**1. Introduction**

Skeletal muscle is comprised of multinucleated myofibers and has excellent regeneration capability, which deteriorates progressively with age, restraining the voluntary functions of daily life. The regenerative capacity is mostly facilitated by muscle satellite or stem cells (MSCs) that reside between the basal lamina and sarcolemma, a distinct 'niche' in the muscle fibers [1,2]. MSCs vigorously regulate myofiber growth, and MSC progression is typically regulated by the expression of myogenic transcription factors (Pax3, Pax7, myoblast determination protein; MYOD, and myogenin; MYOG) [3]. After injury, quiescent Pax7<sup>+</sup> MSCs are triggered to undergo sequential activation, proliferation and differentiation involving MYOD, Myf5 and MYOG to generate multinucleated myotubes [4]. MSC differentiation is indispensable in the regeneration of skeletal muscle and is typically regulated by multiple signaling pathways and by the interaction of several extracellular matrix components with MSCs. Fibromodulin was reported to have a robust role in muscle regeneration by enhancing the recruitment of MSCs to injury sites [5].

Thyroid hormones (THs, thyroxin; T4 and triiodothyronine; T3) have vital roles in the development of various tissues, as well as in postnatal life, by modulating gene expressions [6,7]. THs regulate the expression of various proteins crucial for muscle development and contractility [8–10]. Indeed, the foremost targets of THs are muscles, as they regulate the expression of several genes at the transcriptional level [11,12]. The effects of TH signaling in the development and function of skeletal muscle are the result of a remarkably complex mechanism [11]. Generally, to retain homeostasis, regeneration capability, and development, binding of T3 to thyroid hormone receptors (TR) is essential [13]. TRs are encoded by two genes (THRA and THRB), and alternate splicing of each gene produces TRα1, TRβ1, and TRβ2 receptor subtypes. TRα is the predominant subtype in cardiac and skeletal muscle [14]. TRα has a key role in regulation of heart rate and basal metabolism [15]. Transcription of MYOD is directly regulated by T3 [16]. Therefore, TH signaling can control several events during myogenesis via direct and/or indirect regulation of myogenic gene expression.

Retinoids (synthetic vitamin A derivatives) can influence development and metabolism through nuclear hormone receptors (retinoic acid receptor and retinoid X receptor, RXR). RXR forms heterodimers with retinoic acid, TH, and vitamin D receptors, enhancing transcriptional function on their respective response elements [17]. Three different RXR isoforms (RXRα, β and γ) have been characterized. RXRγ is the dominant isoform in adult heart and skeletal muscle [18].

Exosomes are small (40–100 nm) membrane vesicles of endocytic origin that are released from most cell types into the extracellular environment [19]. Exosomes were first defined in 1983, and interest in these vesicles increased markedly after finding that they contain mRNA and microRNA [20]. Exosomes have been shown to facilitate cellular communication by transporting proteins, cytokines, and nucleic acids and to sustain the normal physiological function of cells [21].

Transthyretin (TTR) is a 55-kDa homotetrameric transporter protein for T4 and retinol-binding protein in the blood [22,23]. The liver is the main contributing organ for TTR synthesis in plasma. TTR null (TTR−/−) mice exhibit a delayed suckling-to-weaning transition, delayed growth, reduced muscle mass, and stunted longitudinal bone growth [24]. Among the transporters existing in blood, thyroxine-binding globulin (TBG) has the highest affinity for T4 and T3 (1.0 <sup>×</sup> 1010 and 4.6 <sup>×</sup> 108 <sup>M</sup><sup>−</sup>1, respectively), followed by TTR (7.0 <sup>×</sup> 107 and 1.4 <sup>×</sup> 107 <sup>M</sup><sup>−</sup>1) and albumin (7.0 <sup>×</sup> 105 and 1.0 <sup>×</sup> 105 <sup>M</sup><sup>−</sup>1) [25]. The binding efficacy of TH distributor proteins determines the transportation times for distribution of THs to tissues, thus, TTR (with transitional affinity), more than TBG, is responsible for instant delivery of THs to tissues [6,25].

Though it is known that human placenta, trophoblasts, JEG-3 and HepG2 cells secrete and internalize TTR [26–28], its cellular uptake in skeletal muscle has not been fully described. We have demonstrated that TTR initiates myoblast differentiation by inducing the expression of myogenic genes involved in the early phase of myogenesis and the associated calcium channels [6], and we have elucidated its functional role in maintaining the cellular T4 level. Furthermore, we reported that TTR enhances recruitment of MSCs to the site of injury, thereby regulating muscle regeneration [29]. However, the detailed mechanism of TTR with T4 in MSCs differentiation into muscle cells is unclear. In the current work, we have confirmed TTR secretion and internalization in myoblast cell. We found that TTR uptake and internalization by myoblast cells is increased by T4. By using microarray analysis and other studies, we have elucidated that TTR and TH coordinate with each other to modulate gene expression in muscle growth, development, and homeostasis.
