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

缺乏体力活动和骨骼肌废用是心血管疾病（CVD）的危险因素， 这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 不活动广泛存在于各种慢性疾病和损伤、肥胖、衰老和 久坐不动的生活方式，并导致毛细血管退化，这有助于肌肉萎缩， 高血压和胰岛素抵抗。有效预防和治疗的关键障碍 肌肉不活动引起的毛细血管消退的原因是对潜在的 机制等 脑源性神经营养因子（BDNF）最初在脑中发现，但现在被认为是 也作为肌因子在骨骼肌中产生。我们最近的数据显示， 肌肉的BDNF原释放增加，成熟BDNF释放减少。我们进一步观察到， pro-BDNF诱导内皮细胞凋亡，而成熟的BDNF可减轻这种作用。 这项研究将测试一个中心假设，即增加前BDNF和减少成熟BDNF 由于受损的BDNF裂解，从不活动的骨骼肌中释放， 毛细血管退化。三个具体目标将追求（1）定义肌肉的作用 衍生的pro-BDNF在毛细血管消退中的作用;（2）确定肌肉成熟BDNF在毛细血管消退中的作用。 毛细血管消退;（3）描绘异常BDNF切割作为潜在的 从不活动的肌肉释放异常的前和成熟的BDNF的机制。 在这些研究的基础上，我们将测试是否阻断前BDNF受体通路， 刺激成熟BDNF受体途径，或增强BDNF切割功能 将是预防和治疗肌肉失活引起的潜在治疗方法， 毛细血管消退以降低CVD的风险。

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.