Maintenance of skeletal muscle mass relies on the dynamic balance between anabolic and catabolic processes and is important for motility, systemic energy homeostasis, and viability. We identified direct target genes of the glucocorticoid receptor (GR) in skeletal muscle, i.e., REDD1 and KLF15. As well as REDD1, KLF15 inhibits mTOR activity, but via a distinct mechanism involving BCAT2 gene activation. Moreover, KLF15 upregulates the expression of the E3 ubiquitin ligases atrogin-1 and MuRF1 genes and negatively modulates myofiber size. Thus, GR is a liaison involving a variety of downstream molecular cascades toward muscle atrophy. Notably, mTOR activation inhibits GR transcription function and efficiently counteracts the catabolic processes provoked by glucocorticoids. This mutually exclusive crosstalk between GR and mTOR, a highly coordinated interaction between the catabolic hormone signal and the anabolic machinery, may be a rational mechanism for fine-tuning of muscle volume and a potential therapeutic target for muscle wasting.

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Nishitani, Shinobu, Kenji Takehana, Shoji Fujitani, and Ichiro Sonaka. Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. It is well established that impaired glucose metabolism is a frequent complication in patients with hepatic cirrhosis. We previously showed that leucine, one of the branchedchain amino acids (BCAA), promotes glucose uptake under insulinfree conditions in isolated skeletal muscle from normal rats. The aim of the present study was to evaluate the effects of BCAA on glucose metabolism in a rat model of CCl4-induced cirrhosis (CCl4 rats). Oral glucose tolerance tests were performed on BCAA-treated CCl4 rats. In the CCl4 rats, treatment with leucine or isoleucine, but not valine, improved glucose tolerance significantly, with the effect of isoleucine being greater than the effect of leucine. Glucose uptake experiments using isolated soleus muscle from the CCl4 rats revealed that leucine and isoleucine, but not valine, promoted glucose uptake under insulinfree conditions. To clarify the mechanism of the blood glucoselowering effects of BCAA, we collected soleus muscles from BCAAtreated CCl4 rats with or without a glucose load. These samples were used to determine the subcellular location of glucose transporter proteins and glycogen synthase (GS) activity. Oral administration of leucine or isoleucine without a glucose load induced GLUT4 and GLUT1 translocation to the plasma membrane. GS activity was augmented only in leucine-treated rats and was completely inhibited by rapamycin, an inhibitor of mammalian target of rapamycin. In summary, we found that leucine and isoleucine improved glucose metabolism in CCl4 rats by promoting glucose uptake in skeletal muscle. This effect occurred as a result of upregulation of GLUT4 and GLUT1 and also by mammalian target of rapamycin-dependent activation of GS in skeletal muscle. From these results, we consider that BCAA treatment may have beneficial effects on glucose metabolism in cirrhotic patients. mammalian target of rapamycin; glycogen synthase; GLUT4; GLUT1; rat model of carbon tetrachloride-induced cirrhosis IT HAS LONG BEEN RECOGNIZED that cirrhosis is associated with impaired glucose metabolism, with the majority of patients (60 -80%) being glucose intolerant and 10 -15% eventually developing overt diabetes mellitus (24). The characteristics of glucose intolerance in cirrhotic patients are unusual, because although these patients exhibit fasting hypoglycemia, they also have postprandial hyperglycemia and continuous hyperinsulinemia (11). Despite being hyperinsulinemic, many cirrhotic individuals have impaired glucose tolerance or are overtly diabetic.Hyperinsulinemia in the face of hyperglycemia suggests the presence of insulin resistance (6,26,30). In this condition, it is believed that postprandial glucose uptake is not carried out promptly in insulin-sensitive tissues, such as skeletal muscle and adipose tissue, and that glycogen synthesis is not promoted in skeletal muscle or liver. Indeed, there is considerable eviden...

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