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

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.

Cross-Talk Between Extracellular Matrix and Skeletal Muscle: Implications for Myopathies

“…The developmental process of multinucleated myofibers with contractile capability from MSCs is termed myogenesis, and involves cell cycle arrest, cell fusion, increases in nuclear sizes, and the peripheral localization of nuclei (Charge and Rudnicki, 2004). Myogenesis is a decidedly regulated mechanism that is determined by the co-expressions of Pax3, Pax7, and myogenicregulatory factors such as Myf5, Mrf4, MyoD, and myogenin in MSCs (Zammit and Beauchamp, 2001;Relaix et al, 2005;Baig et al, 2019;Kim et al, 2019;Lee et al, 2019).…”

Adaptive Thermogenesis Driving Catch-Up Fat Is Associated With Increased Muscle Type 3 and Decreased Hepatic Type 1 Iodothyronine Deiodinase Activities: A Functional and Proteomic Study

“…Noteworthy, in SS, in both muscles, our results indicate a significant down-representation of transthyretin (TTR), the transporter protein for T 4 in the blood ( 39 – 42 ). The liver is considered the main contributing organ for TTR release, but a recent study has shown TTR synthesis in muscle cells, where the protein has been suggested to exocytose through exosomes and bring back T 4 inside the cells for conversion to T3 ( 43 ). The reduced representation levels of TTR in tibialis anterior and soleus of SS animals appear coherent with a locally reduced T3 bioavailability.…”

Multiple Roles in Neuroprotection for the Exercise Derived Myokine Irisin

“…FNDC5 was initially introduced as a regulator of myoblast differentiation (Ferrer-Martinez et al, 2002). Fndc5 knockdown in muscle stem cells decreased the expression of myogenic genes and myotube formation without any effects on muscle growth (Lee et al, 2019). Recently, it was shown that inhibiting Fndc5 expression induces autophagy and causes skeletal muscle atrophy (Pan et al, 2019).…”