**Transthyretin Maintains Muscle Homeostasis through the Novel Shuttle Pathway of Thyroid Hormones during Myoblast Di**ff**erentiation**

**Eun Ju Lee 1,**†**, Sibhghatulla Shaikh 1,**†**, Dukhwan Choi 1, Khurshid Ahmad 1, Mohammad Hassan Baig 1, Jeong Ho Lim 1, Yong-Ho Lee 2, Sang Joon Park 3, Yong-Woon Kim 4, So-Young Park <sup>4</sup> and Inho Choi 1,\***


Received: 8 October 2019; Accepted: 2 December 2019; Published: 4 December 2019

**Abstract:** Skeletal muscle, the largest part of the total body mass, influences energy and protein metabolism as well as maintaining homeostasis. Herein, we demonstrate that during murine muscle satellite cell and myoblast differentiation, transthyretin (TTR) can exocytose via exosomes and enter cells as TTR- thyroxine (T4) complex, which consecutively induces the intracellular triiodothyronine (T3) level, followed by T3 secretion out of the cell through the exosomes. The decrease in T3 with the TTR level in 26-week-old mouse muscle, compared to that in 16-week-old muscle, suggests an association of TTR with old muscle. Subsequent studies, including microarray analysis, demonstrated that T3-regulated genes, such as FNDC5 (Fibronectin type III domain containing 5, irisin) and RXRγ (Retinoid X receptor gamma), are influenced by TTR knockdown, implying that thyroid hormones and TTR coordinate with each other with respect to muscle growth and development. These results suggest that, in addition to utilizing T4, skeletal muscle also distributes generated T3 to other tissues and has a vital role in sensing the intracellular T4 level. Furthermore, the results of TTR function with T4 in differentiation will be highly useful in the strategic development of novel therapeutics related to muscle homeostasis and regeneration.

**Keywords:** muscle satellite cell; transthyretin; thyroid hormone; myogenesis; exosomes; skeletal muscle
