Transthyretin Maintains Muscle Homeostasis through the Novel Shuttle Pathway of Thyroid Hormones during Myoblast Differentiation

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 (T(4)) complex, which consecutively induces the intracellular triiodothyronine (T(3)) level, followed by T(3) secretion out of the cell through the exosomes. The decrease in T(3) 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 T(3)-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 T(4), skeletal muscle also distributes generated T(3) to other tissues and has a vital role in sensing the intracellular T(4) level. Furthermore, the results of TTR function with T(4) in differentiation will be highly useful in the strategic development of novel therapeutics related to muscle homeostasis and regeneration.