MiR-206 Attenuates Denervation-Induced Skeletal Muscle Atrophy in Rats Through Regulation of Satellite Cell Differentiation via TGF-β1, Smad3, and HDAC4 Signaling

Abstract

BackgroundDenervation-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/MethodsThe 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.ResultsAfter 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-β1/Smad3 axis.ConclusionsTGF-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.

Effects of aerobic and inspiratory training on skeletal muscle microRNA‐1 and downstream‐associated pathways in patients with heart failure

“…In particular, class IIa HDACs (HDACs 4, 5, 7, and 9) plays an important role in the maintenance of muscle mass and protein degradation during muscle wasting . The reduced levels of HDAC4 promote myoblast differentiation, while increased levels of HDAC4 enhances skeletal muscle atrophy . Chen et al .…”

MicroRNAs in muscle wasting

“…These miRs are under the transcriptional control of myogenic regulatory factors such as MyoD, myogenin, Myf5, and MRF4. 11 In patients with chronic obstructive pulmonary disease (COPD), an up-regulation of miR-542-3p/5p in quadricep muscle has been described, which caused muscle wasting and reduced mitochondrial function when overexpressed in mice possibly due to a suppression of the mitochondrial ribosomal protein MRPS10, reduced 12S ribosomal RNA expression, and increased TGF-b signalling. 5 Two key players of muscle wasting are the E3 ubiquitin ligases MAFbx and MuRF-1, the latter being the only E3 ubiquitin ligase known to target contractile proteins in catabolic conditions 6 and which can be inhibited by small molecules.…”

“…9 In a rat model of paralysed muscle by spinal cord injury, a down-regulation of miRs 23a, 23b, 27b, 145, and 206 was observed 56 days after injury, 10 while injection of 30 μg of mir-206 attenuated muscle loss in a rat denervation model. 11 In patients with chronic obstructive pulmonary disease (COPD), an up-regulation of miR-542-3p/5p in quadricep muscle has been described, which caused muscle wasting and reduced mitochondrial function when overexpressed in mice possibly due to a suppression of the mitochondrial ribosomal protein MRPS10, reduced 12S ribosomal RNA expression, and increased TGF-b signalling. 12 In patients with COPD with a low fat free mass, an increased expression of miR-675 in quadricep muscle was shown to repress muscle regeneration in vitro.…”

MicroRNA regulators of cholinergic signaling link neuromuscular, cardiac and metabolic systems

“…Predictably, miR-206, having an identical seed sequence to miR-1, also regulates HDAC4 levels (33). Multiple studies have provided evidence for the important role of miR-206 in muscle regeneration and protection from muscular atrophy (53). In a mouse model for ALS, miR-206 KO mutants showed faster progression of the disease, most likely due to delayed muscle re-innervation compared to mice with the functioning miR-206 allele (33).…”