Werneck-de-Castro Joao P, Fonseca Tatiana L, Ignacio Daniele L, Fernandes Gustavo W, Andrade-Feraud Cristina M, Lartey Lattoya J, Ribeiro Marcelo B, Ribeiro Miriam O, Gereben Balazs, Bianco Antonio C
Division of Endocrinology and Metabolism (J.P.W.d.C., T.L.F., G.W.F., A.C.B.), Rush University Medical Center, Chicago Illinois 60612; Division of Endocrinology, Diabetes, and Metabolism (J.P.W.d.C., D.L.I., C.M.A.F., L.J.L., M.B.R.), University of Miami Miller School of Medicine, Miami, Florida 33101-6960; Biophysics Institute and School of Physical Education and Sports (J.P.W.d.C., D.L.I., M.B.R.), Federal University of Rio de Janeiro, 21941-901 Rio de Janeiro, Brazil; Developmental Disorders Program (M.O.R.), Center for Biological and Health Sciences, Mackenzie Presbyterian University, 01302 Sao Paulo, Brazil; Department of Endocrine Neurobiology (B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083 Hungary; and Translational Medicine (G.W.F.), Federal University of Sao Paulo, 01302-907 Sao Paulo, Brazil.
Endocrinology. 2015 Oct;156(10):3842-52. doi: 10.1210/en.2015-1246. Epub 2015 Jul 27.
The type 2 deiodinase (D2) activates the prohormone T4 to T3. D2 is expressed in skeletal muscle (SKM), and its global inactivation (GLOB-D2KO mice) reportedly leads to skeletal muscle hypothyroidism and impaired differentiation. Here floxed Dio2 mice were crossed with mice expressing Cre-recombinase under the myosin light chain 1f (cre-MLC) to disrupt D2 expression in the late developmental stages of skeletal myocytes (SKM-D2KO). This led to a loss of approximately 50% in D2 activity in neonatal and adult SKM-D2KO skeletal muscle and about 75% in isolated SKM-D2KO myocytes. To test the impact of Dio2 disruption, we measured soleus T3 content and found it to be normal. We also looked at the expression of T3-responsive genes in skeletal muscle, ie, myosin heavy chain I, α-actin, myosin light chain, tropomyosin, and serca 1 and 2, which was preserved in neonatal SKM-D2KO hindlimb muscles, at a time that coincides with a peak of D2 activity in control animals. In adult soleus the baseline level of D2 activity was about 6-fold lower, and in the SKM-D2KO soleus, the expression of only one of five T3-responsive genes was reduced. Despite this, adult SKM-D2KO animals performed indistinguishably from controls on a treadmill test, running for approximately 16 minutes and reached a speed of about 23 m/min; muscle strength was about 0.3 mN/m·g body weight in SKM-D2KO and control ankle muscles. In conclusion, there are multiple sources of D2 in the mouse SKM, and its role is limited in postnatal skeletal muscle fibers.
2型脱碘酶（D2）可将激素原T4激活为T3。D2在骨骼肌（SKM）中表达，据报道其全身失活（GLOB-D2KO小鼠）会导致骨骼肌甲状腺功能减退和分化受损。在此，将携带floxed Dio2的小鼠与在肌球蛋白轻链1f（cre-MLC）控制下表达Cre重组酶的小鼠杂交，以在骨骼肌细胞发育后期（SKM-D2KO）破坏D2的表达。这导致新生和成年SKM-D2KO骨骼肌中D2活性丧失约50%，在分离的SKM-D2KO肌细胞中丧失约75%。为了测试Dio2破坏的影响，我们测量了比目鱼肌的T3含量，发现其正常。我们还研究了骨骼肌中T3反应性基因的表达，即肌球蛋白重链I、α-肌动蛋白、肌球蛋白轻链、原肌球蛋白以及肌浆网钙ATP酶1和2，在新生SKM-D2KO后肢肌肉中这些基因的表达得以保留，这一时期与对照动物中D2活性的峰值一致。在成年比目鱼肌中，D2活性的基线水平约低6倍，在SKM-D2KO比目鱼肌中，五个T3反应性基因中只有一个的表达降低。尽管如此，成年SKM-D2KO动物在跑步机测试中的表现与对照无明显差异，跑步约16分钟，速度约为23米/分钟；SKM-D2KO和对照踝关节肌肉的肌肉力量约为0.3毫牛顿/米·克体重。总之，小鼠SKM中存在多种D2来源，其在出生后骨骼肌纤维中的作用有限。
