Protein kinase D controls voluntary-running-induced skeletal muscle remodelling.
Protein kinase D controls voluntary-running-induced skeletal muscle remodelling.
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DOI：
10.1042/bj20101980
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发表时间：
2011-12-15
期刊：
影响因子：
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通讯作者：
Hausser A
中科院分区：
文献类型：
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作者：
Ellwanger K;Kienzle C;Lutz S;Jin ZG;Wiekowski MT;Pfizenmaier K;Hausser A
骨骼肌通过激活协调基因表达以维持肌肉表现的信号通路来响应运动。MEF2（肌细胞增强因子2）依赖于MHC（肌球蛋白重链）基因的转录激活促进了从快肌纤维向慢肌纤维的转化，MEF2的活性通过与IIa类hdac（组蛋白去乙酰化酶）的相互作用受到严格调节。已知PKD（蛋白激酶D）可直接磷酸化骨骼肌IIa类hdac，介导其核输出，从而抑制MEF2。在本研究中，我们报道了在骨骼肌中诱导条件表达显性阴性PKD1kd（激酶死亡PKD1）蛋白的转基因小鼠的产生，以评估PKD在肌肉功能中的作用。在对照小鼠中，通过mhc异型的间接免疫荧光测量，长期自愿跑步实验导致从IIb + IId/x型到IIa型植物肌纤维的转换。在表达PKD1kd的小鼠中，这种纤维类型开关明显受损。与对照组小鼠相比，这些小鼠表现出肌肉纤维成分的改变和跑步性能的下降。因此，我们的研究结果表明，PKD活性对于体内运动诱导的mef2依赖性骨骼肌重塑至关重要。
Skeletal muscle responds to exercise by activation of signalling pathways that co-ordinate gene expression to sustain muscle performance. MEF2 (myocyte enhancer factor 2)-dependent transcriptional activation of MHC (myosin heavy chain) genes promotes the transformation from fast-twitch into slow-twitch fibres, with MEF2 activity being tightly regulated by interaction with class IIa HDACs (histone deacetylases). PKD (protein kinase D) is known to directly phosphorylate skeletal muscle class IIa HDACs, mediating their nuclear export and thus derepression of MEF2. In the present study, we report the generation of transgenic mice with inducible conditional expression of a dominant-negative PKD1kd (kinase-dead PKD1) protein in skeletal muscle to assess the role of PKD in muscle function. In control mice, long-term voluntary running experiments resulted in a switch from type IIb + IId/x to type IIa plantaris muscle fibres as measured by indirect immunofluorescence of MHCs isoforms. In mice expressing PKD1kd, this fibre type switch was significantly impaired. These mice exhibited altered muscle fibre composition and decreased running performance compared with control mice. Our findings thus indicate that PKD activity is essential for exercise-induced MEF2-dependent skeletal muscle remodelling in vivo.