Brigham and Women's Hospital, Boston, Massachusetts.
University of Naples "Federico II," Napoli, Italy.
Endocrinology. 2019 May 1;160(5):1205-1222. doi: 10.1210/en.2019-00088.
The type 2 iodothyronine-deiodinase (D2) enzyme converts T4 to T3, and mice deficient in this enzyme [D2 knockout (D2KO) mice] have decreased T3 derived from T4 in skeletal muscle despite normal circulating T3 levels. Because slow skeletal muscle is particularly susceptible to changes in T3 levels, we expected D2 inactivation to result in more pronounced slow-muscle characteristics in the soleus muscle, mirroring hypothyroidism. However, ex vivo studies of D2KO soleus revealed higher rates of twitch contraction and relaxation and reduced resistance to fatigue. Immunostaining of D2KO soleus showed that these properties were associated with changes in muscle fiber type composition, including a marked increase in the number of fast, glycolytic type IIB fibers. D2KO soleus muscle fibers had a larger cross-sectional area, and this correlated with increased myonuclear accretion in myotubes formed from D2KO skeletal muscle precursor cells differentiated in vitro. Consistent with our functional findings, D2KO soleus gene expression was markedly different from that in hypothyroid wild-type (WT) mice. Comparison of gene expression between euthyroid WT and D2KO mice indicated that PGC-1α, a T3-dependent regulator of slow muscle fiber type, was decreased by ∼50% in D2KO soleus. Disruption of Dio2 in the C2C12 myoblast cell line led to a significant decrease in PGC-1α expression and a faster muscle phenotype upon differentiation. These results indicate that D2 loss leads to significant changes in soleus contractile function and fiber type composition that are inconsistent with local hypothyroidism and suggest that reduced levels of PCG-1α may contribute to the observed phenotypical changes.
2 型碘甲状腺原氨酸脱碘酶（D2）可将 T4 转化为 T3，而缺乏这种酶的小鼠（D2 敲除（D2KO）小鼠）尽管循环 T3 水平正常，但骨骼肌中来自 T4 的 T3 减少。由于慢肌对 T3 水平的变化特别敏感，我们预计 D2 失活会导致比目鱼肌中更明显的慢肌特征，类似于甲状腺功能减退症。然而，D2KO 比目鱼肌的离体研究显示，其抽搐收缩和松弛的速度更快，抗疲劳能力降低。D2KO 比目鱼肌的免疫染色显示，这些特性与肌肉纤维类型组成的变化有关，包括快速、糖酵解型 IIB 纤维数量的显著增加。D2KO 比目鱼肌纤维的横截面积更大，这与体外分化的 D2KO 骨骼肌前体细胞形成的肌管中肌核积累增加有关。与我们的功能发现一致，D2KO 比目鱼肌的基因表达与甲状腺功能减退症野生型（WT）小鼠的表达明显不同。在甲状腺功能正常的 WT 和 D2KO 小鼠之间比较基因表达表明，PGC-1α（一种 T3 依赖性慢肌纤维类型调节剂）在 D2KO 比目鱼肌中的表达降低了约 50%。在 C2C12 成肌细胞系中破坏 Dio2 导致 PGC-1α 表达显著降低，分化后肌肉表型更快。这些结果表明，D2 缺失导致比目鱼肌收缩功能和纤维类型组成的显著变化，与局部甲状腺功能减退症不一致，并表明 PGC-1α 水平降低可能导致观察到的表型变化。
