MicroRNA-206 Is Highly Expressed in Newly Formed Muscle Fibers: Implications Regarding Potential for Muscle Regeneration and Maturation in Muscular Dystrophy

Abstract

ABSTRACT. miR-1, miR-133a, and miR-206 are muscle-specific microRNAs expressed in skeletal muscles and have been shown to contribute to muscle development. To gain insight into the pathophysiological roles of these three microRNAs in dystrophin-deficient muscular dystrophy, their expression in the tibialis anterior (TA) muscles of mdx mice and CXMDJ dogs were evaluated by semiquantitative RT-PCR and in situ hybridization. Their temporal and spatial expression patterns were also analyzed in C2C12 cells during muscle differentiation and in cardiotoxin (CTX)-injured TA muscles to examine how muscle degeneration and regeneration affect their expression. In dystrophic TA muscles of mdx mice, miR-206 expression was significantly elevated as compared to that in control TA muscles of age-matched B10 mice, whereas there were no differences in miR-1 or miR-133a expression between B10 and mdx TA muscles. On in situ hybridization analysis, intense signals for miR-206 probes were localized in newly formed myotubes with centralized nuclei, or regenerating muscle fibers, but not in intact pre-degenerated fibers or numerous small mononucleated cells, possibly proliferating myoblasts and inflammatory infiltrates. Similar increased expression of miR-206 was also found in C2C12 differentiation and CTX-induced regeneration, in which differentiated myotubes or regenerating fibers showed abundant expression of miR-206. However, CXMDJ TA muscles contained smaller amounts of miR-206, miR-1, and miR-133a than controls. They exhibited more severe and more progressive degenerative alterations than mdx TA muscles. Taken together, these observations indicated that newly formed myotubes showed markedly increased expression of miR-206, which might reflect active regeneration and efficient maturation of skeletal muscle fibers.

PI3K/AKT signaling determines a dynamic switch between distinct KSRP functions favoring skeletal myogenesis

“…36 Adult skeletal muscle regenerates in response to injuries with a process in which PI3K/AKT signaling activation has an essential role (reviewed in Schiaffino and Mammucari 37 and Supplementary Figure S1a). As the regenerative process has been recently linked to induction of myomiR expression 38 we asked whether Ksrp knockout affects miomyR processing in injury-dependent muscle regeneration.…”

TIMP3: a physiological regulator of adult myogenesis

“…Connexin43 is a major component of gap junctions and has been shown to be important for muscle regeneration and in vitro differentiation (Araya et al, 2005). Both miR-1 and miR-206 are induced during myogenesis (Rao et al, 2006;Yuasa et al, 2008) in a MyoD-and Myf5-dependent manner (Rosenberg et al, 2006;Sweetman et al, 2008), and promote myogenesis (Chen et al, 2006;Kim et al, 2006;Rosenberg et al, 2006). To evaluate whether the two microRNAs mediate TIMP3 downregulation, synthesized miR-1 or miR-206 was transfected into proliferating C2C12 myoblasts.…”

“…As with miR-1, miR-206 is induced in differentiating myoblasts (Rao et al, 2006) and regenerating muscle (Yuasa et al, 2008) by the muscle regulatory factors (MRFs) MyoD and Myf5 (Rosenberg et al, 2006;Sweetman et al, 2008); and has a crucial role in the promotion of myogenesis (Chen et al, 2006;Kim et al, 2006). However, the mechanism through which miR-206 promotes myogenesis is just emerging, despite the fact that miR-206 is Fig.…”

microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice

“…The skeletal muscle-specific miRNA miR-206 is required for efficient regeneration of neuromuscular synapses after acute nerve injury, and the absence of miR-206 accelerates disease progression of amyotrophic lateral sclerosis (ALS) in mice (23). miR-206 is upregulated during skeletal muscle regeneration and has been reported to repress proliferation and promote differentiation of SCs in vitro (24,25). However, the functions of miR-206 in skeletal muscle regeneration in vivo have not been determined.…”