Neuronal innervation regulates the secretion of neurotrophic myokines and exosomes from skeletal muscle

• 成果类型: Article
• 署名作者: Huang, Kai - Yu; Upadhyay, Gaurav; Ahn, Yujin; Sakakura, Masayoshoi; Pagan-Diaz, Gelson J.; Cho, Younghak; Weiss, Amanda C.; Huang, Chen; Mitchell, Jennifer W.; Li, Jiahui; Tan, Yanqi; Deng, Yu- Heng; Mohr, Austin Ellis-; Dou, Zhi; Zhang, Xiaotain; Kang, Sehong; Chen, Qian; Sweedler, Jonathan, V; Im, Sung Gap; Bashir, Rashid; Chung, Hee Jung; Popescu, Gabriel; Gillette, Martha U.; Gazzola, Mattia; Kong, Hyunjoon
• 署名单位: University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; Chan Zuckerberg Initiative (CZI); University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; Korea Advanced Institute of Science & Technology (KAIST); Korea Advanced Institute of Science & Technology (KAIST); University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; Korea University; Korea Institute of Science & Technology (KIST)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13706
• DOI: 10.1073/pnas.2313590121
• 发表日期: 2024-05-07
• 关键词: critical illness; endocrine organ; differentiation; dysfunction; proliferation; neurogenesis; microrna-206; dystrophy; mir-206; MODEL

摘要

Myokines and exosomes, originating from skeletal muscle, are shown to play a significant role in maintaining brain homeostasis. While exercise has been reported to promote muscle secretion, little is known about the effects of neuronal innervation and activity on the yield and molecular composition of biologically active molecules from muscle. As neuromuscular diseases and disabilities associated with denervation impact muscle metabolism, we hypothesize that neuronal innervation and firing may play a pivotal role in regulating secretion activities of skeletal muscles. We examined this hypothesis using an engineered neuromuscular tissue model consisting of skeletal muscles innervated by motor neurons. The innervated muscles displayed elevated expression of mRNAs encoding neurotrophic myokines, such as interleukin - 6, brain - derived neurotrophic factor, and FDNC5, as well as the mRNA of peroxisome - proliferator - activated receptor gamma coactivator 1 alpha , a key regulator of muscle metabolism. Upon glutamate stimulation, the innervated muscles secreted higher levels of irisin and exosomes containing more diverse neurotrophic microRNAs than neuron - free muscles. Consequently, biological factors secreted by innervated muscles enhanced branching, axonal transport, and, ultimately, spontaneous network activities of primary hippocampal neurons in vitro. Overall, these results reveal the importance of neuronal innervation in modulating muscle - derived factors that promote neuronal function and suggest that the engineered neuromuscular tissue model holds significant promise as a platform for producing neurotrophic molecules.