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The role of microRNAs in muscle wasting and recovery during critical illness: a systematic review microRNAs在危重疾病期间肌肉萎缩和恢复中的作用:系统综述
JCSM rapid communications
Pub Date : 2023-08-17 DOI: 10.1002/rco2.80
Maria Borja-Gonzalez, Sarah Coyne, Sarah Fagan, Jose C. Casas-Martinez, Anthony J. Sannicandro, Bairbre McNicholas, Kevin O'Connell, John G. Laffey, Rónán O'Caoimh, Brian McDonagh, Katarzyna Goljanek-Whysall

Introduction

Critical illness associated with intensive care unit (ICU) admission often results in persistent skeletal muscle wasting and may lead to frailty in older and patients with multi-morbidity. Early recognition of patients at high-risk of long-term complications could provide opportunities to minimize the impact of critical illness and improve health and quality of life. MicroRNAs (miRs) are short, non-coding RNAs that regulate approximately two-thirds of the human genome and are involved in most biological processes. Multiple studies have demonstrated their role in muscle development and disease and their potential as biomarkers of muscle wasting.

Aim and methods

This systematic review examined the potential of miRs as biomarkers and therapeutics for muscle wasting during and following critical illness. PubMed and Scopus databases were searched for terms associated with critical illness, ICU, muscle wasting, frailty and microRNAs from inception to June 2022 (PROSPERO number CRD42022339531).

Results

Out of 537 articles, seven studies met the inclusion criteria and examined skeletal muscle and circulating miRs in the context of muscle wasting and/or frailty related to critical illness. Across the seven studies, 27 different miRs were identified that were reported to be dysregulated in the muscle and four in the blood, plasma or serum of critically ill patients. Four miRs were reported to be altered in both muscle and blood during critical illness and their levels moderately correlated with parameters of muscle function. These included canonical muscle-enriched miRs (myomiRs), such as miR-133, miR-1 and miR-181, which correlated with muscle strength in critically ill patients. However, most of the miRs reported to be dysregulated in the muscle following critical illness were examined in one article only.

Conclusions

This systematic review highlights the potential of miRs as biomarkers of skeletal muscle wasting and ICU-associated weakness following critical illness, suggesting the need for larger validation studies using unbiased techniques. We have described circulating and muscle microRNAs, which correlated with muscle parameters during critical illness. However, the limited number of studies in this area highlights the requirement for further studies before these could be considered in clinical practice.

与重症监护室（ICU）入院相关的危重症通常会导致持续的骨骼肌萎缩，并可能导致老年人和多发病患者的虚弱。早期识别长期并发症高危患者可以提供机会，最大限度地减少危重症的影响，改善健康和生活质量。微小RNA（miRs）是一种短的非编码RNA，调节大约三分之二的人类基因组，并参与大多数生物过程。多项研究已经证明了它们在肌肉发育和疾病中的作用，以及它们作为肌肉萎缩生物标志物的潜力。这篇系统综述考察了miR作为生物标志物和治疗危重症期间和之后肌肉萎缩的潜力。PubMed和Scopus数据库检索了从开始到2022年6月与危重症、ICU、肌肉萎缩、虚弱和微小RNA相关的术语（PROSPERO编号CRD42022339531）。在537篇文章中，有7项研究符合纳入标准，并在与危重症相关的肌肉萎缩和/或虚弱的背景下检查了骨骼肌和循环miR。在这七项研究中，发现了27种不同的miR，据报道，它们在危重患者的肌肉中失调，在血液、血浆或血清中失调。据报道，在危重症期间，肌肉和血液中有四种miR发生了改变，它们的水平与肌肉功能参数适度相关。其中包括典型的富含肌肉的miR（myomiRs），如miR-133、miR-1和miR-181，它们与危重患者的肌肉力量相关。然而，据报道，大多数miR在危重症后肌肉中失调，仅在一篇文章中进行了检测。这篇系统综述强调了miR作为危重症后骨骼肌萎缩和ICU相关虚弱的生物标志物的潜力，表明需要使用无偏技术进行更大规模的验证研究。我们已经描述了循环和肌肉微小RNA，它们与危重症期间的肌肉参数相关。然而，该领域的研究数量有限，这突出了在临床实践中考虑这些研究之前需要进一步研究。
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引用次数: 0
Exercise intervention during chemotherapy for pancreatic cancer: Changes in body composition and function 胰腺癌化疗期间的运动干预:身体成分和功能的变化
JCSM rapid communications
Pub Date : 2023-05-03 DOI: 10.1002/rco2.74
Kathryn H. Schmitz, Robert D. Boutin, James P. Yoon, Melanie Potiaumpai, Leon Lenchik, Carissa M. White, Victor Chang

