Objective

The Vitamin D receptor (VDR) has been positively associated with skeletal muscle mass, function and regeneration. Mechanistic studies have focused on the loss of the receptor, with in vivo whole-body knockout models demonstrating reduced myofibre size and function and impaired muscle development. To understand the mechanistic role upregulation of the VDR elicits in muscle mass/health, we studied the impact of VDR over-expression (OE) in vivo before exploring the importance of VDR expression upon muscle hypertrophy in humans.

Methods

Wistar rats underwent in vivo electrotransfer (IVE) to overexpress the VDR in the Tibialis anterior (TA) muscle for 10 days, before comprehensive physiological and metabolic profiling to characterise the influence of VDR-OE on muscle protein synthesis (MPS), anabolic signalling and satellite cell activity. Stable isotope tracer (D₂O) techniques were used to assess sub-fraction protein synthesis, alongside RNA-Seq analysis. Finally, human participants underwent 20 wks of resistance exercise training, with body composition and transcriptomic analysis.

Results

Muscle VDR-OE yielded total protein and RNA accretion, manifesting in increased myofibre area, i.e., hypertrophy. The observed increases in MPS were associated with enhanced anabolic signalling, reflecting translational efficiency (e.g., mammalian target of rapamycin (mTOR-signalling), with no effects upon protein breakdown markers being observed. Additionally, RNA-Seq illustrated marked extracellular matrix (ECM) remodelling, while satellite cell content, markers of proliferation and associated cell-cycled related gene-sets were upregulated. Finally, induction of VDR mRNA correlated with muscle hypertrophy in humans following long-term resistance exercise type training.

Conclusion

VDR-OE stimulates muscle hypertrophy ostensibly via heightened protein synthesis, translational efficiency, ribosomal expansion and upregulation of ECM remodelling-related gene-sets. Furthermore, VDR expression is a robust marker of the hypertrophic response to resistance exercise in humans. The VDR is a viable target of muscle maintenance through testable Vitamin D molecules, as active molecules and analogues.

中文翻译：

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维生素 D 受体 (VDR) 的过度表达会导致骨骼肌肥大。

客观的

维生素 D 受体 (VDR) 与骨骼肌质量、功能和再生呈正相关。机制研究集中在受体的丢失上，体内全身敲除模型表明肌纤维大小和功能减少以及肌肉发育受损。为了解 VDR 在肌肉质量/健康中引发的机制作用上调，我们在探索 VDR 表达对人类肌肉肥大的重要性之前研究了体内VDR 过度表达 (OE) 的影响。

方法

Wistar 大鼠接受体内电转移 (IVE) 以在胫骨前肌 (TA) 肌肉中过度表达 VDR 10 天，然后进行全面的生理和代谢分析以表征 VDR-OE 对肌肉蛋白质合成 (MPS)、合成代谢信号和卫星细胞活动。稳定同位素示踪剂 (D ₂ O) 技术与 RNA-Seq 分析一起用于评估亚组分蛋白质合成。最后，人类参与者接受了 20 周的阻力运动训练，并进行了身体成分和转录组学分析。

结果

肌肉 VDR-OE 产生总蛋白质和 RNA 增加，表现为肌纤维面积增加，即肥大。观察到的 MPS 增加与增强的合成代谢信号有关，反映了翻译效率（例如，雷帕霉素的哺乳动物靶标（mTOR 信号），对观察到的蛋白质分解标记物没有影响。此外，RNA-Seq 显示了标记的细胞外基质 (ECM)重塑，同时卫星细胞含量、增殖标志物和相关细胞周期相关基因组被上调。最后，VDR mRNA 的诱导与长期抵抗运动类型训练后人类的肌肉肥大相关。

结论

VDR-OE 表面上通过提高蛋白质合成、翻译效率、核糖体扩张和 ECM 重塑相关基因组的上调来刺激肌肉肥大。此外，VDR 表达是人类抵抗运动肥大反应的有力标志。VDR 是通过可测试的维生素 D 分子（作为活性分子和类似物）维持肌肉的可行目标。