Stress-associated cardiovascular reaction masks heart rate dependence on physical load in mice

When tested on the treadmill mice do not display a graded increase of heart rate (HR), but rather a sharp shift of cardiovascular indices to high levels at the onset of locomotion. We hypothesized that under test conditions cardiovascular reaction to physical load in mice is masked with stress-associated HR increase. To test this hypothesis we monitored mean arterial pressure (MAP) and heart rate in C57BL/6 mice after exposure to stressful stimuli, during spontaneous locomotion in the open-field test, treadmill running or running in a wheel installed in the home cage. Mice were treated with beta1-adrenoblocker atenolol (2mg/kg ip, A), cholinolytic ipratropium bromide (2mg/kg ip, I), combination of blockers (A+I), anxiolytic diazepam (5mg/kg ip, D) or saline (control trials, SAL). MAP and HR in mice increased sharply after handling, despite 3weeks of habituation to the procedure. Under stressful conditions of open field test cardiovascular parameters in mice were elevated and did not depend on movement speed. HR values did not differ in I and SAL groups and were reduced with A or A+I. HR was lower at rest in D pretreated mice. In the treadmill test HR increase over speeds of 6, 12 and 18m/min was roughly 1/7-1/10 of HR increase observed after placing the mice on the treadmill. HR could not be increased with cholinolytic (I), but was reduced after sympatholytic (A) or A+I treatment. Anxiolytic (D) reduced heart rate at lower speeds of movement and its overall effect was to unmask the dependency of HR on running speed. During voluntary running in non-stressful conditions of the home cage HR in mice linearly increased with increasing running speeds. We conclude that in test situations cardiovascular reactions in mice are governed predominantly by stress-associated sympathetic activation, rendering efforts to evaluate HR and MAP reactions to workload unreliable

Митохондрии как важная мишень при поиске новых препаратов для лечения болезни Альцгеймера и старческих деменций

The review and summarizes own and literature data about the role of mitochondria as the important target in the search for drugs for the treatment of neurodegenerative diseases. Aging is a major risk factor for sporadic forms of various neurodegenerative diseases, including Alzheimer′s disease. One of the most argued and currently accepted theories is the Mitochondrial Free Radical Theory of Aging. Mitochondrial hypotheses of the development of sporadic forms of neurodegenerative diseases particularly Alzheimer′s disease, are closely connected with it. Impairments of mitochondrial functions lead to a decrease in their ability to regulate calcium homeostasis in the cell and to a decrease in the threshold for the induction of mitochondrial permeability transition (MPT) pores. MPT inhibitors can be considered as a promising approach to the treatment of neurodegenerative diseases, since these drugs can not only exhibit the properties of neuroprotectors, but also can provide normalization of synaptic activity due to increased calcium capacity of mitochondria. The review presents data on the number of MPT inhibitors, including endogenous compounds melatonin and N-acetylserotonin, their bioisosteric analogue Dimebon and a number of other compounds. The use of mitochondria as a basis for the formation of screening strategy for the search for compounds for the treatment of neurodegenerative diseases is of particular interest – both as a test of their potential toxicity, and as a basis for the creation of metabolic stimulants and drugs with neuroprotective and cognitive-stimulating effect.Обобщены собственные и литературные данные, обосновывающие роль митохондрий как важнейшей мишени при поиске препаратов для лечения нейродегенеративных заболеваний. Старение является основным фактором риска спорадических форм различных нейродегенеративных заболеваний, в том числе и болезни Альцгеймера (БА). Одной из наиболее аргументированных и принятых в настоящее время является свободнорадикальная митохондриальная теория старения. Именно с ней тесно связаны и митохондриальные гипотезы развития спорадических форм нейродегенеративных заболеваний и, в частности, БА. Нарушение митохондриальных функций приводит к снижению их способности регулировать гомеостаз кальция в клетке и снижению порога для индукции поры митохондриальной проницаемости (МРТ). Ингибиторы МРТ можно рассматривать как перспективный подход к терапии нейродегенеративных заболеваний, так как эти препараты могут не только проявлять свойства нейропротекторов, но и обеспечивать нормализацию синаптической активности благодаря увеличенной кальциевой ёмкости митохондрий. В обзоре представлены данные о ряде ингибиторов МРТ, включая эндогенные соединения – мелатонин, N-ацетилсеротонин, их биоизостерный аналог димебон и ряд других соединений. Использование митохондрий как основы для формирования скрининговой стратегии поиска соединений для лечения нейродегенеративных заболеваний представляет особый интерес и как тестирование их потенциальной токсичности, и как основа для создания метаболических стимуляторов и препаратов, обладающих нейропротекторным и когнитивно-стимулирующим действием

Torque Production at Different Velocities as a Predictor of the Proportion of Fast-twitch Muscle Fibers in Skeletal Muscles of Athletes

© 2020, Pleiades Publishing, Inc. Abstract: The aim of the study was to evaluate the possibility to predict the muscle fiber-type proportion in men of different sports specialization by testing the maximal torque production by knee extensors at different velocities. For this reason the proportion of fast- and slow-twitch muscle fibers (MFs) in m. vastus lateralis of 23 athletes (11 endurance and 12 power athletes), as well the maximal torque production of knee extensors at various angular velocities in isokinetic mode were determined. The group of strength trained athletes significantly exceeded the group of endurance trained athletes in body mass, body mass index, volume of the m. quadriceps femoris, maximum torque production, and specific force at angular velocities 30, 180 and 300 degrees per second. In contrast to cross-sectional area (CSA) of slow-twitch MFs, the average CSA of fast-twitch MFs and the proportion of fast-twitch MFs in the group of power athletes significantly exceeded those in the group of endurance athletes. In the combined group of volunteers (n = 23), the proportion of fast-twitch MFs significantly correlated with the torque production at high angular velocities (r = 0.51 and p = 0.01 at 180 deg/s; r = 0.47 and p = 0.02 at 300 deg/s). We did not find any correlation between these parameters in the separate groups of power and endurance athletes. The results indicate a low accuracy in predicting the proportion of fast-twitch MF in m. vastus lateralis in athletes using the maximal torque production of knee extensors at different angular velocities. Significant correlation between the proportion of fast-twitch MF and maximal torque at high angular velocities in the general group (n = 23) was due to the presence of two significantly different subgroups

Regulation of Proteins in Human Skeletal Muscle: The Role of Transcription

© 2020, The Author(s). Regular low intensity aerobic exercise (aerobic training) provides effective protection against various metabolic disorders. Here, the roles played by transient transcriptome responses to acute exercise and by changes in baseline gene expression during up-regulation of protein content in human skeletal muscle were investigated after 2 months of aerobic training. Seven untrained males were involved in a 2 month aerobic cycling training program. Mass-spectrometry and RNA sequencing were used to evaluate proteome and transcriptome responses to training and acute exercise. We found that proteins with different functions are regulated differently at the transcriptional level; for example, a training-induced increase in the content of extracellular matrix-related proteins is regulated at the transcriptional level, while an increase in the content of mitochondrial proteins is not. An increase in the skeletal muscle content of several proteins (including mitochondrial proteins) was associated with increased protein stability, which is related to a chaperone-dependent mechanism and/or reduced regulation by proteolysis. These findings increase our understanding of the molecular mechanisms underlying regulation of protein expression in human skeletal muscle subjected to repeated stress (long term aerobic training) and may provide an opportunity to control the expression of specific proteins (e.g., extracellular matrix-related proteins, mitochondrial proteins) through physiological and/or pharmacological approaches