Background

Patients with pancreatic cancer often lose weight during chemotherapy with associated changes in body composition. The goal of the present analysis was to describe changes in body composition in pancreatic cancer patients on an exercise regimen. The long-term goal is to determine whether an exercise intervention may attenuate changes in body composition and function.

Methods

Twenty-two pancreatic cancer patients of all stages who were to receive chemotherapy were recruited into a pre-post exercise intervention study. A standard exercise prescription was individualized to include aerobic, resistance, stretch, and balance exercises. Pre- and post-intervention computed tomography-derived measures of body composition [skeletal muscle index (SMI), skeletal muscle density, visceral fat area, and subcutaneous fat area] and physical function measures (grip strength, timed up and go, 30-s chair stand, and tandem balance stand) were evaluated using paired t-tests, χ2 tests, and Pearson correlation coefficients.

Results

The subjects were, on average, 62 years of age, 55% were female, 95% non-Hispanic White, and 45% were Stage IV. Body composition changes included a median 4.6% decrease in SMI (P = 0.04), 7.91% increase in skeletal muscle density (P = 0.05), 25.07% decrease in visceral fat area (P = 0.0001), and 22.08% decrease in subcutaneous fat area (P = 0.001). Adherence to aerobic and strength exercise was 65% and 57%, respectively. Some physical function measures improved, though not significantly: chair stands increased from a mean of 11.5 to 13.0 (P = 0.59) and timed up and go improved from a mean of 11.7 to 10.3 (P = 0.26). Change in right hand grip strength was marginally positively associated with changes in SMI (r = 0.53, P = 0.06). Improvements in skeletal muscle density were seen in 63% of patients, including Stage IV patients but did not correlate with change in function.

Conclusions

Exercise is feasible during neoadjuvant chemotherapy for pancreatic cancer patients of all stages and may assist with maintaining physical function and improving body composition. Further research is needed.

癌症胰腺癌患者通常在化疗期间体重减轻，并伴有身体成分的变化。本分析的目的是描述癌症患者在运动方案下身体成分的变化。长期目标是确定运动干预是否可以减弱身体成分和功能的变化。
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引用次数: 0
A Toll-like receptor-4/NLRP3 inflammasome pathway promotes inflammation in skeletal muscle of chronic kidney disease patients Toll样受体- 4/NLRP3炎症小体通路促进慢性肾病患者骨骼肌炎症
JCSM rapid communications
Pub Date : 2023-03-28 DOI: 10.1002/rco2.75
Daniela Verzola, Pasquale Esposito, Samantha Milanesi, Michela Saio, Daniela Picciotto, Marco Frascio, Alessandro Laudon, Giacomo Garibotto, Giuliano Brunori, Francesca Viazzi

Background

An emerging hypothesis is that the activation of innate immunity in the muscle of patients with chronic kidney disease (CKD) is implicated in the development and progression of wasting and cachexia. We previously observed that Toll-like receptor-4 (TLR4) and its downward NF-κB-dependent pro-inflammatory pathways are activated in CKD muscle. It is however unknown if TLR4 can activate the TLR4/NOD, LRR, and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway, which is implicated in cardiovascular disease and frailty, clinical settings that are commonly observed in CKD patients.

Methods

In a case–control cohort study, we hypothesized that a TLR4/NLRP3 inflammasome pathway is activated in skeletal muscle in uraemia. First, we studied the regulation TLR4/NLRP3/caspase-1 in skeletal muscle biopsies (20M/11F) obtained from 31 non-diabetic CKD5 patients (eGFR 8 ± 1 mL/min 1.73 m2) scheduled for peritoneal dialysis catheter insertion and 15 controls (10M/5F, eGFR 99 ± 6 mL/min 1.73 m2). Second, the effects of uraemic serum on the TLR4/NLRP3 inflammasome pathway were studied in C2C12 cells.

