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Comment on ‘Prevalence of sarcopenia in patients with chronic kidney disease: a global systematic review and meta-analysis’ 就 "慢性肾病患者肌肉疏松症的患病率:全球系统回顾和荟萃分析 "发表评论。
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-05-15 DOI: 10.1002/jcsm.13490
Xiao-Ming Zhang, Zaigui Luo, Xiao-Min Xie, Yunzhi Yang
<p>We have recently had the pleasure of delving into an article titled ‘Prevalence of Sarcopenia in Patients with Chronic Kidney Disease: A Global Systematic Review and Meta-Analysis’ authored by Duarte and their esteemed colleagues.<span><sup>1</sup></span> This meticulously conducted study amalgamated data from 140 research papers, encompassing a staggering 42 041 patients across 25 different countries. The findings revealed a worldwide prevalence of sarcopenia among individuals with chronic kidney disease (CKD) at 24.5% (95% confidence interval [CI]: 20.9–28.3). We were deeply intrigued by the manifold clinical implications that this study has unearthed. Notably, it marks a significant milestone in our comprehension of the impact of sarcopenia within CKD populations. The global perspective it provides serves as a beacon, underscoring the imperative need for standardized screening and management protocols.</p><p>Additionally, the authors astutely recommend that future research endeavours shift their focus towards longitudinal studies aimed at unravelling causality alongside interventions that may ameliorate the deleterious effects of sarcopenia in CKD patients. We extend our hearty congratulations to the authors for their admirable work. Nevertheless, we believe certain salient issues warrant meticulous examination to enhance the accuracy and reliability of this research.</p><p>Firstly, upon scrutinizing <i>tab. S2</i>, it has come to our attention that the authors have provided an overview of the characteristics of the included 140 studies. Notably, we discern that while 115 studies furnished data on the prevalence of sarcopenia among CKD patients, <i>fig. 2A</i> illustrates a meta-analysis involving 114 articles. This discrepancy raises concerns about the potential omission of a study in the meta-analysis. To rectify this discrepancy, we undertook a re-analysis of the 115 included studies, yielding a pooled prevalence of sarcopenia among CKD patients closely mirroring Duarte's findings, at 24.4% (95% CI: 21.5–27.4%), as shown in <i>Figure</i> 1.</p><p>Secondly, we advocate for a subgroup analysis based on study design aimed at exploring potential variations in sarcopenia prevalence within this cohort. Our findings indicate that the pooled prevalence of sarcopenia stands at 24.3% (95% CI: 21.0–27.7%) for cross-sectional studies, 23.8% (95% CI: 16.7–31.8%) for prospective cohort studies and 28.3% (95% CI: 18.3–39.5%) for retrospective cohort studies, with no statistically significant differences observed (<i>P</i> = 0.77).</p><p>Thirdly, it is worth noting that sarcopenic obesity emerges as a significant concern among CKD patients. While the article states that ‘Five included studies reported the prevalence of sarcopenic obesity’, we have identified six studies in <i>fig. 4</i> of Duarte's study. Therefore, we suggest a revision of the statement to accurately reflect this: Six included studies reported the prevalence of sarcopenic obesity. More
最近,我们有幸阅读了由 Duarte 和他们尊敬的同事撰写的一篇题为《慢性肾病患者肌肉疏松症的患病率》的文章1:1 这项精心进行的研究综合了 140 篇研究论文的数据,涉及 25 个不同国家的 42 041 名患者。研究结果显示,全球慢性肾脏病(CKD)患者中肌肉疏松症的发病率为 24.5%(95% 置信区间 [CI]:20.9-28.3)。我们对这项研究揭示的多方面临床意义深感兴趣。值得注意的是,它是我们了解肌少症对慢性肾脏病人群影响的一个重要里程碑。此外,作者还敏锐地建议,未来的研究工作应将重点转向纵向研究,旨在揭示因果关系,同时采取干预措施,以减轻肌少症对 CKD 患者的有害影响。我们衷心祝贺作者们所做的令人钦佩的工作。然而,我们认为某些突出的问题值得仔细研究,以提高这项研究的准确性和可靠性。首先,在仔细阅读表 S2 后,我们注意到作者概述了所纳入的 140 项研究的特点。值得注意的是,我们发现虽然有 115 项研究提供了有关肌肉疏松症在慢性肾脏病患者中发病率的数据,但图 2A 展示的是一项涉及 114 篇文章的荟萃分析。这种差异让人担心荟萃分析可能会遗漏某项研究。为了纠正这一差异,我们对纳入的 115 项研究进行了重新分析,得出的 CKD 患者肌肉疏松症的总体患病率与 Duarte 的研究结果基本一致,为 24.4%(95% CI:21.5-27.4%),如图 1 所示。其次,我们主张根据研究设计进行亚组分析,旨在探讨该队列中肌肉疏松症患病率的潜在差异。我们的研究结果表明,在横断面研究中,肌肉疏松症的总体患病率为 24.3%(95% CI:21.0-27.7%);在前瞻性队列研究中,患病率为 23.8%(95% CI:16.7-31.8%);在回顾性队列研究中,患病率为 28.3%(95% CI:18.3-39.5%)。文章称 "五项纳入研究报告了肌松性肥胖的发生率",而我们在杜阿尔特研究的图 4 中发现了六项研究。因此,我们建议修改该表述,以准确反映这一点:六项纳入研究报告了肌肉疏松性肥胖症的发病率。此外,鉴于肌松性肥胖是老年学研究中的一个新概念2 ,如果作者能提供更详细的信息,说明每项纳入研究中定义肌松性肥胖所使用的具体临界值,将对我们的读者大有裨益。第四,考虑到肌肉疏松症会随着年龄的增长而加剧3 ,我们有理由推测,65 岁及以上患有慢性肾脏病的人可能会比年轻人更容易患上肌肉疏松症。我们的亚组分析确实证实了这一假设,显示老年组群的患病率为 28%(95% CI:23-34%),而 65 岁以下组群的患病率为 22%(95% CI:18-25%),差异显著(P = 0.04)。最后,根据 PRISMA 2020 清单中列出的原则,我们鼓励作者进行敏感性分析,以评估其综合结果的稳健性。总之,我们对作者出色的系统综述和荟萃分析表示赞赏,他们的特点是进行了全面的检索和严格的统计分析,同时我们敦促作者仔细检查已发现的错误。此外,我们主张进行更多的亚组分析,并强调进行敏感性分析以加强研究可信度的重要性。
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引用次数: 0
Skeletal muscle hypertrophy rewires glucose metabolism: An experimental investigation and systematic review 骨骼肌肥大重塑葡萄糖代谢:实验研究和系统回顾
IF 8.9 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-05-14 DOI: 10.1002/jcsm.13468
Philipp Baumert, Sakari Mäntyselkä, Martin Schönfelder, Marie Heiber, Mika Jos Jacobs, Anandini Swaminathan, Petras Minderis, Mantas Dirmontas, Karin Kleigrewe, Chen Meng, Michael Gigl, Ildus I. Ahmetov, Tomas Venckunas, Hans Degens, Aivaras Ratkevicius, Juha J. Hulmi, Henning Wackerhage
<div> <section> <h3> Background</h3> <p>Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy.</p> </section> <section> <h3> Methods</h3> <p>We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U-<sup>13</sup>C<sub>6</sub>]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level.</p> </section> <section> <h3> Results</h3> <p>The metabolomics analysis in myotubes revealed insulin-like growth factor-1 (IGF-1)-induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose-5-phosphate/ribulose-5-phosphate: +40%; <i>P</i> = 0.01) and serine synthesis pathway (serine: −36.8%; <i>P</i> = 0.009). Like the hypertrophy stimulation with IGF-1 in myotubes in vitro, the concentration of the dipeptide <span>l</span>-carnosine was decreased by 26.6% (<i>P</i> = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose-6-phosphate, fructose-6-phosphate or glucose-1-phosphate) decreased by 32.2% (<i>P</i> = 0.004) in the overloaded muscle in vivo while increasing in the IGF-1-stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U-<sup>13</sup>C<sub>6</sub>]glucose is increasingly incorporated by ~13% (<i>P</i> = 0.001) into the non-essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (<i>P</i> = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (<i>P</i> < 0.001), highlighting the importance of the serine synthesis pathway for maintaining muscle size. Utilizing data from the UK Biobank (<i>n</i> = 450 243), we then discerned genetic variations linked to the serine synthesis pathway (<i>PHGDH</i> and <i>PSPH</i>) and to its downstream enzyme (<i>SHMT1</i>), revealing their association with appendicular lean mass in humans (<i>P</i> < 5.0e-8).</p> </section>
背景:即使在有氧的情况下,增殖的癌细胞也会将其新陈代谢转向糖酵解,特别是产生糖酵解中间产物作为合成代谢反应的底物。我们假设在骨骼肌肥大过程中也会发生类似的代谢重塑:我们在体外肥大的 C2C12 肌管和体内肥大的小鼠足底肌肉中使用了质谱仪,并评估了代谢组学变化和[U-13C6]葡萄糖示踪剂的结合情况。我们对丝氨酸合成途径的关键酶磷酸甘油酸脱氢酶(Phgdh)进行了酶抑制,以进一步进行机理分析,并对肌肉生长过程中代谢组学的变化与已发表的研究结果进行了系统回顾。最后,利用英国生物数据库将研究结果与人群水平联系起来:结果:肌管中的代谢组学分析显示,胰岛素样生长因子-1(IGF-1)诱导的代谢物浓度改变了合成代谢途径,如磷酸戊糖(核糖-5-磷酸/核酮糖-5-磷酸:+40%;P = 0.01)和丝氨酸合成途径(丝氨酸:-36.8%;P = 0.009)。与 IGF-1 对体外肌管肥大的刺激一样,二肽 l-carnosine 的浓度在体内骨骼肌生长过程中也降低了 26.6% (P = 0.001)。然而,磷酸化糖(葡萄糖-6-磷酸、果糖-6-磷酸或葡萄糖-1-磷酸)在体内超负荷肌肉中减少了 32.2%(P = 0.004),而在体外 IGF-1 刺激的肌管中却增加了。系统综述显示,与肌肉肥大有关的 10 种代谢物与糖酵解及其相互关联的合成代谢途径直接相关。我们证明,在肥大肌管中,[U-13C6]葡萄糖的标记碳越来越多地结合到非必需氨基酸中,增加了约13%(P = 0.001),同时介质丝氨酸的消耗也增加了(P = 0.006)。抑制 Phgdh 可抑制生长肌管中肌肉蛋白质合成的 58.1%(P 结论:Phgdh 可抑制生长肌管中肌肉蛋白质合成的 58.1%):了解调节骨骼肌质量的机制将有助于开发治疗肌无力的有效方法。我们的研究结果为肌肉生长过程中糖酵解中间产物进入合成代谢途径(如丝氨酸合成)提供了证据。
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引用次数: 0
