Metabolomic responses to acute exercise and AMPK-glycogen binding disruption in mice

Background: Exercise is widely accepted as a potent intervention to promote whole-body metabolic health and help prevent and/or treat metabolic diseases. Exercise represents a major challenge to energy homeostasis, both at the whole-body and cellular level. Numerous molecular metabolic responses to acute exercise are activated to preserve energy homeostasis. Central to maintaining cellular energy balance is the AMP-activated protein kinase (AMPK), a heterotrimeric enzyme that senses cellular energy levels by competitively binding to adenosine mono-, di- and triphosphate (AMP, ADP and ATP, respectively). In response to energy stress, AMPK becomes activated and switches on energy-producing catabolic processes while simultaneously switching off energy-consuming anabolic processes. Through its regulatory β subunit, AMPK also binds glycogen – an important energy reserve primarily stored in liver and skeletal muscle. Although growing evidence from AMPK double knock-in (DKI) mice has highlighted physiological consequences of disrupting AMPK-glycogen binding in exercise and metabolic control, the underlying molecular pathways and mechanisms remain unclear. Metabolomics is the unbiased collection and study of small molecules (< 1500 daltons) involved in metabolic reactions to capture molecular snapshots of metabolic pathways, for example associated with given stimuli (e.g., exercise) or genotype. Therefore, metabolomic analysis of biofluids and tissues represents a promising approach to better understand the molecular metabolic responses to acute exercise and the physiological effects of disrupting AMPK-glycogen binding in vivo. Methods: Plasma, gastrocnemius muscle and liver samples were collected from age-matched male WT and DKI mice with disrupted AMPK-glycogen binding at rest and immediately following 30-min submaximal treadmill running. An untargeted mass spectrometry-based metabolomic approach was utilised to determine changes in plasma and/or tissue metabolites occurring in response to acute exercise and the disruption of AMPK-glycogen interactions in DKI mice. Complementary whole-body mouse phenotyping and real-time metabolic phenotyping assays using the Seahorse XFe24 Analyzer and Oroboros O2k high-resolution respirometer were performed to compare energy metabolism and substrate utilisation profiles in mouse embryonic fibroblast (MEF) cells and skeletal muscle from WT and DKI mice. Results/Discussion: Relative to WT mice, DKI mice had reduced maximal running speed, concomitant with increased total body mass and adiposity. In plasma, a total of 83 metabolites were identified/annotated, with 17 metabolites significantly different in exercised versus rested mice. These included amino acids, acylcarnitines and steroid hormones. Distinct plasma metabolite profiles were observed between the rest and exercise conditions and between WT and DKI mice at rest, while metabolite profiles of both genotypes converged following exercise. These differences in metabolite profiles were primarily explained by exercise-associated increases in acylcarnitines and steroid hormones as well as decreases in amino acids and derivatives following exercise. DKI mice showed greater decreases in plasma amino acid levels following exercise versus WT. In liver and skeletal muscle, 150 and 92 metabolites were identified/annotated, respectively. Similar to the plasma metabolite responses observed across genotypes and conditions, significant overall metabolite profile shifts were observed between WT and DKI mice at rest, as well as significant metabolite profile differences between the rested and exercised conditions. Differential muscle metabolite responses to acute exercise were also observed between genotypes. Markers of mitochondrial respiration in permeabilised gastrocnemius fibres were not affected by AMPK DKI mutation, although there were reduced total ATP rate and relative contribution of glycolysis in DKI versus WT MEF cells. Conclusion: The plasma metabolomic analyses performed in Study 1 represent the first study to map mouse plasma metabolomic changes following acute exercise in WT mice and the effects of disrupting AMPK-glycogen interactions using DKI mice. Untargeted metabolomics uncovered alterations in plasma, skeletal muscle and liver metabolite profiles between rested and exercised mice in both genotypes, and between genotypes at rest. This study has uncovered known and previously unreported plasma metabolite responses to acute exercise in WT mice, as well as greater decreases in amino acids following exercise in DKI plasma. These mouse tissue metabolomic datasets, combined with cell and tissue respirometry data complement previous whole-body, tissue and molecular characterisation of WT and DKI mice, revealing potential metabolic pathways and novel molecular biomarkers underlying exercise’s metabolic health benefits and the physiological effects of disrupting AMPK-glycogen binding in mice

Black Holes in Type IIA String on Calabi-Yau Threefolds with Affine ADE Geometries and q-Deformed 2d Quiver Gauge Theories

