Eldecalcitol prevents muscle loss and osteoporosis in disuse muscle atrophy via NF-κB signaling in mice

IF 5.3 2区 医学 Q2 CELL BIOLOGY Skeletal Muscle Pub Date : 2023-12-19 DOI:10.1186/s13395-023-00332-0
Haichao Zhang, Yanping Du, Wenjing Tang, Minmin Chen, Weijia Yu, Zheng Ke, Shuangshuang Dong, Qun Cheng
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Abstract

We investigated the effect of eldecalcitol on disuse muscle atrophy. C57BL/6J male mice aged 6 weeks were randomly assigned to control, tail suspension (TS), and TS-eldecalcitol–treated groups and were injected intraperitoneally twice a week with either vehicle (control and TS) or eldecalcitol at 3.5 or 5 ng for 3 weeks. Grip strength and muscle weights of the gastrocnemius (GAS), tibialis anterior (TA), and soleus (SOL) were determined. Oxidative stress was evaluated by malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase. Bone microarchitecture was analyzed using microcomputed tomography. The effect of eldecalcitol on C2C12 myoblasts was analyzed by measuring myofibrillar protein MHC and the atrophy markers Atrogin-1 and MuRF-1 using immunofluorescence. The influence of eldecalcitol on NF-κB signaling pathway and vitamin D receptor (VDR) was assessed through immunofluorescence, (co)-immunoprecipitation, and VDR knockdown studies. Eldecalcitol increased grip strength (P < 0.01) and restored muscle loss in GAS, TA, and SOL (P < 0.05 to P < 0.001) induced by TS. An improvement was noted in bone mineral density and bone architecture in the eldecalcitol group. The impaired oxidative defense system was restored by eldecalcitol (P < 0.05 to P < 0.01 vs. TS). Eldecalcitol (10 nM) significantly inhibited the expression of MuRF-1 (P < 0.001) and Atrogin-1 (P < 0.01), increased the diameter of myotubes (P < 0.05), inhibited the expression of P65 and P52 components of NF-κB and P65 nuclear location, thereby inhibiting NF-κB signaling. Eldecalcitol promoted VDR binding to P65 and P52. VDR signaling is required for eldecalcitol-mediated anti-atrophy effects. In conclusion, eldecalcitol exerted its beneficial effects on disuse-induced muscle atrophy via NF-κB inhibition.
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艾地骨化醇通过 NF-κB 信号转导防止小鼠肌肉损失和废用性肌肉萎缩中的骨质疏松症
我们研究了艾地卡糖醇对废用性肌肉萎缩的影响。将年龄为6周的C57BL/6J雄性小鼠随机分配到对照组、尾悬液(TS)组和TS-艾地卡醇处理组,每周腹腔注射两次载体(对照组和TS组)或3.5或5纳克的艾地卡醇,连续注射3周。测定腓肠肌(GAS)、胫骨前肌(TA)和比目鱼肌(SOL)的握力和肌肉重量。通过丙二醛、超氧化物歧化酶、谷胱甘肽过氧化物酶和过氧化氢酶评估氧化应激。使用微型计算机断层扫描分析了骨的微观结构。通过使用免疫荧光法测定肌纤维蛋白 MHC 以及萎缩标志物 Atrogin-1 和 MuRF-1,分析了长骨钙醇对 C2C12 肌细胞的影响。通过免疫荧光、(共)免疫沉淀和 VDR 敲除研究评估了艾地卡糖醇对 NF-κB 信号通路和维生素 D 受体(VDR)的影响。艾地卡糖醇增加了握力(P<0.01),并恢复了TS诱导的GAS、TA和SOL的肌肉损失(P<0.05至P<0.001)。在长骨钙醇组中,骨矿物质密度和骨结构均有所改善。与 TS 相比,氧化防御系统受损的情况得到了恢复(P < 0.05 至 P < 0.01)。艾地卡糖醇(10 nM)能显著抑制MuRF-1(P<0.001)和Atrogin-1(P<0.01)的表达,增加肌管直径(P<0.05),抑制NF-κB的P65和P52成分的表达以及P65的核位置,从而抑制NF-κB信号转导。艾地卡糖醇促进了 VDR 与 P65 和 P52 的结合。艾地卡糖醇介导的抗萎缩作用需要VDR信号。总之,艾地卡糖醇通过抑制NF-κB对废用诱导的肌肉萎缩产生有益影响。
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来源期刊
Skeletal Muscle
Skeletal Muscle CELL BIOLOGY-
CiteScore
9.10
自引率
0.00%
发文量
25
审稿时长
12 weeks
期刊介绍: The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.
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