FOXO1, a member of the FOXO forkhead type transcription factors, is markedly up-regulated in skeletal muscle in energy-deprived states such as fasting and severe diabetes, but its functions in skeletal muscle have remained poorly understood. In this study, we created transgenic mice specifically overexpressing FOXO1 in skeletal muscle. These mice weighed less than the wildtype control mice, had a reduced skeletal muscle mass, and the muscle was paler in color. Microarray analysis revealed that the expression of many genes related to the structural proteins of type I muscles (slow twitch, red muscle) was decreased. Histological analyses showed a marked decrease in size of both type I and type II fibers and a significant decrease in the number of type I fibers in the skeletal muscle of FOXO1 mice. Enhanced gene expression of a lysosomal proteinase, cathepsin L, which is known to be up-regulated during skeletal muscle atrophy, suggested increased protein degradation in the skeletal muscle of FOXO1 mice. Running wheel activity (spontaneous locomotive activity) was significantly reduced in FOXO1 mice compared with control mice. Moreover, the FOXO1 mice showed impaired glycemic control after oral glucose and intraperitoneal insulin administration. These results suggest that FOXO1 negatively regulates skeletal muscle mass and type I fiber gene expression and leads to impaired skeletal muscle function. Activation of FOXO1 may be involved in the pathogenesis of sarcopenia, the age-related decline in muscle mass in humans, which leads to obesity and diabetes.

We have conducted an in silico data base search for and cloned a novel G-protein-coupled receptor (GPCR) named TG1019. Dot and Northern blotting analyses showed that transcripts of the novel GPCR were expressed in various tissues except brain, and the expression was more intense in liver, kidney, peripheral leukocyte, lung, and spleen than in other tissues. By GTP␥S binding assay using the TG1019-G␣ i1 -protein fusion expressed in insect cells, eicosanoids, and polyunsaturated fatty acids such as 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE), 5(S)-hydroperoxy-6E,8Z, 11Z,14Z-eicosatetraenoic acid, and arachidonic acid were identified to exhibit agonistic activities against TG1019. 5-oxo-ETE was the most potent to enhance the specific binding by 6-fold at a maximum effect dose of submicromolar to micromolar order with an ED 50 value of 5.7 nM. Conversely, polyunsaturated fatty acids such as docosahexaenoic acid and eicosapentaenoic acid showed antagonistic activities against TG1019. In Chinese hamster ovary cells transiently expressing TG1019, the forskolin-stimulated production of cAMP was inhibited up to ϳ70% by 5-oxo-ETE, with an IC 50 value of 33 nM. This inhibition was sensitive to pretreatment of the cells with pertussis toxin.

Lipoprotein lipase (LPL) plays a role in lipid usage in skeletal muscle by hydrolyzing plasma triglycerides into fatty acids, which are further utilized for L L-oxidation. Lipid usage is stimulated during fasting, diabetes mellitus and exercise, concomitant with enhanced LPL expression in skeletal muscle. Here we show that the forkhead type transcription factor FKHR is strongly induced in skeletal muscle in fasting mice, in mice with streptozotocin-induced diabetes and in mice after treadmill running. Ectopic expression of FKHR enhanced LPL gene expression in C2C12 muscle cells in culture. These results implicate FKHR as an important modulator of lipid metabolism in skeletal muscle.

Without increasing adverse events, the endo-knife with a water-jet function efficiently reduced the operation time of colorectal ESD in patients with large superficial colorectal neoplasms. (University hospital Medical Information Network Clinical Trials Registry number UMIN000001302).

6‐Aminohexanoic‐acid‐oligomer hydrolase of Flavobacterium sp. KI72 was purified to homogeneity by column chromatography three times, and by preparative polyacrylamide gel electrophoresis twice. The purified enzyme had the following characteristics. The molecular weight was estimated to be 84000 by Sephadex G‐200 molecular‐sieve chromatography. The enzyme consisted of two homologous subunits of 42000, judged from sodium dodecylsulfate/polyacrylamide gel electrophoresis. The optimum pH for activity was between 8 and 9, the optimum temperature was 40° C for a 1‐h reaction. The Michaelis‐Menten constants and turnover numbers for the 6‐aminohexanoic acid dimer and trimer were 5.9 mM and 2.4 s−1, and 6.2 mM and 2.0 s−1 respectively. The enzyme was inhibited by 0.37 mM diisopropylfluorophosphate and by 0.013 mM p‐chloromercuribenzoate. The enzyme was active on 6‐aminohexanoic acid oligomers from dimer to hexamer and icosamer but not on hectamer, and the activity decreased with the increase of the polymerization number of the ougomer. The oligomers were hydrolyzed so as to remove the 6‐aminohexanoic acid residue successively from the amino terminus. The enzyme could not hydrolyze other linear amides, cyclic amides, dipeptides, tripeptides or casein. 6‐Aminohexanoic‐acid‐oligomer hydrolase was classified as a new member of the linear amidases (EC 3.5.1.‐).