Sexual Dimorphism of Skeletal Muscle

骨骼肌的性别二态性

基本信息

批准号：
8090311
负责人：
VIRGINIA H HUXLEY
金额：
$ 18.67万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8090311
关键词：
Abdomen Abdominal Muscles Acetylcholine Acute Address Adenosine Age Animals Atrial Natriuretic Factor Behavior Biochemical Blood Blood Vessels Blood capillaries Blood flow Caliber Cardiovascular Diseases Data Disease Disease susceptibility Disodium Salt Nitroprusside Dose Endothelin Endothelium Excision Exposure to Female Fiber Foundations Functional disorder Future Genes Genetic Gonadal Steroid Hormones Health Human Hypertension In Situ Incidence Isoproterenol Knowledge Learning Life Liquid substance Measures Metabolic Microcirculation Modeling Movement Mus Muscle Muscle Contraction Muscle function Non-Insulin-Dependent Diabetes Mellitus Nutrient Organ Oxygen Perfusion Permeability Pharmacology Physiological Preparation Process Property Proteins Regulation Relaxation Respiratory Transport Rodent Secondary to Severities Sex Characteristics Signal Transduction Skeletal Muscle Study models Testis Tissues Vascular Diseases Vascular blood supply abdominal wall arteriole capillary cremaster muscle data exchange in vivo intravital microscopy macromolecule male model development nerve supply prevent public health relevance respiratory gas response response to injury sex sexual dimorphism solute treatment strategy vasoactive agent venule wasting

项目摘要

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.

描述（由申请人提供）：骨骼肌（SKM）微脉管系统已在健康和疾病中的呼吸气体和营养交换、体积分布和进入器官内和器官内的血流控制方面进行了广泛研究。 R21 是对 PFA 要求开发模型以研究男性和女性功能的回应。这一点非常重要，因为大多数 SKM 研究都是在男性（动物和人类）中进行的，并假设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。广泛用于体内研究的一种模型是啮齿动物提睾肌，这是一种源自腹壁的薄肌肉，负责升高和降低睾丸。令人惊讶的是，目前还没有具有同等代谢和纤维类型的微血管骨骼肌制剂可以替代提睾肌，从而有利于男性和女性的研究。该提案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缺陷。该假设认为，同一物种的年龄匹配的雄性和雌性之间的微血管骨骼肌功能没有差异。因此，将从年龄和品系匹配的雌性和雄性小鼠中原位分离腹部肌肉微血管，以实现 3 个目标：目标 1 将通过从微血管直径到选定内皮的测量来评估血流调节是否存在性别二态性依赖和独立代理。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）男性的小动脉将产生更大的基础张力，b）男性和女性之间内皮依赖性扩张的剂量反应关系将有所不同。目标 2 将通过微血管溶质渗透性 (Ps) 的测量来评估交换调节是否存在性别二态性。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) 男性的小静脉将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，以及 c) 血管活性药物将产生各种交换反应反映了调节男性和女性血管和组织区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）并交换微血管的数据（目标 2），因为微血管位于活体组织中并与组织分离。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、生化和生理学研究奠定基础。我们必须验证一种用于研究两性微血管功能的模型，以明智地理解调节健康血管功能和疾病功能障碍的性别依赖性机制。以知识为基础，针对男性和女性的需求，提供预防和治疗血管疾病的合理手段。）公共健康相关性：该项目旨在开发和验证骨骼肌模型，用于研究同一物种（小鼠）年龄匹配的雄性和雌性动物中最小血管的主要功能。微循环的 2 个主要功能 1) 血液流向代谢组织，2) 将营养物质从血液转移到组织，以及将废物从组织转移到血液，这些功能在男性和女性之间在健康和心血管疾病方面似乎有所不同包括高血压和继发于 2 型糖尿病的疾病。当物质在血液和组织之间分布时，液体也会在隔室之间移动。因此，如果男性和女性之间的外汇监管不同，那么交易量分布也可能会有所不同。因此，有必要建立一个模型来了解性别之间的差异和相似之处，因为来自男性的数据、疾病的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。