In most cells, mitochondria are highly dynamic organelles that constantly fuse, divide and move. These processes allow mitochondria to redistribute in a cell and exchange contents among the mitochondrial population, and subsequently repair damaged mitochondria. However, most studies on mitochondrial dynamics have been performed on cultured cell lines and neurons, and little is known about whether mitochondria are dynamic organelles in vivo, especially in the highly specialized and differentiated adult skeletal muscle cells. Using mitochondrial matrix-targeted photoactivatable green fluorescent protein (mtPAGFP) and electroporation methods combined with confocal microscopy, we found that mitochondria are dynamic in skeletal muscle in vivo, which enables mitochondria exchange contents within the whole mitochondrial population through nanotunneling-mediated mitochondrial fusion. Mitochondrial network promotes rapid transfer of mtPAGFP within the cell. More importantly, the dynamic behavior was impaired in high-fat diet (HFD)-induced obese mice, accompanying with disturbed mitochondrial respiratory function and decreased ATP content in skeletal muscle. We further found that proteins controlling mitochondrial fusion MFN1 and MFN2 but not Opa1 were decreased and proteins governing mitochondrial fission Fis1 and Drp1 were increased in skeletal muscle of HFD-induced mice when compared to normal diet-fed mice. Altogether, we conclude that mitochondria are dynamic organelles in vivo in skeletal muscle, and it is essential in maintaining mitochondrial respiration and bioenergetics.

Purpose Liraglutide (LIRA), a Glucagon-like peptide-1 receptor agonist (GLP-1RA), showed potent cardioprotective effects of diabetic cardiomyopathy (DCM) with the mechanism remained incompletely understood. Methods T2DM rats were used as study subjects and randomly divided into four groups: 1) CON group, 2) CON + L group, 3) DM group and 4) DM + L group. All rats received either saline or LIRA 0.2 mg/kg (by i.p injection) per day for 4 weeks. After the model was successfully established, cardiac function was determined by invasive hemodynamic evaluation methods. Immunohistochemistry and western blot were performed to understand the molecular mechanism between cardiac function and LIRA. Cultured H9C2 cells with small interfering RNA (siRNA) of Cav3 under high glucose (HG), western blot was performed to understand the molecular mechanism between Cav3 and RyR2 with LIRA. Results Based on our results, LIRA treatment showed a trend to enhance LVSP (110.76 ± 5.61 mmHg) and ± dp/dtmax (5860.41 ± 200.32 mmHg and 3996.8 ± 179.3 mmHg), decreased LVEDP (7.23 ± 0.58 mmHg). The expression of Cav3, eNOS and RyR2 was significantly decreased in the myocardium in DM group, which increased in DM + L group after LIRA administrated. LIRA improved cardiac systolic and diastolic function, attenuate diabetic cardiomyopathy injury by improving Cav3/eNOS/NO signaling and increasing interaction of Cav3 and ryanodine receptor 2 (RyR2) in diabetic cardiac tissues. Conclusion In summary, we found that Liraglutide ameliorates cardiac dysfunction in rats with type 2 diabetes mellitus via improving Cav3/eNOS/NO signaling and increasing interaction of Cav3 and RyR2.

Background Liraglutide (LIRA), a Glucagon-like peptide-1 receptor agonist (GLP-1RA), showed potent cardioprotective effects with the mechanism remained incompletely understood. Caveolin-3 (Cav3) is the cardiomyocytes specific caveolae structural protein, decreased in the diabetic heart. Therefore, this study aimed to investigate whether LIRA exerts its effect on cardiac function in rats with type 2 diabetes mellitus (T2DM) via enhance Cav3 expression. Methods T2DM rats were used as study subjects and randomly divided into four groups: 1) CON group, 2) CON+L group, 3) DM group and 4) DM+L group. All rats received either saline or LIRA 0.2 mg/kg (by i.p injection) per day for 4 weeks. After the model was successfully established, cardiac function was determined by invasive hemodynamic evaluation methods. Immunohistochemistry and western blot were performed to understand the molecular mechanism between cardiac function and LIRA. Results Based on our results, DM group displayed higher blood glucose than Con group (20.57±2.75 mol/L vs. 4.34±0.21 mol/L), while blood glucose level in DM+L group was lower than DM group after received LIRA (10.36±1.84 mol/L). LVSP (91.39±4.98 mmHg), LV +dp/dtmax (4040.74±197.72 mmHg/s) were significantly reduced in DM group, and diabetic rats also exhibited reduced -dp/dtmax (2926.5±142.3 mmHg/s) and elevated LVEDP (10.87±0.83 mmHg). LIRA treatment showed a trend to enhance LVSP (110.76±5.61 mmHg) and ± dp/dtmax (5860.41±200.32 mmHg and 3996.8±179.3 mmHg), decreased LVEDP (7.23±0.58 mmHg). The expression of Cav3, eNOS and RyR2 was significantly decreased in the myocardium in DM group, which increased in DM+L group after LIRA administrated. Hemodynamic data showed DM rats exhibited impairment of myocardial function, while LIRA improved cardiac systolic and diastolic function, attenuate diabetic cardiomyopathy injury by improving Cav3/eNOS/NO signaling, reducing ROS level in cardiac tissues, and increasing interaction of Cav3 and ryanodine receptor 2 (RyR2). Conclusions Liraglutide ameliorates cardiac dysfunction in rats with type 2 diabetes mellitus via reducing ROS level in cardiac tissues, improving Cav3/eNOS/NO signaling and increasing interaction of Cav3 and RyR2. Keywords Type-2 diabetes Mellitus, liraglutide, caveolin-3, ryanodine receptor2, myocardial dysfunction