Body weight and composition endpoints in cancer cachexia clinical trials: Systematic Review 4 of the cachexia endpoints series 癌症恶病质临床试验中的体重和成分终点:恶病质终点系列系统回顾 4》。
IF 8.9 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-05-13 DOI: 10.1002/jcsm.13478
Leo R. Brown, Mariana S. Sousa, Michael S. Yule, Vickie E. Baracos, Donald C. McMillan, Jann Arends, Trude R. Balstad, Asta Bye, Olav Dajani, Ross D. Dolan, Marie T. Fallon, Christine Greil, Marianne J. Hjermstad, Gunnhild Jakobsen, Matthew Maddocks, James McDonald, Inger O. Ottestad, Iain Phillips, Judith Sayers, Melanie R. Simpson, Ola M. Vagnildhaug, Tora S. Solheim, Barry J.A. Laird, Richard J.E. Skipworth, the Cancer Cachexia Endpoints Working Group

Significant variation exists in the outcomes used in cancer cachexia trials, including measures of body composition, which are often selected as primary or secondary endpoints. To date, there has been no review of the most commonly selected measures or their potential sensitivity to detect changes resulting from the interventions being examined. The aim of this systematic review is to assess the frequency and diversity of body composition measures that have been used in cancer cachexia trials. MEDLINE, Embase and Cochrane Library databases were systematically searched between January 1990 and June 2021. Eligible trials examined adults (≥18 years) who had received an intervention aiming to treat or attenuate the effects of cancer cachexia for >14 days. Trials were also of a prospective controlled design and included body weight or at least one anthropometric, bioelectrical or radiological endpoint pertaining to body composition, irrespective of the modality of intervention (e.g., pharmacological, nutritional, physical exercise and behavioural) or comparator. Trials with a sample size of <40 patients were excluded. Data extraction used Covidence software, and reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. This review was prospectively registered (PROSPERO: CRD42022276710). A total of 84 clinical trials, comprising 13 016 patients, were eligible for inclusion. Non-small-cell lung cancer and pancreatic cancer were studied most frequently. The majority of trial interventions were pharmacological (52%) or nutritional (34%) in nature. The most frequently reported endpoints were assessments of body weight (68 trials, n = 11 561) followed by bioimpedance analysis (BIA)-based estimates (23 trials, n = 3140). Sixteen trials (n = 3052) included dual-energy X-ray absorptiometry (DEXA)-based endpoints, and computed tomography (CT) body composition was included in eight trials (n = 841). Discrepancies were evident when comparing the efficacy of interventions using BIA-based estimates of lean tissue mass against radiological assessment modalities. Body weight, BIA and DEXA-based endpoints have been most frequently used in cancer cachexia trials. Although the optimal endpoints cannot be determined from this review, body weight, alongside measurements from radiological body composition analysis, would seem appropriate. The choice of radiological modality is likely to be dependent on the trial setting, population and intervention in question. CT and magnetic resonance imaging, which have the ability to accurately discriminate tissue types, are likely to be more sensitive and provide greater detail. Endpoints are of particular importance when aligned with the intervention's mechanism of action and/or intended patient benefit.

癌症恶病质试验中使用的结果存在很大差异,包括通常被选为主要或次要终点的身体组成指标。迄今为止,尚未对最常选择的测量方法或其检测干预措施导致的变化的潜在灵敏度进行过综述。本系统综述旨在评估癌症恶病质试验中使用的身体成分测量方法的频率和多样性。系统检索了1990年1月至2021年6月期间的MEDLINE、Embase和Cochrane图书馆数据库。符合条件的试验研究了接受旨在治疗或减轻癌症恶病质影响的干预措施超过 14 天的成人(≥18 岁)。试验也应采用前瞻性对照设计,并包括体重或至少一个与身体成分有关的人体测量、生物电或放射学终点,而不论干预方式(如药物、营养、体育锻炼和行为)或比较者。样本量为
{"title":"Body weight and composition endpoints in cancer cachexia clinical trials: Systematic Review 4 of the cachexia endpoints series","authors":"Leo R. Brown,&nbsp;Mariana S. Sousa,&nbsp;Michael S. Yule,&nbsp;Vickie E. Baracos,&nbsp;Donald C. McMillan,&nbsp;Jann Arends,&nbsp;Trude R. Balstad,&nbsp;Asta Bye,&nbsp;Olav Dajani,&nbsp;Ross D. Dolan,&nbsp;Marie T. Fallon,&nbsp;Christine Greil,&nbsp;Marianne J. Hjermstad,&nbsp;Gunnhild Jakobsen,&nbsp;Matthew Maddocks,&nbsp;James McDonald,&nbsp;Inger O. Ottestad,&nbsp;Iain Phillips,&nbsp;Judith Sayers,&nbsp;Melanie R. Simpson,&nbsp;Ola M. Vagnildhaug,&nbsp;Tora S. Solheim,&nbsp;Barry J.A. Laird,&nbsp;Richard J.E. Skipworth,&nbsp;the Cancer Cachexia Endpoints Working Group","doi":"10.1002/jcsm.13478","DOIUrl":"10.1002/jcsm.13478","url":null,"abstract":"<p>Significant variation exists in the outcomes used in cancer cachexia trials, including measures of body composition, which are often selected as primary or secondary endpoints. To date, there has been no review of the most commonly selected measures or their potential sensitivity to detect changes resulting from the interventions being examined. The aim of this systematic review is to assess the frequency and diversity of body composition measures that have been used in cancer cachexia trials. MEDLINE, Embase and Cochrane Library databases were systematically searched between January 1990 and June 2021. Eligible trials examined adults (≥18 years) who had received an intervention aiming to treat or attenuate the effects of cancer cachexia for &gt;14 days. Trials were also of a prospective controlled design and included body weight or at least one anthropometric, bioelectrical or radiological endpoint pertaining to body composition, irrespective of the modality of intervention (e.g., pharmacological, nutritional, physical exercise and behavioural) or comparator. Trials with a sample size of &lt;40 patients were excluded. Data extraction used Covidence software, and reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. This review was prospectively registered (PROSPERO: CRD42022276710). A total of 84 clinical trials, comprising 13 016 patients, were eligible for inclusion. Non-small-cell lung cancer and pancreatic cancer were studied most frequently. The majority of trial interventions were pharmacological (52%) or nutritional (34%) in nature. The most frequently reported endpoints were assessments of body weight (68 trials, <i>n</i> = 11 561) followed by bioimpedance analysis (BIA)-based estimates (23 trials, <i>n</i> = 3140). Sixteen trials (<i>n</i> = 3052) included dual-energy X-ray absorptiometry (DEXA)-based endpoints, and computed tomography (CT) body composition was included in eight trials (<i>n</i> = 841). Discrepancies were evident when comparing the efficacy of interventions using BIA-based estimates of lean tissue mass against radiological assessment modalities. Body weight, BIA and DEXA-based endpoints have been most frequently used in cancer cachexia trials. Although the optimal endpoints cannot be determined from this review, body weight, alongside measurements from radiological body composition analysis, would seem appropriate. The choice of radiological modality is likely to be dependent on the trial setting, population and intervention in question. CT and magnetic resonance imaging, which have the ability to accurately discriminate tissue types, are likely to be more sensitive and provide greater detail. Endpoints are of particular importance when aligned with the intervention's mechanism of action and/or intended patient benefit.</p>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 3","pages":"816-852"},"PeriodicalIF":8.9,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13478","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140910821","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
