Targeting interleukin-1 for reversing fat browning and muscle wasting in infantile nephropathic cystinosis.
Targeting interleukin-1 for reversing fat browning and muscle wasting in infantile nephropathic cystinosis.
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DOI：
10.1002/jcsm.12744
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Mak RH
中科院分区：
文献类型：
--
作者：
Cheung WW;Hao S;Zheng R;Wang Z;Gonzalez A;Zhou P;Hoffman HM;Mak RH
Ctns −/−小鼠是一种婴儿肾病性胱氨酸病的小鼠模型，表现出高代谢，脂肪组织布朗宁和严重的肌肉萎缩。炎性细胞因子如白细胞介素（IL）-1触发炎症级联反应，可能是恶病质的重要原因。我们采用遗传学和药理学方法来研究IL-1阻断对Ctns −/−小鼠的影响。我们产生了Ctns −/− Il 1 β −/−小鼠，并使用IL-1受体拮抗剂阿那白滞素（2.5 mg/kg/天，IP）或生理盐水作为溶剂处理Ctns −/−和野生型对照小鼠6周。在这些小鼠品系中的每一个中，我们表征了恶病质表型，其包括厌食症、体重、脂肪量和瘦体重减轻、代谢率升高和体内肌肉功能（转杆活动和握力）降低。我们通过测量脂肪组织和骨骼肌中解偶联蛋白（UCPs）和三磷酸腺苷的蛋白质含量来定量能量稳态。我们测量骨骼肌纤维面积和肌内脂肪浸润。我们还研究了调节脂肪组织布朗宁和肌肉质量代谢的分子的表达。最后，我们评估了阿那白滞素对Ctns −/−小鼠肌肉转录组的影响。与野生型对照小鼠相比，Ctns −/−小鼠的骨骼肌IL-1β表达显著升高。相对于Ctns −/−小鼠，Ctns −/− Il 1 β −/−小鼠的恶病质完全正常化。我们发现阿那白滞素减弱了Ctns −/−小鼠的恶病质表型。阿那白滞素使Ctns −/−小鼠脂肪组织和肌肉中的UCP和三磷酸腺苷含量正常化。阿那白滞素减弱Ctns −/−小鼠腹股沟白色脂肪组织中米色脂肪细胞生物标志物（UCP-1、CD 137、Tmem 26和Tbx 1）和脂肪细胞组织布朗宁相关分子（Cox 2/Pgf 2 α、Tlr 2、Myd 88和Traf 6）的异常表达。此外，阿那白滞素使Ctns −/−小鼠的腓肠肌重量和纤维大小正常化，并减弱肌肉脂肪浸润。这伴随着Ctns −/−小鼠腓肠肌中肌肉萎缩信号通路增加（ERK 1/2、JNK、p38 MAPK和核因子-κB p65的蛋白含量增加以及Atrogin-1和Myostatin的mRNA表达增加）和肌生成过程减少（MyoD和Myogenin的mRNA表达减少）的纠正。之前，我们通过RNaseq鉴定了Ctns-/-小鼠中前20个差异表达的骨骼肌基因。这20个基因的异常表达与肌肉萎缩、能量消耗增加和脂解有关。我们发现阿那白滞素减弱了Ctns −/−小鼠中前20个差异表达的肌肉基因中的12个。阿那白滞素可能为婴儿肾病性胱氨酸病患者提供一种新的靶向治疗方法。
Ctns −/− mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Inflammatory cytokines such as interleukin (IL)‐1 trigger inflammatory cascades and may be an important cause for cachexia. We employed genetic and pharmacological approaches to investigate the effects of IL‐1 blockade in Ctns −/− mice. We generated Ctns −/− Il1β −/− mice, and we treated Ctns −/− and wild‐type control mice with IL‐1 receptor antagonist, anakinra (2.5 mg/kg/day, IP) or saline as vehicle for 6 weeks. In each of these mouse lines, we characterized the cachexia phenotype consisting of anorexia, loss of weight, fat mass and lean mass, elevation of metabolic rate, and reduced in vivo muscle function (rotarod activity and grip strength). We quantitated energy homeostasis by measuring the protein content of uncoupling proteins (UCPs) and adenosine triphosphate in adipose tissue and skeletal muscle. We measured skeletal muscle fiber area and intramuscular fatty infiltration. We also studied expression of molecules regulating adipose tissue browning and muscle mass metabolism. Finally, we evaluated the impact of anakinra on the muscle transcriptome in Ctns −/− mice. Skeletal muscle expression of IL‐1β was significantly elevated in Ctns −/− mice relative to wild‐type control mice. Cachexia was completely normalized in Ctns −/− Il1β −/− mice relative to Ctns −/− mice. We showed that anakinra attenuated the cachexia phenotype in Ctns −/− mice. Anakinra normalized UCPs and adenosine triphosphate content of adipose tissue and muscle in Ctns −/− mice. Anakinra attenuated aberrant expression of beige adipose cell biomarkers (UCP‐1, CD137, Tmem26, and Tbx1) and molecules implicated in adipocyte tissue browning (Cox2/Pgf2α, Tlr2, Myd88, and Traf6) in inguinal white adipose tissue in Ctns −/− mice. Moreover, anakinra normalized gastrocnemius weight and fiber size and attenuated muscle fat infiltration in Ctns −/− mice. This was accompanied by correction of the increased muscle wasting signalling pathways (increased protein content of ERK1/2, JNK, p38 MAPK, and nuclear factor‐κB p65 and mRNA expression of Atrogin‐1 and Myostatin) and the decreased myogenesis process (decreased mRNA expression of MyoD and Myogenin) in the gastrocnemius muscle of Ctns −/− mice. Previously, we identified the top 20 differentially expressed skeletal muscle genes in Ctns −/− mice by RNAseq. Aberrant expression of these 20 genes have been implicated in muscle wasting, increased energy expenditure, and lipolysis. We showed that anakinra attenuated 12 of those top 20 differentially expressed muscle genes in Ctns −/− mice. Anakinra may provide a targeted novel therapy for patients with infantile nephropathic cystinosis.
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DOI：
10.1084/jem.20111020
发表时间：
2011-11-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Braun TP;Zhu X;Szumowski M;Scott GD;Grossberg AJ;Levasseur PR;Graham K;Khan S;Damaraju S;Colmers WF;Baracos VE;Marks DL
通讯作者：
Marks DL
影响因子：
2.7
作者：
Kafadar, Kimberly A.;Yi, Lin;Ahmad, Yusra;So, Leslie;Rossi, Fabio;Pavlath, Grace K.
通讯作者：
Pavlath, Grace K.
影响因子：
3.8
作者：
Ballak DB;Stienstra R;Tack CJ;Dinarello CA;van Diepen JA
通讯作者：
van Diepen JA
影响因子：
8.7
作者：
Dinarello CA
通讯作者：
Dinarello CA
影响因子：
3.5
作者：
Huang N;Kny M;Riediger F;Busch K;Schmidt S;Luft FC;Slevogt H;Fielitz J
通讯作者：
Fielitz J