Sexual Dimorphism of Skeletal Muscle

描述（由申请人提供）：在健康和疾病情况下，已对骨骼肌（SKM）微血管系统在呼吸气体和营养交换、体积分布以及进入器官和器官内的血流控制方面进行了广泛研究。该R21是对PFA要求开发用于研究男性和女性功能的模型的响应。这是非常重要的，因为大多数SKM研究都是在男性（动物和人类）中进行的，假设数据同样适用于两性。过去十年来积累的多项研究证据清楚地表明，这种假设是错误的。一种广泛用于体内研究的模型是啮齿动物提睾肌，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，没有微血管骨骼肌制备等效的代谢和纤维类型的替代品，目前的提睾肌，促进研究的男性和女性。本提案旨在通过验证雄性和雌性啮齿动物的腹壁骨骼肌制备来纠正这一缺陷。这一假设是，微血管骨骼肌功能在相同物种的年龄匹配的男性和女性之间没有差异。因此，将从年龄和品系匹配的雌性和雄性小鼠原位和分离的腹肌微血管中进行3个目的：目的1将评估从微血管直径到选定的内皮依赖性和非依赖性试剂的测量是否存在关于血流调节的性二态性。鉴于最近的数据，我们预计将拒绝我们的假设，因为我们预计a）雄性动物的小动脉将产生更高的基础张力，B）雄性和雌性动物之间内皮依赖性舒张的剂量-反应关系将不同。目的2将评估是否存在性二态性方面的交换调节措施，从措施的微血管溶质渗透性（Ps）。根据我们的数据，我们预期会拒绝我们的假设，因为我们预期a）男性的小静脉比女性的小静脉更易渗漏，B）基底小动脉和毛细血管屏障特性不会因性别而异，以及c）血管活性药物将产生各种交换反应，反映调节男性和女性血管和组织室之间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），并在微血管位于活组织中时和从组织中分离后交换微血管的数据（目标2）。这是进行这些比较的绝佳机会，因为并非所有组织都适合原位研究，并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男性和女性微血管功能的遗传、生物化学和生理学研究奠定基础。我们必须验证两性微血管功能研究的模型，以智能地理解健康和疾病功能障碍中调节血管功能的性别依赖机制。以知识为基础，并提供合理的手段，预防和治疗血管疾病的具体需要的男性和女性。 公共卫生相关性：本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）的最小血管的主要功能。微循环的两个主要功能1）血液流向代谢组织，和2）营养物质从血液到组织的运动以及废物从组织到血液的清除，在健康和心血管疾病（包括高血压和继发于2型糖尿病）方面，男性和女性之间似乎存在差异。由于物质在血液和组织之间分布，因此液体也会在隔室之间移动;因此，如果雄性和雌性之间的交换调节不同，则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并不同样适用于女性。

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.