Inflammation-associated intramyocellular lipid alterations in human pancreatic cancer cachexia 人胰腺癌恶病质中与炎症相关的细胞内脂质改变
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-05-09 DOI: 10.1002/jcsm.13474
Min Deng, Jianhua Cao, Gregory van der Kroft, David P.J. van Dijk, Merel R. Aberle, Andrej Grgic, Ulf P. Neumann, Georg Wiltberger, Benjamin Balluff, Frank G. Schaap, Ron M.A. Heeren, Steven W.M. Olde Damink, Sander S. Rensen
<div> <section> <h3> Background</h3> <p>Cancer cachexia is a multifactorial metabolic syndrome characterized by systemic inflammation and ongoing skeletal muscle loss resulting in weakness, poor quality of life, and decreased survival. Whereas lipid accumulation in skeletal muscle is associated with cancer cachexia as well as the prognosis of cancer patients, surprisingly little is known about the nature of the lipids that accumulate in the muscle during cachexia, and whether this is related to inflammation. We aimed to identify the types and distributions of intramyocellular lipids in patients with and without cancer cachexia.</p> </section> <section> <h3> Methods</h3> <p>Rectus abdominis muscle biopsies were collected during surgery of patients with pancreatic ductal adenocarcinoma (<i>n</i> = 10 without cachexia, <i>n</i> = 20 cachectic without inflammation (CRP < 10 mg/L), <i>n</i> = 10 cachectic with inflammation (CRP ≥ 10 mg/L). L3-CT scans were analysed to assess body composition based on validated thresholds in Hounsfield units (HU). Muscle sections were stained with Oil-Red O and H&E to assess general lipid accumulation and atrophy. Untargeted lipidomic analyses were performed on laser-microdissected myotubes using LC–MS/MS. The spatial distribution of intramyocellular lipids with differential abundance between groups was visualized by mass-spectrometry imaging. Genes coding for inflammation markers and enzymes involved in <i>de novo</i> ceramide synthesis were studied by qPCR.</p> </section> <section> <h3> Results</h3> <p>Muscle radiation attenuation was lower in cachectic patients with inflammation (median 24.3 [18.6–30.8] HU) as compared with those without inflammation (34.2 [29.3–38.7] HU, <i>P</i> = 0.033) or no cachexia (37.4 [33.9–42.9] HU, <i>P</i> = 0.012). Accordingly, intramyocellular lipid content was lower in non-cachectic patients (1.9 [1.6–2.1]%) as compared with those with cachexia with inflammation (5.5 [4.5–7.3]%, <i>P</i> = 0.002) or without inflammation (4.8 [2.6–6.0]%, <i>P</i> = 0.017). Intramyocellular lipid accumulation was associated with both local IL-6 mRNA levels (<i>r</i><sub><i>s</i></sub> = 0.57, <i>P</i> = 0.015) and systemic CRP levels (<i>r</i><sub><i>s</i></sub> = 0.49, <i>P</i> = 0.024). Compared with non-cachectic subjects, cachectic patients had a higher relative abundance of intramyocellular glycerophospholipids and a lower relative abundance of glycerolipids. Furthermore, increases in several intramyocellular lipids such as SM(d36:1), PC(34:1), and TG(48:1) were found in cachectic patients with inflammation and correlated with specific cachexia features. Altered intramyocellular lipid species
背景:癌症恶病质是一种多因素代谢综合征,其特点是全身炎症和骨骼肌持续丧失,导致虚弱、生活质量低下和生存率下降。骨骼肌中的脂质积累与癌症恶病质以及癌症患者的预后有关,但令人惊讶的是,人们对恶病质期间肌肉中积累的脂质的性质以及这是否与炎症有关知之甚少。我们的目的是确定癌症恶病质患者和非癌症恶病质患者细胞内脂质的类型和分布:方法:我们在胰腺导管腺癌患者(无恶病质患者 10 人,无炎症恶病质患者 20 人)手术期间收集了腹直肌活检组织:与无炎症(34.2 [29.3-38.7] HU,P = 0.033)或无恶病质(37.4 [33.9-42.9] HU,P = 0.012)的患者相比,有炎症的恶病质患者肌肉辐射衰减较低(中位 24.3 [18.6-30.8] HU)。因此,与有炎症的恶病质患者(5.5 [4.5-7.3]%,P = 0.002)或无炎症的恶病质患者(4.8 [2.6-6.0]%,P = 0.017)相比,无恶病质患者的肌细胞内脂质含量较低(1.9 [1.6-2.1]%)。肌细胞内脂质积累与局部 IL-6 mRNA 水平(rs = 0.57,P = 0.015)和全身 CRP 水平(rs = 0.49,P = 0.024)相关。与非钙化患者相比,钙化患者细胞内甘油磷脂的相对丰度较高,而甘油脂类的相对丰度较低。此外,在伴有炎症的恶病质患者中发现了几种细胞内脂质的增加,如SM(d36:1)、PC(34:1)和TG(48:1),并与特定的恶病质特征相关。在恶病质和非恶病质患者的肌肉切片中,PC(34:1)、LPC(18:2)和TG(48:1)等改变的细胞内脂质种类分布不均,有的区域脂质含量丰富,有的区域则几乎没有:恶病质患者的肌细胞内脂质蓄积与局部和全身炎症有关,其特点是甘油三酯和甘油磷脂等明确的脂质种类发生了变化。
{"title":"Inflammation-associated intramyocellular lipid alterations in human pancreatic cancer cachexia","authors":"Min Deng,&nbsp;Jianhua Cao,&nbsp;Gregory van der Kroft,&nbsp;David P.J. van Dijk,&nbsp;Merel R. Aberle,&nbsp;Andrej Grgic,&nbsp;Ulf P. Neumann,&nbsp;Georg Wiltberger,&nbsp;Benjamin Balluff,&nbsp;Frank G. Schaap,&nbsp;Ron M.A. Heeren,&nbsp;Steven W.M. Olde Damink,&nbsp;Sander S. Rensen","doi":"10.1002/jcsm.13474","DOIUrl":"10.1002/jcsm.13474","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Cancer cachexia is a multifactorial metabolic syndrome characterized by systemic inflammation and ongoing skeletal muscle loss resulting in weakness, poor quality of life, and decreased survival. Whereas lipid accumulation in skeletal muscle is associated with cancer cachexia as well as the prognosis of cancer patients, surprisingly little is known about the nature of the lipids that accumulate in the muscle during cachexia, and whether this is related to inflammation. We aimed to identify the types and distributions of intramyocellular lipids in patients with and without cancer cachexia.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Rectus abdominis muscle biopsies were collected during surgery of patients with pancreatic ductal adenocarcinoma (&lt;i&gt;n&lt;/i&gt; = 10 without cachexia, &lt;i&gt;n&lt;/i&gt; = 20 cachectic without inflammation (CRP &lt; 10 mg/L), &lt;i&gt;n&lt;/i&gt; = 10 cachectic with inflammation (CRP ≥ 10 mg/L). L3-CT scans were analysed to assess body composition based on validated thresholds in Hounsfield units (HU). Muscle sections were stained with Oil-Red O and H&amp;E to assess general lipid accumulation and atrophy. Untargeted lipidomic analyses were performed on laser-microdissected myotubes using LC–MS/MS. The spatial distribution of intramyocellular lipids with differential abundance between groups was visualized by mass-spectrometry imaging. Genes coding for inflammation markers and enzymes involved in &lt;i&gt;de novo&lt;/i&gt; ceramide synthesis were studied by qPCR.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Muscle radiation attenuation was lower in cachectic patients with inflammation (median 24.3 [18.6–30.8] HU) as compared with those without inflammation (34.2 [29.3–38.7] HU, &lt;i&gt;P&lt;/i&gt; = 0.033) or no cachexia (37.4 [33.9–42.9] HU, &lt;i&gt;P&lt;/i&gt; = 0.012). Accordingly, intramyocellular lipid content was lower in non-cachectic patients (1.9 [1.6–2.1]%) as compared with those with cachexia with inflammation (5.5 [4.5–7.3]%, &lt;i&gt;P&lt;/i&gt; = 0.002) or without inflammation (4.8 [2.6–6.0]%, &lt;i&gt;P&lt;/i&gt; = 0.017). Intramyocellular lipid accumulation was associated with both local IL-6 mRNA levels (&lt;i&gt;r&lt;/i&gt;&lt;sub&gt;&lt;i&gt;s&lt;/i&gt;&lt;/sub&gt; = 0.57, &lt;i&gt;P&lt;/i&gt; = 0.015) and systemic CRP levels (&lt;i&gt;r&lt;/i&gt;&lt;sub&gt;&lt;i&gt;s&lt;/i&gt;&lt;/sub&gt; = 0.49, &lt;i&gt;P&lt;/i&gt; = 0.024). Compared with non-cachectic subjects, cachectic patients had a higher relative abundance of intramyocellular glycerophospholipids and a lower relative abundance of glycerolipids. Furthermore, increases in several intramyocellular lipids such as SM(d36:1), PC(34:1), and TG(48:1) were found in cachectic patients with inflammation and correlated with specific cachexia features. Altered intramyocellular lipid species ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 4","pages":"1283-1297"},"PeriodicalIF":9.4,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896011","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
Integrated multi-omics approach reveals the role of striated muscle preferentially expressed protein kinase in skeletal muscle including its relationship with myospryn complex 综合多组学方法揭示了骨骼肌中横纹肌优先表达蛋白激酶的作用,包括其与 myospryn 复合物的关系。
IF 8.9 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-05-09 DOI: 10.1002/jcsm.13470
