Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
Division of Nephrology & Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
J Appl Physiol (1985). 2021 Jul 1;131(1):95-106. doi: 10.1152/japplphysiol.00194.2021. Epub 2021 May 20.
Diseases or conditions where diaphragm muscle (DIAm) function is impaired, including chronic obstructive pulmonary disease, cachexia, asthma, and aging, are associated with an increased risk of pulmonary symptoms, longer duration of hospitalizations, and increasing requirements for mechanical ventilation. Vitamin D deficiency is associated with proximal muscle weakness that resolves following therapy with vitamin D. Skeletal muscle expresses the vitamin D receptor (VDR), which responds to the active form of vitamin D, 1,25-dihydroxyvitamin D by altering gene expression in target cells. In knockout mice without skeletal muscle VDRs, there is marked atrophy of muscle fibers and a change in skeletal muscle biochemistry. We used a tamoxifen-inducible skeletal muscle Cre recombinase in mice (+) to assess the role of muscle-specific VDR signaling on DIAm-specific force, fatigability, and fiber type-dependent morphology. + mice treated with vehicle and mice treated with tamoxifen served as controls. Seven days following the final treatment, mice were euthanized, the DIAm was removed, and isometric force and fatigue were assessed in DIAm strips using direct muscle stimulation. The proportion and cross-sectional areas of DIAm fiber types were evaluated by immunolabeling with myosin heavy chain antibodies differentiating type I, IIa and IIx, and/or IIb fibers. We show that in mice with skeletal muscle-specific VDR deletion, maximum specific force and residual force following fatigue are impaired, along with a selective atrophy of type IIx and/or IIb fibers. These results show that the VDR has a significant biological effect on DIAm function independent of systemic effects on mineral metabolism. Vitamin D deficiency and vitamin D receptor (VDR) polymorphisms are associated with adverse pulmonary and diaphragm muscle (DIAm)-associated respiratory outcomes. We used a skeletal muscle-specific tamoxifen-inducible VDR knockout to investigate DIAm dysfunction following reduced VDR signaling. Marked DIAm weakness and atrophy of type IIx and/or IIb fibers are present in muscle-specific tamoxifen-induced VDR knockout mice compared with controls. These results show that the VDR has a significant biological effect on DIAm function independent of systemic effects on mineral metabolism.
膈肌（DIAm）功能受损的疾病或病症，包括慢性阻塞性肺疾病、恶病质、哮喘和衰老，与肺部症状风险增加、住院时间延长和对机械通气的需求增加有关。维生素 D 缺乏与近端肌肉无力有关，这种无力在接受维生素 D 治疗后会得到缓解。骨骼肌表达维生素 D 受体（VDR），它对维生素 D 的活性形式 1,25-二羟维生素 D 作出反应，通过改变靶细胞中的基因表达来发挥作用。在没有骨骼肌 VDR 的敲除小鼠中，肌肉纤维明显萎缩，骨骼肌生物化学发生变化。我们使用了一种在 小鼠中诱导性表达的骨骼肌 Cre 重组酶（+）来评估肌肉特异性 VDR 信号对 DIAm 特异性力、疲劳性和纤维类型依赖性形态的作用。用载体处理的 + 小鼠和用他莫昔芬处理的 小鼠作为对照。最后一次处理后 7 天，处死小鼠，取出 DIAm，用直接肌肉刺激在 DIAm 条上评估等长力和疲劳。通过用肌球蛋白重链抗体进行免疫标记来评估 DIAm 纤维类型的比例和横截面积，这些抗体可区分 I 型、IIa 型和 IIx 型以及/或 IIb 型纤维。我们发现，在骨骼肌特异性 VDR 缺失的小鼠中，最大比力和疲劳后的剩余力受损，同时 IIx 型和/或 IIb 型纤维选择性萎缩。这些结果表明，VDR 对 DIAm 功能具有重要的生物学影响，独立于对矿物质代谢的全身影响。维生素 D 缺乏和维生素 D 受体（VDR）多态性与不良的肺部和膈肌（DIAm）相关的呼吸结局有关。我们使用骨骼肌特异性他莫昔芬诱导的 VDR 敲除来研究 VDR 信号降低后 DIAm 功能障碍。与对照组相比，在骨骼肌特异性他莫昔芬诱导的 VDR 敲除小鼠中，DIAm 明显无力和 IIx 型和/或 IIb 型纤维萎缩。这些结果表明，VDR 对 DIAm 功能具有重要的生物学影响，独立于对矿物质代谢的全身影响。
