The role of pro-BDNF/mature-BDNF balance in skeletal muscle inactivity-induced capillary regression

前 BDNF/成熟 BDNF 平衡在骨骼肌不活动诱导的毛细血管消退中的作用

基本信息

批准号：
10454113
负责人：
Yifan Li
金额：
$ 36.24万
依托单位：
UNIVERSITY OF SOUTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454113
关键词：
Aging Agonist Alteplase Apoptosis Attenuated Bed rest Blood capillaries Blood flow Brain Brain-Derived Neurotrophic Factor Cardiovascular Diseases Cause of Death Cessation of life Chronic Disease Data Denervation Dependovirus Down-Regulation Endothelial Cells Endothelium Enzymes Equilibrium Exercise Growth Health Hindlimb Hypertension Injury Insulin Insulin Resistance Investigation Knock-out Knockout Mice Lysosomes Mediating Modeling Mus Muscle Muscle function Muscular Atrophy NGFR Protein Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Obesity Pathway interactions Patients Play Predisposition Prevention Production Proteins Role Skeletal Muscle Stroke Testing Therapeutic antagonist apoptosis inducing factor base brain dysfunction cardiovascular disorder risk cardiovascular risk factor cleavage factor density design experimental study extracellular genetic approach new therapeutic target novel novel strategies overexpression physical inactivity prevent protective effect receptor release factor sedentary lifestyle skeletal

项目摘要

Physical inactivity and skeletal muscle disuse are a risk factor for cardiovascular disease (CVD), the most prevalent health problem and a leading cause of death in the US. Skeletal muscle inactivity is widely present in various chronic diseases and injuries, obesity, aging, and sedentary life style and leads to capillary regression, which contribute to muscle wasting, hypertension, and insulin resistance. A critical barrier to the effective prevention and treatment of muscle inactivity-induced capillary regression is the poor understanding of the underlying mechanisms. Brain derived neurotrophic factor (BDNF) was originally found in the brain but now recognized to be also produced in skeletal muscle as a myokine. Our recent data showed that inactive muscles had increased pro-BDNF and reduced mature-BDNF release. We further observed that pro-BDNF induced endothelial cell apoptosis, which was mitigated by mature-BDNF. This study will test a central hypothesis that increased pro-BDNF and decreased mature BDNF release from inactive skeletal muscles, due to the impaired BDNF cleavage, play a critical role in capillary regression. Three specific aims will be pursued to (1) define the role of muscle derived pro-BDNF in capillary regression; (2) determine the role of muscle mature-BDNF in capillary regression; and (3) delineate the aberrant BDNF cleavage as an underlying mechanism of the abnormal pro- and mature-BDNF release from the inactive muscles. Based on these investigations, we will test whether blockade of pro-BDNF receptor pathway, stimulation of mature BDNF receptor pathway, or enhancement of BDNF cleavage function would be potential therapeutic approaches to prevent and treat muscle inactivity-induced capillary regression to lower the risk for CVD.

身体不活跃和骨骼肌消失是心血管疾病（CVD）的危险因素，美国最普遍的健康问题和主要的死亡原因。骨骼肌各种慢性疾病和伤害，肥胖，衰老和久坐的生活方式并导致毛细管回归，这有助于肌肉浪费，高血压和胰岛素抵抗。有效预防和治疗的关键障碍肌肉不活跃引起的毛细血管回归是对基础的不良理解机制。最初在大脑中发现了脑衍生的神经营养因子（BDNF），但现在被认为也可以在骨骼肌中作为肌动物产生。我们最近的数据表明非活动肌肉增加了pro-BDNF并减少了成熟的BDNF释放。我们进一步观察到 pro-BDNF诱导的内皮细胞凋亡，由成熟的BDNF降低。这项研究将检验一个中心假设，该假设增加了BDNF并减少成熟的BDNF 由于BDNF裂解受损而释放出无活性的骨骼肌，因此起着至关重要的作用在毛细管回归中。将追求三个具体目标以（1）定义肌肉的作用在毛细管回归中衍生的pro-bdnf；（2）确定肌肉成熟BDNF在毛细管回归；（3）将异常的BDNF乳沟描述为基础异常的促肌和成熟BDNF的机制从非活性肌肉中释放出来。基于这些研究，我们将测试是否封锁Pro-BDNF受体途径，刺激成熟的BDNF受体途径，或增强BDNF裂解功能可能是预防和治疗肌肉不活跃的潜在治疗方法毛细管回归以降低CVD的风险。