Skeletal myogenesis is a multistep process in which multipotent precursor cells give rise to myoblasts that subsequently withdraw from the cell cycle, and differentiate and fuse into multinuclear myotubes and then myofibers [1,2]. Skeletal myogenesis is mainly regulated by the muscle-specific transcription factors, including MyoD, myogenin, myogenic factor 5 (Myf5), myogenic regulatory factor 4 (MRF4) and myocyte enhancer factor-2 (MEF2) [3,4]. Skeletal myogenesis is also controlled by various autocrine/paracrine growth factors and cytokines, such as myostatin [5]. However, the control of skeletal myogenesis is not only restricted to the above mentioned factors, but also might have some novel factors.

Akirin is a nuclear factor required for innate immune responses [6]. The Akirin gene is highly conserved among vertebrates and has two homologues, Akirin1 and Akirin2[7]. Till now, the Akirin gene was cloned from different species such as mice, duck, chicken, turbot and pig [6,8–13] and its expression pattern has been previously examined in different species [8–11,14,15]. Beyond its role in innate immune responses, Akirin has recently been shown to play an important role in skeletal myogenesis [14–19] and be negatively regulated by myostatin in skeletal muscle [14]. In addition, analysis of single-nucleotide polymorphism (SNP) in Japanese black beef cattle reveals that Akirin2 is regarded as a positional functional candidate for the gene responsible for marbling [20]. In this review, we will briefly introduce the finding, structure and tissue distribution of Akirin, the basic biological role of Akirin in skeletal myogenesis and its possible signaling pathway.

In 2008, Akirin was firstly isolated from Drosophila melanogaster using a genome-wide screen by RNA-mediated interference [6]. The Akirin gene is conserved in vertebrates and at least two homologues, named Akirin1 and Akirin2, have been identified [6]. However, the Akirin gene family comprises a single gene (Akirin2) in birds/reptiles, and the teleost species have two to eight Akirin family members [6,7,15,17].

The Akirin protein contains 180–204 amino acid residues with a predicted molecular weight about 20–25 kDa [17]. Homology analysis revealed that the conservation region of Akirin protein exists at the putative N-terminal and C-terminal domains, and a less conservative sequence locates in the middle region of the protein [6,7,17]. All Akirin protein sequences contain a highly conserved N-terminal nuclear localization signal (NLS) (Pro-Val-Lys-Arg-Arg), a functional motif, and Akirin was strictly localized to the nucleus [6,7,17].

The Akirin sequence has no obvious DNA- or RNA-binding motifs, so it cannot directly bind DNA [6], but it can interact with cofactors to promote or repress mRNA transcription including 14-3-3 proteins [21]. The 14-3-3 proteins are phosphoserine/threonine-binding proteins. It has been reported that 14-3-3 proteins can regulate subcellular localization, protein-protein interactions of target proteins, and many cellular activities including the cell cycle, intracellular signaling, apoptosis and malignant transformation [21–23]. There is a growing body of evidence indicating that Akirin2 physically interacts with 14-3-3 proteins in the nucleus to regulate gene expression [7,21]. However, Akirin1 has several low affinity 14-3-3 binding sites [7] and was detected in the nucleus [6], suggesting that the positive function of the Akirin1 may be mediated through binding 14-3-3 proteins [7]. Therefore, an interesting line of future investigation will be to further explore the relationship between Akirin and 14-3-3 proteins and whether the role played by Akirin is accounted for by binding to 14-3-3 proteins.

A large number of studies show that the Akirin is expressed in a variety of different tissues [8–11,14,15]. Marshall et al. found that mouse Akirin1 was expressed in many tissues such as brain, testes, lung, kidney, intestine and liver [14]. They also found that Akirin1 expression was comparatively low in skeletal muscle, while its expression was increased in myostatin-null skeletal muscle [14]. In addition, the Akirin1 expression was detected in inflammatory cells macrophages from peritoneal cavity and bone marrow of mice [16], which imply that Akirin may play an important role in inflammation reaction. More recently, data from our group showed that porcine Akirin2 mRNA was mainly expressed in the lung and modestly expressed in the skeletal muscle and heart [9]. Man et al. reported that chicken Akirin2 mRNA was highly expressed in the brain and oviduct [8]. Moreover, the expression levels of eight Akirin family members were detected in different tissues of Atlantic salmon [15]. These findings suggest that the functions of the Akirin are presented diversely in different tissues and different developmental stages among different species.

Several lines of evidence support a role of Akirin in skeletal myogenesis. First, the expression of Akirin is negatively regulated by myostatin [14,16]. Second, Akirin has been reported to promote myogenic differentiation [14,19]. Finally, Akirin has been shown to induce the quiescent satellite cells (SC) activation and migration [14,18].

The signaling pathway for Akirin remains large unknown. At present, there is growing evidence that Akirin1 can stimulate skeletal muscle cell differentiation and enhance the myotube formation through IGF-II-PI3K-Akt signaling pathway [14]. As a differentiation inducing factor, IGF-II has been shown to enhance the differentiation of myoblasts and the formation of myotubes [32]. It has been reported that over-expression of Akirin1 in C2C12 myoblasts increases the secretion of IGF-II during the myogenic differentiation, and the phosphorylated Akt was also elevated by Akirin1 over-expression [14]. When blocking PI3K pathway by the PI3K specific inhibitor LY294002, the Akirin1 promoter activity is inhibited [14]. Taken together, these results provide evidence that Akirin1 regulates skeletal myogenesis via IGF-II-PI3K-Akt signaling pathway. Further research is required to investigate whether other pathways are involved in the Akirin-mediated skeletal myogenesis.

Skeletal myogenesis has been widespread concern, which is mainly regulated by muscle transcription factors such as MRFs and MEF2. Akirin is a recently discovered nuclear factor that plays an important role in skeletal myogenesis. However, its precise mechanisms are still lacking. Therefore, intensive studies of the molecular mechanism on how Akirin exerts its role in skeletal myogenesis will be critical not only for understanding the control of skeletal myogenesis but also for improving animal meat yield in livestock production.