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Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle 肝脏和肌肉脂肪变性氨基酸传感器Ubr1的鉴定
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-13 DOI: 10.1002/jcsm.13233
Wanni Zhao, Yansong Zhang, Siyuan Lin, Yajuan Li, Alan Jian Zhu, Hanping Shi, Min Liu

Background

Malnutrition is implicated in human metabolic disorders, including hepatic steatosis and myosteatosis. The corresponding nutrient signals and sensors as well as signalling pathways have not yet been well studied. This study aimed to unravel the nutrient-sensing mechanisms in the pathogenesis of steatosis.

Methods

Plin2, a lipid droplet (LD) protein-inhibiting lipolysis, is associated with steatosis in liver and muscle. Taking advantage of the Gal4-UAS system, we used the Drosophila melanogaster wing imaginal disc as an in vivo model to study the regulation of Plin2 proteostasis and LD homeostasis. Drosophila Schneider 2 (S2) cells were used for western blotting, immunoprecipitation assays, amino acid-binding assays and ubiquitination assays to further investigate the regulatory mechanisms of Plin2 in response to nutrient signals. Mouse AML12 hepatocytes, human JHH-7 and SNU-475 hepatoma cells were used for immunofluorescence, western blotting and immunoprecipitation to demonstrate that the mode of Plin2 regulation is evolutionarily conserved. In addition, we purified proteins from HEK293 cells and reconstituted in vitro cell-free systems in amino acid-binding assays, pulldown assays and ubiquitination assays to directly demonstrate the molecular mechanism by which Ubr1 senses amino acids to regulate Plin2 proteostasis.

Results

As a lipolysis inhibitor, Plin2 was significantly elevated in liver (P < 0.05) and muscle (P < 0.05) in patients with steatosis. Consistently, we found that the ubiquitin moiety can be conjugated to any Lys residue in Plin2, ensuring robust clearance of Plin2 by protein degradation. We further demonstrated that the E3 ubiquitin ligase Ubr1 targets Plin2 for degradation in an amino acid-dependent manner. Ubr1 uses two canonical substrate-binding pockets, independent of each other, to bind basic and bulky hydrophobic amino acids, respectively. Mechanistically, amino acid binding allosterically activates Ubr1 by alleviating Ubr1's auto-inhibition. In the absence of amino acids, or when the amino acid-binding capacity of Ubr1 is diminished, Ubr1-mediated Plin2 degradation is inactivated, leading to steatosis.

Conclusions

We identified Ubr1 as an amino acid sensor regulating Plin2 proteostasis, bridging the knowledge gap between steatosis and nutrient sensing. Our work may provide new strategies for the prevention and treatment of steatosis.

营养不良与人类代谢紊乱有关，包括肝脂肪变性和肌骨化病。相应的营养信号和传感器以及信号通路尚未得到很好的研究。本研究旨在揭示脂肪变性发病机制中的营养感测机制。方法脂滴蛋白Plin2是一种抑制脂肪分解的蛋白，与肝脏和肌肉脂肪变性有关。利用Gal4-UAS系统，我们以黑腹果蝇翅膀影像盘为体内模型，研究Plin2蛋白稳态和LD稳态的调控。利用果蝇Schneider 2 (S2)细胞进行western blotting、免疫沉淀、氨基酸结合和泛素化实验，进一步研究Plin2对营养信号的调控机制。利用小鼠AML12肝细胞、人JHH-7和SNU-475肝癌细胞进行免疫荧光、western blotting和免疫沉淀，证实Plin2的调控模式具有进化保守性。此外，我们从HEK293细胞中纯化蛋白质，并通过氨基酸结合实验、拉下实验和泛素化实验重建体外无细胞系统，直接证明了Ubr1感知氨基酸调节Plin2蛋白稳态的分子机制。结果Plin2作为一种脂解抑制剂，在肝脏中显著升高(P <0.05)和肌肉(P <脂肪变性患者0.05)。一致地，我们发现泛素片段可以与Plin2中的任何赖氨酸残基结合，确保蛋白质降解对Plin2的强大清除。我们进一步证明E3泛素连接酶Ubr1以氨基酸依赖的方式靶向Plin2降解。Ubr1使用两个相互独立的典型底物结合口袋，分别结合碱性和大体积疏水氨基酸。机制上，氨基酸结合变构激活Ubr1，减轻Ubr1的自抑制作用。在缺乏氨基酸的情况下，或者当Ubr1的氨基酸结合能力降低时，Ubr1介导的Plin2降解就会失活，导致脂肪变性。我们发现Ubr1是调节Plin2蛋白停滞的氨基酸传感器，弥合了脂肪变性和营养感知之间的知识差距。我们的工作可能为脂肪变性的预防和治疗提供新的策略。
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引用次数: 1
A Phase 1 study for safety and pharmacokinetics of BIO101 (20-hydroxyecdysone) in healthy young and older adults BIO101(20-羟基蜕皮激素)在健康年轻人和老年人中的安全性和药代动力学的1期研究
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-13 DOI: 10.1002/jcsm.13195
Waly Dioh, Cendrine Tourette, Susanna Del Signore, Louiza Daudigny, Philippe Dupont, Christine Balducci, Pierre J. Dilda, René Lafont, Stanislas Veillet

Background

Sarcopenia is an age-related skeletal muscle disorder characterized by loss of muscle mass and strength leading to mobility disability. 20-Hydroxyecdysone (20E) is a polyhydroxylated plant steroid that demonstrates pharmacological effects in many disease animal models including ageing/sarcopenia. BIO101 is a 20E purified investigational drug (≥97%) that previously demonstrated good toxicology profiles in rat and dog. BIO101 is evaluated in healthy young and older adults in a Phase 1 study.

Methods

This study is a Single Ascending Dose (SAD) followed by a 14-day Multiple Ascending Dose (MAD). In SAD, BIO101 was administered orally to 16 young adults at doses from 100 to 1400 mg and to 8 older adults (age ≥65 years) at 1400 mg. In MAD, doses of 350 mg once daily (qd), 350 mg twice daily (bid) and 450 mg bid were administered to 10 older adults. The primary objective was to evaluate safety and pharmacokinetics (PK), including dosing of circulating metabolites. Pharmacodynamic effects were investigated with regard to myostatin, procollagen-III-amino-terminal propeptide (PIIINP), myoglobin, creatine-kinase Muscle Brain (CKMB), renin and aldosterone plasma/serum levels.

