The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo.
The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo.
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DOI：
10.1113/jp280652
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发表时间：
2021-03
期刊：
影响因子：
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通讯作者：
Atherton PJ
中科院分区：
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作者：
Bass JJ;Kazi AA;Deane CS;Nakhuda A;Ashcroft SP;Brook MS;Wilkinson DJ;Phillips BE;Philp A;Tarum J;Kadi F;Andersen D;Garcia AM;Smith K;Gallagher IJ;Szewczyk NJ;Cleasby ME;Atherton PJ
维生素D受体（VDR）表达减少导致骨骼肌萎缩。萎缩通过分解代谢过程发生，即诱导自噬，而合成代谢保持不变。VDR基因敲低导致线粒体功能和相关基因集表达受损。体外VDR敲低可诱导分化受损的肌原性失调。这些结果突出了VDR在骨骼肌质量调节中的自主作用。据估计，维生素D缺乏症影响着世界上约40%的人口，并与肌肉维持功能受损有关。维生素D通过维生素D受体（VDR）发挥作用，其表达最近在骨骼肌中得到证实，其下调与肌肉质量减少和功能下降有关。为了确定肌肉萎缩的潜在机制，我们研究了VDR敲低（KD）对体内成熟骨骼肌的影响，以及体外C2C12细胞的成肌调节。雄性Wistar大鼠通过活体电转移（IVE）降低后肢胫骨前肌（TA）的VDR，持续10天。我们进行了全面的代谢和生理分析，以确定VDR的丧失对肌纤维组成、蛋白质合成、合成代谢和分解代谢信号、线粒体表型和基因表达的影响。最后，体外慢病毒转染在C2C12细胞中诱导持续的VDR‐KD来分析肌生成调节。肌肉VDR‐KD通过减少总蛋白含量引起萎缩，导致肌纤维面积减少。观察到自噬过程的激活，对肌肉蛋白质合成或合成代谢信号没有影响。此外，RNA测序分析确定了多个线粒体呼吸相关蛋白和基因组的系统性下调。最后，体外VDR‐敲低会损害肌发生（细胞周期、分化和肌管形成）。综上所述，这些数据表明VDR在肌肉形成和肌肉质量的调节中具有基本的调节作用，从而维持肌肉线粒体功能并限制自噬。维生素D受体（VDR）表达减少导致骨骼肌萎缩。萎缩通过分解代谢过程发生，即诱导自噬，而合成代谢保持不变。VDR基因敲低导致线粒体功能和相关基因集表达受损。体外VDR敲低可诱导分化受损的肌原性失调。这些结果突出了VDR在骨骼肌质量调节中的自主作用。
Reduced vitamin D receptor (VDR) expression prompts skeletal muscle atrophy. Atrophy occurs through catabolic processes, namely the induction of autophagy, while anabolism remains unchanged. In response to VDR‐knockdown mitochondrial function and related gene‐set expression is impaired. In vitro VDR knockdown induces myogenic dysregulation occurring through impaired differentiation. These results highlight the autonomous role the VDR has within skeletal muscle mass regulation. Vitamin D deficiency is estimated to affect ∼40% of the world's population and has been associated with impaired muscle maintenance. Vitamin D exerts its actions through the vitamin D receptor (VDR), the expression of which was recently confirmed in skeletal muscle, and its down‐regulation is linked to reduced muscle mass and functional decline. To identify potential mechanisms underlying muscle atrophy, we studied the impact of VDR knockdown (KD) on mature skeletal muscle in vivo, and myogenic regulation in vitro in C2C12 cells. Male Wistar rats underwent in vivo electrotransfer (IVE) to knock down the VDR in hind‐limb tibialis anterior (TA) muscle for 10 days. Comprehensive metabolic and physiological analysis was undertaken to define the influence loss of the VDR on muscle fibre composition, protein synthesis, anabolic and catabolic signalling, mitochondrial phenotype and gene expression. Finally, in vitro lentiviral transfection was used to induce sustained VDR‐KD in C2C12 cells to analyse myogenic regulation. Muscle VDR‐KD elicited atrophy through a reduction in total protein content, resulting in lower myofibre area. Activation of autophagic processes was observed, with no effect upon muscle protein synthesis or anabolic signalling. Furthermore, RNA‐sequencing analysis identified systematic down‐regulation of multiple mitochondrial respiration‐related protein and genesets. Finally, in vitro VDR‐knockdown impaired myogenesis (cell cycling, differentiation and myotube formation). Together, these data indicate a fundamental regulatory role of the VDR in the regulation of myogenesis and muscle mass, whereby it acts to maintain muscle mitochondrial function and limit autophagy. Reduced vitamin D receptor (VDR) expression prompts skeletal muscle atrophy. Atrophy occurs through catabolic processes, namely the induction of autophagy, while anabolism remains unchanged. In response to VDR‐knockdown mitochondrial function and related gene‐set expression is impaired. In vitro VDR knockdown induces myogenic dysregulation occurring through impaired differentiation. These results highlight the autonomous role the VDR has within skeletal muscle mass regulation.