Motivated by studies on 4d black holes and q-deformed 2d Yang Mills theory, and borrowing ideas from compact geometry of the blowing up of affine ADE singularities, we build a class of local Calabi-Yau threefolds (CY^{3}) extending the local 2-torus model \mathcal{O}(m)\oplus \mathcal{O}(-m)\to T^{2\text{}} considered in hep-th/0406058 to test OSV conjecture. We first study toric realizations of T^{2} and then build a toric representation of X_{3} using intersections of local Calabi-Yau threefolds \mathcal{O}(m)\oplus \mathcal{O}(-m-2)\to \mathbb{P}^{1}. We develop the 2d \mathcal{N}=2 linear \sigma-model for this class of toric CY^{3}s. Then we use these local backgrounds to study partition function of 4d black holes in type IIA string theory and the underlying q-deformed 2d quiver gauge theories. We also make comments on 4d black holes obtained from D-branes wrapping cycles in \mathcal{O}(\mathbf{m}) \oplus \mathcal{O}(\mathbf{-m-2}%) \to \mathcal{B}_{k} with \mathbf{m=}(m_{1},...,m_{k}) a k-dim integer vector and \mathcal{B}_{k} a compact complex one dimension base consisting of the intersection of k 2-spheres S_{i}^{2} with generic intersection matrix I_{ij}. We give as well the explicit expression of the q-deformed path integral measure of the partition function of the 2d quiver gauge theory in terms of I_{ij}.Comment: 36 pages, latex, 9 figures. References adde

NC Calabi-Yau Orbifolds in Toric Varieties with Discrete Torsion

Using the algebraic geometric approach of Berenstein et {\it al} (hep-th/005087 and hep-th/009209) and methods of toric geometry, we study non commutative (NC) orbifolds of Calabi-Yau hypersurfaces in toric varieties with discrete torsion. We first develop a new way of getting complex $d$ mirror Calabi-Yau hypersurfaces $H_{\Delta}^{\ast d}$ in toric manifolds $M_{\Delta }^{\ast (d+1)}$ with a $C^{\ast r}$ action and analyze the general group of the discrete isometries of $H_{\Delta}^{\ast d}$. Then we build a general class of $d$ complex dimension NC mirror Calabi-Yau orbifolds where the non commutativity parameters $\theta_{\mu \nu}$ are solved in terms of discrete torsion and toric geometry data of $M_{\Delta}^{(d+1)}$ in which the original Calabi-Yau hypersurfaces is embedded. Next we work out a generalization of the NC algebra for generic $d$ dimensions NC Calabi-Yau manifolds and give various representations depending on different choices of the Calabi-Yau toric geometry data. We also study fractional D-branes at orbifold points. We refine and extend the result for NC $T^{2})/(\mathbf{{Z_{2}}\times {Z_{2})}}$ to higher dimensional torii orbifolds in terms of Clifford algebra.Comment: 38 pages, Late

On Non Commutative G2 structure

Using an algebraic orbifold method, we present non-commutative aspects of $G_2$ structure of seven dimensional real manifolds. We first develop and solve the non commutativity parameter constraint equations defining $G_2$ manifold algebras. We show that there are eight possible solutions for this extended structure, one of which corresponds to the commutative case. Then we obtain a matrix representation solving such algebras using combinatorial arguments. An application to matrix model of M-theory is discussed.Comment: 16 pages, Latex. Typos corrected, minor changes. Version to appear in J. Phys.A: Math.Gen.(2005

Metabolomics and lipidomics: Expanding the molecular landscape of exercise biology

Dynamic changes in circulating and tissue metabolites and lipids occur in response to exercise-induced cellular and whole-body energy demands to maintain metabolic homeostasis. The metabolome and lipidome in a given biological system provides a molecular snapshot of these rapid and complex metabolic perturbations. The application of metabolomics and lipidomics to map the metabolic responses to an acute bout of aerobic/endurance or resistance exercise has dramatically expanded over the past decade thanks to major analytical advancements, with most exercise-related studies to date focused on analyzing human biofluids and tissues. Experimental and analytical con-siderations, as well as complementary studies using animal model systems, are warranted to help overcome challenges associated with large human interindividual variability and decipher the breadth of molecular mechanisms underlying the metabolic health-promoting effects of exercise. In this review, we provide a guide for exercise researchers regarding analytical techniques and experimental workflows commonly used in metabolomics and lipidomics. Furthermore, we discuss advancements in human and mammalian exercise research utilizing metabolomic and lipidomic approaches in the last decade, as well as highlight key technical considerations and remaining knowledge gaps to continue expanding the molecular landscape of exercise biology

On Local Calabi-Yau Supermanifolds and Their Mirrors

We use local mirror symmetry to study a class of local Calabi-Yau super-manifolds with bosonic sub-variety V_b having a vanishing first Chern class. Solving the usual super- CY condition, requiring the equality of the total U(1) gauge charges of bosons \Phi_{b} and the ghost like fields \Psi_{f} one \sum_{b}q_{b}=\sum_{f}Q_{f}, as \sum_{b}q_{b}=0 and \sum_{f}Q_{f}=0, several examples are studied and explicit results are given for local A_{r} super-geometries. A comment on purely fermionic super-CY manifolds corresponding to the special case where q_{b}=0, \forall b and \sum_{f}Q_{f}=0 is also made.\bigskipComment: 17 page

