冬眠哺乳动物──天然的心血管医学研究模型

本文在简要概括本实验室和国际研究进展的基础上,归纳提出了冬眠动物心血管系统具有耐低体温、抗心律失常、耐缺氧等几大机能特点,并着重指出,冬眠动物适应于特殊生理条件所形成的心血管系统机能稳定性,及其背后的调节途径,对于医学研究有重要参考价值,因而作者倡导利用我国动物资源,从医学角度研究冬眠动物。     

科眠哺乳动物——天然的血管医学研究模型

本文在简要概括本实验室和国际天空进展的基础上,归纳了提出了冬眠动物心血管系统具有耐低抗温,抗心律失常,需缺氧等几大机能特点,并着重指出,冬眠动物适应于特殊生理条件所形成的心血管系统机能稳定性,及其背后的调节途径,对于医院研究有重要参考价值,因而作者倡导利用我国动物资源,从医学角度研究冬眠动物。     

冬眠与免疫

免疫系统是机体防御机制的重要组份。冬眠季节,冬眠动物免疫系统的结构退化、机能抑制,与动物整体的活动相适应,春季恢复。综述民哺乳动物中枢与外周淋巴器官和免疫反应的季节性变化。对调控免疫系统变化的环境因素和受环境因素影响的内源性生理节律对免疫系统冬眠季节的抑制机理作了介绍,更从冬眠对免疫的抑制联系到冬眠净化机体内外环境、冬眠与肿瘤、冬眠与辐射乃至冬眠与长寿等临床关心的实验研究作了简要介绍。     

达乌尔黄鼠冷暴露、冬眠及激醒时的外周甲状腺激素水平变化

探讨了达乌尔黄鼠在冷暴露、冬眠及激醒时的外周甲状腺激素水平变化和激素代谢。达乌尔黄鼠在非冬眠季节 ( 7～ 8月 )冷暴露 ( 4℃± 2℃ ) 1天 ,导致血清T3和T4浓度迅速增加 ,T3/T4不变 ;经 4周冷驯化后 ,T3维持在高水平上 ,T4降低 ,T3/T4增加 ,外周组织中的T4脱碘酶活性升高。表明冬眠动物与非冬眠动物的甲状腺机能及其激素代谢的冷适应性调节一致。在冬眠季 ( 12～ 1月 )的冬眠和激醒过程中 ,外周组织的T4脱碘酶活性、血清T3和T4水平比常温达乌尔黄鼠的高 ,显著高于夏季的水平 ,T3/T4不变。表明达乌尔黄鼠甲状腺机能及其激素水平存在季节性变化。     

热带动物也“冬眠”

在人们印象中,只有生活在塞冷冬季的动物才冬眠。德国马尔堡大学的科学家在近日出版的《自然》杂志上报告说,他们在热带非洲也发现了一种“冬眠”动物。一种生活在马达加斯加的狐猴会在炎热的环境中“冬眠”7个月之久,远远超过了一些在北半球生活的动物冬眠的时间。这也是科学家迄今发现的第1种“冬眠”的热带动物。报告称,这种动物冬眠时会寻找一个僻静的树洞,即便周围温度达到30℃左右,也不会苏醒。地面测验表明,“冬眠”期间,这种动物的体温不靠自身的新陈代谢控制,而是“被动地”随着周围环境不断变化。热带动物也“冬眠”     

旱獭在生物医学中的应用

旱獭,又名土拨鼠,属于啮齿目,松鼠科,旱獭属动物。它是使用最广的野生哺乳动物之一,同时它又是一冬眠动物,具有冬眠动物的特性,在内分泌与代谢机能、食欲、活动量和体重等方面每年都发生周期性的变化。旱獭已广泛应用于肥胖症与能量平衡、内分泌与代谢机能、中枢神经系统调控机制以及心血管疾病、脑血管疾病和瘤形成等方面的研究。自从1978年发现旱獭病毒(WHV)以来,该病毒以及它的宿主———旱獭已被当作研究人乙型肝炎病毒(HBV)感染的最理想模型。由于WHV与HBV在形态学、基因组结构、基因产物、复制、流行病学、感染过程及其病程甚至…     

引起冬眠的物质

冬眠是动物在不利的气候和生活条件下的一种本能的适应。象青蛙、乌龟、刺猬、蝙蝠和蛇等都属于冬眠动物。动物学家把一种能够控制冬眠的动物血液里的物质叫做HIT(英文的缩写,意思是能引致冬眠的物质)。在实验中,研究人员把这种HIT提取出来,注入到没有冬眠习性的猴子的脑部后,猴子的心跳速度减了一半,体温也降了几度,而且还明显地降低了食     

