AMPK is indispensable for overload-induced muscle glucose uptake and glycogenesis but dispensable for inducing hypertrophy in mice

Chronic muscle loading (overload) induces skeletal muscles to undergo hypertrophy and to increase glucose uptake. Although AMP-activated protein kinase (AMPK) reportedly serves as a negative regulator of hypertrophy and a positive regulator of glucose uptake, its role in overload-induced skeletal muscle hypertrophy and glucose uptake is unclear. This study aimed to determine whether AMPK regulates overload-induced hypertrophy and glucose uptake in skeletal muscles. To this end, skeletal muscle overload was induced through unilateral synergist ablations in wild-type (WT) and transgenic mice, expressing the dominant-negative mutation of AMPK (AMPK-DN). After 14 days, parameters, including muscle fiber cross-sectional area (CSA), glycogen level, and in vivo [3 H]-2-deoxy-D-glucose uptake, were assessed. No significant difference was observed in body weight or blood glucose level between the WT and AMPK-DN mice. However, the 14-day muscle overload activated the AMPK pathway in WT mice skeletal muscle, whereas this response was impaired in the AMPK-DN mice. Despite a normal CSA gain in each fiber type, the AMPK-DN mice demonstrated a significant impairment of overload-induced muscle glucose uptake and glycogenesis, compared to WT mice. Moreover, 14-day overload-induced changes in GLUT4 and HKII expression levels were reduced in AMPK-DN mice, compared to WT mice. This study demonstrated that AMPK activation is indispensable for overload-induced muscle glucose uptake and glycogenesis; however, it is dispensable for the induction of hypertrophy in AMPK-DN mice. Furthermore, the AMPK/GLUT4 and HKII axes may regulate overload-induced muscle glucose uptake and glycogenesis

Mice deficient in the Shmt2 gene have mitochondrial respiration defects and are embryonic lethal

Accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been proposed to be responsible for human aging and age-associated mitochondrial respiration defects. However, our previous findings suggested an alternative hypothesis of human aging—that epigenetic changes but not mutations regulate age-associated mitochondrial respiration defects, and that epigenetic downregulation of nuclear-coded genes responsible for mitochondrial translation [e.g., glycine C-acetyltransferase (GCAT), serine hydroxymethyltransferase 2 (SHMT2)] is related to age-associated respiration defects. To examine our hypothesis, here we generated mice deficient in Gcat or Shmt2 and investigated whether they have respiration defects and premature aging phenotypes. Gcat-deficient mice showed no macroscopic abnormalities including premature aging phenotypes for up to 9 months after birth. In contrast, Shmt2-deficient mice showed embryonic lethality after 13.5 days post coitum (dpc), and fibroblasts obtained from 12.5-dpc Shmt2-deficient embryos had respiration defects and retardation of cell growth. Because Shmt2 substantially controls production of N-formylmethionine-tRNA (fMet-tRNA) in mitochondria, its suppression would reduce mitochondrial translation, resulting in expression of the respiration defects in fibroblasts from Shmt2-deficient embryos. These findings support our hypothesis that age-associated respiration defects in fibroblasts of elderly humans are caused not by mtDNA mutations but by epigenetic regulation of nuclear genes including SHMT2

The Mechanism of Chromostereopsis －Measurement of Binocular Disparity and Numerical Evaluation based on Ray-Tracing Simulation－

