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Huntington's disease (HD) is a neurodegenerative genetic disorder. Although described as a brain pathology, there is evidence suggesting that defects in other systems can contribute to disease progression. In line with this, cardiovascular defects are a major cause of death in HD. To date, relatively little is known about the peripheral abnormalities associated with the disease. Here, we applied a range of assays to evaluate cardiac electro‐mechanical properties in vivo, using a previously characterized mouse model of HD (BACHD), and in vitro, using cardiomyocytes isolated from the same mice. We observed conduction disturbances including QT interval prolongation in BACHD mice, indicative of cardiac dysfunction. Cardiomyocytes from these mice demonstrated cellular electro‐mechanical abnormalities, including a prolonged action potential, arrhythmic contractions, and relaxation disturbances. Cellular arrhythmia was accompanied by an increase in calcium waves and increased Ca2+/calmodulin‐dependent protein kinase II activity, suggesting that disruption of calcium homeostasis plays a key part. We also described structural abnormalities in the mitochondria of BACHD‐derived cardiomyocytes, indicative of oxidative stress. Consistent with this, imbalances in superoxide dismutase and glutathione peroxidase activities were detected. Our data provide an in vivo demonstration of cardiac abnormalities in HD together with new insights into the cellular mechanistic basis, providing a possible explanation for the higher cardiovascular risk in HD. Huntington's disease (HD) is a neurodegenerative disorder and the main cause of patients' death is related to cardiovascular defects. Here, we investigated cardiac dysfunction and its mechanisms in 12‐month‐old BACHD mice, which correspond to the late clinical manifestation in humans. Our data provide an in vivo demonstration together with a new evidence of the cellular mechanistic basis in cardiac HD. [ABSTRACT FROM AUTHOR]

Introduction: Congenital Myasthenic Syndromes (CMSs) are part of a rare and diverse group of hereditary genetic disorders characterized by alterations in neuromuscular junction proteins and consequent progressive muscle weakness. Previous studies with transgenic male mice with reduced expression (knockdown, KD) of the Vesicular Acetylcholine (ACh) Transporter (VAChT), an antiporter that transfers ACh from the cytoplasm into synaptic vesicles, demonstrated deleterious effects on skeletal muscle and impairment in physical performance. However, it is unknown the effects of CMS model in female mice and on estrous cycle, which is important in female physiology and its disorder may exacerbate symptoms and alterations in CMS. Although this knowledge is extremely important for health in CMS women, data about menstrual cycle in such patients are poorly available and about estrous cycle in female mice are unknown. Objective: To characterize the frequency of estrous cycle stages in murine model of CSM from 2 to 6 months of age. Methods: Transgenic female mice KD for VAChT (VKD) and wildtype (WT) animals from the C57BL/6J background (6-week-old) were used in the experiment. The murine reproductive cycle is divided in four stages (proestrus, estrus, metestrus and diestrus) that can be determined noninvasively by staining cells (i.e., nucleated epithelial cells, cornified squamous epithelial cells, and leukocytes) with crystal violet solution in vaginal smears. Daily assessment of the relative ratio of cells present in vaginal smears was used to identify murine estrous stages. This procedure was performed for 14 days in each month from 2 to 6 months of age. Statistical analysis was performed using the chi-square test. All experiments and protocols were approved by the Ethics Committee on Animal Use from UFMG. Results: We found in the analyses of average frequency (14 days in each month) of estrous cycle phases that WT mice in proestrus, estrus, metestrus and diestrus were 18.1% 67.7%, 4.4% and 9.9%, respectively, while VKD mice were 13.3%, 68.9%, 7% and 10.8% in the respective phases, indicating that estrous cycle was unaffected in VKD mice. There was no statistical difference (P>0.05) in the frequency of the estrous cycle stages between VKD and WT mice from 2 to 6 monthold. Estrus was the predominant phase of the estrous cycle in both VKD and WT groups in all analyzed time points. Body mass was similar between WT and VKD mice and did not significantly change during the period of the study. Conclusion: These results show that CMS did not cause any alteration in estrous cycle of young, adult VKD mice. However, further studies are needed to investigate female physiology in older animals. [ABSTRACT FROM AUTHOR]

Introduction: Congenital Myasthenic Syndromes (CMSs) comprise rare and diverse hereditary genetic disorders in neuromuscular junction proteins, leading to progressive muscle weakness and impairing the quality of life of these individuals. Among these proteins, those involved in the synthesis (ChAT) and storage (VAChT) of acetylcholine have been shown to be critical to muscle function and homeostasis. Previous studies using VAChT knockdown mice (VKD) expressing ~30% of this protein have demonstrated an impairment in physical performance in male mice. However, it is unknown whether females are also compromised in this CMS model and what age the alterations in performance may occur. Objective: To evaluate aerobic and strength performance and metabolism in female VKD mice from 2 to 6 months of age. Methods: Muscle strength (peak force) was measured monthly by grip strength meter. Aerobic performance (i.e., peak oxygen consumption (VO2peak), time to fatigue (TTF), distance and maximum running speed (Smax)) was also evaluated monthly by incremental load test (ILT) in treadmill in both wildtype (WT) and VKD female mice (2-t o 6-month-old; ~22g). Blood glucose and lactate were also assessed after 5 minutes of ILT. All experiments and protocols were approved by The Ethics Committee on Animal Use from UFMG. Results: Muscle strength was impaired (- 30%, P<0.05) in VKD mice from 4 to 6 months of age. The aerobic performance evaluated by VO2peak (≈ 45%, P<0.05), TTF (≈ 85%, P<0.05), running distance (≈ 90%, P<0.05) and Smax (≈ 70%, P<0.05) were significantly reduced and an increase in blood glucose was observed post-ILT (≈ 30%, P<0.05) in VKD compared to WT in all analyzed time points. However, no significant difference was found in blood lactate in any group (P>0.05). Conclusion: Our findings show that female VKD mice also present a marked decline in both aerobic and strength performance and an unexpected hyperglycemic response to exercise. Next, the cellular and molecular adaptations in skeletal muscle will be analyzed. We also intend to investigate the effects of non-pharmacological treatments, e.g., exercise training and nutrition, to improve physical performance and slow down the progression of CMS model. [ABSTRACT FROM AUTHOR]

Aim:To investigate the presynaptic effects of propofol, a short-acting intravenous anesthetic, in the frog neuromuscular junction.Methods:Frog cutaneous pectoris nerve muscle preparations were prepared. A fluorescent tool (FM1-43) was used to visualize the effect of propofol on synaptic vesicle exocytosos in the frog neuromuscular junction.Results:Low concentrations of propofol, ranging from 10 to 25 μmol/L, enhanced spontaneous vesicle exocytosis monitored by FM1-43 in a Ca2+-dependent and Na+-independent fashion. Higher concentrations of propofol (50, 100, and 200 μmol/L) had no effect on spontaneous exocytosis. By contrast, higher concentrations of propofol inhibited the Na+-dependent exocytosis evoked by 4-aminopyridine but did not affect the Na+-independent exocytosis evoked by KCl. This action was similar and non-additive with that observed by tetrodotoxin, a Na+ channel blocker.Conclusion:Our data suggest that propofol has a dose-dependent presynaptic effect at the neuromuscular transmission which may help to understand some of the clinical effects of this agent on neuromuscular function. [ABSTRACT FROM AUTHOR]

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