中国达乌尔黄鼠的夏季诱发冬眠——对有否冬眠触发物质的探讨

用中国北方草原地区的季节性冬眠动物达乌尔黄鼠,经1981和1984两年的工作,重复了Dawe(1969)注射冷藏的冬眠动物血清,诱发夏季活泼黄鼠冬眠的原始实验。实验成功地实现了在非冬眠季节诱发达乌尔黄鼠冬眠,发现禁食在人工诱发冬眠中起重要作用,却不能证实血源性冬眠触发物(HIT)的存在。     

冬眠调节机制或可治疗胰岛素抵抗

储脂类冬眠动物在每年夏季大量进食以储存脂肪,在冬季通过冬眠降低代谢并缓慢消耗脂肪。冬眠动物在育肥晚期或冬眠早期表现出高血糖及胰岛素抵抗等症状,但在冬眠结束后胰岛素敏感性明显增强。冬眠可改善胰岛素抵抗症状,这可能是通过改变Akt信号转导通路、葡萄糖转运蛋白(GLUT)和PPARγ/PGC-1α转录复合体的表达来实现的。在肥胖及相关代谢疾病迅速增长的今天,深入研究冬眠动物改善胰岛素抵抗症状的调控机制,可为治疗肥胖病人的胰岛素抵抗提供新的途径。     

大鼠和黄鼠心肌细胞钙瞬变记录和钙移除机制分析

用共聚焦显微术在不同温度下记录非冬眠动物大鼠和冬眠动物黄鼠心肌细胞钙瞬变,并分析钙移除速率.结果表明:大鼠细胞钙瞬变舒期水平随降温显著升高,黄鼠基本不变;相同温度下,黄鼠钙瞬变时程较短,钙移除速率较快.CPA(cyclopiazoni cacid)的药理作用显示肌质网是细胞钙移除的主要机制,黄鼠肌质网摄钙速率较大鼠快.肯定了肌质网在冬眠动物心肌细胞耐受低温适应中的关键地位,否定了钠钙交换发挥重要作用的观点,提出了改善非冬眠动物心肌低温耐受性的可能性.     

Cardiac function adaptations in hibernating grizzly bears (Ursus arctos horribilis)

Research on the cardiovascular physiology of hibernating mammals may provide insight into evolutionary adaptations; however, anesthesia used to handle wild animals may affect the cardiovascular parameters of interest. To overcome these potential biases, we investigated the functional cardiac phenotype of the hibernating grizzly bear (Ursus arctos horribilis) during the active, transitional and hibernating phases over a 4 year period in conscious rather than anesthetized bears. The bears were captive born and serially studied from the age of 5 months to 4 years. Heart rate was significantly different from active (82.6 ± 7.7 beats/min) to hibernating states (17.8 ± 2.8 beats/min). There was no difference from the active to the hibernating state in diastolic and stroke volume parameters or in left atrial area. Left ventricular volume:mass was significantly increased during hibernation indicating decreased ventricular mass. Ejection fraction of the left ventricle was not different between active and hibernating states. In contrast, total left atrial emptying fraction was significantly reduced during hibernation (17.8 ± 2.8%) as compared to the active state (40.8 ± 1.9%). Reduced atrial chamber function was also supported by reduced atrial contraction blood flow velocities and atrial contraction ejection fraction during hibernation; 7.1 ± 2.8% as compared to 20.7 ± 3% during the active state. Changes in the diastolic cardiac filling cycle, especially atrial chamber contribution to ventricular filling, appear to be the most prominent macroscopic functional change during hibernation. Thus, we propose that these changes in atrial chamber function constitute a major adaptation during hibernation which allows the myocardium to conserve energy, avoid chamber dilation and remain healthy during a period of extremely low heart rates. These findings will aid in rational approaches to identifying underlying molecular mechanisms.     

Repeated functional convergent effects of NaV1.7 on acid insensitivity in hibernating mammals

Hibernating mammals need to be insensitive to acid in order to cope with conditions of high CO₂; however, the molecular basis of acid tolerance remains largely unknown. The African naked mole-rat (Heterocephalus glaber) and hibernating mammals share similar environments and physiological features. In the naked mole-rat, acid insensitivity has been shown to be conferred by the functional motif of the sodium ion channel Na_V1.7. There is now an opportunity to evaluate acid insensitivity in other taxa. In this study, we tested for functional convergence of Na_V1.7 in 71 species of mammals, including 22 species that hibernate. Our analyses revealed a functional convergence of amino acid sequences, which occurred at least six times independently in mammals that hibernate. Evolutionary analyses determined that the convergence results from both parallel and divergent evolution of residues in the functional motif. Our findings not only identify the functional molecules responsible for acid insensitivity in hibernating mammals, but also open new avenues to elucidate the molecular underpinnings of acid insensitivity in mammals.     

