The Role of Brain-Derived Neurotrophic Factor (BDNF) in Postnatal Muscle Development and Regeneration

Abstract

In adult skeletal muscle, brain-derived neurotrophic factor (BDNF) is expressed in a reserve population of myogenic progenitors known as satellite cells. Previous studies in our laboratory have shown that siRNA-mediated depletion of BDNF results in precocious differentiation of myoblasts in culture, suggesting a role in regulation of myogenic differentiation (J. Neuroscience, 2006). In order to functionally address the role of BDNF in muscle satellite cells and regeneration in vivo, we employed a Cre/Lox approach to generate a mouse in which BDNF is specifically depleted from skeletal muscle cells (BDNF MKO). Cre recombinase expression was driven by the Myf5 promoter, resulting in BDNF depletion during early myogenic lineage determination. For comparative purposes, and to determine the specific role of muscle-derived BDNF, we also examined skeletal muscles of the complete BDNF-/- mouse. In both animal models, expression of myosin heavy chain (MyHC) type IIB was decreased at the transcript and protein levels. In addition, we found decreased expression of the satellite cell marker Pax? compared to control littermates. Because satellite cells are responsible for postnatal growth and repair of skeletal muscle, we next examined the satellite cell pool using primary cultures. BDNFMKO-derived myoblasts exhibited abnormal differentiation, with delayed induction of several molecular markers of differentiation and decreased myotube size. These defects were rescued by the addition of exogenous BDNF. To determine whether in vivo regenerative capacity was compromised in the absence of muscle-BDNF we performed cardiotoxin-induced regeneration assays. Indeed, BDNF-depleted muscle showed delayed expression of several markers of regeneration following injury. Furthermore, we observed delayed appearance of newly regenerated fibers in the absence of muscle-BDNF. Together these findings suggest that muscle-derived BDNF plays at least two functions in skeletal muscle compartment; in promoting expression of MyHC IIB and in regulating myogenic differentiation during regeneration.