07 April 2016 : Animal Research
MiR-206 Attenuates Denervation-Induced Skeletal Muscle Atrophy in Rats Through Regulation of Satellite Cell Differentiation via TGF-β1, Smad3, and HDAC4 Signaling
Qiang Kai HuangBEF, Hu-Yuan QiaoBD, Ming-Huan FuC, Gang LiBD, Wen-Bin LiACD, Zhi ChenAC, Jian WeiBD, Bing-Sheng LiangAEFDOI: 10.12659/MSM.897909
Med Sci Monit 2016; 22:1161-1170
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.
Keywords: Denervation, Cell Differentiation - genetics, Histone Deacetylases - metabolism, Muscle, Skeletal - pathology, Muscular Atrophy - therapy, Myoblasts - metabolism, RNA, Messenger - metabolism, Random Allocation, Real-Time Polymerase Chain Reaction, Satellite Cells, Skeletal Muscle - metabolism, Sciatic Nerve - surgery, Smad3 Protein - metabolism
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