Results

BIO101 showed a good safety profile with only mild to moderate adverse events and a satisfactory pharmacokinetic profile. In SAD, at 100 mg to 1400 mg, mean Cmax and areas under the curve increased less than dose-proportionally. Mean half-life was short (2.4–4.9 h), and mean renal clearance was comparable in all doses (4.05–5.05 L/h). Mean plasma exposure was slightly lower in older adults (22% lower for Cmax and 13%–15% lower for AUCs) compared with young subjects. In MAD, 350 and 450 mg bid led to a slight accumulation over 14 days (mean ratio of accumulation [Rac] of 1.31 in both cohorts). Reduction of biomarkers (myoglobin, CK-MB) mean serum levels (vs. baseline) was observed at 450 mg bid. Two major metabolites of 20E (14-deoxy-20-hydroxyecdysone and 14-deoxypoststerone) were identified and quantified.

Conclusions

BIO101 shows a good safety and pharmacokinetic profile that led to the selection of doses for the subsequent interventional clinical trials of Phase 2 in age-related sarcopenia (SARA-INT) and Phase 3 in Covid-19 (COVA).

骨骼肌减少症是一种与年龄相关的骨骼肌疾病，其特征是肌肉质量和力量的减少导致行动障碍。20-羟基蜕皮激素(20E)是一种多羟基化的植物类固醇，在包括衰老/肌肉减少症在内的许多疾病动物模型中显示出药理作用。BIO101是一种20E纯化的研究药物(≥97%)，先前在大鼠和狗身上显示出良好的毒理学特征。BIO101在健康的年轻人和老年人中进行了1期研究。方法采用单次递增给药(SAD)和14天多次递增给药(MAD)的方法。在SAD研究中，16名年轻成人口服100 - 1400 mg BIO101, 8名老年人口服1400 mg BIO101(年龄≥65岁)。在MAD中，10名老年人分别服用350mg每日一次(qd)、350mg每日两次(bid)和450mg bid。主要目的是评估安全性和药代动力学(PK)，包括循环代谢物的剂量。研究了肌生长抑制素、前胶原蛋白iii -氨基末端前肽(PIIINP)、肌红蛋白、肌酸激酶肌脑(CKMB)、肾素和醛固酮血浆/血清水平的药效学效应。结果BIO101具有良好的安全性，仅出现轻度至中度不良反应，药代动力学指标令人满意。在SAD中，在100 ~ 1400 mg，平均Cmax和曲线下面积的增加小于剂量比例。平均半衰期很短(2.4-4.9 h)，所有剂量的平均肾脏清除率相当(4.05-5.05 L/h)。与年轻受试者相比，老年人的平均血浆暴露量略低(Cmax低22%，auc低13%-15%)。在MAD中，350和450 mg bid在14天内导致轻度积累(两个队列的平均积累比[Rac]为1.31)。生物标志物(肌红蛋白，CK-MB)平均血清水平(与基线相比)在450mg bid时观察到降低。鉴定并定量了20E的两种主要代谢物(14-脱氧-20-羟基蜕皮酮和14-脱氧后酮)。结论BIO101显示出良好的安全性和药代动力学特征，可用于随后针对年龄相关性肌肉减少症(SARA-INT)和Covid-19 (COVA)的2期和3期干预性临床试验的剂量选择。
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引用次数: 4
Corrigendum to I.S. Sinam et al. J of Cachexia, Sarcopenia and Muscle, 13, 3122–3136. DOI: 10.1002/jcsm.13100 I.S. Sinam等人的勘误表。[J] .中国医学杂志，2014,31(2):332 - 336。DOI: 10.1002 / jcsm.13100
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-11 DOI: 10.1002/jcsm.13231
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (Grant Number: 2022R1A2B5B03001929) and Korea Health Technology R&D Project, through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HR22C1832); (I-K. L); NRF grant funded by the Ministry of Science and ICT (NRF-2021R1A5A2021614 and NRF-2020R1C1C1012729) and Korea Health Technology R&D Project, through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HR22C1832); (J.-H.J.); NRF-2021R1F1A1061393 (D. C.); NRF-2022R1A2C1007857 (T. T.). CORR IGENDUM
致谢部分不完整。正确的答谢全文如下:
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引用次数: 0
Corrigendum to Yang et al. J of Cachexia, Sarcopenia and Muscle, 13, 728–742. https://doi.org/10.1002/jcsm.12882 Yang等人的勘误表。恶病质与肌肉减少症杂志，13,728-742。https://doi.org/10.1002/jcsm.12882
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-11 DOI: 10.1002/jcsm.13232

The correspondence address for author Ping Hu were previously incomplete. The complete correspondence address for Ping Hu is shown below:

Department of Pediatric Orthopedics, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Guangzhou Laboratory, Guangzhou, China; Max Planck Center for Tissue Stem Cells and Regenerative Medicine, Bioland Laboratory, Guangzhou, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.

作者胡平的通信地址此前不完整。胡萍的完整通信地址如下:中国上海交通大学医学院附属新华医院小儿骨科;广州实验室，中国广州;马克斯·普朗克组织干细胞与再生医学研究中心，广州生物岛实验室;中国科学院干细胞与再生研究所，北京。
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引用次数: 0
A novel orthotopic mouse model replicates human lung cancer cachexia 一种新的原位小鼠模型复制了人类肺癌恶病质
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-06 DOI: 10.1002/jcsm.13222
Wouter R.P.H. van de Worp, Jan Theys, Alba Sanz González, Brent van der Heyden, Frank Verhaegen, Duncan Hauser, Florian Caiment, Hubertus J.M. Smeets, Annemie M.W.J. Schols, Ardy van Helvoort, Ramon C.J. Langen

Introduction

Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour-bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle-specific alterations associated with human lung cancer cachexia.

Methods

Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour-bearing group. Syngeneic lung epithelium-derived adenocarcinoma cells (K-rasG12D; p53R172HΔG) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis.

