Electrical stimulation of hindlimb skeletal muscle has beneficial effects on sublesional bone in a rat model of spinal cord injury

Authors: ZHAO, WEI - James J Peters Vamc; PENG, YUANZHEN - James J Peters Vamc; HU, YIZHONG - Columbia University - New York; GUO, X. EDWARD - Columbia University - New York; LI, JILIANG - Indiana University-Purdue University; Cao, Jay; PAN, JIANGPING - James J Peters Vamc; FENG, JIAN - Texas A&M University; CARDOZA, CHRISTOPHER - James J Peters Vamc; JARVIS, JONATHAN - John Moores University; BAUMAN, WILLIAM - James J Peters Vamc; QIN, WEIPING - James J Peters Vamc

Submitted to: Bone
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/16/2020
Publication Date: 12/19/2020
Citation: Zhao, W., Peng, Y., Hu, Y., Guo, X., Li, J., Cao, J.J., Pan, J., Feng, J., Cardoza, C., Jarvis, J., Bauman, W.A., Qin, W. 2020. Electrical stimulation of hindlimb skeletal muscle has beneficial effects on sublesional bone in a rat model of spinal cord injury. Bone. 144. Article 115825. https://doi.org/10.1016/j.bone.2020.115825.
DOI: https://doi.org/10.1016/j.bone.2020.115825

Interpretive Summary: Spinal cord injury is a lifelong and life changing injury affecting as many as 337,000 Americans. Spinal cord injury results in severe immobilization, paralysis, muscle wasting, loss of strength, and rapid, severe bone loss. In this study, we investigated the effects of extended electrical stimulation and/or testosterone enanthate on muscle and bone in a spinal cord injury rat model. We found that either electrical stimulation or the combination of electrical stimulation and testosterone enanthate decreased mRNA levels of muscle atrophy markers and increased muscle mass of soleus, plantaris, and extensor digitorum longus in rats with spinal cord injury. Either testosterone enanthate, electrical stimulation, or testosterone enanthate and electrical stimulation together increased bone mineral density and bone mass of rats with spinal cord injury. Data from this study demonstrate that electrical stimulation combined with testosterone enanthate treatment can be used to improve muscle and bone mass in animals with spinal cord injury.

Technical Abstract: Spinal cord injury (SCI) results in marked atrophy of sublesional skeletal muscle and substantial loss of bone. In this study, the effects of prolonged electrical stimulation (ES) and /or testosterone enanthate (TE) on muscle mass and bone formation in a rat model of SCI were tested. Compared to sham-transected animals, a significant reduction of the mass of soleus, plantaris, and extensor digitorum longus (EDL) was observed in animals 6 weeks post-SCI. Notably, ES or ES+TE resulted in the increased masses of these muscles. ES or ES+TE significantly decreased mRNA levels of muscle atrophy markers (e.g., MAFbx and MurF1) in the EDL. Significant decreases in bone mineral density (BMD) (-27%) and trabecular bone volume (-49.3%) at the distal femur were observed in animals 6 weeks post injury. TE, ES and ES+TE treatment significantly increased BMD by +6.4%, +5.4%, +8.5% and bone volume by +22.2%, and +56.2% and+ 60.2%, respectively. Notably, ES alone or ES+TE resulted in almost complete restoration of cortical stiffness estimated by finite element analysis in SCI animals. Osteoblastogenesis was evaluated by colony-forming unit-fibroblastic (CFU-F) staining using bone marrow mesenchymal stem cells obtained from the femur. SCI decreased the CFU-F+ cells by -56.8% compared to sham animals. TE or ES+TE treatment after SCI increased osteoblastogenesis by +74.6% and +67.2%, respectively. An osteoclastogenesis assay revealed significantly increased TRAP+ multinucleated cells (+34.8%) in SCI animals compared to sham animals. TE, ES and TE+ES treatment following SCI markedly decreased TRAP+ cells by -51.3%, -40.3% and -46.9%, respectively. Collectively, our findings demonstrate that after neurologically complete paralysis, ES generated sufficient dynamic contractile force to initiate muscle hypertrophy, downregulate genes involved in muscle atrophy, and restored mechanical loading to sublesional bone to a degree that allowed for preservation of bone by inhibition of bone resorption and/or by facilitating bone formation.