Qifei Li, Jasmine Lin, Shiyu Luo, Klaus Schmitz-Abe, Rohan Agrawal, Melissa Meng, Behzad Moghadaszadeh, Alan H. Beggs, Xiaoli Liu, Mark A. Perrella, Pankaj B. Agrawal
<div> <section> <h3> Background</h3> <p>Autosomal-recessive mutations in <i>SPEG</i> (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy with or without dilated cardiomyopathy (CNM5). Loss of SPEG is associated with defective triad formation, abnormal excitation–contraction coupling, calcium mishandling and disruption of the focal adhesion complex in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes and molecular functions.</p> </section> <section> <h3> Methods</h3> <p>Skeletal muscles from 2-month-old SPEG-deficient (<i>Speg</i>-CKO) and wild-type (WT) mice were used for RNA sequencing (<i>n</i> = 4 per genotype) to profile transcriptomics and mass spectrometry (<i>n</i> = 4 for WT; <i>n</i> = 3 for <i>Speg</i>-CKO mice) to profile proteomics and phosphoproteomics. In addition, interactomics was performed using the SPEG antibody on pooled muscle lysates (quadriceps, gastrocnemius and triceps) from WT and <i>Speg</i>-CKO mice. Based on the multi-omics results, we performed quantitative real-time PCR, co-immunoprecipitation and immunoblot to verify the findings.</p> </section> <section> <h3> Results</h3> <p>We identified that SPEG interacts with myospryn complex proteins CMYA5, FSD2 and RyR1, which are critical for triad formation, and that SPEG deficiency results in myospryn complex abnormalities (protein levels decreased to 22 ± 3% for CMYA5 [<i>P</i> < 0.05] and 18 ± 3% for FSD2 [<i>P</i> < 0.01]). Furthermore, SPEG phosphorylates RyR1 at S2902 (phosphorylation level decreased to 55 ± 15% at S2902 in <i>Speg</i>-CKO mice; <i>P</i> < 0.05), and its loss affects JPH2 phosphorylation at multiple sites (increased phosphorylation at T161 [1.90 ± 0.24-fold], S162 [1.61 ± 0.37-fold] and S165 [1.66 ± 0.13-fold]; decreased phosphorylation at S228 and S231 [39 ± 6%], S234 [50 ± 12%], S593 [48 ± 3%] and S613 [66 ± 10%]; <i>P</i> < 0.05 for S162 and <i>P</i> < 0.01 for other sites). On analysing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix–receptor interaction (<i>P</i> < 1e<sup>−15</sup>) and peroxisome proliferator-activated receptor signalling (<i>P</i> < 9e<sup>−14</sup>).</p> </section> <section> <h3> Conclusions</h3> <p>We have elucidated the critical role of SPEG in the triad as it works closely with myospryn complex proteins (CMYA5, FSD2 and RyR1), it regulates phosphorylation levels of vari
背景:SPEG(横纹肌优先表达蛋白激酶)的常染色体重复突变与伴有或不伴有扩张型心肌病(CNM5)的中心核肌病有关。SPEG 的缺失与骨骼肌中三联体形成缺陷、异常兴奋-收缩耦合、钙处理不当和病灶粘附复合体的破坏有关。为了阐明潜在的分子通路,我们利用多组学工具和分析方法全面了解了复杂的生物过程和分子功能:方法:用2个月大的SPEG缺陷(Speg-CKO)小鼠和野生型(WT)小鼠的骨骼肌进行RNA测序(每个基因型4只),以分析转录组学,并用质谱(WT小鼠4只;Speg-CKO小鼠3只)分析蛋白质组学和磷酸化蛋白质组学。此外,还使用 SPEG 抗体对 WT 和 Speg-CKO 小鼠的肌肉裂解液(股四头肌、腓肠肌和肱三头肌)进行了相互作用组学分析。根据多组学结果,我们进行了定量实时 PCR、共免疫沉淀和免疫印迹来验证研究结果:结果:我们发现SPEG与肌鞘复合体蛋白CMYA5、FSD2和RyR1相互作用,这些蛋白对三联体的形成至关重要,SPEG缺乏会导致肌鞘复合体异常(CMYA5的蛋白水平下降至22 ± 3% [P-15])和过氧化物酶体增殖激活受体信号转导异常(P-14):我们阐明了 SPEG 在三联体中的关键作用,因为它与 myospryn 复合蛋白(CMYA5、FSD2 和 RyR1)密切协作,调节 JPH2 和 RyR1 中 S2902 多个残基的磷酸化水平,其缺乏与多个通路的失调有关。该研究确定了独特的 SPEG 相互作用蛋白及其磷酸化功能,并强调了使用多组学方法全面评估各种遗传疾病相关蛋白分子功能的重要性。
{"title":"Integrated multi-omics approach reveals the role of striated muscle preferentially expressed protein kinase in skeletal muscle including its relationship with myospryn complex","authors":"Qifei Li,&nbsp;Jasmine Lin,&nbsp;Shiyu Luo,&nbsp;Klaus Schmitz-Abe,&nbsp;Rohan Agrawal,&nbsp;Melissa Meng,&nbsp;Behzad Moghadaszadeh,&nbsp;Alan H. Beggs,&nbsp;Xiaoli Liu,&nbsp;Mark A. Perrella,&nbsp;Pankaj B. Agrawal","doi":"10.1002/jcsm.13470","DOIUrl":"10.1002/jcsm.13470","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Autosomal-recessive mutations in &lt;i&gt;SPEG&lt;/i&gt; (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy with or without dilated cardiomyopathy (CNM5). Loss of SPEG is associated with defective triad formation, abnormal excitation–contraction coupling, calcium mishandling and disruption of the focal adhesion complex in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes and molecular functions.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Skeletal muscles from 2-month-old SPEG-deficient (&lt;i&gt;Speg&lt;/i&gt;-CKO) and wild-type (WT) mice were used for RNA sequencing (&lt;i&gt;n&lt;/i&gt; = 4 per genotype) to profile transcriptomics and mass spectrometry (&lt;i&gt;n&lt;/i&gt; = 4 for WT; &lt;i&gt;n&lt;/i&gt; = 3 for &lt;i&gt;Speg&lt;/i&gt;-CKO mice) to profile proteomics and phosphoproteomics. In addition, interactomics was performed using the SPEG antibody on pooled muscle lysates (quadriceps, gastrocnemius and triceps) from WT and &lt;i&gt;Speg&lt;/i&gt;-CKO mice. Based on the multi-omics results, we performed quantitative real-time PCR, co-immunoprecipitation and immunoblot to verify the findings.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We identified that SPEG interacts with myospryn complex proteins CMYA5, FSD2 and RyR1, which are critical for triad formation, and that SPEG deficiency results in myospryn complex abnormalities (protein levels decreased to 22 ± 3% for CMYA5 [&lt;i&gt;P&lt;/i&gt; &lt; 0.05] and 18 ± 3% for FSD2 [&lt;i&gt;P&lt;/i&gt; &lt; 0.01]). Furthermore, SPEG phosphorylates RyR1 at S2902 (phosphorylation level decreased to 55 ± 15% at S2902 in &lt;i&gt;Speg&lt;/i&gt;-CKO mice; &lt;i&gt;P&lt;/i&gt; &lt; 0.05), and its loss affects JPH2 phosphorylation at multiple sites (increased phosphorylation at T161 [1.90 ± 0.24-fold], S162 [1.61 ± 0.37-fold] and S165 [1.66 ± 0.13-fold]; decreased phosphorylation at S228 and S231 [39 ± 6%], S234 [50 ± 12%], S593 [48 ± 3%] and S613 [66 ± 10%]; &lt;i&gt;P&lt;/i&gt; &lt; 0.05 for S162 and &lt;i&gt;P&lt;/i&gt; &lt; 0.01 for other sites). On analysing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix–receptor interaction (&lt;i&gt;P&lt;/i&gt; &lt; 1e&lt;sup&gt;−15&lt;/sup&gt;) and peroxisome proliferator-activated receptor signalling (&lt;i&gt;P&lt;/i&gt; &lt; 9e&lt;sup&gt;−14&lt;/sup&gt;).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We have elucidated the critical role of SPEG in the triad as it works closely with myospryn complex proteins (CMYA5, FSD2 and RyR1), it regulates phosphorylation levels of vari","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 3","pages":"1003-1015"},"PeriodicalIF":8.9,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13470","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896032","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
Reduced temporal muscle thickness predicts shorter survival in patients undergoing chronic subdural haematoma drainage 颞肌厚度减少预示着接受慢性硬膜下血肿引流术的患者生存期缩短。
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-05-08 DOI: 10.1002/jcsm.13489
Tommi K. Korhonen, Otso Arponen, Moritz Steinruecke, Ilaria Pecorella, Harry Mee, Stefan Yordanov, Edoardo Viaroli, Mathew R. Guilfoyle, Angelos Kolias, Ivan Timofeev, Peter Hutchinson, Adel Helmy

Background

Chronic subdural haematoma (CSDH) drainage is a common neurosurgical procedure. CSDHs cause excess mortality, which is exacerbated by frailty. Sarcopenia contributes to frailty – its key component, low muscle mass, can be assessed using cross-sectional imaging. We aimed to examine the prognostic role of temporal muscle thickness (TMT) measured from preoperative computed tomography head scans among patients undergoing surgical CSDH drainage.

Methods

We retrospectively identified all patients who underwent CSDH drainage within 1 year of February 2019. We measured their mean TMT from preoperative computed tomography scans, tested the reliability of these measurements, and evaluated their prognostic value for postoperative survival.

