Aim: Cardiovascular complications, including cardiac arrhythmias, result in high morbidity and mortality in patients with type-2 diabetes mellitus (T2DM). Clinical and experimental data suggest electrophysiological impairment of the natural pacemaker of the diabetic heart. The present study examined sinoatrial node (SAN) arrhythmias in a mouse model of T2DM and physiologically probed their underlying cause. Methods: Electrocardiograms were obtained from conscious diabetic db/db and lean control db/+ mice. In vivo SAN function was probed through pharmacological autonomic modulation with isoprenaline, atropine and carbachol. Blood pressure stability and heart rate variability (HRV) were evaluated. Intrinsic SAN function was evaluated through ex vivo imaging of spontaneous Ca 2+ transients in isolated SAN preparations. Results: While lean control mice showed constant RR intervals during isoprenaline challenge, the diabetic mice experienced SAN arrhythmias with large RR fluctuations in a dose-dependent manner. These arrhythmias were completely abolished by atropine pre-treatment, while carbachol pretreatment significantly increased SAN arrhythmia frequency in the diabetic mice. Blood pressure and HRV were comparable in db/db and db/+ mice, suggesting that neither augmented baroreceptor feedback nor autonomic neuropathy is a likely arrhythmia mechanism. Cycle length response to isoprenaline was comparable in isolated SAN preparations from db/db and db/+ mice; however, Ca 2+ spark frequency was significantly increased in db/db mice compared to db/+ at baseline and after isoprenaline. Conclusion: Our results demonstrate a dysfunction of cardiac pacemaking in an animal model of T2DM upon challenge with a β-adrenergic agonist. Ex vivo, higher Ca 2+ spark frequency is present in diabetic mice, which may be directly linked to in vivo arrhythmias. K E Y W O R D Sautonomic nervous system, baroreflex, calcium, electrophysiology, isoprenaline, type-2 diabetes
Dysfunction of the sinoatrial node (SAN), the natural heart pacemaker, is common in heart failure (HF) patients. SAN spontaneous activity relies on various ion currents in the plasma membrane (voltage clock), but intracellular Ca2+ ([Ca2+]i) release via ryanodine receptor 2 (RYR2; Ca2+ clock) plays an important synergetic role. Whereas remodeling of voltage-clock components has been revealed in HF, less is known about possible alterations to the Ca2+ clock. Here, we analyzed [Ca2+]i handling in SAN from a mouse HF model after transverse aortic constriction (TAC) and compared it with sham-operated animals. ECG data from awake animals showed slower heart rate in HF mice upon autonomic nervous system blockade, indicating intrinsic sinus node dysfunction. Confocal microscopy analyses of SAN cells within whole tissue showed slower and less frequent [Ca2+]i transients in HF. This correlated with fewer and smaller spontaneous Ca2+ sparks in HF SAN cells, which associated with lower RYR2 protein expression level and reduced phosphorylation at the CaMKII site. Moreover, PLB phosphorylation at the CaMKII site was also decreased in HF, which could lead to reduced sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) function and lower sarcoplasmic reticulum Ca2+ content, further depressing the Ca2+ clock. The inhibition of CaMKII with KN93 slowed [Ca2+]i transient rate in both groups, but this effect was smaller in HF SAN, consistent with less CaMKII activation. In conclusion, our data uncover that the mechanism of intrinsic pacemaker dysfunction in HF involves reduced CaMKII activation.
Obesity in pregnant women presents a risk to fetal health, leading to numerous metabolic syndromes and chronic inflammation risks. Previously, physical exercise was considered to be one of the primary treatments for obesity. However, the effect of fat consumption throughout the life cycle on physical endurance capacity remains unknown. A total of two groups of female mice (age, 6 weeks; C57BL/6J) were fed with a normal chow diet and a moderate high fat diet (MHFD), during pregnancy and lactation (8 weeks), with the offspring receiving the same diet as the mother. When filial mice were 8, 16 and 24 weeks old, they were tested for endurance, blood pressure (BP) and glucose tolerance, as well as adipose tissue infiltration and macrophage subtype. Compared with the control group, filial mice in MHFD groups exhibited increased BP and glucose levels and larger adipose cells (~4‑fold). During adolescence, the obese filial mice demonstrated increased endurance compared with controls. Endurance declines in middle and old age; the endurance of aged obese mice was 29% that of lean ones. In addition, body coordination and movement memory did not notably change. The expression of cluster of differentiation 68, one of the most reliable markers of macrophages, increased by 2.48‑fold, demonstrating that macrophages were recruited and underwent infiltration. In addition, increased tumor necrosis factor‑α and decreased interleukin‑10 expression demonstrated that infiltrated macrophages are polarized to the M1 state, which weakens physical endurance and resists type M2 macrophages, which exhibit repairing functions. In conclusion, hereditary MHFD weakens physical endurance and alters the metabolic characteristics of C57BL/6 offspring.
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