An oleanolic acid derivative reduces denervation-induced muscle atrophy via activation of CNTF-mediated JAK2/STAT3 signaling pathway

Abstract Denervation caused by sciatic nerve injury has brought great harm to the patients, especially denervation-induced muscle atrophy. The body stress produces a large number of Schwann cells when the sciatic nerve is injured, and the cells secrete some cytokines including ciliary neurotrophic factor (CNTF) that not only play a role in promoting the repair of sciatic nerve, but also maintain the normal physiological function of the muscles surrounding the damaged nerves. CNTF upregulates janus kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3) signals in myoblasts, and consequently accelerates the proliferation and differentiation of myoblasts. This effect on myoblasts is the most effective way to relieve muscle atrophy. Therefore, increasing CNTF is a promising direction to improve muscle atrophy. In the present study, an oleanolic acid derivative, HA-19, increased the proliferation of Schwann cells, and elevated CNTF production of the cells. HA-19 up-regulated the phosphorylation of JAK2 and STAT3 not only by directly acting on myoblasts, but also by increasing the secretion of CNTF of Schwann cells; and consequently, promoted the proliferation and differentiation of myoblasts. In denervation-induced muscle atrophy mice model, treatment with HA-19 significantly increased the weights of tibialis anterior (TA), gastrocnemius (Gastroc.), extensor digitorum longus (EDL), soleus and quadriceps (Quad.) under atrophied state. And, very interestingly, these muscles under normal condition were also strengthened by HA-19. Our finding demonstrated that HA-19 has a great potential as a lead compound for the drug discovery of anti-denervation-induced muscle atrophy.