Endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and mitochondrial biogenesis were assessed following varying intensities of exercise training. The animals were randomly assigned to receive either low- (LIT, n=7) or high intensity training (HIT, n=7), or were assigned to a control group (n=7). Over 5 weeks, the animals in the LIT were exercised on a treadmill with a 10° incline for 60 min at a speed of 20 m/min group, and in the HIT group at a speed of 34 m/min for 5 days a week. No statistically significant differences were found in the body weight, plasma triglyceride, and total cholesterol levels across the three groups, but fasting glucose and insulin levels were significantly lower in the exercise-trained groups. Additionally, no statistically significant differences were observed in the levels of PERK phosphorylation in skeletal muscles between the three groups. However, compared to the control and LIT groups, the level of BiP was lower in the HIT group. Compared to the control group, the levels of ATF4 in skeletal muscles and CHOP were significantly lower in the HIT group. The HIT group also showed increased PGC-1α mRNA expression in comparison with the control group. Furthermore, both of the trained groups showed higher levels of mitochondrial UCP3 than the control group. In summary, we found that a 5-week high-intensity exercise training routine resulted in increased mitochondrial biogenesis and decreased ER stress and apoptotic signaling in the skeletal muscle tissue of rats.

Alcoholic liver disease (ALD) is a worldwide health problem and hepatocyte apoptosis has been associated with the development/progression of ALD. However, no definite effective pharmacotherapy for ALD is currently available. Cilostazol, a selective type III phosphodiesterase inhibitor has been shown to protect hepatocytes from ethanol-induced apoptosis. In the present study, the underlying mechanisms for the protective effects of cilostazol were examined. Primary rat hepatocytes were treated with ethanol in the presence or absence of cilostazol. Cell viability and intracellular cAMP were measured. Apoptosis was detected by Hoechst staining, TUNEL assay, and caspase-3 activity assay. The roles of cAMP and AMP-activated protein kinase (AMPK) pathways in the action of CTZ were explored using pharmacological inhibitors and siRNAs. Liver from mice received ethanol (5 g/kg body weight) by oral gavage following cilostazol treatment intraperitoneally was obtained for measurement of apoptosis and activation of AMPK pathway. Cilostazol inhibited ethanol-induced hepatocyte apoptosis and potentiated the increases in cAMP level induced by forskolin. However, the anti-apoptotic effect of cilostazol was not reversed by an inhibitor of adenylyl cyclase. Interestingly, cilostazol activated AMPK and increased the level of LC3-II, a marker of autophagy. The inhibition of AMPK abolished the effects of cilostazol on LC3-II expression and apoptosis. Moreover, the inhibition of LKB1 and CaMKK2, upstream kinases of AMPK, dampened cilostazol-inhibited apoptosis as well as AMPK activation. In conclusion, cilostazol protected hepatocytes from apoptosis induced by ethanol mainly via AMPK pathway which is regulated by both LKB1 and CaMKK2. Our results suggest that cilostazol may have potential as a promising therapeutic drug for treatment of ALD.

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OBJECTIVE To investigate cardiac structural and functional changes by tissue Doppler imaging (TDI) and strain imaging in dogs with spontaneous type 1 diabetes mellitus. ANIMALS 30 client-owned dogs, of which 10 had normotensive type 1 diabetes mellitus and 20 were healthy. PROCEDURES All dogs underwent physical examination, laboratory analyses, standard echocardiography, and TDI. RESULTS On TDI and strain imaging, transmitral peak early diastolic velocity (E)-to-tissue Doppler–derived peak early diastolic velocity at basal segment (E') of septum ratio, E:lateral E’ ratio, and septal tissue Doppler–derived peak late diastolic velocity at basal segment (A') were significantly higher and the septal E':A’ ratio and lateral longitudinal strain were significantly lower for diabetic dogs than for control dogs. Furthermore, in diabetic dogs, serum glucose and fructosamine concentrations after a 12-hour period of food withholding were positively correlated with regional systolic functional variables (septal and lateral longitudinal strain) and left ventricular filling pressure indices (E:septal E’ and E:lateral E’ ratios) but were negatively correlated with diastolic functional variables (E:transmitral peak late diastolic velocity and septal and lateral E':A’ ratios). CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that myocardial function in diabetic dogs may be altered before the development of clinical heart-associated signs and that the change may be more readily detected by TDI and strain imaging than by conventional echocardiography. In addition, findings indicated that hyperglycemia could have detrimental effects on myocardial function, independent of hypertension, other cardiac diseases, and left ventricular hypertrophy, in dogs with type 1 diabetes.