title: MiR-206 Attenuates Denervation-Induced Skeletal Muscle Atrophy in Rats Through Regulation of Satellite Cell Differentiation via TGF-β1, Smad3, and HDAC4 Signaling.
abstract: BACKGROUND Denervation-induced skeletal muscle atrophy results in significant biochemical and physiological changes potentially leading to devastating outcomes including increased mortality. Effective treatments for skeletal muscle diseases are currently not available. Muscle-specific miRNAs, such as miR-206, play an important role in the regulation of muscle regeneration. The aim of the present study was to examine the beneficial effects of miR-206 treatment during the early changes in skeletal muscle atrophy, and to study the underlying signaling pathways in a rat skeletal muscle atrophy model. MATERIAL AND METHODS The rat denervation-induced skeletal muscle atrophy model was established. miRNA-206 was overexpressed with or without TGF-β1 inhibitor in the rats. The mRNA and protein expression of HDAC4, TGF-β1, and Smad3 was determined by real-time PCR and western blot. The gastrocnemius muscle cross-sectional area and relative muscle mass were measured. MyoD1, TGF-β1, and Pax7 were determined by immunohistochemical staining. RESULTS After sciatic nerve surgical transection, basic muscle characteristics, such as relative muscle weight, deteriorated continuously during a 2-week period. Injection of miR-206 (30 μg/rat) attenuated morphological and physiological deterioration of muscle characteristics, prevented fibrosis effectively, and inhibited the expression of TGF-β1 and HDAC4 as assessed 2 weeks after denervation. Moreover, miR-206 treatment increased the number of differentiating (MyoD1+/Pax7+) satellite cells, thereby protecting denervated muscles from atrophy. Interestingly, the ability of miR-206 to govern HDAC4 expression and to attenuate muscle atrophy was weakened after pharmacological blockage of the TGF-b1/Smad3 axis. CONCLUSIONS TGF-β1/Smad3 signaling pathway is one of the crucial signaling pathways by which miR-206 counteracts skeletal muscle atrophy by affecting proliferation and differentiation of satellite cells. miR-206 may be a potential target for development of a new strategy for treatment of patients with early denervation-induced skeletal muscle atrophy.
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland).
authors.forename: Qiang Kai
authors.initials: QK
authors.lastname: Huang
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland).
authors.forename: Hu-Yuan
authors.initials: HY
authors.lastname: Qiao
authors.affiliation: Division of Cardiovascular Disease, Department of Gerontology, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China (mainland).
authors.forename: Ming-Huan
authors.initials: MH
authors.lastname: Fu
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland).
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland).
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Li
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland).
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland).
authors.forename: Jian
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland).
authors.forename: Bing-Sheng
authors.initials: BS
authors.lastname: Liang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D003714:Denervation; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000294:innervation* / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D032446:Myoblasts / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism; D012584:Sciatic Nerve / Q000601:surgery; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D053773:Transforming Growth Factor beta1; C559944:HDAC4 protein, rat; D006655:Histone Deacetylases