Results

Two-third of the tumour-bearing mice developed cachexia based on predefined criteria. Final body weight (−13.7 ± 5.7%; P < 0.01), muscle mass (−13.8 ± 8.1%; P < 0.01) and muscle strength (−25.5 ± 10.5%; P < 0.001) were reduced in cachectic mice compared with sham controls and median survival time post-surgery was 33.5 days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (Fbxo32 and Trim63) and autophagy-lysosomal pathway (Gabarapl1 and Bnip3), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E-BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin-2 (P < 0.001) and CXCL1/KC (P < 0.01) expression levels in blood plasma and increased mRNA expression of IκBα (P < 0.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal

癌症恶病质在肺癌中非常普遍，是一种以骨骼肌质量不自主丧失为特征的衰弱综合征，与临床预后差、生存率降低和对肿瘤治疗的负面影响相关。各种肺肿瘤动物模型被用来探索癌症恶病质的潜在机制。然而，这些模型并不能模拟肺癌和相关肌肉萎缩的解剖学和免疫学特征。克服这些缺点对于将实验结果转化为临床至关重要。因此，我们评估了同基因的原位肺癌小鼠模型是否复制了与人类肺癌恶病质相关的全身和肌肉特异性改变。方法选取11周龄具有免疫功能的雄性129S2/Sv小鼠，随机分为(1)假对照组和(2)荷瘤组。同基因肺上皮源性腺癌细胞(K-rasG12D;p53R172HΔG)接种于小鼠左肺叶肺内。每天测量体重和食物摄入量。在基线和术后每周，测量握力，并使用微锥束CT成像评估肿瘤生长和肌肉体积。在达到预定的替代生存终点后，对动物实施安乐死，并收集下后肢骨骼肌进行生化分析。结果三分之二的荷瘤小鼠根据预先设定的标准发生恶病质。最终体重(−13.7±5.7%;P & lt;0.01)，肌肉质量(−13.8±8.1%;P & lt;0.01)和肌力(−25.5±10.5%;P & lt;0.001)，术后中位生存时间为33.5天。与对照组相比，病毒症小鼠骨骼肌中蛋白水解标志物，泛素蛋白酶体系统(Fbxo32和Trim63)和自噬-溶酶体途径(Gabarapl1和Bnip3)均显著上调，而蛋白合成标志物(Akt、S6和4E-BP1的相对磷酸化)显著降低。恶病质小鼠表现出戊素-2 (P <0.001)和CXCL1/KC (P <0.01)表达水平升高，IκBα mRNA表达升高(P <0.05)，提示存在全身性炎症。引人注目的是，小鼠骨骼肌的RNA测序、途径富集和miRNA表达分析强烈反映了肺癌恶病质患者肌肉活检中观察到的改变。结论建立了免疫正常小鼠肺癌恶病质原位模型。由于该模型模拟了肺癌患者恶病质特异性的关键方面，因此非常适合进一步研究肺癌恶病质的潜在机制，并测试新的干预策略的效果。
{"title":"A novel orthotopic mouse model replicates human lung cancer cachexia","authors":"Wouter R.P.H. van de Worp,&nbsp;Jan Theys,&nbsp;Alba Sanz González,&nbsp;Brent van der Heyden,&nbsp;Frank Verhaegen,&nbsp;Duncan Hauser,&nbsp;Florian Caiment,&nbsp;Hubertus J.M. Smeets,&nbsp;Annemie M.W.J. Schols,&nbsp;Ardy van Helvoort,&nbsp;Ramon C.J. Langen","doi":"10.1002/jcsm.13222","DOIUrl":"https://doi.org/10.1002/jcsm.13222","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour-bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle-specific alterations associated with human lung cancer cachexia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour-bearing group. Syngeneic lung epithelium-derived adenocarcinoma cells (<i>K-ras</i><sup><i>G12D</i></sup>; <i>p53</i><sup><i>R172HΔG</i></sup>) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Two-third of the tumour-bearing mice developed cachexia based on predefined criteria. Final body weight (−13.7 ± 5.7%; <i>P</i> &lt; 0.01), muscle mass (−13.8 ± 8.1%; <i>P</i> &lt; 0.01) and muscle strength (−25.5 ± 10.5%; <i>P</i> &lt; 0.001) were reduced in cachectic mice compared with sham controls and median survival time post-surgery was 33.5 days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (<i>Fbxo32</i> and <i>Trim63</i>) and autophagy-lysosomal pathway (<i>Gabarapl1</i> and <i>Bnip3</i>), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E-BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin-2 (<i>P</i> &lt; 0.001) and CXCL1/KC (<i>P</i> &lt; 0.01) expression levels in blood plasma and increased mRNA expression of IκBα (<i>P</i> &lt; 0.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1410-1423"},"PeriodicalIF":8.9,"publicationDate":"2023-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13222","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6097676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Specific miRNAs are associated with human cancer cachexia in an organ-specific manner 特异性mirna以器官特异性的方式与人类癌症恶病质相关
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-06 DOI: 10.1002/jcsm.13224
Tanja Krauss, Simone Heisz, Julius Honecker, Olga Prokopchuk, Marc Martignoni, Klaus-Peter Janssen, Melina Claussnitzer, Hans Hauner, Claudine Seeliger

Background

Cancer cachexia (CCx) is a complex and multi-organ wasting syndrome characterized by substantial weight loss and poor prognosis. An improved understanding of the mechanisms involved in the onset and progression of cancer cachexia is essential. How microRNAs contribute to the clinical manifestation and progression of CCx remains elusive. The aim of this study was to identify specific miRNAs related to organ-specific CCx and explore their functional role in humans.

Methods

miRNA patterns in serum and in cachexia target organs (liver, muscle and adipose tissue) from weight stable (N ≤ 12) and cachectic patients (N ≤ 23) with gastrointestinal cancer were analysed. As a first step, a miRNA array (158 miRNAs) was performed in pooled serum samples. Identified miRNAs were validated in serum and corresponding tissue samples. Using in silico prediction, related genes were identified and evaluated. The findings were confirmed in vitro by siRNA knock-down experiments in human visceral preadipocytes and C2C12 myoblast cells and consecutive gene expression analyses.