The annual involution and regeneration of the thymus in hibernating animals and perspectives of its studies in gerontology and stem cell proliferation

Data on a unique phenomenon of annual involution and neogenesis of thymus gland in hibernating animals are reviewed. In accordance with morphological findings, the annual thymus involution in hibernating animals is close to the age-dependent thymus involution occurring in all mammals once in a lifetime. In opposite, thymus involution in hibernating animals is totally different from the accidental involution. During hibernation, the thymus tissue is substituted by the brown fat tissue. In the spring, thymus gland neogenesis stats with intensive growth of epithelial tissue followed by lymphocyte infiltration and exhaustion of brown tissue. Morphological changes in the thymus gland within the annual cycle were compared with seasonal dynamics of structural and functional changes in peripheral lymphoid organs (spleen, lymphoglandular, peritoneal fluid). A general regularity was observed involving a decreased functional activity of immune cells in autumn, its sharp depression during winter hibernation, and obvious increase in summer with the onset of a season of animal activity. It is supposed that a sharp increase in the tumor necrosis factor (TNF) production observed during short-term awakenings in winter may serve an important link in this unique immune adaptation mechanism. The season changes in cellular TNF secretion suggest a mobilization of protective resources in hibernating animals in autumn and winter, i.e. in seasons when the thymus gland activity is depressed. The annual involution of thymus gland cannot be related to droppings in the environmental or body temperatures, as it comes long before their fall. Additionally, it is not related to ageing, as it occurs already in young hibernating animals. The role of hormones, including melatonine and corticosteroids, in mechanisms regulating thymus gland involution in hibernating animals is discussed.     

A comparison of oleamide in the brains of hibernating and non-hibernating Richardson's ground squirrel (Spermophilus richardsonii) and its inability to bind to brain fatty acid binding protein

Hibernation has been suggested to cause sleep debt, and since oleamide is elevated in the central nervous system of sleep-deprived mammals we hypothesized that brains from hibernating mammals would contain more oleamide than those that were not hibernating. Oleamide was 2.6-fold greater in brains of hibernating Richardson's ground squirrel (Spermophilus richardsonii) than in euthermic brains. Additionally, brain fatty acid-binding protein did not bind oleamide and does not represent a solubilized pool of oleamide.     

Protein synthesis in cardiac cells and the ultrastructural dynamics of cardiomyocytes of hibernating animals during the hibernation cycle

A significant increase in protein synthesis correlating with ultrastructural dynamics of cardiomyocyte organelle convertions has been demonstrated in cardiomyocytes of ground squirrel during arousal from hibernation. In hibernating ground squirrels, the ultrastructure of protein-synthesizing organelles and of the cardiomyocyte nucleus points out to the readiness of cells to active synthesis of proteins. In the perinuclear area of cardiomyocytes abundant ribosomes, elements of endoplasmic reticulum and Golgi complex, mitochondria and high-energy substrates--glycogen and lipid inclusions--are seen. The cardiomyocyte nuclei are large, with highly convoluted borders and abundant pores, their nucleolar structure is granular, the chromatin is mainly diffuse. The potency of cardiomyocyte protein-synthesizing system of hibernating ground squirrels is realized every time at periodical arousals during hibernation. The role of cyclic changes of protein synthesis rate in adaptation of cells of hibernating mammals to functioning at various temperatures is discussed.     

Homocysteine Homeostasis and Betaine-Homocysteine S-Methyltransferase Expression in the Brain of Hibernating Bats

Elevated homocysteine is an important risk factor that increases cerebrovascular and neurodegenerative disease morbidity. In mammals, B vitamin supplementation can reduce homocysteine levels. Whether, and how, hibernating mammals, that essentially stop ingesting B vitamins, maintain homocysteine metabolism and avoid cerebrovascular impacts and neurodegeneration remain unclear. Here, we compare homocysteine levels in the brains of torpid bats, active bats and rats to identify the molecules involved in homocysteine homeostasis. We found that homocysteine does not elevate in torpid brains, despite declining vitamin B levels. At low levels of vitamin B6 and B12, we found no change in total expression level of the two main enzymes involved in homocysteine metabolism (methionine synthase and cystathionine β-synthase), but a 1.85-fold increase in the expression of the coenzyme-independent betaine-homocysteine S-methyltransferase (BHMT). BHMT expression was observed in the amygdala of basal ganglia and the cerebral cortex where BHMT levels were clearly elevated during torpor. This is the first report of BHMT protein expression in the brain and suggests that BHMT modulates homocysteine in the brains of hibernating bats. BHMT may have a neuroprotective role in the brains of hibernating mammals and further research on this system could expand our biomedical understanding of certain cerebrovascular and neurodegenerative disease processes.     