　色立体視は，背景と2 色以上の領域で構成される平面パタンにおいて，特定の色が進出あるいは後退して知覚される現象である．そのメカニズムは，眼球光学系の軸外色収差に基づく両眼立体視とされているが，それだけでは十分に説明出来ない現象も報告されている．本研究では，軸外色収差による両眼視差量を実験により求め，背景色による奥行きの逆転現象と奥行き量の変化について調べた．また，精密模型眼を用いて光線追跡による数値シミュレーションを行い，実験結果を定量的に説明できることを示した．さらに，自然視の色立体視で顕著な個人差の原因について，シミュレーション結果に基づく考察を加えた． Chromostereopsis is a visual perception where a specifi c color is perceived closer to or farther from the observer than the other colors in a plane pattern that consists of at least two colors with a background color. The mechanism responsible for this phenomenon is considered to be binocular stereopsis by chromatic aberration of the eyeball optical subsystem; however, previous quantitative evaluations have been unsatisfactory. In this paper, we experimentally and numerically study a reversal phenomenon of the depth by background color and a change in the magnitude of this depth. Furthermore, we discuss individual differences in the depth perception in the chromostereopsis on the basis of numerical simulation results

Disruption of the mouse Shmt2 gene confers embryonic anaemia via foetal liver-specific metabolomic disorders

In a previous study, we proposed that age-related mitochondrial respiration defects observed in elderly subjects are partially due to age-associated downregulation of nuclear-encoded genes, including serine hydroxymethyltransferase 2 (SHMT2), which is involved in mitochondrial one-carbon (1C) metabolism. This assertion is supported by evidence that the disruption of mouse Shmt2 induces mitochondrial respiration defects in mouse embryonic fibroblasts generated from Shmt2-knockout E13.5 embryos experiencing anaemia and lethality. Here, we elucidated the potential mechanisms by which the disruption of this gene induces mitochondrial respiration defects and embryonic anaemia using Shmt2-knockout E13.5 embryos. The livers but not the brains of Shmt2-knockout E13.5 embryos presented mitochondrial respiration defects and growth retardation. Metabolomic profiling revealed that Shmt2 deficiency induced foetal liver-specific downregulation of 1C-metabolic pathways that create taurine and nucleotides required for mitochondrial respiratory function and cell division, respectively, resulting in the manifestation of mitochondrial respiration defects and growth retardation. Given that foetal livers function to produce erythroblasts in mouse embryos, growth retardation in foetal livers directly induced depletion of erythroblasts. By contrast, mitochondrial respiration defects in foetal livers also induced depletion of erythroblasts as a consequence of the inhibition of erythroblast differentiation, resulting in the manifestation of anaemia in Shmt2-knockout E13.5 embryos.Peer reviewe

マウス胸腺脂肪化時期の検討

The thymus has an important role in the immune reaction. The lymphocytes localized both in thymic cortex and in medulla, known as T cells, proliferate in an environment of the epithelial reticular cells. T cells educated to react against non-self materials enter the circulation and function in peripheral immunity. Thymus of the mouse has almost developed and grown to its natal size by the 18 days gestation. After the birth thymus grows at a somewhat slower rate until puberty. It subsequently shows a decrease both in size and in weight. That is due to the decrease in the lymphocyte-accumulated region and to the partial replacement by fat tissue. The process is so-called age"involution". Fat cells are classified as connective-tissue cells. They must develop and proliferate in the capsule or in the trabecula of the thymus after birth, because no typical fat cells containing lipid droplets are observed at birth.We examined when fat cells appeared in the thymus after the birth. Fat cells are known to express leptin, so that the appearance of leptin mRNA was detected by the PCR method. The expression of leptin was detected as early as in the thymus of the 3 week-old mouse and increased with the age. It is sugested that fat tissue development begins immediately after the birth and precedes to the age involution in the thymus, although that the cortex and medulla develops until puberty

Harmonizing solubility measurement to lower inter-laboratory variance – progress of consortium of biopharmaceutical tools (CoBiTo) in Japan

The purpose of the present study was to harmonize the protocol of equilibrium solubility measurements for poorly water-soluble drugs to lower inter-laboratory variance. The “mandatory” and “recommended” procedures for the shake-flask method were harmonized based on the knowledge and experiences of each company and information from the literature. The solubility of model drugs was measured by the harmonized protocol (HP) and the non-harmonized proprietary protocol of each company (nonHP). Albendazole, griseofulvin, dipyridamole, and glibenclamide were used as model drugs. When using the nonHP, the solubility values showed large inter-laboratory variance. In contrast, inter-laboratory variance was markedly reduced when using the HP