Results

One hundred and eighty-eight (122, 65% males) patients (median age 78 years, IQR 70–85 years) were included. Thirty-four (18%) patients died within 2 years, and 51 (27%) died at a median follow-up of 39 months (IQR 34–42 months). Intra- and inter-observer reliability of TMT measurements was good-to-excellent (ICC 0.85–0.97, P < 0.05). TMT decreased with age (Pearson's r = −0.38, P < 0.001). Females had lower TMT than males (P < 0.001). The optimal TMT cut-off values for predicting two-year survival were 4.475 mm for males and 3.125 mm for females. TMT below these cut-offs was associated with shorter survival in both univariate (HR 3.24, 95% CI 1.85–5.67) and multivariate (HR 1.86, 95% CI 1.02–3.36) analyses adjusted for age, ASA grade and bleed size. The effect of TMT on mortality was not mediated by age.

Conclusions

In patients with CSDH, TMT measurements from preoperative imaging were reliable and contained prognostic information supplemental to previously known predictors of poor outcomes.

背景:慢性硬膜下血肿(CSDH)引流术是一种常见的神经外科手术。CSDH 会导致过高的死亡率,而虚弱则会加剧死亡率。肌肉疏松症是导致虚弱的原因之一,其关键因素是肌肉质量低,可通过横断面成像进行评估。我们的目的是研究通过术前计算机断层扫描头部扫描测量的颞肌厚度(TMT)在接受 CSDH 手术引流的患者中的预后作用:我们回顾性地识别了自2019年2月起1年内接受CSDH引流术的所有患者。我们通过术前计算机断层扫描测量了他们的平均 TMT,测试了这些测量值的可靠性,并评估了它们对术后生存的预后价值:共纳入 188 名患者(122 人,65% 为男性)(中位年龄 78 岁,IQR 70-85 岁)。34名患者(18%)在两年内死亡,51名患者(27%)在中位随访39个月(IQR为34-42个月)时死亡。TMT测量的观察者内部和观察者之间的可靠性为良好至优秀(ICC 0.85-0.97,P 结论:TMT测量的可靠性为良好至优秀(ICC 0.85-0.97,P 结论:TMT测量的可靠性为良好至优秀):在 CSDH 患者中,术前成像的 TMT 测量结果是可靠的,并且包含预后信息,补充了之前已知的不良预后预测因素。
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引用次数: 0
Meta-analysis on the interrelationship between sarcopenia and mild cognitive impairment, Alzheimer's disease and other forms of dementia 关于肌肉疏松症与轻度认知障碍、阿尔茨海默氏病及其他形式痴呆症之间相互关系的元分析。
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-05-07 DOI: 10.1002/jcsm.13485
Nadjia Amini, Mounir Ibn Hach, Laurence Lapauw, Jolan Dupont, Laura Vercauteren, Sabine Verschueren, Jos Tournoy, Evelien Gielen
<p>Sarcopenia has been associated with adverse health outcomes, including cognitive dysfunction. However, its specific interrelationship with neurocognitive disorders such as mild cognitive impairment (MCI), Alzheimer's disease (AD) or other types of dementia has not been thoroughly explored. This meta-analysis aims to summarize the existing evidence on this interrelationship. This systematic review was pre-registered on PROSPERO (CRD42022366309) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Databases, including PubMed, Embase, CINAHL, Scopus, Web of Science, PEDro, SPORTDiscus and the Cochrane Central Register of Controlled Trials, and the data registry ClinicalTrials.gov were searched from inception to 8 June 2023. Observational studies (cross-sectional and cohort) and interventional studies reporting on the association and prevalence of sarcopenia in MCI, AD or other types of dementia in adults ≥50 years were included. For the meta-analysis, pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated for the association of sarcopenia with the neurocognitive disorders using random-effects/fixed-effects models. Subgroup analyses were performed to identify potential sources of heterogeneity. A total of 77 studies consisting of 92 058 subjects were finally included in the qualitative analysis (71 cross-sectional, 4 cohort and 2 interventional studies). Studies were heterogeneous, using different diagnostic criteria to define both sarcopenia and cognitive status. The majority of studies (<i>n</i> = 38) included Asian community-dwelling older adults. Most studies investigated the association of sarcopenia with AD (33/77) and MCI (32/77). For studies focusing on other forms of dementia, two studies included Lewy body dementia and one study included Parkinson's dementia, whereas the remaining studies did not specify dementia aetiology (<i>n</i> = 21). Three cohort studies explored the association between sarcopenia and incident MCI, whereas only one cohort study explored the association between dementia and incident sarcopenia. Two interventional studies investigated whether an exercise programme could prevent the progression of sarcopenia in older adults with dementia or AD. The information for the meta-analysis was extracted from 26 studies. Sarcopenia was significantly associated with MCI (pooled OR = 1.58, 95% CI 1.42–1.76) (<i>n</i> = 14), AD (pooled OR = 2.97, 95% CI 2.15–4.08) (<i>n</i> = 3) and non-AD dementia (pooled OR = 1.68, 95% CI 1.09–2.58) (<i>n</i> = 9). The significance and magnitude of the associations differed in subgroup analyses by study design, population, definition of sarcopenia or used tool to measure cognitive status. This meta-analysis showed that sarcopenia is significantly associated with MCI, AD and other types of dementia. These findings suggest the importance of early screening and prevention of sarcopenia in older people with cognitive d
肌肉疏松症与认知功能障碍等不良健康后果有关。然而,其与轻度认知障碍(MCI)、阿尔茨海默病(AD)或其他类型痴呆症等神经认知障碍的具体相互关系尚未得到深入探讨。本荟萃分析旨在总结有关这种相互关系的现有证据。本系统综述已在 PROSPERO 上预先注册(CRD42022366309),并根据《2020 年系统综述和荟萃分析首选报告项目》指南进行报告。检索的数据库包括 PubMed、Embase、CINAHL、Scopus、Web of Science、PEDro、SPORTDiscus 和 Cochrane Central Register of Controlled Trials,以及数据登记处 ClinicalTrials.gov,检索时间从开始至 2023 年 6 月 8 日。这些研究包括观察性研究(横断面研究和队列研究)和干预性研究,报告了肌肉疏松症与 MCI、AD 或其他类型痴呆症的相关性和患病率。在荟萃分析中,采用随机效应/固定效应模型计算了肌肉疏松症与神经认知障碍的相关性的集合几率比(OR)及 95% 置信区间(CI)。研究人员还进行了分组分析,以确定潜在的异质性来源。最终,共有 77 项研究(71 项横断面研究、4 项队列研究和 2 项干预研究)、92 058 名受试者被纳入定性分析。这些研究各不相同,使用不同的诊断标准来定义肌肉疏松症和认知状况。大多数研究(n = 38)的研究对象是居住在社区的亚裔老年人。大多数研究调查了肌肉疏松症与注意力缺失症(33/77)和重症肌无力症(32/77)的关系。至于针对其他形式痴呆症的研究,有两项研究包括路易体痴呆症,一项研究包括帕金森氏痴呆症,而其余研究则未说明痴呆症的病因(n = 21)。三项队列研究探讨了肌肉疏松症与MCI发病之间的关系,而只有一项队列研究探讨了痴呆症与肌肉疏松症发病之间的关系。两项干预性研究调查了运动计划是否能预防患有痴呆症或注意力缺失症的老年人肌肉疏松症的恶化。荟萃分析的信息来自 26 项研究。肌肉疏松症与 MCI(汇总 OR = 1.58,95% CI 1.42-1.76)(n = 14)、AD(汇总 OR = 2.97,95% CI 2.15-4.08)(n = 3)和非 AD 痴呆症(汇总 OR = 1.68,95% CI 1.09-2.58)(n = 9)明显相关。在亚组分析中,根据研究设计、研究人群、肌肉疏松症定义或用于测量认知状态的工具的不同,相关性的意义和程度也有所不同。这项荟萃分析表明,肌肉疏松症与 MCI、AD 及其他类型的痴呆症密切相关。这些研究结果表明,在有认知功能障碍的老年人中,早期筛查和预防肌肉疏松症非常重要,但还需要进一步的纵向研究来明确其中的因果关系。
{"title":"Meta-analysis on the interrelationship between sarcopenia and mild cognitive impairment, Alzheimer's disease and other forms of dementia","authors":"Nadjia Amini,&nbsp;Mounir Ibn Hach,&nbsp;Laurence Lapauw,&nbsp;Jolan Dupont,&nbsp;Laura Vercauteren,&nbsp;Sabine Verschueren,&nbsp;Jos Tournoy,&nbsp;Evelien Gielen","doi":"10.1002/jcsm.13485","DOIUrl":"10.1002/jcsm.13485","url":null,"abstract":"&lt;p&gt;Sarcopenia has been associated with adverse health outcomes, including cognitive dysfunction. However, its specific interrelationship with neurocognitive disorders such as mild cognitive impairment (MCI), Alzheimer's disease (AD) or other types of dementia has not been thoroughly explored. This meta-analysis aims to summarize the existing evidence on this interrelationship. This systematic review was pre-registered on PROSPERO (CRD42022366309) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Databases, including PubMed, Embase, CINAHL, Scopus, Web of Science, PEDro, SPORTDiscus and the Cochrane Central Register of Controlled Trials, and the data registry ClinicalTrials.gov were searched from inception to 8 June 2023. Observational studies (cross-sectional and cohort) and interventional studies reporting on the association and prevalence of sarcopenia in MCI, AD or other types of dementia in adults ≥50 years were included. For the meta-analysis, pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated for the association of sarcopenia with the neurocognitive disorders using random-effects/fixed-effects models. Subgroup analyses were performed to identify potential sources of heterogeneity. A total of 77 studies consisting of 92 058 subjects were finally included in the qualitative analysis (71 cross-sectional, 4 cohort and 2 interventional studies). Studies were heterogeneous, using different diagnostic