated by the class II histone deacetylase (HDAC) family of transcriptional repressors, in particular HDAC5, through their interaction with myocyte enhancer factor 2 transcription factors. HDAC5 kinases, including 5′-AMP-activated protein kinase and protein kinase D, appear to regulate skeletal muscle metabolic gene transcription by inactivating HDAC5 and inducing HDAC5 nuclear export. These mechanisms appear to participate in exercise-induced gene expression and could be important for skeletal muscle adaptations to exercise.
Publisher: Wiley
Date: 05-2017
DOI: 10.1111/JNE.12470
Abstract: The amyloid precursor protein (APP) is a transmembrane protein that can be cleaved by proteases through two different pathways to yield a number of small peptides, each with distinct physiological properties and functions. It has been extensively studied in the context of Alzheimer's disease, with the APP-derived amyloid β (Aβ) peptide being a major constituent of the amyloid plaques observed in this disease. It has been known for some time that APP can regulate neuronal metabolism however, the present review examines the evidence indicating that APP and its peptides can also regulate key metabolic processes such as insulin action, lipid synthesis and storage and mitochondrial function in peripheral tissues. This review presents the hypothesis that amyloidogenic processing of APP in peripheral tissues plays a key role in the response to nutrient excess and that this could contribute to the pathogenesis of metabolic diseases such as obesity and type 2 diabetes (T2D).
Publisher: Portland Press Ltd.
Date: 26-01-2010
DOI: 10.1042/CS20090533
Abstract: Skeletal muscle phenotype plays a critical role in human performance and health, and skeletal muscle oxidative capacity is a key determinant of exercise tolerance. More recently, defective muscle oxidative metabolism has been implicated in a number of conditions associated with the metabolic syndrome, cardiovascular disease and muscle-wasting disorders. AMPK (AMP-activated protein kinase) is a critical regulator of cellular and organismal energy balance. AMPK has also emerged as a key regulator of skeletal muscle oxidative function, including metabolic enzyme expression, mitochondrial biogenesis and angiogenesis. AMPK mediates these processes primarily through alterations in gene expression. The present review examines the role of AMPK in skeletal muscle transcription and provides an overview of the known transcriptional substrates mediating the effects of AMPK on skeletal muscle phenotype.
Publisher: Wiley
Date: 20-12-2005
Abstract: Overexpression of GLUT4 exclusively in skeletal muscle enhances insulin action and improves glucose homeostasis. Transgenic studies have discovered two regions on the GLUT4 promoter conserved across several species that are required for normal GLUT4 expression in skeletal muscle. These regions contain binding motifs for the myocyte enhancer factor 2 (MEF2) family and GLUT4 enhancer factor (GEF). A single bout of exercise increases both GLUT4 transcription and mRNA abundance however, the molecular mechanisms mediating this response remain largely unexplored. Thus, the aim of this study was to determine whether a single, acute bout of exercise increased the DNA-binding activities of MEF2 and GEF in human skeletal muscle. Seven subjects performed 60 min of cycling at approximately 70% of VO2peak. After exercise, the DNA-binding activities of both the MEF2A/D heterodimer and GEF were increased (P<0.05). There was no change in nuclear MEF2D or GEF abundance after exercise, but nuclear MEF2A abundance was increased (P<0.05). These data demonstrate that exercise increases MEF2 and GEF DNA binding and imply that these transcription factors could be potential targets for modulating GLUT4 expression in human skeletal muscle.
Publisher: Informa UK Limited
Date: 13-04-2019
Publisher: Wiley
Date: 2008
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S40170-019-0207-X
Abstract: Increased flux through both glycolytic and oxidative metabolic pathways is a hallmark of breast cancer cells and is critical for their growth and survival. As such, targeting this metabolic reprograming has received much attention as a potential treatment approach. However, the heterogeneity of breast cancer cell metabolism, even within classifications, suggests a necessity for an in idualised approach to treatment in breast cancer patients. The metabolic phenotypes of a erse panel of human breast cancer cell lines representing the major breast cancer classifications were assessed using real-time metabolic flux analysis. Flux linked to ATP production, pathway reserve capacities and specific macromolecule oxidation rates were quantified. Suspected metabolic vulnerabilities were targeted with specific pathway inhibitors, and relative cell viability was assessed using the crystal violet assay. Measures of AMPK and mTORC1 activity were analysed through immunoblotting. Breast cancer cells displayed heterogeneous energy requirements and utilisation of non-oxidative and oxidative energy-producing pathways. Quantification of basal glycolytic and oxidative reserve capacities identified cell lines that were highly dependent on in idual pathways, while assessment of substrate oxidation relative to total oxidative capacity revealed cell lines that were highly dependent on in idual macromolecules. Based on these findings, mild mitochondrial inhibition in ESH-172 cells, including with the anti-diabetic drug metformin, and mild glycolytic inhibition in Hs578T cells reduced relative viability, which did not occur in non-transformed MCF10a cells. The effects on viability were associated with AMPK activation and inhibition of mTORC1 signalling. Hs578T were also found to be highly dependent on glutamine oxidation and inhibition of this process also impacted viability. Together, these data highlight that systematic flux analysis in breast cancer cells can identify targetable metabolic vulnerabilities, despite heterogeneity in metabolic profiles between in idual cancer cell lines.
Publisher: Wiley
Date: 14-03-2012
DOI: 10.1111/J.1463-1326.2012.01585.X
Abstract: The aim of the study was to determine the effect of a single bout of exercise on GLUT4 gene expression in muscle of patients with type 2 diabetes (T2D) and control subjects, matched for age and body mass index. Nine patients with T2D and nine control subjects performed 60 min of cycling exercise at ~55% peak power (W(max) ). Skeletal muscle biopsies were obtained at baseline, immediately post and 3-h post exercise. GLUT4 mRNA expression increased (p < 0.05) to a similar extent immediately post exercise in control (~60%) and T2D (~66%) subjects, and remained elevated (p < 0.05) 3-h post exercise with no differences between groups. Similarly, p-AMP-activated protein kinase, p38 mitogen-activated kinase and proliferator-activated receptor gamma co-activator-alpha mRNA expression were increased (p < 0.05) post exercise, and were not different between the groups. In conclusion, a single bout of exercise increased skeletal muscle GLUT4 mRNA expression in patients with T2D to a similar extent as in control subjects.
Publisher: Informa UK Limited
Date: 21-05-2019
Publisher: Elsevier BV
Date: 07-2014
Location: Australia
No related grants have been discovered for Sean McGee.