Muscular G9a regulates muscle-liver-fat axis by musclin under overnutrition in female mice

Crosstalk among different tissues and organs is a hotspot in metabolic research. Recent studies have revealed the regulatory roles of a number of myokines in metabolism. Here, we report that female mice muscle-specific lacking histone methylase G9a (<i>Ehmt2</i>^CkmmKO<i> </i>or <i>Ehmt2</i>^HSA KO) are resistant to high-fat-diet (HFD) induced obesity and hepatic steatosis. Furthermore, we identified significantly upregulated circulating level of musclin, a myokine, in HFD-fed <i>Ehmt2</i>^CkmmKO or <i>Ehmt2</i>^HSA KO female mice. Similarly, upregulated musclin was observed in mice injected with two structurally different inhibitors for G9a methylase activity, BIX01294 and A366. Moreover, injection of recombinant full-length musclin or its functional core domain, inhibited the HFD-induced obesity and hepatic steatosis in wildtype female and male mice. Mechanistically, G9a methylase activity-dependently regulated muscular musclin level by binding to its promoter, also by regulating p-Foxo1/Foxo1 level <i>in vivo</i> and <i>in vitro</i>. Collectively, these data suggested a critical role for G9a in the ‘muscle-liver-fat’ metabolic axis, at least for female mice. Musclin may serve as a potential therapeutic candidate for obesity and associated diseases.

Muscular G9a regulates muscle-liver-fat axis by musclin under overnutrition in female mice

Crosstalk among different tissues and organs is a hotspot in metabolic research. Recent studies have revealed the regulatory roles of a number of myokines in metabolism. Here, we report that female mice muscle-specific lacking histone methylase G9a (<i>Ehmt2</i>^CkmmKO<i> </i>or <i>Ehmt2</i>^HSA KO) are resistant to high-fat-diet (HFD) induced obesity and hepatic steatosis. Furthermore, we identified significantly upregulated circulating level of musclin, a myokine, in HFD-fed <i>Ehmt2</i>^CkmmKO or <i>Ehmt2</i>^HSA KO female mice. Similarly, upregulated musclin was observed in mice injected with two structurally different inhibitors for G9a methylase activity, BIX01294 and A366. Moreover, injection of recombinant full-length musclin or its functional core domain, inhibited the HFD-induced obesity and hepatic steatosis in wildtype female and male mice. Mechanistically, G9a methylase activity-dependently regulated muscular musclin level by binding to its promoter, also by regulating p-Foxo1/Foxo1 level <i>in vivo</i> and <i>in vitro</i>. Collectively, these data suggested a critical role for G9a in the ‘muscle-liver-fat’ metabolic axis, at least for female mice. Musclin may serve as a potential therapeutic candidate for obesity and associated diseases.

A Novel Efflux System in Inducibly Erythromycin-Resistant Strains of Streptococcus pyogenes

ABSTRACT Streptococcus pyogenes strains inducibly resistant (iMLS phenotype) to macrolide, lincosamide, and streptogramin B (MLS) antibiotics can be subdivided into three phenotypes: iMLS-A, iMLS-B, and iMLS-C. This study focused on inducibly erythromycin-resistant S. pyogenes strains of the iMLS-B and iMLS-C types, which are very similar and virtually indistinguishable in a number of phenotypic and genotypic features but differ clearly in their degree of resistance to MLS antibiotics (high in the iMLS-B type and low in the iMLS-C type). As expected, the iMLS-B and iMLS-C test strains had the erm(A) methylase gene; the iMLS-A and the constitutively resistant (cMLS) isolates had the erm(B) methylase gene; and a control M isolate had the mef(A) efflux gene. mre(A) and msr(A), i.e., other macrolide efflux genes described in gram-positive cocci, were not detected in any test strain. With a radiolabeled erythromycin method for determination of the intracellular accumulation of the drug in the absence or presence of an efflux pump inhibitor, active efflux of erythromycin was observed in the iMLS-B isolates as well as in the M isolate, whereas no efflux was demonstrated in the iMLS-C isolates. By the triple-disk (erythromycin plus clindamycin and josamycin) test, performed both in normal test medium and in the same medium supplemented with the efflux pump inhibitor, under the latter conditions iMLS-B and iMLS-C strains were no longer distinguishable, all exhibiting an iMLS-C phenotype. In conjugation experiments with an iMLS-B isolate as the donor and a Rifr Fusr derivative of an iMLS-C isolate as the recipient, transconjugants which shared the iMLS-B type of the donor under all respects, including the presence of an efflux pump, were obtained. These results indicate the existence of a novel, transferable efflux system, not associated with mef(A) or with other known macrolide efflux genes, that is peculiar to iMLS-B strains. Whereas the low-level resistance of iMLS-C strains to MLS antibiotics is apparently due to erm(A)-encoded methylase activity, the high-level resistance of iMLS-B strains appears to depend on the same methylase activity plus the new efflux system.

Decrease in DNA methylase activity during preimplantation development in the mouse

During early mouse development, there are large-scale changes in DNA methylation. These changes may be due to the availability or stability of the enzyme, DNA methyltransferase (methylase), which is responsible for maintenance of DNA methylation. A microassay for methylase activity in preimplantation embryos shows that the level of maternally inherited enzyme is extremely high in the egg and that this activity is stable for the first three cleavage divisions. However, from the 8-cell to the blastocyst stage, there is a marked and absolute decrease in enzyme activity.