Results

In the muscle of CKD subjects, NLRP3 mRNA as well as its protein were overexpressed (by ~16-fold, respectively, P < 0.05 both vs. controls). Both IL-1β and IL-18 mRNA expressions were also up-regulated (~11.8–3.2-fold, respectively, P < 0.05). Also, cleaved caspase-1 was overexpressed in CKD muscle samples (P < 0.001 vs. controls). Both muscle NLRP3 mRNA (n = 22, r = −0.606, P < 0.01) and logIL-1 β protein (n = 26, r = −0.460, P < 0.02) were inversely associated with residual renal function, which suggests that the inflammasome is progressively activated in skeletal muscle of CKD patients as the residual renal function deteriorates. In addition, we observed that in C2C12 myotubes, uraemic serum up-regulates NLRP3 mRNA (~11-fold increase, P < 0.05), cleaved caspase-1 (by ~5-fold, P < 0.05), Il-1β mRNA (~3-fold increase, P < 0.05) and oxidative stress markers respect to normal serum. These effects were prevented by TAK-242, a selective TLR4 inhibitor.

Conclusions

Overall, our data demonstrate the activation of TLR4/NLRP3/caspase-1 inflammasome and its downward inflammatory cascade in the muscle of subjects with advanced-stage CKD and suggest targeting TLR4/NLRP3 inflammasome a

一种新出现的假说是，慢性肾脏病（CKD）患者肌肉中先天免疫的激活与消瘦和恶病质的发展和进展有关。我们之前观察到，Toll样受体-4（TLR4）及其向下的NF-κB依赖性促炎途径在CKD肌肉中被激活。然而，尚不清楚TLR4是否能激活TLR4/NOD、LRR和pyrin结构域含蛋白3（NLRP3）炎症小体途径，这与心血管疾病和虚弱有关，临床环境在CKD患者中常见。
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引用次数: 1
Body mass index and natriuretic peptides trends before and after left ventricular assist device 左心室辅助装置前后的体重指数和利钠肽趋势
JCSM rapid communications
Pub Date : 2023-03-18 DOI: 10.1002/rco2.76
Jessica Schultz, Amanda R. Vest, Maria Masotti, Austin Hoeg, Levi Teigen, Ranjit John, Andrew Shaffer, Tamas Alexy, Cindy Martin, Rebecca Cogswell

Background

It is unknown to what degree of sarcopenia related to heart failure (HF) is reversible with resolution of the HF syndrome. We evaluated whether (1) weight loss prior to left ventricular assist device (LVAD) is associated with pre-operative sarcopenia as quantified on pre-operative chest CTs and (2) determine the relationship between weight recovery (increase) after LVAD implantation and reduction of NT-proBNP levels.

Methods

In a large single-centre cohort (n = 502), CT measures of sarcopenia (pectoralis muscle mass indexed to body surface area and tissue attenuation) were correlated with pre-LVAD BMI trend (n = 190). BMI and NT-proBNP trends before and after LVAD implantation were evaluated (n = 403). Linear effects modelling was performed to test the association between NT-proBNP and BMI trends.

Results

A downtrending BMI prior to LVAD was associated with pectoralis muscle tissue attenuation (P < 0.05). BMI declined prior to LVAD, declined further early post-implant, and then increased between 100 and 300 days post-implant (average per cent change in BMI in Year 1, 7.6%, 95% CI: 6.3–8.8%). NT-proBNP decreased during the first 100 post LVAD days (−5.4%, 95% CI: −6.6 to −4.2%). Post-LVAD NT-proBNP and BMI trends were significantly associated, with a decrease of 1 unit log NT-proBNP associated with an increase in BMI of 0.81 kg/m2 (CI: 0.53–1.09, P < .001). The rise in post-LVAD BMI occurred after the reduction in NT-proBNP levels. Patients who failed to gain weight post-LVAD had the highest 6-month post-LVAD natriuretic peptides (lowest per cent BMI gain tertile NT-proBNP: 2208 vs. highest 1635 pg/mL, P < 0.001).

Conclusions

Weight recovery during LVAD support occurs after the reduction in natriuretic peptide levels. Failure to gain weight during LVAD support was associated with persistently elevated natriuretic peptide levels. These data collectively suggest that recovery of body mass may be dependent upon recovery of the HF syndrome.

