Selenomethionine promotes ANXA2 phosphorylation for proliferation and protein synthesis of myoblasts and skeletal muscle growth

Selenium (Se) is an essential trace element for many living organisms. Plants and microorganisms take up several inorganic forms of Se such as selenite and selenate and convert them into organic forms mostly as selenomethionine (Se-Met) and fewer as selenocysteine (Se-Cys). These two amino acids can replace methionine or cysteine in Se-containing proteins. Se-Met can be incorporated into tissues with strong protein synthesis, whereas Se-Cys is often located in the active center of some oxidoreductases [1,2]. Se-Met is essential for the proper functioning of the immune system, fertility, thyroid, and brain. Higher animals and human are unable to synthesize Se-Met, and need to intake it from dietary sources such as edible plant products [3,4]. At a low dose, Se-Met has a beneficial effect, while at a high dose it exhibits an inhibitory or toxic effect [1,5,6]. Se-Met deficiency can produce harmful effects on the nervous, cardiovascular, immune systems and muscle growth of animals [2].

Increasing evidences have shown that Se-Met can regulate cellular physiology through distinct signaling pathways. The kinase mechanistic target of rapamycin (mTOR) is the most important signaling hub for cell proliferation and protein synthesis and inhibition of autophagy, functioning through phosphorylating downstream targets such as S6K1, 4E-BP1, AKT, PKC, IGF-IR and ULK1 [7]. p-mTOR can also enter nucleus to regulate gene expression. Amino acids are required for mTOR activation, and in recent years several amino acid sensors have been found [8]. Several previous studies have demonstrated that Se-Met can activate the PI3K-AKT-mTOR signaling pathway, inhibit autophagy and promote cell proliferation [9,10], but it is yet unknown how cells sense Se-Met and thereby activate this signaling pathway. Se-Met reversed the oxidative damage of zearalenone by the Nrf2/Keap1-ARE pathway [11]. Se-Met suppressed the TLR4-NF-κB-NLRP3 signaling pathway in liver tissue and inhibited LPS-induced inflammation [12]. Se-Met increased Bcl-2 but decreased Bax, Cyt-c, and caspase-3 levels in mice intestinal tissues and inhibited apoptosis [13]. These reports have pointed out that Se-Met plays a protective role for cellular function through regulating various cellular signaling pathways in different tissues and cells. However, we still know little about its detailed molecular mechanism, which needs to be further studied.

The normal growth and development of muscle tissues is closely related to human health and related diseases. Besides, the amount of skeletal muscle tissues in animals is the most important economic indicator of animal meat production. The skeletal muscle myogenesis is dependent on the ability of myoblasts to proliferate, synthesize proteins and fuse into myotubes [14], [15], [16], [17]. mTOR has been proved the central signaling for proliferation and differentiation of myoblasts [18,19]. Previous reports have confirmed the protective role of Se in muscle growth, and Se deficiency (< 0.1 mg/kg diet) can cause a myo-degenerative syndrome (also known as white muscle disease) [20]. A recent report showed that Se-Met can partly alleviate the inhibition of heat stress on myogenesis of C2C12 myoblasts [21]. However, it is largely unclear the role of Se-Met on proliferation and protein synthesis of myoblasts.

Amino acids can stimulate mTOR phosphorylation (activation) through distinct sensing pathways [8,22,23]. Annexin A2 (ANXA2) is a member of the Annexin family, which can bind cell membrane and plays important roles in transducing lots of signals of extracellular stimuli to intracellular downstream signaling pathways [24,25]. ANXA2 can be phosphorylated for activation by protein kinases such as PKCα [26,27], which is a member of the PKC family of serine/threonine kinases functioning in the early stage sensing of cells to extracellular stimuli [28]. A previous report showed that ANXA2 mediated the stimulation of methionine (Met) and leucine (Leu) on the PI3K-mTOR signaling [29]. Compared with other amino acids, there are few studies on the signal transduction pathway for Se-Met sensing, and it is unknown whether Se-Met can regulate the mTOR signaling and cellular physiology through ANXA2-associated signaling pathway.

Based on these above research progress, the role and molecular mechanism of Se-Met in myoblast proliferation and muscle growth need to be further studied. In this study, we aim to determine the role of Se-Met on the proliferation and protein synthesis of C2C12 myoblasts and skeletal muscle growth of mice, and explore the corresponding molecular mechanism.

留言 (0)

沒有登入
gif