Hepatocyte Growth Factor Regulates the miR-206-HDAC4 Cascade to Control Neurogenic Muscle Atrophy following Surgical Denervation in Mice
| Autor: | Jaeman Lee, Sun-Young Kim, Kyeong Ryang Ko, Junghun Lee, Wooshik Choi |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Genetically modified mouse neurogenic muscle atrophy medicine.medical_specialty Article 03 medical and health sciences Downregulation and upregulation Internal medicine Drug Discovery Medicine Progenitor cell Denervation business.industry miR-206 lcsh:RM1-950 HDAC4 Muscle atrophy hepatocyte growth factor lcsh:Therapeutics. Pharmacology 030104 developmental biology Endocrinology Molecular Medicine Hepatocyte growth factor medicine.symptom Stem cell business C2C12 Smad3 medicine.drug |
| Zdroj: | Molecular Therapy: Nucleic Acids, Vol 12, Iss, Pp 568-577 (2018) Molecular Therapy. Nucleic Acids |
| ISSN: | 2162-2531 |
| Popis: | Hepatocyte growth factor (HGF) has been well characterized for its roles in the migration of muscle progenitors during embryogenesis and the differentiation of muscle stem cells, but its function in adult neurogenic muscle atrophic conditions is poorly understood. Here we investigated whether HGF/c-met signaling has any effects on muscle-atrophic conditions. It was found that HGF expression was upregulated in skeletal muscle tissue following surgical denervation and in hSOD1-G93A transgenic mice showing severe muscle loss. Pharmacological inhibition of the c-met receptor decreased the expression level of pri-miR-206, enhanced that of HDAC4 and atrogenes, and resulted in increased muscle atrophy. In C2C12 cells, HGF inhibited phosphorylation of Smad3 and relieved TGF-β-mediated suppression of miR-206 expression via JNK. When extra HGF was exogenously provided through intramuscular injection of plasmid DNA expressing HGF, the extent of muscle atrophy was reduced, and the levels of all affected biochemical markers were changed accordingly, including those of primary and mature miR-206, HDAC4, and various atrogenes. Taken together, our finding suggested that HGF might play an important role in regard to neurogenic muscle atrophy and that HGF might be used as a platform to develop therapeutic agents for neuromuscular disorders. Graphical Abstract |
| Databáze: | OpenAIRE |
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