目前尚不清楚与心力衰竭（HF）相关的少肌症在多大程度上可以逆转HF综合征。我们评估了（1）左心室辅助装置（LVAD）前的体重减轻是否与术前胸部CT量化的术前少肌症有关，以及（2）确定LVAD植入后体重恢复（增加）与NT-proBNP水平降低之间的关系。
{"title":"Body mass index and natriuretic peptides trends before and after left ventricular assist device","authors":"Jessica Schultz,&nbsp;Amanda R. Vest,&nbsp;Maria Masotti,&nbsp;Austin Hoeg,&nbsp;Levi Teigen,&nbsp;Ranjit John,&nbsp;Andrew Shaffer,&nbsp;Tamas Alexy,&nbsp;Cindy Martin,&nbsp;Rebecca Cogswell","doi":"10.1002/rco2.76","DOIUrl":"10.1002/rco2.76","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>It is unknown to what degree of sarcopenia related to heart failure (HF) is reversible with resolution of the HF syndrome. We evaluated whether (1) weight loss prior to left ventricular assist device (LVAD) is associated with pre-operative sarcopenia as quantified on pre-operative chest CTs and (2) determine the relationship between weight recovery (increase) after LVAD implantation and reduction of NT-proBNP levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In a large single-centre cohort (<i>n</i> = 502), CT measures of sarcopenia (pectoralis muscle mass indexed to body surface area and tissue attenuation) were correlated with pre-LVAD BMI trend (<i>n</i> = 190). BMI and NT-proBNP trends before and after LVAD implantation were evaluated (<i>n</i> = 403). Linear effects modelling was performed to test the association between NT-proBNP and BMI trends.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A downtrending BMI prior to LVAD was associated with pectoralis muscle tissue attenuation (<i>P</i> &lt; 0.05). BMI declined prior to LVAD, declined further early post-implant, and then increased between 100 and 300 days post-implant (average per cent change in BMI in Year 1, 7.6%, 95% CI: 6.3–8.8%). NT-proBNP decreased during the first 100 post LVAD days (−5.4%, 95% CI: −6.6 to −4.2%). Post-LVAD NT-proBNP and BMI trends were significantly associated, with a decrease of 1 unit log NT-proBNP associated with an increase in BMI of 0.81 kg/m<sup>2</sup> (CI: 0.53–1.09, <i>P</i> &lt; .001). The rise in post-LVAD BMI occurred after the reduction in NT-proBNP levels. Patients who failed to gain weight post-LVAD had the highest 6-month post-LVAD natriuretic peptides (lowest per cent BMI gain tertile NT-proBNP: 2208 vs. highest 1635 pg/mL, <i>P</i> &lt; 0.001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Weight recovery during LVAD support occurs after the reduction in natriuretic peptide levels. Failure to gain weight during LVAD support was associated with persistently elevated natriuretic peptide levels. These data collectively suggest that recovery of body mass may be dependent upon recovery of the HF syndrome.</p>\u0000 </section>\u0000 </div>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"6 1","pages":"42-49"},"PeriodicalIF":0.0,"publicationDate":"2023-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/rco2.76","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41649925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Different reversibility of skeletal muscle mass and strength in elderly Japanese women after the first wave of COVID-19 第一波COVID - 19后日本老年妇女骨骼肌质量和力量的不同可逆性
JCSM rapid communications
Pub Date : 2023-02-27 DOI: 10.1002/rco2.73
Bo-Kyung Son, Toshiyuki Imoto, Tomohiro Inoue, Takatoshi Nishimura, Weida Lyu, Tomoki Tanaka, Katsuya Iijima

Background

Restrictions on outdoor movements due to the coronavirus disease (COVID-19) pandemic have led to a decreased physical activity; this can lead to sarcopenia and frailty in older adults. Our recent study has demonstrated a significant decrease in the trunk muscle mass immediately after the pandemic's first wave (April–May 2020) among Japanese community-dwelling older women. In the present study, we further examined whether muscle mass recovery or deterioration occurs after 1 year of the pandemic's first wave by comparing physical measurements among the following assessment periods: before the first wave, immediately after the first wave, and at 1-year follow-up thereafter.

Methods

This study included 77 women (78.0 ± 5.7 years) who underwent physical measurements for muscle mass, grip strength, one-leg stand-up ability (3 s), and oral motor skills and answered questionnaires on sociality (social network, participation, and support) in the three assessment periods.

