Sexual Dimorphism of Skeletal Muscle

描述(由申请人提供)：骨骼肌(SKM)微血管系统在呼吸气体和营养交换、体积分布和血流控制方面已被广泛研究，在健康和疾病中，进入和内部器官。该R21是对PFA要求开发用于研究男性和女性功能的模型的回应。这一点非常重要，因为大多数关于SKM的研究都是在男性(动物和人类)中进行的，并假定数据同样适用于两性。过去十年积累的多项研究的证据表明，这一假设是错误的。一种被广泛用于活体研究的模型是啮齿类动物的发育器，这是一种来自腹壁的薄肌肉，可以升高和降低睾丸。令人惊讶的是，目前还没有同等代谢和纤维型的微血管骨骼肌制剂来替代发情母体，这有利于男性和女性的研究。这项建议旨在通过验证雄性和雌性啮齿动物的腹壁骨骼肌准备来纠正这一不足。这一假设是，同一物种的年龄匹配的男性和女性之间的微血管骨骼肌功能没有差异。因此，将在年龄和品系匹配的雌性和雄性小鼠的原位和分离的腹肌微血管中进行3项目标：目标1将评估从微血管直径到选定的内皮依赖和非依赖性药物在血流调节方面是否存在性别二型性。鉴于最近的数据，我们预计将否定我们的假设，因为我们预计a)男性小动脉将发展出更大的基础张力，以及b)内皮依赖性扩张的剂量-反应关系将在男性和女性之间有所不同。目的2将从微血管溶质通透性(Ps)的测量中评估在交换调节方面是否存在性别二型性。鉴于我们的数据，我们预计将否定我们的假设，因为我们预计a)来自男性的小静脉将比来自女性的微静脉更容易渗漏，b)基础小动脉和毛细血管屏障属性将不会因性别而异，以及c)血管活性物质将产生各种交换反应，反映性别特定的机制调节男性和女性血管和组织间溶质分配的差异。目标3将比较性别、年龄、器官和物种匹配直径(目标1)，并交换位于活组织中的微血管数据(目标2)，然后从组织中分离出来。这是一个进行这些比较的绝佳机会，因为并不是所有的组织都可以进行原位研究，而且假设来自分离血管的数据反映了组织中的行为。该项目的数据将为未来对男性和女性微血管功能的遗传、生化和生理学研究奠定基础。我们必须验证一个研究两性微血管功能的模型，以便智能地理解性别依赖的机制，调节健康的血管功能和疾病的功能障碍。以知识为基础，针对男性和女性的具体需求，为防治血管疾病提供合理的手段。 公共卫生相关性：该项目旨在开发和验证骨骼肌模型，用于研究年龄匹配的同种雄性和雌性动物--小鼠--最小血管的主要功能。微循环的两个主要功能1)流向新陈代谢组织的血液，2)营养物质从血液到组织的移动以及从组织到血液的废物清除，在健康和心血管疾病(包括高血压和继发性2型糖尿病)方面似乎在男性和女性之间存在差异。当物质在血液和组织之间分配时，液体也会在隔室之间流动；因此，如果男性和女性之间的交换规则不同，那么体积分布也可能不同。因此，必须有一个模型来了解两性之间的差异和相似之处，因为来自男性的数据、疾病发病率和严重程度以及随后的治疗策略不会同样适用于女性。

DESCRIPTION (provided by applicant): Skeletal muscle (SKM) microvasculature has been studied extensively with respect to respiratory gas and nutrient exchange, volume distribution, and blood flow control, into and within the organ, in health and disease. This R21 is in response to a PFA requesting development of models for the study of function in males and females. This is terribly important as most studies of SKM have been conducted in males (animals and humans) with the presumption that the data apply equally to both sexes. Evidence from multiple studies accumulated over the last decade is making it clear that this assumption in error. One model used widely for in vivo study is the rodent cremaster, a thin muscle derived from the abdominal wall that raises and lowers the testes. Surprisingly, no microvascular skeletal muscle preparation of equivalent metabolic and fiber type substitutes presently for the cremaster that facilitates study of both males and females. This proposal aims to rectify this lack by validating the abdominal wall skeletal muscle preparation in males and female rodents. The hypothesis is that microvascular skeletal muscle functions do not differ between age-matched males and females of the same species. Accordingly, 3 aims will be carried out in in situ and isolated abdominal muscle microvessels from age- and strain-matched female and male mice: Aim 1 will assess whether sexual dimorphism exists with respect to blood flow regulation from measures from microvascular diameter to selected endothelium-dependent and -independent agents. Given recent data we expect to reject our hypothesis as we anticipate that a) arterioles from males will develop greater basal tone and b) the dose-response relationship for the endothelium-dependent dilation will differ between males and females. Aim 2 will assess whether sexual dimorphism exists with respect to exchange regulation from measures from measures of microvessel solute permeability (Ps). Given our data, we expect to reject our hypothesis as we anticipate that a) venules from males will be leakier than those from females, b) basal arteriole and capillary barrier properties will not differ by sex, and c) the vasoactive agents will produce a variety of exchange responses reflecting differences in sex-specific mechanisms regulating solute distribution between the vascular and tissue compartments of males and females. Aim 3 will compare the sex, age, organ and species matched diameter (Aim 1) and exchange data (Aim 2) from microvessels as they lay in the living tissue and following isolation from the tissue. This is an incredibly opportunity to make these comparisons as not all tissues are amenable to study in situ and it is assumed that the data from the isolated vessels reflect the behavior in the tissue. Data from this project will form the foundation for future genetic, biochemical, and physiologic studies of microvascular function in males and females. It is imperative that we validate a model for study of microvascular function in both sexes to understand intelligently the sex-dependent mechanisms regulating vascular function in health and dysfunction in disease. With the knowledge the foundation, and provide rational means for prevent and treating vascular disease specific to the needs of males and females.) PUBLIC HEALTH RELEVANCE: This project is to develop and validate a skeletal muscle model for the study of the primary functions of the smallest blood vessels in age-matched male and female animals of the same species, the mouse. The 2 primary functions of the microcirculation 1) blood flow to metabolizing tissue, and 2) the movement of nutrients from blood to tissue as well as the removal of wastes from tissue to blood, appear to differ between males and females in health and cardiovascular disease including hypertension and secondary to type 2 diabetes. As materials distribute themselves between blood and tissue, so too will fluids move between compartments; thus if exchange regulation differs between males and females it is likely that volume distribution will also differ. Therefore it is imperative to have access to a model to learn the differences and similarities between the sexes as the data from males, disease incidence and severity and subsequent treatment strategies will not apply equally to females.