criteria to define both sarcopenia and cognitive status. The majority of studies (&lt;i&gt;n&lt;/i&gt; = 38) included Asian community-dwelling older adults. Most studies investigated the association of sarcopenia with AD (33/77) and MCI (32/77). For studies focusing on other forms of dementia, two studies included Lewy body dementia and one study included Parkinson's dementia, whereas the remaining studies did not specify dementia aetiology (&lt;i&gt;n&lt;/i&gt; = 21). Three cohort studies explored the association between sarcopenia and incident MCI, whereas only one cohort study explored the association between dementia and incident sarcopenia. Two interventional studies investigated whether an exercise programme could prevent the progression of sarcopenia in older adults with dementia or AD. The information for the meta-analysis was extracted from 26 studies. Sarcopenia was significantly associated with MCI (pooled OR = 1.58, 95% CI 1.42–1.76) (&lt;i&gt;n&lt;/i&gt; = 14), AD (pooled OR = 2.97, 95% CI 2.15–4.08) (&lt;i&gt;n&lt;/i&gt; = 3) and non-AD dementia (pooled OR = 1.68, 95% CI 1.09–2.58) (&lt;i&gt;n&lt;/i&gt; = 9). The significance and magnitude of the associations differed in subgroup analyses by study design, population, definition of sarcopenia or used tool to measure cognitive status. This meta-analysis showed that sarcopenia is significantly associated with MCI, AD and other types of dementia. These findings suggest the importance of early screening and prevention of sarcopenia in older people with cognitive d","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 4","pages":"1240-1253"},"PeriodicalIF":9.4,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140875358","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
Metabolomic analysis of dietary-restriction-induced attenuation of sarcopenia in prematurely aging DNA repair-deficient mice 对饮食限制诱导的早衰 DNA 修复缺陷小鼠肌肉疏松症减轻情况的代谢组学分析
IF 8.9 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-30 DOI: 10.1002/jcsm.13433
Yupeng He, Wei Yang, Luojiao Huang, Marlien Admiraal-van Mever, Rawi Ramautar, Amy Harms, Yvonne Rijksen, Renata M.C. Brandt, Sander Barnhoorn, Kimberly Smit, Dick Jaarsma, Peter Lindenburg, Jan H. J. Hoeijmakers, Wilbert P. Vermeij, Thomas Hankemeier
<div> <section> <h3> Background</h3> <p>Sarcopenia is characterized by loss of skeletal muscle mass and function, and is a major risk factor for disability and independence in the elderly. Effective medication is not available. Dietary restriction (DR) has been found to attenuate aging and aging-related diseases, including sarcopenia, but the mechanism of both DR and sarcopenia are incompletely understood.</p> </section> <section> <h3> Methods</h3> <p>In this study, mice body weight, fore and all limb grip strength, and motor learning and coordination performance were first analysed to evaluate the DR effects on muscle functioning. Liquid chromatography–mass spectrometry (LC–MS) was utilized for the metabolomics study of the DR effects on sarcopenia in progeroid DNA repair-deficient <i>Ercc1</i><sup><i>∆/</i>−</sup> and <i>Xpg</i><sup><i>−/−</i></sup> mice, to identify potential biomarkers for attenuation of sarcopenia.</p> </section> <section> <h3> Results</h3> <p>Muscle mass was significantly (<i>P</i> < 0.05) decreased (13–20%) by DR; however, the muscle quality was improved with retained fore limbs and all limbs grip strength in <i>Ercc1</i><sup><i>∆/</i>−</sup> and <i>Xpg</i><sup><i>−/−</i></sup> mice. The LC–MS results revealed that metabolites and pathways related to oxidative-stress, that is, GSSG/GSH (<i>P</i> < 0.01); inflammation, that is, 9-HODE, 11-HETE (<i>P</i> < 0.05), PGE<sub>2</sub>, PGD<sub>2</sub>, and TXB<sub>2</sub> (<i>P</i> < 0.01); and muscle growth (PGF<sub>2α</sub>) (<i>P</i> < 0.01) and regeneration stimulation (PGE<sub>2</sub>) (<i>P</i> < 0.05) are significantly downregulated by DR. On the other hand, anti-inflammatory indicator and several related metabolites, that is, β-hydroxybutyrate (<i>P</i> < 0.01), 14,15-DiHETE (<i>P</i> < 0.0001), 8,9-EET, 12,13-DiHODE, and PGF<sub>1</sub> (<i>P</i> < 0.05); consumption of sources of energy (i.e., muscle and liver glycogen); and energy production pathways, that is, glycolysis (glucose, glucose-6-P, fructose-6-P) (<i>P</i> < 0.01), tricarboxylic acid cycle (succinyl-CoA, malate) (<i>P</i> < 0.001), and gluconeogenesis-related metabolite, alanine (<i>P</i> < 0.01), are significantly upregulated by DR. The notably (<i>P</i> < 0.01) down-modulated muscle growth (PGF<sub>2α</sub>) and regeneration (PGE<sub>2</sub>) stimulation metabolite and the increased consumption of glycogen in muscle and liver may be related to the significantly (<i>P</i> < 0.01) lower body weight and muscle mass by DR. The downregulated oxidative stress, pro-inflammatory mediators, and upregulated anti-inflammatory metabolites resulted in a lower energy expenditure, w
肌肉疏松症的特点是骨骼肌质量和功能丧失,是导致老年人残疾和自立的主要风险因素。目前尚无有效的治疗药物。研究发现,饮食限制(DR)可减轻衰老和与衰老相关的疾病,包括肌肉疏松症,但对饮食限制和肌肉疏松症的机理尚不完全清楚。
{"title":"Metabolomic analysis of dietary-restriction-induced attenuation of sarcopenia in prematurely aging DNA repair-deficient mice","authors":"Yupeng He,&nbsp;Wei Yang,&nbsp;Luojiao Huang,&nbsp;Marlien Admiraal-van Mever,&nbsp;Rawi Ramautar,&nbsp;Amy Harms,&nbsp;Yvonne Rijksen,&nbsp;Renata M.C. Brandt,&nbsp;Sander Barnhoorn,&nbsp;Kimberly Smit,&nbsp;Dick Jaarsma,&nbsp;Peter Lindenburg,&nbsp;Jan H. J. Hoeijmakers,&nbsp;Wilbert P. Vermeij,&nbsp;Thomas Hankemeier","doi":"10.1002/jcsm.13433","DOIUrl":"10.1002/jcsm.13433","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Sarcopenia is characterized by loss of skeletal muscle mass and function, and is a major risk factor for disability and independence in the elderly. Effective medication is not available. Dietary restriction (DR) has been found to attenuate aging and aging-related diseases, including sarcopenia, but the mechanism of both DR and sarcopenia are incompletely understood.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In this study, mice body weight, fore and all limb grip strength, and motor learning and coordination performance were first analysed to evaluate the DR effects on muscle functioning. Liquid chromatography–mass spectrometry (LC–MS) was utilized for the metabolomics study of the DR effects on sarcopenia in progeroid DNA repair-deficient &lt;i&gt;Ercc1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;∆/&lt;/i&gt;−&lt;/sup&gt; and &lt;i&gt;Xpg&lt;/i&gt;&lt;sup&gt;&lt;i&gt;−/−&lt;/i&gt;&lt;/sup&gt; mice, to identify potential biomarkers for attenuation of sarcopenia.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Muscle mass was significantly (&lt;i&gt;P&lt;/i&gt; &lt; 0.05) decreased (13–20%) by DR; however, the muscle quality was improved with retained fore limbs and all limbs grip strength in &lt;i&gt;Ercc1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;∆/&lt;/i&gt;−&lt;/sup&gt; and &lt;i&gt;Xpg&lt;/i&gt;&lt;sup&gt;&lt;i&gt;−/−&lt;/i&gt;&lt;/sup&gt; mice. The LC–MS results revealed that metabolites and pathways related to oxidative-stress, that is, GSSG/GSH (&lt;i&gt;P&lt;/i&gt; &lt; 0.01); inflammation, that is, 9-HODE, 11-HETE (&lt;i&gt;P&lt;/i&gt; &lt; 0.05), PGE&lt;sub&gt;2&lt;/sub&gt;, PGD&lt;sub&gt;2&lt;/sub&gt;, and TXB&lt;sub&gt;2&lt;/sub&gt; (&lt;i&gt;P&lt;/i&gt; &lt; 0.01); and muscle growth (PGF&lt;sub&gt;2α&lt;/sub&gt;) (&lt;i&gt;P&lt;/i&gt; &lt; 0.01) and regeneration stimulation (PGE&lt;sub&gt;2&lt;/sub&gt;) (&lt;i&gt;P&lt;/i&gt; &lt; 0.05) are significantly downregulated by DR. On the other hand, anti-inflammatory indicator and several related metabolites, that is, β-hydroxybutyrate (&lt;i&gt;P&lt;/i&gt; &lt; 0.01), 14,15-DiHETE (&lt;i&gt;P&lt;/i&gt; &lt; 0.0001), 8,9-EET, 12,13-DiHODE, and PGF&lt;sub&gt;1&lt;/sub&gt; (&lt;i&gt;P&lt;/i&gt; &lt; 0.05); consumption of sources of energy (i.e., muscle and liver glycogen); and energy production pathways, that is, glycolysis (glucose, glucose-6-P, fructose-6-P) (&lt;i&gt;P&lt;/i&gt; &lt; 0.01), tricarboxylic acid cycle (succinyl-CoA, malate) (&lt;i&gt;P&lt;/i&gt; &lt; 0.001), and gluconeogenesis-related metabolite, alanine (&lt;i&gt;P&lt;/i&gt; &lt; 0.01), are significantly upregulated by DR. The notably (&lt;i&gt;P&lt;/i&gt; &lt; 0.01) down-modulated muscle growth (PGF&lt;sub&gt;2α&lt;/sub&gt;) and regeneration (PGE&lt;sub&gt;2&lt;/sub&gt;) stimulation metabolite and the increased consumption of glycogen in muscle and liver may be related to the significantly (&lt;i&gt;P&lt;/i&gt; &lt; 0.01) lower body weight and muscle mass by DR. The downregulated oxidative stress, pro-inflammatory mediators, and upregulated anti-inflammatory metabolites resulted in a lower energy expenditure, w","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 3","pages":"868-882"},"PeriodicalIF":8.9,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13433","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140817416","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
