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
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.