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

• 批准号: 10191017
• 负责人: Yifan Li
• 金额: $ 36.27万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10191017
• 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; Impairment; 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; apoptosis inducing factor; base; 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

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.

缺乏运动和骨骼肌停用是心血管疾病(CVD)的风险因素， 是美国最普遍的健康问题，也是导致死亡的主要原因。骨骼肌 缺乏运动广泛存在于各种慢性病和损伤、肥胖、衰老和 久坐不动的生活方式，导致毛细血管退化，从而导致肌肉萎缩， 高血压和胰岛素抵抗。有效防治的关键障碍 对肌肉不活动导致的毛细血管倒退的根本原因是认识不足 机制。 脑源性神经营养因子(BDNF)最初发现于大脑，但现在被认为是 在骨骼肌中也作为一种肌动因子产生。我们最近的数据显示，不活跃的 肌肉中BDNF原增多，成熟BDNF释放减少。我们进一步观察到， Pro-BDNF可诱导内皮细胞凋亡，成熟的BDNF可减轻这种作用。 这项研究将检验一个中心假设，即增加前BDNF和减少成熟BDNF 由于脑源性神经营养因子的切割受损，从不活跃的骨骼肌中释放出的神经营养因子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来(1)确定肌肉的作用 (2)确定肌肉成熟-BDNF在毛细血管回归中的作用。 毛细血管回归；以及(3)将异常的BDNF裂解描述为潜在的 非活动肌肉异常释放前体和成熟脑源性神经营养因子的机制。 在这些研究的基础上，我们将测试是否阻断前BDNF受体途径， 刺激成熟的脑源性神经营养因子受体途径或增强脑源性神经营养因子的切割功能 将是预防和治疗肌肉不活动引起的潜在治疗方法 毛细血管回归以降低心血管疾病的风险。