Systemic ablation of vitamin D receptor leads to skeletal muscle glycogen storage disorder in mice.
Systemic ablation of vitamin D receptor leads to skeletal muscle glycogen storage disorder in mice.
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DOI：
10.1002/jcsm.12841
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Arimbasseri GA
中科院分区：
文献类型：
--
作者：
Das A;Gopinath SD;Arimbasseri GA
维生素D缺乏会导致包括骨骼肌在内的多个器官系统的病变。严重缺乏维生素D的患者表现出肌肉无力，容易频繁福尔斯。缺乏功能性维生素D受体（VDR）的小鼠在断奶后立即发生严重的骨骼肌萎缩。但是，当维生素D信号受损时，肌病的根本原因尚不清楚。由于维生素D缺乏也会导致代谢变化，因此我们假设缺乏VDR的小鼠骨骼肌萎缩可能具有代谢起源。我们分析了野生型（WT）小鼠以及维生素D受体缺失（vdr−/−）小鼠的骨骼肌蛋白质稳态、能量代谢、全身葡萄糖稳态和肌糖原水平。还使用蛋白质印迹法分析了信号传导途径以及糖原合成和利用机制的失调。进行qRT-PCR测定以了解mRNA水平的变化。vdr−/−的骨骼肌表现出更高的肌肉特异性E3泛素连接酶的表达水平，并显示出增加的蛋白质泛素化，这表明蛋白质降解的上调。Foxo 1转录因子在vdr−/−中被激活，而Foxo 3因子不受影响。在vdr−/−小鼠中，空腹蛋白质合成以及mTORC 1途径严重下调。vdr−/−组骨骼肌ATP水平较低（0.58 ± 0.18 μmol/mL vs. 1.6 ± 0.0.14 μmol/mL，P = 0.006），导致AMPK活性增加。肌肉能量剥夺不是由线粒体活性降低引起的，因为我们发现vdr−/−肌肉中的呼吸复合物II活性高于WT（0.29 ± 0.007 mU/μL vs. 0.16 ± 0.005 mU/μL）。vdr−/−小鼠的空腹血糖水平较低（95 ± 14.5 mg/dL vs. 148.6 ± 6.1 mg/dL，P = 0.0017），同时表现出高乳酸血症（7.42 ± 0.31 nmol/μL vs. 4.95 ± 0.44 nmol/μL，P = 0.0032），表明这些小鼠存在全身性能量缺乏。这些小鼠中的胰岛素水平响应于腹膜内葡萄糖注射而显著降低（0.69 ± 0.08 pg/mL对1.11 ± 0.09 pg/mL，P = 0.024）。这些小鼠的骨骼肌表现出以糖原积累增加为特征的糖原储存障碍。vdr−/−肌肉中的糖原储存障碍是由糖原合成酶活性增加和糖原磷酸化酶活性降低驱动的。增加的糖原表达支持这些肌肉中更高水平的糖原合成。结果表明，缺乏维生素D信号导致骨骼肌糖原储存缺陷，从而导致肌肉能量剥夺。vdr−/−骨骼肌无法利用糖原导致葡萄糖稳态的系统性缺陷，这反过来又导致骨骼肌蛋白质稳态缺陷和萎缩。
Vitamin D deficiency leads to pathologies of multiple organ systems including skeletal muscle. Patients with severe vitamin D deficiency exhibit muscle weakness and are susceptible to frequent falls. Mice lacking a functional vitamin D receptor (VDR) develop severe skeletal muscle atrophy immediately after weaning. But the root cause of myopathies when vitamin D signalling is impaired is unknown. Because vitamin D deficiency leads to metabolic changes as well, we hypothesized that the skeletal muscle atrophy in mice lacking VDR may have a metabolic origin. We analysed wild‐type (WT) mice as well as vitamin D receptor null (vdr−/−) mice for skeletal muscle proteostasis, energy metabolism, systemic glucose homeostasis, and muscle glycogen levels. Dysregulation of signalling pathways as well as the glycogen synthesis and utilization machinery were also analysed using western blots. qRT–PCR assays were performed to understand changes in mRNA levels. Skeletal muscles of vdr−/− exhibited higher expression levels of muscle‐specific E3 ubiquitin ligases and showed increased protein ubiquitination, suggesting up‐regulation of protein degradation. Foxo1 transcription factor was activated in vdr−/− while Foxo3 factor was unaffected. Fasting protein synthesis as well as mTORC1 pathways were severely down‐regulated in vdr−/− mice. Skeletal muscle ATP levels were low in vdr−/− (0.58 ± 0.18 μmol/mL vs. 1.6 ± 0.0.14 μmol/mL, P = 0.006), leading to increased AMPK activity. Muscle energy deprivation was not caused by decreased mitochondrial activity as we found the respiratory complex II activity in vdr−/− muscles to be higher compared with WT (0.29 ± 0.007 mU/μL vs. 0.16 ± 0.005 mU/μL). vdr−/− mice had lower fasting blood glucose levels (95 ± 14.5 mg/dL vs. 148.6 ± 6.1 mg/dL, P = 0.0017) while they exhibited hyperlactataemia (7.42 ± 0.31 nmol/μL vs. 4.95 ± 0.44 nmol/μL, P = 0.0032), suggesting systemic energy deficiency in these mice. Insulin levels in these mice were significantly lower in response to intraperitoneal glucose injection (0.69 ± 0.08 pg/mL vs. 1.11 ± 0.09 pg/mL, P = 0.024). Skeletal muscles of these mice exhibit glycogen storage disorder characterized by increased glycogen accumulation. The glycogen storage disorder in vdr−/− muscles is driven by increased glycogen synthase activity and decreased glycogen phosphorylase activity. Increased glycogenin expression supports higher levels of glycogen synthesis in these muscles. The results presented show that lack of vitamin D signalling leads to a glycogen storage defect in the skeletal muscles, which leads to muscle energy deprivation. The inability of vdr−/− skeletal muscles to use glycogen leads to systemic defects in glucose homeostasis, which in turn leads to proteostasis defects in skeletal muscles and atrophy.
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影响因子：
1.9
作者：
Iijima H;Iwano R;Tanaka Y;Muroya K;Fukuda T;Sugie H;Kurosawa K;Adachi M
通讯作者：
Adachi M
影响因子：
4.8
作者：
Lecker, SH;Jagoe, RT;Goldberg, AL
通讯作者：
Goldberg, AL
影响因子：
3.8
作者：
Fyfe, John C.;Kurzhals, Rebeccah L.;Henthorn, Paula S.
通讯作者：
Henthorn, Paula S.
DOI：
10.1073/pnas.97.1.38
发表时间：
2000-01-04
影响因子：
11.1
作者：
Chibalin, AV;Yu, M;Zierath, JR
通讯作者：
Zierath, JR
影响因子：
7.7
作者：
Hunter RW;Treebak JT;Wojtaszewski JF;Sakamoto K
通讯作者：
Sakamoto K