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The effects of dihydrotestosterone on amino acid transport in ageing mammalian skeletal muscle fibres

二氢睾酮对衰老哺乳动物骨骼肌纤维氨基酸转运的影响

基本信息

批准号：
BB/J01754X/1
负责人：
Gabriel Mutungi
金额：
$ 48.32万
依托单位：
University of East Anglia
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FJ01754X%2F1
关键词：
effects dihydrotestosterone amino acid transport

项目摘要

Ageing leads to a gradual decline in skeletal muscle mass and strength, commonly referred to as sarcopenia. Sarcopenia occurs mostly in people >80yrs (and rodents >2 years old) and its consequences include inactivity, increased susceptibility to falls and eventually to loss of independence. As the number of people over 80yrs in the United Kingdom is expected to double in the next 20 years, from 2.7 million in 2006 to 5.4 million by 2031, the percentage of the population suffering from sarcopenia and the demands this imposes on the NHS and society in general is expected to rise accordingly. Despite its physical and socioeconomic importance, little is known about the causes of sarcopenia. In this study we propose that it occurs because of a decrease in the ability of skeletal muscle cells to transport amino acids (the building blocks of proteins ) into and out of the cells. We also suggest that this decline is due to a reduction in the number of the transporters/pumps that move amino acids into and out of the cells or is due to a decrease in the concentration of hormones such as the male sex hormones that normally stimulate these pumps.To test these suggestions we plan to investigate; (1) the effects of age on the number of amino acid transporters and their ability to move amino acids into and out of mouse skeletal muscle cells. (2) Whether treating muscle cells with dihydrotestosterone (DHT), the active metabolite of testosterone, can reverse these age-dependent changes. (3) Finally we will test whether treating mice >560 days old with DHT for 4 weeks reverses/slows down sarcopenia. We will also investigate whether DHT treatment increases the transport amino acids and the synthesis of new proteins.Three types of experiments will be used in the study. The first type will use mice of different ages (range 60-730 days) kept under normal laboratory conditions. Small muscle fibre bundles isolated from the edl and soleus muscles of each age group will then be used to investigate the effects of age on the expression and physiological function of various amino acid transporters and the cellular and molecular mechanisms underlying these changes.Most previous studies have investigated the effects of testosterone treatment on skeletal muscle mass and strength and no studies have investigated those of DHT treatment. Therefore, the second experiment will investigate the effects of treating young, old and senescent mice with DHT for at least 4 weeks. Small muscle fibre bundles isolated from the edl and soleus of treated and untreated mice will then be used to investigate the effects of DHT treatment on skeletal muscle mass, strength, the expression and function of various amino acid transporters, the uptake of isoleucine (Ile) and MeAIB and the incorporation of Ile into proteins.In the third experiment, the acute effects of DHT treatment on force production, amino acid transport and incorporation into proteins in muscle fibre bundles isolated from the edl and soleus of senescent mice will be investigated. The cellular and molecular mechanisms underlying these effects will also be investigated.Most of these experiments will be performed using CD1 mice because they are inexpensive, have similar genetic variations as normal mouse and human populations and suffer from severe sarcopenia from 24 months onwards.The results from these experiments will provide important information on the role a decline in amino acid transport and reduced bioavailability of anabolic steroids, play in sarcopenia. They will also increase our understanding of the changes that occur in skeletal muscle with ageing and the mechanisms underlying these changes. They will also provide information on whether DHT treatment can delay/slow the development of sarcopenia as well as the mechanisms underlying its effects. These findings will be important in the development of new ways of managing sarcopenia in the future.

衰老导致骨骼肌质量和强度逐渐下降，通常称为肌肉减少症。肌肉减少症主要发生在> 80岁的人（和>2岁的啮齿动物）中，其后果包括不活动，增加对福尔斯的易感性，并最终失去独立性。由于英国80岁以上的人口数量预计将在未来20年内翻一番，从2006年的270万增加到2031年的540万，患有肌肉减少症的人口比例以及对NHS和整个社会的需求预计将相应增加。尽管它的身体和社会经济的重要性，很少有人知道肌肉减少症的原因。在这项研究中，我们提出，它的发生是因为骨骼肌细胞运输氨基酸（蛋白质的构建模块）进出细胞的能力下降。我们还认为这种下降是由于将氨基酸移入和移出细胞的转运蛋白/泵的数量减少，或者是由于激素浓度的减少，例如通常刺激这些泵的雄性激素。（1）年龄对氨基酸转运蛋白数量及其将氨基酸移入和移出小鼠骨骼肌细胞的能力的影响。(2)用睾酮的活性代谢物二氢睾酮（DHT）治疗肌肉细胞是否可以逆转这些年龄依赖性变化。(3)最后，我们将测试用DHT治疗>560日龄的小鼠4周是否逆转/减缓肌肉减少症。我们还将研究DHT处理是否增加了转运氨基酸和新蛋白质的合成。第一种类型将使用在正常实验室条件下饲养的不同年龄（范围60-730天）的小鼠。小肌肉纤维束分离出的edl和比目鱼肌的每个年龄组，然后将被用来调查年龄的影响，对各种氨基酸转运蛋白的表达和生理功能和这些变化的细胞和分子机制，大多数以前的研究已经调查了睾酮治疗对骨骼肌质量和强度的影响，没有研究调查的DHT治疗。因此，第二个实验将研究用DHT治疗年轻、年老和衰老小鼠至少4周的效果。然后将从处理和未处理的小鼠的edl和比目鱼肌分离的小肌纤维束用于研究DHT处理对骨骼肌质量、强度、各种氨基酸转运蛋白的表达和功能、异亮氨酸（Ile）和MeAIB的摄取以及Ile掺入蛋白质的影响。将研究从衰老小鼠的EDL和比目鱼肌分离的肌纤维束中的氨基酸转运和掺入蛋白质中。这些效应背后的细胞和分子机制也将被研究。这些实验中的大多数将使用CD 1小鼠进行，因为它们便宜，具有与正常小鼠和人类群体相似的遗传变异，并且从24个月开始患有严重的肌肉减少症。这些实验的结果将提供关于氨基酸转运下降和合成代谢的生物利用度降低的作用的重要信息。类固醇，在肌肉减少症中发挥作用。它们还将增加我们对骨骼肌随着衰老发生的变化以及这些变化背后的机制的理解。他们还将提供有关DHT治疗是否可以延迟/减缓肌肉减少症的发展以及其作用机制的信息。这些发现将是重要的，在未来的管理肌肉减少症的新方法的发展。