SAT-560 Role of COUP-TFII and Thyroid Hormone Receptor α in Skeletal Muscle Loss

Abstract

Myopathic changes including muscular dystrophy and weakness are commonly described in hypothyroid and hyperthyroid patients. The genomic actions of triiodothyronine (T3) are mediated by thyroid hormone nuclear receptors (TRs), which act as ligand-inducible transcription factors in almost all tissues, including skeletal muscle. Impaired skeletal muscle regeneration and sarcopenia with aging have been reported in a mouse model of Resistance to Thyroid Hormone (RTH) carrying a frame-shift mutation in the TRα gene (TRα1PV). One salient finding was a significantly smaller pool of PAX7-positive satellite cells (SCs) in the skeletal muscle of TRα1PV mice. Moreover, SC function during skeletal muscle injury was impaired four days after cardiotoxin (CTX)-induced skeletal muscle injury with a decreased activation of SC and a reduced proliferation of Myf5 expressing cells. TRα plays an important role in the maintenance of muscle mass and skeletal muscle regeneration after injury with aging, and loss of skeletal muscle mass with aging in TRα1PV mice was reported to be associated with loss of SC pool {1,2}. Interestingly, overexpression of the nuclear orphan receptor Chicken Ovalbumin Upstream Promoter-factor II (COUP-TFII or NR2F2) in murine satellite cells have been shown to induce a similar skeletal muscle phenotype, including skeletal muscle loss with aging, and inhibit myogenesis through modulation of Myf5 and MyoD expression {3}. We detected a higher expression of COUP-TFII in C2C12, a murine myoblast cell line, during proliferation and a decline during differentiation into myotube. Moreover, we analyzed the skeletal muscle of mice at different ages and we found a higher expression of COUP-TFII in the first 2 months of life followed by a decline with age. Thus, suggesting the important role of COUP-TFII in modulating post-natal myogenesis and onset of sarcopenia with aging. In proliferating C2C12 myoblasts and SCs from wild-type and TRα1PV mice, we demonstrated via co-immunoprecipitation that COUP-TFII and TRα interact. In addition, the skeletal muscle of TRα1PV mice showed significantly higher expression of COUP-TFII compared to their WT siblings, and in TRα1PV mice COUP-TFII expression remained higher with skeletal muscle aging. These results suggest a COUP-TFII role in skeletal muscle loss with aging and impaired skeletal muscle regeneration in TRαPV mice that may be mediated by COUP-TFII-TRα interaction. These new insights can provide a therapeutic target to prevent or treat myopathies, such as sarcopenia and Duchenne-like muscular dystrophy. 1. Milanesi A et al, Endocrinology 2015. 2. Milanesi A et al, Thyroid, 2017. 3. Lee HJ et al, Scientific Reports 2017. Sources of Research Support: NIH grants and VA MERIT GRANT.