Results

The frequency of going out and the subjective vitality were significantly decreased immediately after the first wave; these recovered at the 1-year follow-up (P < 0.001). When comparing muscular measures, the trunk muscle mass index preferentially decreased immediately after the first wave but recovered significantly at the 1-year follow-up (P < 0.001). Conversely, the appendicular skeletal muscle mass index (ASMI) and grip strength continued to decrease until the 1-year follow-up (P < 0.001 and P = 0.03, respectively). The ability to perform a one-leg stand-up for 3 s and the oral motor skills did not change significantly across the assessment periods. The prevalence of pre-sarcopenia and sarcopenia tended to increase during these periods (P = 0.068). The reduction and subsequent recovery patterns for sociality were similar to those observed for the trunk muscle mass.

Conclusions

Our findings demonstrated differences in the reversibility of skeletal muscle mass and strength at 1 year after the first wave of the COVID-19 pandemic: the trunk muscle mass declined acutely and recovered rapidly, whereas the ASMI and grip strength declined continuously. These differences in the skeletal muscle recovery and deterioration might help formulate short-term or long-term strategies for COVID-19-related sarcopenia prevention in community-dwelling older adults.

冠状病毒病（COVID-19）大流行对户外活动的限制导致体育活动减少；这会导致老年人少肌症和虚弱。我们最近的研究表明，在第一波疫情（2020年4月至5月）后，居住在日本社区的老年女性的躯干肌肉量立即显著减少。在本研究中，我们通过比较以下评估期的身体测量结果，进一步检查了在第一波疫情爆发1年后肌肉质量是否恢复或恶化：第一波疫情之前、第一波疫情之后以及之后1年的随访。
{"title":"Different reversibility of skeletal muscle mass and strength in elderly Japanese women after the first wave of COVID-19","authors":"Bo-Kyung Son,&nbsp;Toshiyuki Imoto,&nbsp;Tomohiro Inoue,&nbsp;Takatoshi Nishimura,&nbsp;Weida Lyu,&nbsp;Tomoki Tanaka,&nbsp;Katsuya Iijima","doi":"10.1002/rco2.73","DOIUrl":"10.1002/rco2.73","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Restrictions on outdoor movements due to the coronavirus disease (COVID-19) pandemic have led to a decreased physical activity; this can lead to sarcopenia and frailty in older adults. Our recent study has demonstrated a significant decrease in the trunk muscle mass immediately after the pandemic's first wave (April–May 2020) among Japanese community-dwelling older women. In the present study, we further examined whether muscle mass recovery or deterioration occurs after 1 year of the pandemic's first wave by comparing physical measurements among the following assessment periods: before the first wave, immediately after the first wave, and at 1-year follow-up thereafter.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study included 77 women (78.0 ± 5.7 years) who underwent physical measurements for muscle mass, grip strength, one-leg stand-up ability (3 s), and oral motor skills and answered questionnaires on sociality (social network, participation, and support) in the three assessment periods.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The frequency of going out and the subjective vitality were significantly decreased immediately after the first wave; these recovered at the 1-year follow-up (<i>P</i> &lt; 0.001). When comparing muscular measures, the trunk muscle mass index preferentially decreased immediately after the first wave but recovered significantly at the 1-year follow-up (<i>P</i> &lt; 0.001). Conversely, the appendicular skeletal muscle mass index (ASMI) and grip strength continued to decrease until the 1-year follow-up (<i>P</i> &lt; 0.001 and <i>P</i> = 0.03, respectively). The ability to perform a one-leg stand-up for 3 s and the oral motor skills did not change significantly across the assessment periods. The prevalence of pre-sarcopenia and sarcopenia tended to increase during these periods (<i>P</i> = 0.068). The reduction and subsequent recovery patterns for sociality were similar to those observed for the trunk muscle mass.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings demonstrated differences in the reversibility of skeletal muscle mass and strength at 1 year after the first wave of the COVID-19 pandemic: the trunk muscle mass declined acutely and recovered rapidly, whereas the ASMI and grip strength declined continuously. These differences in the skeletal muscle recovery and deterioration might help formulate short-term or long-term strategies for COVID-19-related sarcopenia prevention in community-dwelling older adults.</p>\u0000 </section>\u0000 ","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"6 1","pages":"26-32"},"PeriodicalIF":0.0,"publicationDate":"2023-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/rco2.73","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49229886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Patient-derived pancreatic tumour organoid implantation establishes novel pre-cachexia mouse models 患者源性胰腺肿瘤类器官植入建立了新的前恶病质小鼠模型
JCSM rapid communications
Pub Date : 2022-11-03 DOI: 10.1002/rco2.71
Merel R. Aberle, Rianne D.W. Vaes, Wouter R.P.H. van de Worp, Ludwig J. Dubois, Natasja G. Lieuwes, Rianne Biemans, Ramon C.J. Langen, Frederik-Jan van Schooten, Ronald M. van Dam, Steven W.M. Olde Damink, Sander S. Rensen

