BACKGROUND Ctns-/- mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Ctns-/- mice are 25(OH)D3 and 1,25(OH)2 D3 insufficient. We investigated whether vitamin D repletion could ameliorate adipose tissue browning and muscle wasting in Ctns-/- mice. METHODS Twelve-month-old Ctns-/- mice and wild-type controls were treated with 25(OH)D3 and 1,25(OH)2 D3 (75 μg/kg/day and 60 ng/kg/day, respectively) or an ethylene glycol vehicle for 6 weeks. Serum chemistry and parameters of energy homeostasis were measured. We quantitated total fat mass and studied expression of molecules regulating adipose tissue browning, energy metabolism, and inflammation. We measured lean mass content, skeletal muscle fibre size, in vivo muscle function (grip strength and rotarod activity), and expression of molecules regulating muscle metabolism. We also analysed the transcriptome of skeletal muscle in Ctns-/- mice using RNAseq. RESULTS Supplementation of 25(OH)D3 and 1,25(OH)2 D3 normalized serum concentration of 25(OH)D3 and 1,25(OH)2 D3 in Ctns-/- mice, respectively. Repletion of vitamin D partially or fully normalized food intake, weight gain, gain of fat, and lean mass, improved energy homeostasis, and attenuated perturbations of uncoupling proteins and adenosine triphosphate content in adipose tissue and muscle in Ctns-/- mice. Vitamin D repletion attenuated elevated expression of beige adipose cell biomarkers (UCP-1, CD137, Tmem26, and Tbx1) as well as aberrant expression of molecules implicated in adipose tissue browning (Cox2, Pgf2α, and NF-κB pathway) in inguinal white adipose tissue in Ctns-/- mice. Vitamin D repletion normalized skeletal muscle fibre size and improved in vivo muscle function in Ctns-/- mice. This was accompanied by correcting the increased muscle catabolic signalling (increased protein contents of IL-1β, IL-6, and TNF-α as well as an increased gene expression of Murf-2, atrogin-1, and myostatin) and promoting the decreased muscle regeneration and myogenesis process (decreased gene expression of Igf1, Pax7, and MyoD) in skeletal muscles of Ctns-/- mice. Muscle RNAseq analysis revealed aberrant gene expression profiles associated with reduced muscle and neuron regeneration, increased energy metabolism, and fibrosis in Ctns-/- mice. Importantly, repletion of 25(OH)D3 and 1,25(OH)2 D3 normalized the top 20 differentially expressed genes in Ctns-/- mice. CONCLUSIONS We report the novel findings that correction of 25(OH)D3 and 1,25(OH)2 D3 insufficiency reverses cachexia and may improve quality of life by restoring muscle function in an animal model of infantile nephropathic cystinosis. Mechanistically, vitamin D repletion attenuates adipose tissue browning and muscle wasting in Ctns-/- mice via multiple cellular and molecular mechanisms.

中文翻译：

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补充维生素D可改善婴儿肾病性胱氨酸病相关恶病质的脂肪组织褐变和肌肉消耗。

背景技术Ctns-/-小鼠是小儿肾病性胱氨酸病的小鼠模型，表现出代谢亢进，脂肪组织褐变和严重的肌肉消瘦。Ctns-/-小鼠的25（OH）D3和1,25（OH）2 D3不足。我们调查了维生素D的补充是否可以改善Ctns-/-小鼠的脂肪组织褐变和肌肉消耗。方法用25（OH）D3和1,25（OH）2 D3（分别为75μg/ kg /天和60 ng / kg /天）处理12个月大的Ctns-/-小鼠和野生型对照。或使用乙二醇载体6周。测量血清化学和能量稳态参数。我们量化了总脂肪量，并研究了调节脂肪组织褐变，能量代谢和炎症的分子的表达。我们测量了瘦肉含量，骨骼肌纤维大小，体内肌肉功能（抓地力和旋转杆活动），和调节肌肉新陈代谢的分子的表达。我们还使用RNAseq分析了Ctns-/-小鼠骨骼肌的转录组。结果分别在Ctns-/-小鼠中补充25（OH）D3和1,25（OH）2 D3归一化血清浓度25（OH）D3和1,25（OH）2 D3。补充维生素D可部分或完全使食物摄入正常化，体重增加，脂肪增加和瘦肉，能量稳态提高，Ctns-/-小鼠脂肪组织和肌肉中解偶联蛋白和三磷酸腺苷含量的摄动减弱。维生素D的补充减弱腹股沟白脂肪中米色脂肪细胞生物标志物（UCP-1，CD137，Tmem26和Tbx1）的高表达以及与脂肪组织褐变有关的分子的异常表达（Cox2，Pgf2α和NF-κB途径）。 Ctns-/-小鼠体内的组织。维生素D补充可使Ctns-/-小鼠的骨骼肌纤维大小正常化，并改善体内肌肉功能。这伴随着纠正增加的肌肉分解代谢信号（IL-1β，IL-6和TNF-α的蛋白质含量增加以及Murf-2，atrogin-1和myostatin的基因表达增加）并促进其降低。 Ctns-/-小鼠骨骼肌的肌肉再生和肌生成过程（Igf1，Pax7和MyoD的基因表达降低）。肌肉RNAseq分析揭示了与Ctns-/-小鼠肌肉和神经元再生减少，能量代谢增加和纤维化相关的异常基因表达谱。重要的是，25（OH）D3和1,25（OH）2 D3的补充使Ctns-/-小鼠中排名前20位的差异表达基因正常化。结论我们报告了25（OH）D3和1的更正的新发现。25（OH）2 D3功能不足可逆转恶病质，并可以通过在婴幼儿肾病性胱氨酸病的动物模型中恢复肌肉功能来改善生活质量。从机制上讲，维生素D的补充通过多种细胞和分子机制减轻了Ctns-/-小鼠的脂肪组织褐变和肌肉消耗。