Thyroid hormones (THs) influence the differentiation, growth and energy metabolism of almost all cells and tissues. The biological action of thyroid hormones is mediated through the interaction of the active hormone, T3, with nuclear thyroid hormone receptors and their binding to chromatin. The thyroid gland produces T3 (the most biologically active form of thyroid hormone) and T4 (a weaker receptor ligand than T3) in a ratio of approximately 1:14. Thus, a crucial step for the activation of TH signaling is the T4-to-T3 conversion, catalyzed by the type 2 deiodinase enzyme (D2) in the target cells. Conversely, termination of TH action is mostly achieved through the action of the type 3 deiodinase (D3), which catalyzes the conversion of both T3 and T4 into inactive metabolites.
Skeletal muscle is a well-known target tissue of TH, which is a major determinant of muscle functions, and thyroid dysfunctions are leading causes of many myopathies by mechanisms. Our data have demonstrated that the local activation of TH action by the type 2 deiodinase (D2) enzyme is critical in triggering the accelerated muscle catabolism that causes muscle loss in multiple disease states. Inactivation of TH by genetic D2-depletion or by muscle-specific overexpression of the TH inactivating enzyme, type 3 deiodinase (D3), significantly prevents skeletal muscle atrophy induced by denervation or by cancer cachexia. Importantly, attenuation of TH signaling in vivo not only reduced muscle mass loss, but also increased the survival rates in cancer cachexia studies. Furthermore, expression of the E3 ligases Atrogin-1 and MuRF1, two mediators of muscle atrophy, was reduced in D2KO and D3-overexpressing mice, consistent with a critical role for TH in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.
The overall objective of STARS is to address the functional role of TH in muscle weakness and atrophic syndromes and to determine the molecular mechanisms by which TH induces massive muscle wasting. Moreover, a key goal of STARS is to assess the therapeutic ability of TH modulators in the muscle atrophy diseases.