Background

The poor survival of pancreatic cancer patients is largely attributable to cachexia, a syndrome of severe weight and muscle loss. To investigate the aetiology of cancer cachexia, preclinical models that closely recapitulate the human disease process are essential. Patient derived tumour organoids are promising novel cancer models, but their ability to induce cachexia in mice has not been investigated. We developed two pancreatic tumour organoid-based mouse models and demonstrate their potential for cancer cachexia research.

Methods

Two patients with pancreatic cancer, from whom tumour organoid cultures were previously established, were selected based on their cachexia phenotype. Patient 09 was characterized as cachectic according to the international consensus definition of cancer cachexia, whereas patient 12 was classified as non-cachectic. Organoid cultures PANCO-09b and PANCO-12a in basement membrane extract (BME) were injected subcutaneously into the flanks of 9-weeks old NMRI-Foxn1nu mice (n = 8/group). A control group was injected with BME only (n = 4). Body weight was monitored every 2–3 days for 38 days. Hind limb muscle wet and dry weights were measured. Adipocyte size in inguinal white adipose tissue was measured using haematoxylin and eosin-stained sections. Expression of genes associated with cancer cachexia in muscle and liver tissue was analysed using qPCR.

Results

Engraftment of tumour organoids was successful in 87.5% of PANCO-09b implanted mice and in 50% of PANCO-12a mice, with similar average tumour weights at endpoint (34.4 ± 25.1 mg vs. 32.8 ± 40.2 mg, respectively, P = 0.450). All groups initially gained weight, but PANCO-12a implanted mice progressively lost an average body weight of 1.7 ± 0.8 g from day 28 onwards. PANCO-12a-implanted mice gained significantly less weight from baseline than controls (0.7 ± 0.6 g, P = 0.027). Overall body weight gain of PANCO-09b mice was also lower but not significantly different from controls (2.0 ± 1.2 g vs. 2.9 ± 1.6 g, P = 0.961). Wet weights of hind leg muscles were negatively correlated with tumour weight but did not differ between groups. Adipocytes of PANCO-12a implanted mice were smaller compared to SHAM as well as PANCO09b mice (P < 0.0001), indicative of white adipose tissue wasting.

