Tian Tina, Kim David, Yu Kuai, Hartzell H Criss, Ward Patricia J
Medical Scientist Training Program, Emory University School of Medicine, Atlanta, GA 30307, USA; Neuroscience Graduate Program, Laney Graduate School, Emory University, Atlanta, GA 30307, USA; Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30307, USA.
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30307, USA.
Neurobiol Dis. 2025 Jun 1;209:106893. doi: 10.1016/j.nbd.2025.106893. Epub 2025 Mar 29.
Renewed scientific interest in sympathetic modulation of muscle and neuromuscular junctions has spurred a flurry of new discoveries with major implications for motor diseases. However, the role sympathetic axons play in the persistent dysfunction that occurs after nerve injuries remains to be explored. Peripheral nerve injuries are common and lead to motor, sensory, and autonomic deficits that result in lifelong disabilities. Given the importance of sympathetic signaling in muscle metabolic health and maintaining bodily homeostasis, it is imperative to understand the regenerative capacity of sympathetic axons after injury. Therefore, we tested sympathetic axon regeneration and functional reinnervation of skin and muscle, both acute and long-term, using a battery of anatomical, pharmacological, chemogenetic, cell culture, analytical chemistry, and electrophysiological techniques. We employed several established growth-enhancing interventions, including electrical stimulation and conditioning lesion, as well as an innovative tool called bioluminescent optogenetics. Our results indicate that sympathetic regeneration is not enhanced by any of these treatments and may even be detrimental to sympathetic regeneration. Despite the complete return of motor reinnervation after sciatic nerve injury, gastrocnemius muscle atrophy and deficits in muscle cellular energy charge, as measured by relative ATP, ADP, and AMP concentrations, persisted long after injury, even with electrical stimulation. We suggest that these long-term deficits in muscle energy charge and atrophy are related to the deficiency in sympathetic axon regeneration. New studies are needed to better understand the mechanisms underlying sympathetic regeneration to develop therapeutics that can enhance the regeneration of all axon types.
对交感神经对肌肉和神经肌肉接头调节作用的重新科学关注引发了一系列新发现，这些发现对运动疾病具有重大意义。然而，交感神经轴突在神经损伤后持续功能障碍中所起的作用仍有待探索。周围神经损伤很常见，会导致运动、感觉和自主神经功能缺陷，从而导致终身残疾。鉴于交感神经信号在肌肉代谢健康和维持身体内环境稳态中的重要性，了解损伤后交感神经轴突的再生能力至关重要。因此，我们使用了一系列解剖学、药理学、化学遗传学、细胞培养、分析化学和电生理技术，测试了急性和长期情况下交感神经轴突在皮肤和肌肉中的再生以及功能再支配情况。我们采用了几种已确立的促进生长的干预措施，包括电刺激和预处理损伤，以及一种名为生物发光光遗传学的创新工具。我们的结果表明，这些治疗方法均未增强交感神经再生，甚至可能对交感神经再生有害。尽管坐骨神经损伤后运动再支配完全恢复，但即使经过电刺激，腓肠肌萎缩以及通过相对ATP、ADP和AMP浓度测量的肌肉细胞能量电荷缺陷在损伤后仍持续很长时间。我们认为，肌肉能量电荷和萎缩的这些长期缺陷与交感神经轴突再生不足有关。需要开展新的研究，以更好地了解交感神经再生的潜在机制，从而开发出能够增强所有轴突类型再生的治疗方法。
