Persistent COUP-TFII expression underlies the myopathy and impaired muscle regeneration observed in resistance to thyroid hormone-alpha.
Persistent COUP-TFII expression underlies the myopathy and impaired muscle regeneration observed in resistance to thyroid hormone-alpha.
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DOI：
10.1038/s41598-021-84080-5
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发表时间：
2021-02-25
影响因子：
4.6
通讯作者：
Milanesi A
中科院分区：
文献类型：
--
作者：
Aguiari P;Liu YY;Petrosyan A;Cheng SY;Brent GA;Perin L;Milanesi A
甲状腺激素信号传导通过激活甲状腺核受体α（THRA）在肌肉发育和功能、肌肉质量的维持以及损伤后的再生中起着至关重要的作用。携带THRA基因移码突变的甲状腺激素抗性小鼠模型（THRA-PV）与骨骼肌老化加速损失和损伤后再生受损有关。核孤儿受体鸡卵清蛋白上游启动子因子II（COUP-TFII，或Nr 2f 2）的表达持续在成肌分化过程中的THRA-PV成肌细胞和骨骼肌的老年THRA-PV小鼠，它是已知的负调控肌发生。在这里，我们报告说，在小鼠成肌细胞COUP-TFII与THRA相互作用，并调节THRA结合甲状腺反应元件（TREs）。COUP-TFII表达的沉默恢复了THRA-PV成肌细胞的体外成肌潜能，并使mRNA表达谱更接近WT成肌细胞。此外，COUP-TFII沉默逆转THRA-PV成肌细胞的转录组学特征，并导致参与肌肉功能和细胞外基质重塑/沉积的途径的重新激活。这些发现表明THRA-PV小鼠中持续的COUP-TFII表达是导致异常肌肉表型的原因。总之，COUP-TFII和THRA在出生后的肌肉发生过程中合作，COUP-TFII是关键的加速骨骼肌损失与老化和受损的肌肉再生后，THRA-PV小鼠损伤。
Thyroid hormone signaling plays an essential role in muscle development and function, in the maintenance of muscle mass, and in regeneration after injury, via activation of thyroid nuclear receptor alpha (THRA). A mouse model of resistance to thyroid hormone carrying a frame-shift mutation in the THRA gene (THRA-PV) is associated with accelerated skeletal muscle loss with aging and impaired regeneration after injury. The expression of nuclear orphan receptor chicken ovalbumin upstream promoter-factor II (COUP-TFII, or Nr2f2) persists during myogenic differentiation in THRA-PV myoblasts and skeletal muscle of aged THRA-PV mice and it is known to negatively regulate myogenesis. Here, we report that in murine myoblasts COUP-TFII interacts with THRA and modulates THRA binding to thyroid response elements (TREs). Silencing of COUP-TFII expression restores in vitro myogenic potential of THRA-PV myoblasts and shifts the mRNA expression profile closer to WT myoblasts. Moreover, COUP-TFII silencing reverses the transcriptomic profile of THRA-PV myoblasts and results in reactivation of pathways involved in muscle function and extracellular matrix remodeling/deposition. These findings indicate that the persistent COUP-TFII expression in THRA-PV mice is responsible for the abnormal muscle phenotype. In conclusion, COUP-TFII and THRA cooperate during post-natal myogenesis, and COUP-TFII is critical for the accelerated skeletal muscle loss with aging and impaired muscle regeneration after injury in THRA-PV mice.
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影响因子：
11.2
作者：
Navab, R;Gonzalez-Santos, JM;Hu, J
通讯作者：
Hu, J
影响因子：
4.8
作者：
Calonge, MJ;Seoane, J;Massagué, J
通讯作者：
Massagué, J
DOI：
10.1073/pnas.1222334110
发表时间：
2013-05-07
影响因子：
11.1
作者：
Fozzatti, Laura;Kim, Dong Wook;Cheng, Sheue-Yann
通讯作者：
Cheng, Sheue-Yann
影响因子：
--
作者：
BERRODIN, TJ;MARKS, MS;LAZAR, MA
通讯作者：
LAZAR, MA
影响因子：
15.9
作者：
Brent, Gregory A.
通讯作者：
Brent, Gregory A.