Results

Validating the results of the array, a 2-fold down-regulation of miR-122-5p (P = 0.0396) and a 4.5-fold down-regulation of miR-194-5p (P < 0.0001) in serum of CCx patients in comparison with healthy controls were detected. Only miR-122-5p correlated with weight loss and CCx status (P = 0.0367). Analysing corresponding tissues six muscle and eight visceral adipose tissue (VAT) cachexia-associated miRNAs were identified. miR-27b-3p, miR-375 and miR-424-5p were the most consistently affected miRNAs in tissues of CCx patients correlating negatively with the severity of body weight loss (P = 0.0386, P = 0.0112 and P = 0.0075, respectively). We identified numerous putative target genes of the miRNAs in association with muscle atrophy and lipolysis pathways. Knock-down experiments in C2C12 myoblast cells revealed an association of miR-27b-3p and the in silico predicted atrophy-related target genes IL-15 and TRIM63. Both were up-regulated in miR-27b-3p knock-down cells (P < 0.05). Concordantly, in muscle tissue of CCx individuals, significant higher expression levels of IL-15 (P = 0.0237) and TRIM63 (P = 0.0442) were detected. miR-424-5p was identified to regulate the expression of lipase genes. Knock-down experiments in human visceral preadipocytes revealed an inverse association of miR-424-5p with its predicted target genes LIPE, PNPLA2, MGLL and <

癌症恶病质(CCx)是一种复杂的多器官消耗综合征，以体重减轻和预后差为特征。提高对癌症恶病质发生和发展的机制的理解是必要的。microRNAs如何促进CCx的临床表现和进展仍然是一个谜。本研究的目的是鉴定与器官特异性CCx相关的特异性mirna，并探索它们在人类中的功能作用。方法分析体重稳定(N≤12)和病毒质(N≤23)胃肠道肿瘤患者血清及恶病质靶器官(肝脏、肌肉和脂肪组织)的miRNA谱。作为第一步，在汇集的血清样本中进行miRNA阵列(158个miRNA)。在血清和相应的组织样本中验证鉴定的mirna。利用计算机预测，对相关基因进行了鉴定和评价。通过体外人内脏前脂肪细胞和C2C12成肌细胞siRNA敲除实验和连续基因表达分析，证实了这一发现。验证该阵列的结果，miR-122-5p下调2倍(P = 0.0396)， miR-194-5p下调4.5倍(P <与健康对照相比，CCx患者血清中有0.0001)。只有miR-122-5p与体重减轻和CCx状态相关(P = 0.0367)。分析了相应的组织，鉴定了6个肌肉和8个内脏脂肪组织(VAT)恶病质相关的mirna。miR-27b-3p、miR-375和miR-424-5p是CCx患者组织中受影响最一致的mirna，与体重减轻严重程度呈负相关(P = 0.0386、P = 0.0112和P = 0.0075)。我们确定了许多与肌肉萎缩和脂肪分解途径相关的mirna的假定靶基因。在C2C12成肌细胞中进行敲除实验，发现miR-27b-3p与计算机预测的萎缩相关靶基因IL-15和TRIM63存在关联。两者在miR-27b-3p敲除细胞中均上调(P <0.05)。同时，在CCx个体的肌肉组织中，IL-15 (P = 0.0237)和TRIM63 (P = 0.0442)的表达水平显著升高。发现miR-424-5p调节脂肪酶基因的表达。人内脏前脂肪细胞的敲除实验显示，miR-424-5p与其预测的靶基因LIPE、PNPLA2、MGLL和LPL呈负相关(P <0.01)。鉴定出的mirna，特别是miR-122-5p、miR-27b-3p、miR-375和miR-424-5p，代表了人类CCx的特征，并可能通过调节分解代谢信号参与组织损耗和骨骼肌萎缩。需要进一步的研究来探索鉴定的mirna作为早期检测癌症恶病质的筛选工具的潜力。
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引用次数: 0
Sarcopenia-defining parameters, but not sarcopenia, are associated with cognitive domains in middle-aged and older European men 在欧洲中老年男性中，肌肉减少症的定义参数与认知领域有关，而不是肌肉减少症
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-06 DOI: 10.1002/jcsm.13229
Nadjia Amini, Jolan Dupont, Laurence Lapauw, Laura Vercauteren, Leen Antonio, Terence W. O'Neill, Dirk Vanderschueren, Neil Pendleton, Giulia Rastrelli, Mario Maggi, Felipe F. Casanueva, Jolanta S?owikowska-Hilczer, Margus Punab, Ilpo T. Huhtaniemi, Frederick C.W. Wu, Sabine Verschueren, Jos Tournoy, Evelien Gielen

Background

Previous research suggests that sarcopenia is associated with lower cognitive functioning. Evidence on the longitudinal relationship between cognition and sarcopenia, according to the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2), is scarce. This study aimed to investigate both cross-sectional and longitudinal associations between sarcopenia and its defining parameters (muscle strength, muscle mass and physical performance) and cognitive performance in middle-aged and older men.

Methods

This was a secondary analysis of data from the European Male Ageing Study (EMAS), a multicentre cohort study of men aged 40–79 years, recruited from population registers in eight European centres. Cognitive functioning was assessed by using a battery of three neuropsychological tests, measuring fluid intelligence: Rey–Osterrieth Complex Figure (ROCF-Copy and ROCF-Recall), Camden Topographical Recognition Memory (CTRM) and Digit Symbol Substitution Test (DSST). Sarcopenia-defining parameters appendicular lean mass (aLM), gait speed (GS), chair stand test (CST) and handgrip strength (HGS) were measured. Sarcopenia was diagnosed according to the criteria of the EWGSOP2. All measurements were performed at baseline and after a follow-up of 4.3 years. Cross-sectional associations between cognition, sarcopenia-defining parameters and prevalent sarcopenia (EWGSOP2) were analysed. Longitudinally, the predictive value of baseline cognition on decline in sarcopenia-defining parameters, onset of new sarcopenia and vice versa was examined. Linear and logistic regression were used and adjusted for putative confounders.