Concerted regulation of skeletal muscle metabolism and contractile properties by the orphan nuclear receptor Nr2f6 孤儿核受体 Nr2f6 对骨骼肌代谢和收缩特性的协同调控
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-29 DOI: 10.1002/jcsm.13480
Dimitrius Santiago P. S. F. Guimarães, Ninon M. F. Barrios, André Gustavo de Oliveira, David Rizo-Roca, Maxence Jollet, Jonathon A.B. Smith, Thiago R. Araujo, Marcos Vinicius da Cruz, Emilio Marconato Jr., Sandro M. Hirabara, André S. Vieira, Anna Krook, Juleen R. Zierath, Leonardo R. Silveira
<div> <section> <h3> Background</h3> <p>The maintenance of skeletal muscle plasticity upon changes in the environment, nutrient supply, and exercise depends on regulatory mechanisms that couple structural and metabolic adaptations. The mechanisms that interconnect both processes at the transcriptional level remain underexplored. Nr2f6, a nuclear receptor, regulates metabolism and cell differentiation in peripheral tissues. However, its role in the skeletal muscle is still elusive. Here, we aimed to investigate the effects of Nr2f6 modulation on muscle biology <i>in vivo</i> and <i>in vitro</i>.</p> </section> <section> <h3> Methods</h3> <p>Global RNA-seq was performed in Nr2f6 knockdown C2C12 myocytes (<i>N</i> = 4–5). Molecular and metabolic assays and proliferation experiments were performed using stable Nr2f6 knockdown and Nr2f6 overexpression C2C12 cell lines (<i>N</i> = 3–6). Nr2f6 content was evaluated in lipid overload models <i>in vitro</i> and <i>in vivo</i> (<i>N</i> = 3–6). <i>In vivo</i> experiments included Nr2f6 overexpression in mouse <i>tibialis anterior</i> muscle, followed by gene array transcriptomics and molecular assays (<i>N</i> = 4), <i>ex vivo</i> contractility experiments (<i>N</i> = 5), and histological analysis (<i>N</i> = 7). The conservation of Nr2f6 depletion effects was confirmed in primary skeletal muscle cells of humans and mice.</p> </section> <section> <h3> Results</h3> <p>Nr2f6 knockdown upregulated genes associated with muscle differentiation, metabolism, and contraction, while cell cycle-related genes were downregulated. In human skeletal muscle cells, Nr2f6 knockdown significantly increased the expression of myosin heavy chain genes (two-fold to three-fold) and siRNA-mediated depletion of Nr2f6 increased maximal C2C12 myocyte's lipid oxidative capacity by 75% and protected against lipid-induced cell death. Nr2f6 content decreased by 40% in lipid-overloaded myotubes and by 50% in the skeletal muscle of mice fed a high-fat diet. Nr2f6 overexpression in mice resulted in an atrophic and hypoplastic state, characterized by a significant reduction in muscle mass (15%) and myofibre content (18%), followed by an impairment (50%) in force production. These functional phenotypes were accompanied by the establishment of an inflammation-like molecular signature and a decrease in the expression of genes involved in muscle contractility and oxidative metabolism, which was associated with the repression of the uncoupling protein 3 (20%) and PGC-1α (30%) promoters activity following Nr2f6 overexpression <i>in vitro</i>. Additionally, Nr2f6 regulated core components of the cell division machinery, effectively decoupling muscle
骨骼肌在环境、营养供应和运动发生变化时能否保持可塑性,取决于将结构适应和代谢适应结合起来的调控机制。在转录水平上将这两个过程相互关联的机制仍未得到充分探索。Nr2f6 是一种核受体,可调节外周组织的新陈代谢和细胞分化。然而,它在骨骼肌中的作用仍然难以捉摸。在这里,我们旨在研究 Nr2f6 调节对体内和体外肌肉生物学的影响。
{"title":"Concerted regulation of skeletal muscle metabolism and contractile properties by the orphan nuclear receptor Nr2f6","authors":"Dimitrius Santiago P. S. F. Guimarães,&nbsp;Ninon M. F. Barrios,&nbsp;André Gustavo de Oliveira,&nbsp;David Rizo-Roca,&nbsp;Maxence Jollet,&nbsp;Jonathon A.B. Smith,&nbsp;Thiago R. Araujo,&nbsp;Marcos Vinicius da Cruz,&nbsp;Emilio Marconato Jr.,&nbsp;Sandro M. Hirabara,&nbsp;André S. Vieira,&nbsp;Anna Krook,&nbsp;Juleen R. Zierath,&nbsp;Leonardo R. Silveira","doi":"10.1002/jcsm.13480","DOIUrl":"10.1002/jcsm.13480","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The maintenance of skeletal muscle plasticity upon changes in the environment, nutrient supply, and exercise depends on regulatory mechanisms that couple structural and metabolic adaptations. The mechanisms that interconnect both processes at the transcriptional level remain underexplored. Nr2f6, a nuclear receptor, regulates metabolism and cell differentiation in peripheral tissues. However, its role in the skeletal muscle is still elusive. Here, we aimed to investigate the effects of Nr2f6 modulation on muscle biology &lt;i&gt;in vivo&lt;/i&gt; and &lt;i&gt;in vitro&lt;/i&gt;.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Global RNA-seq was performed in Nr2f6 knockdown C2C12 myocytes (&lt;i&gt;N&lt;/i&gt; = 4–5). Molecular and metabolic assays and proliferation experiments were performed using stable Nr2f6 knockdown and Nr2f6 overexpression C2C12 cell lines (&lt;i&gt;N&lt;/i&gt; = 3–6). Nr2f6 content was evaluated in lipid overload models &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt; (&lt;i&gt;N&lt;/i&gt; = 3–6). &lt;i&gt;In vivo&lt;/i&gt; experiments included Nr2f6 overexpression in mouse &lt;i&gt;tibialis anterior&lt;/i&gt; muscle, followed by gene array transcriptomics and molecular assays (&lt;i&gt;N&lt;/i&gt; = 4), &lt;i&gt;ex vivo&lt;/i&gt; contractility experiments (&lt;i&gt;N&lt;/i&gt; = 5), and histological analysis (&lt;i&gt;N&lt;/i&gt; = 7). The conservation of Nr2f6 depletion effects was confirmed in primary skeletal muscle cells of humans and mice.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Nr2f6 knockdown upregulated genes associated with muscle differentiation, metabolism, and contraction, while cell cycle-related genes were downregulated. In human skeletal muscle cells, Nr2f6 knockdown significantly increased the expression of myosin heavy chain genes (two-fold to three-fold) and siRNA-mediated depletion of Nr2f6 increased maximal C2C12 myocyte's lipid oxidative capacity by 75% and protected against lipid-induced cell death. Nr2f6 content decreased by 40% in lipid-overloaded myotubes and by 50% in the skeletal muscle of mice fed a high-fat diet. Nr2f6 overexpression in mice resulted in an atrophic and hypoplastic state, characterized by a significant reduction in muscle mass (15%) and myofibre content (18%), followed by an impairment (50%) in force production. These functional phenotypes were accompanied by the establishment of an inflammation-like molecular signature and a decrease in the expression of genes involved in muscle contractility and oxidative metabolism, which was associated with the repression of the uncoupling protein 3 (20%) and PGC-1α (30%) promoters activity following Nr2f6 overexpression &lt;i&gt;in vitro&lt;/i&gt;. Additionally, Nr2f6 regulated core components of the cell division machinery, effectively decoupling muscle","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 4","pages":"1335-1347"},"PeriodicalIF":9.4,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13480","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140808679","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