Comparison of non-invasive peripheral venous saturations with venous blood co-oximetry

The estimation of venous oxygen saturations using photoplethysmography (PPG) may be useful as a noninvasive continuous method of detecting changes in regional oxygen supply and demand (e.g. in the splanchnic circulation). The aim of this research was to compare PPG-derived peripheral venous oxygen saturations directly with venous saturation measured from co-oximetry blood samples, to assess the feasibility of non-invasive local venous oxygen saturation. This paper comprises two similar studies: one in healthy spontaneously-breathing volunteers and one in mechanically ventilated anaesthetised patients. In both studies, PPG-derived estimates of peripheral venous oxygen saturations (SxvO2) were compared with co-oximetry samples (ScovO2) of venous blood from the dorsum of the hand. The results were analysed and correlation between the PPG-derived results and co-oximetry was tested for. In the volunteer subjects,moderate correlation (r = 0.81) was seen between SxvO2 values and co-oximetry derived venous saturations (ScovO2), with a mean (±SD) difference of +5.65 ± 14.3% observed between the two methods. In the anaesthetised patients SxvO2 values were only 3.81% lower than SpO2 and tended to underestimate venous saturation (mean difference = –2.67 ± 5.89%) while correlating weakly with ScovO2 (r = 0.10). The results suggest that significant refinement of the technique is needed to sufficiently improve accuracy to produce clinically meaningful measurement of peripheral venous oxygen saturation. In anaesthetised patients the use of the technique may be severely limited by cutaneous arteriovenous shunting

Effect of respiratory-induced intensity variations on finger SpO(2) measurements in volunteers

Photoplethysmographic (PPG) signals were recorded from the fingers of 16 healthy volunteers with periods of timed and forced respiration. The aim of this pilot study was to compare estimations of arterial oxygen saturation (SpO2) recorded using a dedicated pulse oximetry system while subjects were breathing regularly with and without a mouthpiece containing a flow resistor. The experiments were designed to mimic the effects of mechanical ventilation in anesthetized patients. The effect of estimated airway pressures of ±15 cmH2O caused observable modulation in the recorded red and PPG signals. SpO2 values were calculated from the pre-recorded PPG signals. Mean SpO2 values were 95.4% with the flow resistor compared with 97.3% with no artificial resistance, with statistical significance demonstrated using a Student's t-test (P = 0.006)

Development of a Reflectance Photoplethysmographic Sensor used for the Assessment of Perfusion of Free Jejunum Flaps: a case report

Free jejunum flaps have been widely used as a reconstruction option after total laryngopharyngectomy. Monitoring of flap perfusion assists in early detection of flap failure, increasing the possibility of flap salvage. Considering the free jejunum flap is a hidden flap there is still no single reliable, non invasive perfusion monitoring technique to assist in recognizing flap failure. We have developed a dual-wavelength photoplethysmographic (PPG) sensor and processing system to investigate the ability of the system in detecting flap perfusion. This is a case report of evaluation of the new prototype reflectance PPG sensor on one patient undergoing total laryngopharyngectomy and reconstruction with a free jejunum flap. PPG signals were successfully obtained intra-operatively which suggest that photoplethysmography may be a suitable method for assessing free jejunum flap perfusion

Fano hypersurfaces and Calabi-Yau supermanifolds

In this paper, we study the geometrical interpretations associated with Sethi's proposed general correspondence between N = 2 Landau-Ginzburg orbifolds with integral \hat{c} and N = 2 nonlinear sigma models. We focus on the supervarieties associated with \hat{c} = 3 Gepner models. In the process, we test a conjecture regarding the superdimension of the singular locus of these supervarieties. The supervarieties are defined by a hypersurface \widetilde{W} = 0 in a weighted superprojective space and have vanishing super-first Chern class. Here, \widetilde{W} is the modified superpotential obtained by adding as necessary to the Gepner superpotential a boson mass term and/or fermion bilinears so that the superdimension of the supervariety is equal to \hat{c}. When Sethi's proposal calls for adding fermion bilinears, setting the bosonic part of \widetilde{W} (denoted by \widetilde{W}_{bos}) equal to zero defines a Fano hypersurface embedded in a weighted projective space. In this case, if the Newton polytope of \widetilde{W}_{bos} admits a nef partition, then the Landau-Ginzburg orbifold can be given a geometrical interpretation as a nonlinear sigma model on a complete intersection Calabi-Yau manifold. The complete intersection Calabi-Yau manifold should be equivalent to the Calabi-Yau supermanifold prescribed by Sethi's proposal.Comment: 24 pages, uses JHEP3.cls; v2: minor corrections, references adde