Results

In the whole cohort (n = 3233), ROCF-Copy (β = 0.016; P < 0.05), ROCF-Recall (β = 0.010; P < 0.05), CTRM (β = 0.015; P < 0.05), DSST score (β = 0.032; P < 0.05) and fluid cognition (β = 0.036; P < 0.05) were significantly and independently associated with GS at baseline. In the Leuven + Manchester subcohorts (n = 456), ROCF-Copy (β = 1.008; P < 0.05), ROCF-Recall (β = 0.908; P < 0.05) and fluid cognition (β = 1.482; P < 0.05) were associated with HGS. ROCF-Copy (β = 0.394; P < 0.05), ROCF-Recall (β = 0.316; P < 0.05), DSST (β = 0.393; P < 0.05) and fluid cognition (β = 0.765; P < 0.05) were associated with aLM. The prevalence of sarcopenia in this population was 17.8%. No associations were detected between cognition and prevalent or incident sarcopenia. Longitudinal analy

先前的研究表明，肌肉减少症与认知功能低下有关。根据欧洲老年人肌肉减少症工作组(EWGSOP2)修订的标准，关于认知和肌肉减少症之间纵向关系的证据很少。本研究旨在调查中老年男性肌肉减少症及其定义参数(肌肉力量、肌肉质量和身体表现)和认知表现之间的横断面和纵向关系。方法:本研究是对欧洲男性老龄化研究(EMAS)数据的二次分析，EMAS是一项多中心队列研究，从8个欧洲中心的人口登记处招募40-79岁的男性。认知功能通过三组神经心理测试来评估，测量流体智力:Rey-Osterrieth复杂图形(ROCF-Copy和ROCF-Recall)， Camden地形识别记忆(CTRM)和数字符号替代测试(DSST)。测量肌肉减少症定义参数阑尾瘦质量(aLM)、步态速度(GS)、椅立测试(CST)和握力(HGS)。根据EWGSOP2标准诊断肌少症。所有的测量都是在基线和随访4.3年后进行的。分析认知、肌少症定义参数和普遍肌少症(EWGSOP2)之间的横断面关联。纵向上，基线认知对肌少症定义参数下降的预测价值，新肌少症的发病，反之亦然。采用线性和逻辑回归，并对假定的混杂因素进行调整。结果在整个队列中(n = 3233)， ROCF-Copy (β = 0.016;P & lt;0.05)， rocf召回率(β = 0.010;P & lt;0.05)， CTRM (β = 0.015;P & lt;0.05)， DSST评分(β = 0.032;P & lt;0.05)和流体认知(β = 0.036;P & lt;0.05)与基线时GS显著独立相关。在鲁汶+曼彻斯特亚组(n = 456)中，ROCF-Copy (β = 1.008;P & lt;0.05)， rocf召回率(β = 0.908;P & lt;0.05)和流体认知(β = 1.482;P & lt;0.05)与HGS相关。ROCF-Copy (β = 0.394;P & lt;0.05)， rocf召回率(β = 0.316;P & lt;0.05)， DSST (β = 0.393;P & lt;0.05)和流体认知(β = 0.765;P & lt;0.05)与aLM相关。该人群中肌肉减少症的患病率为17.8%。没有发现认知和普遍或偶然的肌肉减少症之间的关联。纵向分析显示，基线时较低的ROCF-Copy评分与≥70岁男性的CST增加相关(β = - 0.599;P & lt;0.05)。此外，ROCF-Recall的降低与GS的降低相关，DSST的降低与CST的增加相关(β = 0.155;P & lt;0.0001， β =−0.595;P & lt;分别为0.001)，在认知和肌肉功能变化最大的人群中。结论:骨骼肌减少症与该人群的认知表现无关，而骨骼肌减少症的几个组成部分与特定领域的认知表现有关。纵向上，认知子域的基线和变化预测了特定亚组肌肉功能的变化。
{"title":"Sarcopenia-defining parameters, but not sarcopenia, are associated with cognitive domains in middle-aged and older European men","authors":"Nadjia Amini,&nbsp;Jolan Dupont,&nbsp;Laurence Lapauw,&nbsp;Laura Vercauteren,&nbsp;Leen Antonio,&nbsp;Terence W. O'Neill,&nbsp;Dirk Vanderschueren,&nbsp;Neil Pendleton,&nbsp;Giulia Rastrelli,&nbsp;Mario Maggi,&nbsp;Felipe F. Casanueva,&nbsp;Jolanta S?owikowska-Hilczer,&nbsp;Margus Punab,&nbsp;Ilpo T. Huhtaniemi,&nbsp;Frederick C.W. Wu,&nbsp;Sabine Verschueren,&nbsp;Jos Tournoy,&nbsp;Evelien Gielen","doi":"10.1002/jcsm.13229","DOIUrl":"https://doi.org/10.1002/jcsm.13229","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Previous research suggests that sarcopenia is associated with lower cognitive functioning. Evidence on the longitudinal relationship between cognition and sarcopenia, according to the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2), is scarce. This study aimed to investigate both cross-sectional and longitudinal associations between sarcopenia and its defining parameters (muscle strength, muscle mass and physical performance) and cognitive performance in middle-aged and older men.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This was a secondary analysis of data from the European Male Ageing Study (EMAS), a multicentre cohort study of men aged 40–79 years, recruited from population registers in eight European centres. Cognitive functioning was assessed by using a battery of three neuropsychological tests, measuring fluid intelligence: Rey–Osterrieth Complex Figure (ROCF-Copy and ROCF-Recall), Camden Topographical Recognition Memory (CTRM) and Digit Symbol Substitution Test (DSST). Sarcopenia-defining parameters appendicular lean mass (aLM), gait speed (GS), chair stand test (CST) and handgrip strength (HGS) were measured. Sarcopenia was diagnosed according to the criteria of the EWGSOP2. All measurements were performed at baseline and after a follow-up of 4.3 years. Cross-sectional associations between cognition, sarcopenia-defining parameters and prevalent sarcopenia (EWGSOP2) were analysed. Longitudinally, the predictive value of baseline cognition on decline in sarcopenia-defining parameters, onset of new sarcopenia and vice versa was examined. Linear and logistic regression were used and adjusted for putative confounders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the whole cohort (<i>n</i> = 3233), ROCF-Copy (β = 0.016; <i>P</i> &lt; 0.05), ROCF-Recall (β = 0.010; <i>P</i> &lt; 0.05), CTRM (β = 0.015; <i>P</i> &lt; 0.05), DSST score (β = 0.032; <i>P</i> &lt; 0.05) and fluid cognition (β = 0.036; <i>P</i> &lt; 0.05) were significantly and independently associated with GS at baseline. In the Leuven + Manchester subcohorts (<i>n</i> = 456), ROCF-Copy (β = 1.008; <i>P</i> &lt; 0.05), ROCF-Recall (β = 0.908; <i>P</i> &lt; 0.05) and fluid cognition (β = 1.482; <i>P</i> &lt; 0.05) were associated with HGS. ROCF-Copy (β = 0.394; <i>P</i> &lt; 0.05), ROCF-Recall (β = 0.316; <i>P</i> &lt; 0.05), DSST (β = 0.393; <i>P</i> &lt; 0.05) and fluid cognition (β = 0.765; <i>P</i> &lt; 0.05) were associated with aLM. The prevalence of sarcopenia in this population was 17.8%. No associations were detected between cognition and prevalent or incident sarcopenia. Longitudinal analy","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1520-1532"},"PeriodicalIF":8.9,"publicationDate":"2023-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13229","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5719499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
GDNF family receptor alpha-like antagonist antibody alleviates chemotherapy-induced cachexia in melanoma-bearing mice GDNF家族受体α样拮抗剂抗体减轻黑色素瘤小鼠化疗诱导的恶病质
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-05 DOI: 10.1002/jcsm.13219
Beom Yong Lee, Jongwon Jeong, Inseong Jung, Hanchae Cho, Dokyung Jung, Jiwon Shin, Jun-kook Park, Eunju Park, Soojeong Noh, Sanghee Shin, Sungmin Kang, Jong-Ik Heo, Moon-Chang Baek, Kyungmoo Yea