Accelerated sarcopenia precedes learning and memory impairments in the P301S mouse model of tauopathies and Alzheimer's disease P301S小鼠锥体病和阿尔茨海默氏症模型在出现学习和记忆障碍之前会出现加速性肌肉疏松症
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-22 DOI: 10.1002/jcsm.13482
Savannah Longo, María Laura Messi, Zhong-Min Wang, William Meeker, Osvaldo Delbono
<div> <section> <h3> Background</h3> <p>Alzheimer's disease (AD) impairs cognitive functions and peripheral systems, including skeletal muscles. The PS19 mouse, expressing the human tau P301S mutation, shows cognitive and muscular pathologies, reflecting the central and peripheral atrophy seen in AD.</p> </section> <section> <h3> Methods</h3> <p>We analysed skeletal muscle morphology and neuromuscular junction (NMJ) through immunohistochemistry and advanced image quantification. A factorial Analysis of Variance assessed muscle weight, NCAM expression, NMJ, myofibre type distribution, cross-sectional areas, expression of single or multiple myosin heavy-chain isoforms, and myofibre grouping in PS19 and wild type (WT) mice over their lifespan (1–12 months).</p> </section> <section> <h3> Results</h3> <p>Significant weight differences in extensor digitorum longus (EDL) and soleus muscles between WT and PS19 mice were noted by 7–8 months. For EDL muscle in females, WT weighed 0.0113 ± 0.0005 compared with PS19's 0.0071 ± 0.0008 (<i>P</i> < 0.05), and in males, WT was 0.0137 ± 0.0001 versus PS19's 0.0069 ± 0.0006 (<i>P</i> < 0.005). Similarly, soleus muscle showed significant differences; females (WT: 0.0084 ± 0.0004; PS19: 0.0057 ± 0.0005, <i>P</i> < 0.005) and males (WT: 0.0088 ± 0.0003; PS19: 0.0047 ± 0.0004, <i>P</i> < 0.0001). Analysis of the NMJ in PS19 mice revealed a marked reduction in myofibre innervation at 5 months, with further decline by 10 months. NMJ pre-terminals in PS19 mice became shorter and simpler by 5 months, showing a steep decline by 10 months. Genotype and age strongly influenced muscle NCAM immunoreactivity, denoting denervation as early as 5–6 months in EDL muscle Type II fibres, with earlier effects in soleus muscle Type I and II fibres at 3–4 months. Muscle denervation and subsequent myofibre atrophy were linked to a reduction in Type IIB fibres in the EDL muscle and Type IIA fibres in the soleus muscle, accompanied by an increase in hybrid fibres. The EDL muscle showed Type IIB fibre atrophy with WT females at 1505 ± 110 μm<sup>2</sup> versus PS19's 1208 ± 94 μm<sup>2</sup>, and WT males at 1731 ± 185 μm<sup>2</sup> versus PS19's 1227 ± 116 μm<sup>2</sup>. Similarly, the soleus muscle demonstrated Type IIA fibre atrophy from 5 to 6 months, with WT females at 1194 ± 52 μm<sup>2</sup> versus PS19's 858 ± 62 μm<sup>2</sup>, and WT males at 1257 ± 43 μm<sup>2</sup> versus PS19's 1030 ± 55 μm<sup>2</sup>. Atrophy also affected Type IIX, I + IIA, and IIA + IIX fibres in both muscles. The timeline for both myofibre and overall muscle atrophy in PS19 mice was consistent, indicating a simultaneous decline.</p>
背景阿尔茨海默病(AD)损害认知功能和外周系统,包括骨骼肌。我们通过免疫组化和先进的图像量化技术分析了骨骼肌形态和神经肌肉接头(NMJ)。结果7-8个月时,WT小鼠和PS19小鼠的伸拇肌(EDL)和比目鱼肌的体重有显著差异。雌性小鼠的伸拇肌重量为 0.0113 ± 0.0005,而 PS19 小鼠的伸拇肌重量为 0.0071 ± 0.0008(P < 0.05);雄性小鼠的伸拇肌重量为 0.0137 ± 0.0001,而 PS19 小鼠的伸拇肌重量为 0.0069 ± 0.0006(P < 0.005)。同样,比目鱼肌也显示出显著差异;女性(WT:0.0084 ± 0.0004;PS19:0.0057 ± 0.0005,P <;0.005)和男性(WT:0.0088 ± 0.0003;PS19:0.0047 ± 0.0004,P <;0.0001)。对 PS19 小鼠 NMJ 的分析表明,5 个月时肌纤维神经支配明显减少,10 个月时进一步减少。PS19 小鼠的 NMJ 前端在 5 个月时变得更短更简单,到 10 个月时急剧下降。基因型和年龄对肌肉 NCAM 免疫反应有很大影响,EDL 肌 II 型纤维最早在 5-6 个月时就出现了神经支配,比目鱼肌 I 型和 II 型纤维在 3-4 个月时受到的影响更早。肌肉神经支配和随后的肌纤维萎缩与 EDL 肌肉中 IIB 型纤维和比目鱼肌中 IIA 型纤维的减少以及混合纤维的增加有关。EDL 肌肉显示 IIB 型纤维萎缩,WT 女性为 1505 ± 110 μm2 而 PS19 为 1208 ± 94 μm2,WT 男性为 1731 ± 185 μm2 而 PS19 为 1227 ± 116 μm2。同样,比目鱼肌从 5 个月到 6 个月显示出 IIA 型纤维萎缩,WT 女性为 1194 ± 52 μm2 而 PS19 为 858 ± 62 μm2,WT 男性为 1257 ± 43 μm2 而 PS19 为 1030 ± 55 μm2。萎缩还影响到两块肌肉中的 IIX 型、I + IIA 型和 IIA + IIX 型纤维。在 PS19 小鼠中,肌纤维和整体肌肉萎缩的时间线是一致的,这表明肌肉萎缩是同时发生的。
{"title":"Accelerated sarcopenia precedes learning and memory impairments in the P301S mouse model of tauopathies and Alzheimer's disease","authors":"Savannah Longo,&nbsp;María Laura Messi,&nbsp;Zhong-Min Wang,&nbsp;William Meeker,&nbsp;Osvaldo Delbono","doi":"10.1002/jcsm.13482","DOIUrl":"10.1002/jcsm.13482","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Alzheimer's disease (AD) impairs cognitive functions and peripheral systems, including skeletal muscles. The PS19 mouse, expressing the human tau P301S mutation, shows cognitive and muscular pathologies, reflecting the central and peripheral atrophy seen in AD.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We analysed skeletal muscle morphology and neuromuscular junction (NMJ) through immunohistochemistry and advanced image quantification. A factorial Analysis of Variance assessed muscle weight, NCAM expression, NMJ, myofibre type distribution, cross-sectional areas, expression of single or multiple myosin heavy-chain isoforms, and myofibre grouping in PS19 and wild type (WT) mice over their lifespan (1–12 months).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Significant weight differences in extensor digitorum longus (EDL) and soleus muscles between WT and PS19 mice were noted by 7–8 months. For EDL muscle in females, WT weighed 0.0113 ± 0.0005 compared with PS19's 0.0071 ± 0.0008 (&lt;i&gt;P&lt;/i&gt; &lt; 0.05), and in males, WT was 0.0137 ± 0.0001 versus PS19's 0.0069 ± 0.0006 (&lt;i&gt;P&lt;/i&gt; &lt; 0.005). Similarly, soleus muscle showed significant differences; females (WT: 0.0084 ± 0.0004; PS19: 0.0057 ± 0.0005, &lt;i&gt;P&lt;/i&gt; &lt; 0.005) and males (WT: 0.0088 ± 0.0003; PS19: 0.0047 ± 0.0004, &lt;i&gt;P&lt;/i&gt; &lt; 0.0001). Analysis of the NMJ in PS19 mice revealed a marked reduction in myofibre innervation at 5 months, with further decline by 10 months. NMJ pre-terminals in PS19 mice became shorter and simpler by 5 months, showing a steep decline by 10 months. Genotype and age strongly influenced muscle NCAM immunoreactivity, denoting denervation as early as 5–6 months in EDL muscle Type II fibres, with earlier effects in soleus muscle Type I and II fibres at 3–4 months. Muscle denervation and subsequent myofibre atrophy were linked to a reduction in Type IIB fibres in the EDL muscle and Type IIA fibres in the soleus muscle, accompanied by an increase in hybrid fibres. The EDL muscle showed Type IIB fibre atrophy with WT females at 1505 ± 110 μm&lt;sup&gt;2&lt;/sup&gt; versus PS19's 1208 ± 94 μm&lt;sup&gt;2&lt;/sup&gt;, and WT males at 1731 ± 185 μm&lt;sup&gt;2&lt;/sup&gt; versus PS19's 1227 ± 116 μm&lt;sup&gt;2&lt;/sup&gt;. Similarly, the soleus muscle demonstrated Type IIA fibre atrophy from 5 to 6 months, with WT females at 1194 ± 52 μm&lt;sup&gt;2&lt;/sup&gt; versus PS19's 858 ± 62 μm&lt;sup&gt;2&lt;/sup&gt;, and WT males at 1257 ± 43 μm&lt;sup&gt;2&lt;/sup&gt; versus PS19's 1030 ± 55 μm&lt;sup&gt;2&lt;/sup&gt;. Atrophy also affected Type IIX, I + IIA, and IIA + IIX fibres in both muscles. The timeline for both myofibre and overall muscle atrophy in PS19 mice was consistent, indicating a simultaneous decline.&lt;/p&gt;\u0000 ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 4","pages":"1358-1375"},"PeriodicalIF":9.4,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13482","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140634090","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
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Journal of Cachexia Sarcopenia and Muscle
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