Morphological study of the heart innervation of bats Myotis daubentoni and Eptesicus serotinus (Microchiroptera: Vespertilionidae) during hibernation

The capability of bats to have heart rates fewer than 10 beats/min during hibernation and greater than 700 beats/min during flight surprises biologists and cardiologists. Cardioacceleration of hibernating bats is considered to be a function of their intracardiac nervous system. In the present study we investigated the morphology of the heart innervation of ten M. daubentoni and four E. serotinus bats during their natural hibernation in order to determine which intracardiac structures may be involved in cardioacceleration during their short-term (in av. 15-30 min) arousal from hibernation. The primary conclusions were as follows: (1) The innervation pattern of bats differs from many mammals in that bats have: (a) a subepicardiac nerve plexus which is vastly developed and contains a large number of intrinsic ganglia on both atria and ventricles, and (b) very small diameter axons within the unmyelinated nerve fibres, from 0.15 to 0.7 microm. (2) During hibernation an intercellular space of the sinoatrial node of M. daubentoni bats was in part filled with a cottony substance which can presumably be considered to be a temporary barrier between the conductive cardiomyocytes and nerve fibres. (3) In the hibernating bats, the acetylcholine vesicles were aggregated in the synaptic bulbs away from the presynaptic membrane. Possibly, the aggregation of the acetylcholine vesicles is capable of modifying cholinergic influences on the heart activity of hibernating bats. (4) The dense cores of catecholamine synaptic vesicles within, adrenergic axon terminals were seldomly observed in hibernating bats. Therefore, catecholamines probably do not play a crucial role in the cardioacceleration of hibernating bats.     

Impaired Skeletal Muscle Regeneration in the Absence of Fibrosis during Hibernation in 13-Lined Ground Squirrels

Skeletal muscle atrophy can occur as a consequence of immobilization and/or starvation in the majority of vertebrates studied. In contrast, hibernating mammals are protected against the loss of muscle mass despite long periods of inactivity and lack of food intake. Resident muscle-specific stem cells (satellite cells) are known to be activated by muscle injury and their activation contributes to the regeneration of muscle, but whether satellite cells play a role in hibernation is unknown. In the hibernating 13-lined ground squirrel we show that muscles ablated of satellite cells were still protected against atrophy, demonstrating that satellite cells are not involved in the maintenance of skeletal muscle during hibernation. Additionally, hibernating skeletal muscle showed extremely slow regeneration in response to injury, due to repression of satellite cell activation and myoblast differentiation caused by a fine-tuned interplay of p21, myostatin, MAPK, and Wnt signaling pathways. Interestingly, despite long periods of inflammation and lack of efficient regeneration, injured skeletal muscle from hibernating animals did not develop fibrosis and was capable of complete recovery when animals emerged naturally from hibernation. We propose that hibernating squirrels represent a new model system that permits evaluation of impaired skeletal muscle remodeling in the absence of formation of tissue fibrosis.     

Diuretic treatment affects the length of torpor bouts in hibernating European ground squirrels (Spermophilus citellus)

During the hibernation season, hibernating mammals show a sequence of torpor bouts that are interrupted by periodic arousals and brief normothermic periods. The functional significance of periodic arousals is still uncertain. We hypothesized that the imbalances in water economy may play a role in the timing of periodic arousals in hibernating species. We applied furosemide, a diuretic drug, to assess whether hibernating European ground squirrels respond to elevated urine production by shortening their torpor bouts. Urine production in the treated squirrels increased and led to more frequent arousals, presumably to restore water balance by recovery of lost water from blood and tissues. The length of the subsequent normothermic phase was not affected by the diuretic treatment. Body mass change correlated primarily with the amount of voided urine. Although our study did not identify the underlying mechanism, our results support the view that water economy, and water loss may play a role in the timing of periodic arousals.     

Mammalian hibernation as a model of disuse osteoporosis: the effects of physical inactivity on bone metabolism, structure, and strength

Reduced skeletal loading typically leads to bone loss because bone formation and bone resorption become unbalanced. Hibernation is a natural model of musculoskeletal disuse because hibernating animals greatly reduce weight-bearing activity, and therefore, they would be expected to lose bone. Some evidence suggests that small mammals like ground squirrels, bats, and hamsters do lose bone during hibernation, but the mechanism of bone loss is unclear. In contrast, hibernating bears maintain balanced bone remodeling and preserve bone structure and strength. Differences in the skeletal responses of bears and smaller mammals to hibernation may be due to differences in their hibernation patterns; smaller mammals may excrete calcium liberated from bone during periodic arousals throughout hibernation, leading to progressive bone loss over time, whereas bears may have evolved more sophisticated physiological processes to recycle calcium, prevent hypercalcemia, and maintain bone integrity. Investigating the roles of neural and hormonal control of bear bone metabolism could give valuable insight into translating the mechanisms that prevent disuse-induced bone loss in bears into novel therapies for treating osteoporosis.