Background

Patients with cancer undergoing chemotherapy experience cachexia with anorexia, body weight loss, and the depletion of skeletal muscles and adipose tissues. Effective treatment strategies for chemotherapy-induced cachexia are scarce. The growth differentiation factor 15 (GDF15)/GDNF family receptor alpha-like (GFRAL)/rearranged during transfection (RET) axis is a critical signalling pathway in chemotherapy-induced cachexia. In this study, we developed a fully human GFRAL antagonist antibody and investigated whether it inhibits the GDF15/GFRAL/RET axis, thereby alleviating chemotherapy-induced cachexia in tumour-bearing mice.

Methods

Anti-GFRAL antibodies were selected via biopanning, using a human combinatorial antibody phage library. The potent GFRAL antagonist antibody A11 was selected via a reporter cell assay and its inhibitory activity of GDF15-induced signalling was evaluated using western blotting. To investigate the in vivo function of A11, a tumour-bearing mouse model was established by inoculating 8-week-old male C57BL/6 mice with B16F10 cells (n = 10–16 mice per group). A11 was administered subcutaneously (10 mg/kg) 1 day before intraperitoneal treatment with cisplatin (10 mg/kg). Animals were assessed for changes in food intake, body weight, and tumour volume. Plasma and key metabolic tissues such as skeletal muscles and adipose tissues were collected for protein and mRNA expression analysis.

Results

A11 reduced serum response element-luciferase reporter activity up to 74% (P < 0.005) in a dose-dependent manner and blocked RET phosphorylation up to 87% (P = 0.0593), AKT phosphorylation up to 28% (P = 0.0593) and extracellular signal regulatory kinase phosphorylation up to 75% (P = 0.0636). A11 inhibited the action of cisplatin-induced GDF15 on the brainstem and decreased GFRAL-positive neuron population expressing c-Fos in the area postrema and nucleus of the solitary tract by 62% in vivo (P < 0.05). In a melanoma mouse model treated with cisplatin, A11 recovered anorexia by 21% (P < 0.05) and tumour-free body weight loss by 13% (P < 0.05). A11 significantly improved the cisplatin-induced loss of skeletal muscles (quadriceps: 21%, gastrocnemius: 9%, soleus: 13%, P < 0.05) and adipose tissues (epididymal white adipose tissue: 37%, inguinal white adipose tissue: 51%, P < 0.05).