Formation of dense partonic matter in relativistic nucleus-nucleus collisions at RHIC: Experimental evaluation by the PHENIX collaboration

Extensive experimental data from high-energy nucleus-nucleus collisions were recorded using the PHENIX detector at the Relativistic Heavy Ion Collider (RHIC). The comprehensive set of measurements from the first three years of RHIC operation includes charged particle multiplicities, transverse energy, yield ratios and spectra of identified hadrons in a wide range of transverse momenta (p_T), elliptic flow, two-particle correlations, non-statistical fluctuations, and suppression of particle production at high p_T. The results are examined with an emphasis on implications for the formation of a new state of dense matter. We find that the state of matter created at RHIC cannot be described in terms of ordinary color neutral hadrons.Comment: 510 authors, 127 pages text, 56 figures, 1 tables, LaTeX. Submitted to Nuclear Physics A as a regular article; v3 has minor changes in response to referee comments. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Transverse energy production and charged-particle multiplicity at midrapidity in various systems from sNN=7.7\sqrt{s_{NN}}=7.7 to 200 GeV

Measurements of midrapidity charged particle multiplicity distributions, $dN_{\rm ch}/d\eta$, and midrapidity transverse-energy distributions, $dE_T/d\eta$, are presented for a variety of collision systems and energies. Included are distributions for Au$+$Au collisions at $\sqrt{s_{_{NN}}}=200$, 130, 62.4, 39, 27, 19.6, 14.5, and 7.7 GeV, Cu$+$Cu collisions at $\sqrt{s_{_{NN}}}=200$ and 62.4 GeV, Cu$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV, U$+$U collisions at $\sqrt{s_{_{NN}}}=193$ GeV, $d$$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV, $^{3}$He$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV, and $p$$+$$p$ collisions at $\sqrt{s_{_{NN}}}=200$ GeV. Centrality-dependent distributions at midrapidity are presented in terms of the number of nucleon participants, $N_{\rm part}$, and the number of constituent quark participants, $N_{q{\rm p}}$. For all $A$$+$$A$ collisions down to $\sqrt{s_{_{NN}}}=7.7$ GeV, it is observed that the midrapidity data are better described by scaling with $N_{q{\rm p}}$ than scaling with $N_{\rm part}$. Also presented are estimates of the Bjorken energy density, $\varepsilon_{\rm BJ}$, and the ratio of $dE_T/d\eta$ to $dN_{\rm ch}/d\eta$, the latter of which is seen to be constant as a function of centrality for all systems.Comment: 706 authors, 32 pages, 20 figures, 34 tables, 2004, 2005, 2008, 2010, 2011, and 2012 data. v2 is version accepted for publication in Phys. Rev.

水田畦畔の植生に与える除草の影響

水田畦畔に生育する植物の多様性維持機構を明らかにするために,京都府精華町下狛,京田辺市上羽山及び宮津市上世屋の5か所のそれぞれの水田畦畔と放棄水田の畦畔において,そこに出現する種の被度及び密度を1999年5月から2000年4月まで経時的に調査した。これらをもとにShannonの情報量を算出し,種多様度とした。水田畦畔ぱ,放棄水田の畦畔と比較して種多様度が高く,出現種数も多い傾向にあり,それらの季節変化が明瞭であった。また,多年生雑草の占める比率は低かった。これは,毎年,年に数回行われる除草によって,セイタカアワダチソウなどの大型の種が優占することが抑制されているためであると考えられた。それぞれの畦畔は異なる植生を示し,また,種多様度の季節変化の様態も多様であった。除草をはじめとする管理方法がそれぞれの畦畔で異なることが,水田を中心とする生態系における植物の多様性を維持する機構として働いていると推定された