ProBDNF as a Myokine in Skeletal Muscle Injury: Role in Inflammation and Potential for Therapeutic Modulation of p75NTR

Brain-derived neurotropic factor (BDNF) is expressed by skeletal muscle as a myokine. Our previous work showed that the active precursor, proBDNF, is the predominant form of BDNF expressed in skeletal muscle, and that following skeletal muscle injury, proBDNF levels are significantly increased. However, the function of the muscle-derived proBDNF in injury-induced inflammation has yet to be fully understood. Using a model of tourniquet-induced ischemia–reperfusion (IR) injury of the hindlimb, this study presents, for the first time, strong and novel evidence that following IR injury, proBDNF is released from skeletal muscle into circulation as an endocrine signaling molecule. Further, this study shows that 1 day post-IR injury, the proBDNF receptor, p75NTR, is upregulated 12-fold in splenic monocytes, which are known to be quickly mobilized to the injury site. We demonstrate that p75NTR plays a role in the activation of splenic monocytes, and that treatment with a p75NTR small-molecule modulator, LM11A-31, significantly reduced monocyte inflammatory responses upon lipopolysaccharide stimulation. Overall, the present study establishes proBDNF as a myokine that plays a significant role in skeletal muscle injury-induced inflammation through its receptor, p75NTR, which may be modulated using LM11A-31 as potential translational therapeutic against injury and inflammation.