Conclusions

背景:接受化疗的癌症患者会经历厌食症、体重减轻、骨骼肌和脂肪组织消耗的恶病质。化疗引起的恶病质的有效治疗策略很少。生长分化因子15 (GDF15)/GDNF家族受体α样(GFRAL)/转染期间重排(RET)轴是化疗诱导恶病质的关键信号通路。在本研究中，我们开发了一种全人GFRAL拮抗剂抗体，并研究其是否抑制GDF15/GFRAL/RET轴，从而减轻化疗诱导的肿瘤小鼠恶病质。方法利用人组合抗体噬菌体文库，通过生物筛选筛选抗gfral抗体。通过报告细胞实验选择强效GFRAL拮抗剂抗体A11，并利用western blotting评估其对gdf15诱导的信号传导的抑制活性。为了研究A11在体内的功能，我们将B16F10细胞接种于8周龄雄性C57BL/6小鼠(每组10-16只)，建立荷瘤小鼠模型。A11于顺铂(10 mg/kg)腹腔注射前1天皮下注射(10 mg/kg)。评估动物的食物摄入量、体重和肿瘤体积的变化。采集血浆及骨骼肌、脂肪组织等关键代谢组织进行蛋白和mRNA表达分析。结果A11使血清反应元素-荧光素酶报告因子活性降低74% (P <0.005)，阻断RET磷酸化高达87% (P = 0.0593)， AKT磷酸化高达28% (P = 0.0593)，细胞外信号调节激酶磷酸化高达75% (P = 0.0636)。A11抑制了顺铂诱导的GDF15对脑干的作用，体内孤束后区和核中表达c-Fos的gfral阳性神经元数量减少62% (P <0.05)。在接受顺铂治疗的黑色素瘤小鼠模型中，A11厌食症的恢复率为21% (P <0.05)，无瘤体重减轻13% (P <0.05)。A11显著改善顺铂诱导的骨骼肌损失(股四头肌:21%，腓肠肌:9%，比目鱼肌:13%，P <0.05)和脂肪组织(附睾白色脂肪组织37%，腹股沟白色脂肪组织51%，P <0.05)。结论GFRAL拮抗剂抗体可缓解化疗引起的恶病质，为化疗引起的恶性肿瘤患者提供新的治疗途径。
{"title":"GDNF family receptor alpha-like antagonist antibody alleviates chemotherapy-induced cachexia in melanoma-bearing mice","authors":"Beom Yong Lee,&nbsp;Jongwon Jeong,&nbsp;Inseong Jung,&nbsp;Hanchae Cho,&nbsp;Dokyung Jung,&nbsp;Jiwon Shin,&nbsp;Jun-kook Park,&nbsp;Eunju Park,&nbsp;Soojeong Noh,&nbsp;Sanghee Shin,&nbsp;Sungmin Kang,&nbsp;Jong-Ik Heo,&nbsp;Moon-Chang Baek,&nbsp;Kyungmoo Yea","doi":"10.1002/jcsm.13219","DOIUrl":"https://doi.org/10.1002/jcsm.13219","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Patients with cancer undergoing chemotherapy experience cachexia with anorexia, body weight loss, and the depletion of skeletal muscles and adipose tissues. Effective treatment strategies for chemotherapy-induced cachexia are scarce. The growth differentiation factor 15 (GDF15)/GDNF family receptor alpha-like (GFRAL)/rearranged during transfection (RET) axis is a critical signalling pathway in chemotherapy-induced cachexia. In this study, we developed a fully human GFRAL antagonist antibody and investigated whether it inhibits the GDF15/GFRAL/RET axis, thereby alleviating chemotherapy-induced cachexia in tumour-bearing mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Anti-GFRAL antibodies were selected via biopanning, using a human combinatorial antibody phage library. The potent GFRAL antagonist antibody A11 was selected via a reporter cell assay and its inhibitory activity of GDF15-induced signalling was evaluated using western blotting. To investigate the <i>in vivo</i> function of A11, a tumour-bearing mouse model was established by inoculating 8-week-old male C57BL/6 mice with B16F10 cells (<i>n</i> = 10–16 mice per group). A11 was administered subcutaneously (10 mg/kg) 1 day before intraperitoneal treatment with cisplatin (10 mg/kg). Animals were assessed for changes in food intake, body weight, and tumour volume. Plasma and key metabolic tissues such as skeletal muscles and adipose tissues were collected for protein and mRNA expression analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A11 reduced serum response element-luciferase reporter activity up to 74% (<i>P</i> &lt; 0.005) in a dose-dependent manner and blocked RET phosphorylation up to 87% (<i>P</i> = 0.0593), AKT phosphorylation up to 28% (<i>P</i> = 0.0593) and extracellular signal regulatory kinase phosphorylation up to 75% (<i>P</i> = 0.0636). A11 inhibited the action of cisplatin-induced GDF15 on the brainstem and decreased GFRAL-positive neuron population expressing c-Fos in the area postrema and nucleus of the solitary tract by 62% <i>in vivo</i> (<i>P</i> &lt; 0.05). In a melanoma mouse model treated with cisplatin, A11 recovered anorexia by 21% (<i>P</i> &lt; 0.05) and tumour-free body weight loss by 13% (<i>P</i> &lt; 0.05). A11 significantly improved the cisplatin-induced loss of skeletal muscles (quadriceps: 21%, gastrocnemius: 9%, soleus: 13%, <i>P</i> &lt; 0.05) and adipose tissues (epididymal white adipose tissue: 37%, inguinal white adipose tissue: 51%, <i>P</i> &lt; 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 ","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1441-1453"},"PeriodicalIF":8.9,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13219","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5705321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
High visceral fat attenuation and long-term mortality in a health check-up population 高内脏脂肪衰减与健康检查人群的长期死亡率
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-05 DOI: 10.1002/jcsm.13226
Jong Hyuk Lee, Seung Ho Choi, Keum Ji Jung, Jin Mo Goo, Soon Ho Yoon

Background

The prognostic role of increased visceral fat attenuation (VFA) remains underexplored. We investigated the long-term prognostic implications of computed tomography (CT)-derived VFA in a health check-up population.

Methods

This study included consecutive individuals who had positron-emission tomography/CT scans for health check-ups between January 2004 and December 2010. The primary outcome was overall survival (OS), and the secondary outcomes were cancer-specific survival (CSS) and non-cancer-specific survival (NCS). Commercially available body composition analysis software was used to obtain abdominal waist VFA, visceral fat volume index (VFI) and skeletal muscle index (SMI) at the L3 level. Sarcopenia was determined using sex-specific SMI references. VFA and VFI were dichotomized using the thresholds for the highest quartiles. The relationship between CT-derived body composition parameters and body mass index (BMI) was evaluated with Pearson correlation coefficients. The prognostic implications of VFA and sarcopenic obesity (SO) defined by VFA were assessed by multivariable Cox regression analysis and Kaplan–Meier plots with log-rank tests.

Results

A total of 2720 individuals (1530 men [56.3%] and 1190 women [43.7%]; median age: 53 years, inter-quartile range: 47–60 years) were included. During the median follow-up of 138 months, 128 individuals (5%) died (cancer mortality: 2%; non-cancer mortality: 3%), with 0.2% (5 of 2720) and 1.1% (30 of 2720) of 1- and 5-year mortality rates. VFA was negatively correlated with BMI (r = −0.62; P < 0.001) and VFI (r = −0.69; P < 0.001). After adjusting for clinical variables, sarcopenia and VFI, high VFA was a negative prognostic factor for OS (hazard ratio [HR]: 1.05 per Hounsfield unit; 95% confidence interval [CI]: 1.02, 1.08; P = 0.001), CSS (HR: 1.07 per Hounsfield unit; 95% CI: 1.02, 1.12; P = 0.006) and NCS (HR: 1.03 per Hounsfield unit; 95% CI: 1.01, 1.06; P = 0.009). Individuals with high VFA had higher high-sensitivity C-reactive protein levels than those with low VFA (0.11 vs. 0.03 mg/dL; P < 0.001). Individuals with SO defined by VFA had worse OS (9% vs. 4%; P < 0.001), CSS (3% vs. 2%; P = 0.02) and NCS (6% vs. 3%; P < 0.001) than those without SO, even in the same BMI (underweight-to-normal BMI, OS: 8% vs. 4%; overweight-to-obese BMI, OS: 38% vs. 4%; P < 0.001 in both) or VFI category (high VFI, OS: 43% vs. 6%; low VFI, OS: 8% vs. 3%; P < 0.001 in both).

