Sexual Dimorphism of Skeletal Muscle

描述（由申请人提供）：骨骼肌（SKM）微血管系统在健康和疾病中已被广泛研究，涉及呼吸气体和营养交换，体积分布和血液流动控制，进入和在器官内。本R21是响应PFA要求开发用于研究男性和女性功能的模型。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）身上进行的，并假设这些数据同样适用于两性。过去十年积累的多项研究证据清楚地表明，这种假设是错误的。在体内研究中广泛使用的一种模型是啮齿动物的乳突肌，这是一种来自腹壁的薄肌肉，可以抬高和降低睾丸。令人惊讶的是，目前还没有类似代谢和纤维类型的微血管骨骼肌制剂可以代替男性和女性的研究。本研究旨在通过验证雄性和雌性啮齿动物腹壁骨骼肌制备来纠正这一缺陷。假设是微血管骨骼肌功能在相同物种的年龄匹配的雄性和雌性之间没有差异。因此，将在原位和分离的年龄和品系匹配的雌性和雄性小鼠的腹肌微血管中进行3个目的：目的1将评估性别二态性是否存在于从微血管直径到选定的内皮依赖和独立药物的血流调节方面。鉴于最近的数据，我们预计会拒绝我们的假设，因为我们预计a)男性的小动脉会产生更大的基底张力，b)内皮依赖性扩张的剂量-反应关系在男性和女性之间会有所不同。目的2将通过测量微血管溶质渗透性（Ps）来评估两性二态性是否存在于交换调节中。根据我们的数据，我们预计会拒绝我们的假设，因为我们预计：a)男性的小静脉比女性的小静脉更渗漏；b)基底小动脉和毛细血管屏障特性不会因性别而异；c)血管活性物质会产生各种交换反应，反映出男性和女性的血管和组织隔间之间调节溶质分布的性别特异性机制的差异。目标3将比较性别、年龄、器官和物种匹配的直径（目标1），并从微血管中交换数据（目标2），因为微血管位于活组织中并从组织中分离出来。这是一个令人难以置信的机会来进行这些比较，因为不是所有的组织都适合原位研究，并且假设来自孤立血管的数据反映了组织中的行为。该项目的数据将为未来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。我们有必要验证两性微血管功能的研究模型，以便更好地理解健康和疾病中血管功能的性别依赖机制。以知识为基础，针对男性和女性的需求，提供合理的预防和治疗血管疾病的手段。

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.