DMH1 Increases Glucose Metabolism through Activating Akt in L6 Rat Skeletal Muscle Cells

Abstract

DMH1(4-[6-(4-Isopropoxyphenyl)pyrazolo [1,5-a]pyrimidin-3-yl] quinoline) is a compound C analogue with the structural modifications at the 3- and 6-positions in pyrazolo[1,5-a]pyrimidine backbone. Compound C was reported to inhibit both AMPK and Akt. Our preliminary work found that DMH1 activated Akt. Since Akt was involved in glucose metabolism, we aimed to identify the effects of DMH1 on glucose metabolism in L6 rat muscle cells and the potential mechanism. Results showed that DMH1 increased lactic acid release and glucose consumption in L6 rat muscle cells in a dose-dependent manner. DMH1 activated Akt in L6 cells. Akt inhibitor inhibited DMH1-induced Akt activation and DMH1-induced increases of glucose uptake and consumption. DMH1 had no cytotoxicity in L6 cells, but inhibited mitochondrial function and reduced ATP production. DMH1 showed no effect on AMPK, but in the presence of Akt inhibitor, DMH1 significantly activated AMPK. Compound C inhibited DMH1-induced Akt activation in L6 cells. Compound C inhibited DMH1-induced increase of glucose uptake, consumption and lactic acid release in L6 cells. DMH1 inhibited PP2A activity, and PP2A activator forskolin reversed DMH1-induced Akt activation. We concluded that DMH1 increased glucose metabolism through activating Akt and DMH1 activated Akt through inhibiting PP2A activity in L6 rat muscle cells. In view of the analogue structure of DMH1 and compound C and the contrasting effects of DMH1 and compound C on Akt, the present study provides a novel leading chemical structure targeting Akt with potential use for regulating glucose metabolism.

Effects of AMP-activated kinase modulators on intracellular Ca2+ signalling and C. elegans lifespan

“…Altogether, these data suggest that the lifespan extension induced by DMH-1 could be related to caloric restriction and mitochondrial dysfunction. This is consistent with the role that DMH-1 might have over AKT (Xie et al, 2014), a serine / threonine protein kinase involved in glucose metabolism and cell proliferation among other multiple cellular processes, such as render cells more sensitive to metabolic stress (Los et al, 2009;Coloff et al, 2011). The limited availability of glucose and metabolic stress would activate survival pathways, as occurs in eat-2 and nuo-6 mutants, responsible for the C. elegans lifespan extension.…”

“…For example, it has been shown that dorsomorphin was able to induce autophagy in cancer cells through Akt inhibition (Vucicevic et al, 2011). Interestingly, one of the analogues used, DMH-1 (dorsomorphin homologue 1), initially developed as a selective BMPRs inhibitor, has also been shown to act on AKT in L6 cells, but in this case through its activation (Xie et al, 2014).…”

“…However, we have to take into account that DMH-1 has been reported to have other effects. For example it has been shown to promote neurogenesis of humaninduced pluripotent stem cells (hiPSCs) (Neely et al, 2012), to increase the number of cardiomyocyte progenitors (Ao et al, 2012) or to increase glucose metabolism by AKT activation mediated by the inhibition of PP2A activity in rat L6 cells (Xie et al, 2014).…”

“…However, BMPR signalling is not the only target of these inhibitors. One of these compounds, DMH-1, which was initially developed as a BMPR selective inhibitor, also activates AKT through the inhibition of PP2A activity in L6 cells, which in turn, increases glucose metabolism (Xie et al, 2014). Interestingly, DMH-1 is a very close dorsomorphin analogue with only two small structural modifications (Hao et al, 2010).…”

Mechanical stretch activates glycometabolism‐related enzymes via estrogen in C2C12 myoblasts

“…In myocytes, glucose enters the cells by means of transport protein GLUT4 that is located in the cell membrane. GLUT4 is regulated by protein kinase B (AKT) which is activated by insulin‐binding receptor substrate (IRS) and phosphatidylinositol 3‐kinase (PI3K; Campbell et al, 2004; Xie et al, 2014). Glucose is then glycolyzed and oxidative‐phosphorylated.…”