Background: Doxorubicin (Dox), an anticancer drug, is known to induce cardiac toxicity by causing mitochondrial dysfunction. Although CaMKII and its phosphorylation targets, Drp1 to control mitochondrial fission and MCU to control mitochondrial Ca 2 + uptake, regulate mitochondrial homeostasis, the involvement of these molecules in the Dox-induced mitochondrial dysfunction remains unclear. Method: To study the effects of Dox on mitochondrial homeostasis, we evaluated mitochondrial membrane potential (MMP), mitophagy, and mitochondrial Ca 2 + content ([Ca 2 +]m) in H9C2 cells with the following fluorescent dyes, JC -1, Mtphagy, and Rhod2-AM, respectively. To examine the activating effect of Dox on CaMKII, we evaluated the phosphorylation levels of CaMKII by western blotting. To test the involvement of CaMKII, Drp1, and MCU in the Dox-induced mitochondrial dysfunction, the specific inhibitors, KN-93, Mdivi-1, and Ru360, respectively, were used. Result: Dox treatment dose-dependently reduced MMP and increased the number of cells with mitophagy and [Ca 2 +] m (p<0.05 in all). Dox treatment significantly increased the phosphorylation levels of CaMKII (p<0.05). The inhibition of CaMKII suppressed the effects of Dox on the MMP and the mitophagy (p<0.05), but not on [Ca2+]m. Contrarily, the inhibition of Drp1 and MCU failed to suppress the decrease in MMP by Dox. Similarly, the inhibition of Drp1 did not reverse the increase in mitophagy by Dox, nor did the inhibition of MCU suppress the elevation of [Ca 2 +]m by Dox. Conclusion: These results suggested that activated CaMKII, but not Drp1 and MCU, is involved in the impairment of MMP leading to Dox-induced mitochondrial dysfunction and that the excessive fission by Drp1 and the increased uptake [Ca 2 +]m by MCU are not the mechanism for the Dox-induced MMP reduction.

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Background: Atrial fibrillation (AF) is the most common arrhythmia. AF is highly correlated with multiple risk factors including heart failure, age, obesity, and type 2 diabetes. Among risk factors, the incidence in obesity is increasing worldwide. Recently, it was reported that SGLT2 inhibitors reduced the incidence of atrial fibrillation. However, it is unclear how the treatment with SGLT2 inhibitors has effects on vulnerability to AF. In this study, we examined the effects on the inducibility and duration of AF by treatment with SGLT2 inhibitors in diet-induced obese mice. Methods: Mice were fed a normal chow diet (NCD) or high-fat diet (HFD). Following diet-loading, we randomly divided the animals into groups: NCD+vehicle, HFD+vehicle, and HFD+ SGLT2 treatments. Induction of AF was performed by transesophageal atrial burst pacing. Furthermore, we evaluated cardiac function, blood pressure, atrial fibrosis, and glucose tolerance at the end of the treatments. Results: The results showed that HFD-fed mice increased the inducibility of AF compared to NCD mice. In addition, treatment with the SGLT2 inhibitor in HFD-fed mice dose-dependently reduced the inducibility and duration of AF. There were no significant differences in cardiac function, blood pressure, and fibrosis among all groups. Impairment of glucose tolerance in HFD-induced obesity was improved by treatment with the SGLT2 inhibitor. Conclusion: Treatment with the SGLT2 inhibitor reduced the inducibility of AF and shortened the duration of AF without affecting atrial structural remodeling, suggesting that the SGLT2 inhibitor effectively prevents AF in obesity.

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Objective: Skeletal muscle fiber conversion bears a part in multiple myopathies, and one of those is Sarcopenia which is known to correlate with aging, nutritional deficiency, and so on. In this study, we focused on muscle specific enriched microRNAs (myomirs) to understand the mechanisms of muscle fiber conversion.Method & Results: In-silico study, we selected the microRNA-133a-3p (miR-133a), a myomir relevant to the skeletal myogenesis. Using the human iPS cell-derived skeletal myogenesis system, we identified that expression level of miR -133a was elevated with a peak at day 5 after the induction of myogenesis. Overexpression of miR-133a mimic or inhibitor at the beginning of myogenesis increased mRNA expression of Myh7, a specific marker of slow oxidative myotube, or Myh1, a marker of fast-type myotube, respectively. Furthermore, we found that, under the serumdeprived culture condition, overexpression of miR-133a mimic preserved the cell feature of oxidative fibers, although miR-133a inhibition deformed the tubular formation of oxidative myotubes. Conclusion: MicroRNA-133a functioned to buttress the gene expression of oxidative fiber-specified myosin heavy chain, and to preserve myotubes from nutritional stress, suggesting the possibility that miR-133a would be a therapeutic target for sarcopenia.