甲状腺激素受体 α 对于维持骨骼肌损伤和衰老时卫星细胞龛至关重要。
Thyroid Hormone Receptor Alpha is Essential to Maintain the Satellite Cell Niche During Skeletal Muscle Injury and Sarcopenia of Aging.
机构信息
1 Division of Endocrinology, Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA , Los Angeles, California.
2 Department of Neurosurgery, Cedars-Sinai Medical Center , Los Angeles, California.
出版信息
Thyroid. 2017 Oct;27(10):1316-1322. doi: 10.1089/thy.2017.0021.
BACKGROUND
Myopathic changes are commonly described in hypothyroid and hyperthyroid patients, including muscular atrophy and weakness. Satellite cells (SCs) play a major role in skeletal muscle maintenance and regeneration after injury. A mouse model of resistance to thyroid hormone-TRα1PV demonstrated impaired skeletal muscle regeneration after injury with significant reduction of SCs, suggesting that exhaustion of the SC pool contributes to the impaired regeneration. To test this hypothesis, SC activation and proliferation were analyzed in vivo in response to skeletal muscle injury and during aging.
METHODS
SCs of TRα1PV male mice were analyzed four days after cardiotoxin-induced muscle injury, and they were compared to wild-type (WT) male animals. TRα-knockdown C2C12 myoblasts were injected into injured skeletal muscle, and four days after transplantation, the in vivo behavior was compared to control C2C12 myoblasts. Skeletal muscle regeneration was compared in younger and older TRα1PV and WT animals.
RESULTS
The total number of SCs in skeletal muscle of TRα1PV mice was significantly lower than control, both before and shortly after muscle injury, with significant impairment of SC activation, consistent with SC pool exhaustion. TRα-knockdown myoblasts showed impaired in vivo proliferation and migration. TRα1PV mice had skeletal muscle loss and significant impairment in skeletal muscle regeneration with aging. This translated to a significant reduction of the SC pool with aging compared to WT mice.
CONCLUSION
TRα plays an important role in the maintenance of the SC pool. Impaired skeletal muscle regeneration in TRα1PV mice is associated with insufficient SC activation and proliferation, as well as the progressive loss of the SC pool with aging. Regulation of the SC pool and SC proliferation provides a therapeutic target to enhance skeletal muscle regeneration and possibly slow age-associated sarcopenia.
背景
甲状腺功能减退症和甲状腺功能亢进症患者常出现肌病变化，包括肌肉萎缩和无力。卫星细胞（SCs）在损伤后维持和再生骨骼肌中起着重要作用。抵抗甲状腺激素-TRα1PV 的小鼠模型显示，损伤后骨骼肌再生受损，SCs 显著减少，表明 SC 池的枯竭导致再生受损。为了验证这一假说，分析了 TRα1PV 雄性小鼠体内对骨骼肌损伤的反应和衰老过程中的 SC 激活和增殖。
方法
在心肌毒素诱导的肌肉损伤后 4 天分析 TRα1PV 雄性小鼠的 SC，并与野生型（WT）雄性动物进行比较。将 TRα 敲低的 C2C12 成肌细胞注射到受损的骨骼肌中，移植后 4 天，将体内行为与对照 C2C12 成肌细胞进行比较。比较年轻和年老的 TRα1PV 和 WT 动物的骨骼肌再生情况。
结果
TRα1PV 小鼠骨骼肌中的 SC 总数明显低于对照，在肌肉损伤前和损伤后不久均明显减少，SC 激活受损，与 SC 池枯竭一致。TRα 敲低的成肌细胞显示体内增殖和迁移受损。TRα1PV 小鼠随着年龄的增长出现骨骼肌丢失和骨骼肌再生显著受损。与 WT 小鼠相比，随着年龄的增长，SC 池显著减少。
结论
TRα 在维持 SC 池方面起着重要作用。TRα1PV 小鼠骨骼肌再生受损与 SC 激活和增殖不足以及随着年龄增长 SC 池逐渐丧失有关。调节 SC 池和 SC 增殖为增强骨骼肌再生和可能减缓与年龄相关的肌肉减少症提供了治疗靶点。
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