背景:内脏脂肪衰减(VFA)增加在预后中的作用仍未得到充分探讨。我们研究了计算机断层扫描(CT)衍生的VFA对健康体检人群的长期预后影响。方法本研究纳入2004年1月至2010年12月连续接受正电子发射断层扫描/CT健康检查的个体。主要终点是总生存期(OS)，次要终点是癌症特异性生存期(CSS)和非癌症特异性生存期(NCS)。采用市售体成分分析软件获取腹腰VFA、内脏脂肪体积指数(VFI)和骨骼肌指数(SMI)在L3水平。骨骼肌减少症的测定采用性别特异性SMI参考文献。使用最高四分位数的阈值对VFA和VFI进行二分类。采用Pearson相关系数评价ct得出的身体成分参数与身体质量指数(BMI)之间的关系。通过多变量Cox回归分析和Kaplan-Meier图进行log-rank检验，评估VFA和由VFA定义的肌少性肥胖(SO)的预后意义。结果共2720例，其中男性1530例(56.3%)，女性1190例(43.7%);中位年龄:53岁，四分位数间距:47-60岁)。在中位随访138个月期间，128人(5%)死亡(癌症死亡率:2%;非癌症死亡率:3%)，1岁和5年死亡率分别为0.2%(5 / 2720)和1.1%(30 / 2720)。VFA与BMI呈负相关(r = - 0.62;P & lt;0.001)和VFI (r = - 0.69;P & lt;0.001)。在调整临床变量、肌肉减少症和VFI后，高VFA是OS的负面预后因素(风险比[HR]: 1.05 / Hounsfield单位;95%置信区间[CI]: 1.02, 1.08;P = 0.001)， CSS (HR: 1.07 / Hounsfield单位;95% ci: 1.02, 1.12;P = 0.006)和NCS (HR: 1.03 / Hounsfield单位;95% ci: 1.01, 1.06;p = 0.009)。高VFA个体的高敏c反应蛋白水平高于低VFA个体(0.11 vs 0.03 mg/dL;P & lt;0.001)。VFA定义的SO患者的OS较差(9% vs. 4%;P & lt;0.001)， CSS (3% vs. 2%;P = 0.02)和NCS (6% vs. 3%;P & lt;0.001)，即使在相同的BMI(体重过轻对正常BMI, OS: 8% vs. 4%;超重到肥胖的BMI, OS: 38% vs. 4%;P & lt;两者均为0.001)或VFI类别(高VFI, OS: 43%对6%;低VFI, OS: 8% vs. 3%;P & lt;两者均为0.001)。结论高VFA与长期死亡率和低度炎症相关。VFA可以通过BMI或VFI进一步划分当前的SO, VFA定义的SO可以识别最容易长期死亡的个体。
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引用次数: 2
Sarcopenia and cardiovascular diseases: A systematic review and meta-analysis 肌肉减少症与心血管疾病:一项系统综述和荟萃分析
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-01 DOI: 10.1002/jcsm.13221
Xinrong Zuo, Xuehong Li, Kuo Tang, Rui Zhao, Minming Wu, Yang Wang, Tao Li

Sarcopenia is an age-related disease and is often accompanied by other diseases. Now, many studies have shown that cardiovascular diseases (CVDs) may raise the incidence rate of sarcopenia. Therefore, the purpose of this study was to conduct a systematic review and meta-analysis to investigate the prevalence of sarcopenia in patients with CVDs compared with the general population, defined as relatively healthy non-hospitalized subjects. The databases of PubMed, Embase, Medline and Web of Science were searched for eligible studies published up to 12 November 2022. Two assessment tools were used to evaluate study quality and the risk of bias. Statistical analysis was conducted using STATA 14.0 and R Version 4.1.2. Thirty-eight out of the 89 629 articles retrieved were included in our review. The prevalence of sarcopenia ranged from 10.1% to 68.9% in patients with CVDs, and the pooled prevalence was 35% (95% confidence interval [95% CI]: 28–42%). The pooled prevalence of sarcopenia was 32% (95% CI: 23–41%) in patients with chronic heart failure (CHF), 61% (95% CI: 49–72%) in patients with acute decompensated heart failure (ADHF), 43% (95% CI: 2–85%) in patients with coronary artery disease, 30% (95% CI: 25–35%) in patients with cardiac arrhythmia (CA), 35% (95% CI: 10–59%) in patients with congenital heart disease and 12% (95% CI: 7–17%) in patients with unclassed CVDs. However, in the general population, the prevalence of sarcopenia varied from 2.9% to 28.6% and the pooled prevalence was 13% (95% CI: 9–17%), suggesting that the prevalence of sarcopenia in patients with CVDs was about twice compared with the general population. The prevalence of sarcopenia was significantly higher only in patients with ADHF, CHF and CA compared with the general population. There is a positive correlation between CVDs and sarcopenia. The prevalence of sarcopenia is higher in patients with CVDs than that in the general population. With global aging, sarcopenia has brought a heavy burden to individuals and society. Therefore, it is important to identify the populations with high-risk or probable sarcopenia in order to do an early intervention, such as exercise, to counteract or slow down the progress of sarcopenia.

肌少症是一种与年龄有关的疾病，常伴有其他疾病。目前，许多研究表明，心血管疾病(cvd)可能会增加肌肉减少症的发病率。因此，本研究的目的是进行系统回顾和荟萃分析，以调查心血管疾病患者与普通人群(定义为相对健康的非住院受试者)中肌肉减少症的患病率。检索PubMed、Embase、Medline和Web of Science数据库，查找截至2022年11月12日发表的符合条件的研究。使用两种评估工具来评估研究质量和偏倚风险。采用STATA 14.0和R Version 4.1.2进行统计分析。我们检索到89 629篇文章，其中38篇纳入我们的综述。心血管疾病患者肌肉减少症的患病率从10.1%到68.9%不等，合并患病率为35%(95%可信区间[95% CI]: 28-42%)。慢性心力衰竭(CHF)患者肌肉减少的总患病率为32% (95% CI: 23-41%)，急性失代偿性心力衰竭(ADHF)患者为61% (95% CI: 49-72%)，冠状动脉疾病患者为43% (95% CI: 2-85%)，心律失常(CA)患者为30% (95% CI: 25-35%)，先天性心脏病患者为35% (95% CI: 10-59%)，未分类心血管疾病患者为12% (95% CI: 7-17%)。然而，在普通人群中，肌肉减少症的患病率从2.9%到28.6%不等，合并患病率为13% (95% CI: 9-17%)，表明心血管疾病患者肌肉减少症的患病率约为普通人群的两倍。与一般人群相比，只有ADHF、CHF和CA患者的肌肉减少症患病率明显更高。心血管疾病与肌肉减少症呈正相关。心血管疾病患者肌肉减少症的患病率高于一般人群。随着全球老龄化，肌肉减少症给个人和社会带来了沉重的负担。因此，重要的是要确定高危人群或可能的肌少症，以便进行早期干预，如运动，以抵消或减缓肌少症的进展。
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