Conclusions

Implantation of human pancreatic tumour organoids into mice negati

胰腺癌患者的低生存率主要归因于恶病质，这是一种严重体重和肌肉损失的综合征。为了研究癌症恶病质的病因，密切概括人类疾病过程的临床前模型是必不可少的。患者来源的肿瘤类器官是很有前途的新型癌症模型，但它们在小鼠体内诱导恶病质的能力尚未得到研究。我们开发了两种基于胰腺肿瘤类器官的小鼠模型，并证明了它们在癌症恶病质研究中的潜力。
{"title":"Patient-derived pancreatic tumour organoid implantation establishes novel pre-cachexia mouse models","authors":"Merel R. Aberle,&nbsp;Rianne D.W. Vaes,&nbsp;Wouter R.P.H. van de Worp,&nbsp;Ludwig J. Dubois,&nbsp;Natasja G. Lieuwes,&nbsp;Rianne Biemans,&nbsp;Ramon C.J. Langen,&nbsp;Frederik-Jan van Schooten,&nbsp;Ronald M. van Dam,&nbsp;Steven W.M. Olde Damink,&nbsp;Sander S. Rensen","doi":"10.1002/rco2.71","DOIUrl":"10.1002/rco2.71","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The poor survival of pancreatic cancer patients is largely attributable to cachexia, a syndrome of severe weight and muscle loss. To investigate the aetiology of cancer cachexia, preclinical models that closely recapitulate the human disease process are essential. Patient derived tumour organoids are promising novel cancer models, but their ability to induce cachexia in mice has not been investigated. We developed two pancreatic tumour organoid-based mouse models and demonstrate their potential for cancer cachexia research.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Two patients with pancreatic cancer, from whom tumour organoid cultures were previously established, were selected based on their cachexia phenotype. Patient 09 was characterized as cachectic according to the international consensus definition of cancer cachexia, whereas patient 12 was classified as non-cachectic. Organoid cultures PANCO-09b and PANCO-12a in basement membrane extract (BME) were injected subcutaneously into the flanks of 9-weeks old NMRI-<i>Foxn1</i><sup><i>nu</i></sup> mice (<i>n</i> = 8/group). A control group was injected with BME only (<i>n</i> = 4). Body weight was monitored every 2–3 days for 38 days. Hind limb muscle wet and dry weights were measured. Adipocyte size in inguinal white adipose tissue was measured using haematoxylin and eosin-stained sections. Expression of genes associated with cancer cachexia in muscle and liver tissue was analysed using qPCR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Engraftment of tumour organoids was successful in 87.5% of PANCO-09b implanted mice and in 50% of PANCO-12a mice, with similar average tumour weights at endpoint (34.4 ± 25.1 mg vs. 32.8 ± 40.2 mg, respectively, <i>P</i> = 0.450). All groups initially gained weight, but PANCO-12a implanted mice progressively lost an average body weight of 1.7 ± 0.8 g from day 28 onwards. PANCO-12a-implanted mice gained significantly less weight from baseline than controls (0.7 ± 0.6 g, <i>P</i> = 0.027). Overall body weight gain of PANCO-09b mice was also lower but not significantly different from controls (2.0 ± 1.2 g vs. 2.9 ± 1.6 g, <i>P</i> = 0.961). Wet weights of hind leg muscles were negatively correlated with tumour weight but did not differ between groups. Adipocytes of PANCO-12a implanted mice were smaller compared to SHAM as well as PANCO09b mice (<i>P</i> &lt; 0.0001), indicative of white adipose tissue wasting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Implantation of human pancreatic tumour organoids into mice negati","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"6 1","pages":"4-17"},"PeriodicalIF":0.0,"publicationDate":"2022-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/rco2.71","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48217491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Risedronate use may blunt appendicular lean mass loss secondary to sleeve gastrectomy: results from a pilot randomized controlled trial 利塞膦酸钠的使用可能会减轻袖式胃切除术后阑尾瘦肿块的损失:一项随机对照试验的结果
JCSM rapid communications
Pub Date : 2022-10-14 DOI: 10.1002/rco2.72
Laura E. Flores, Kristen M. Beavers, Daniel P. Beavers, Katelyn A. Greene, Diana A. Madrid, Ryan M. Miller, Jamy D. Ard, Laura D. Bilek, Ashley A. Weaver

Background

Despite robust weight loss and cardiometabolic benefit, lean mass loss following sleeve gastrectomy (SG) confers health risk. Bisphosphonates are a potential therapeutic agent for lean mass maintenance. Thus, our objective was to explore the effect of 6 months of risedronate (vs. placebo) on change in dual-energy x-ray absorptiometry (DXA)- and computed tomography (CT)-derived lean mass metrics in the year following SG.

Methods

Twenty-four SG patients were randomized to 6 months of 150-mg oral risedronate or placebo capsules (NCT03411902). Body composition was assessed at baseline and 6 months with optional 12-month follow-up using whole-body DXA and CT at the lumbar spine and mid-thigh. Group treatment effects and 95% confidence intervals (CIs) were generated from a mixed model using contrast statements at 6 and 12 months, adjusted for baseline values.

Results

Of 24 participants enrolled [55.7 ± 6.7 years (mean ± SD), 79% Caucasian, 83% women, body mass index (BMI) 44.7 ± 6.3 kg/m2], 21 returned for 6-month testing and 14 returned for 12-month testing. Six-month weight loss was −16.3 kg (−20.0, −12.5) and −20.9 kg (−23.7, −18.1) in the risedronate and placebo groups, respectively (P = 0.057). Primary analysis at 6 months revealed a non-significant sparing of appendicular lean mass in the risedronate group compared with placebo [−1.2 kg (−2.3, −0.1) vs. −2.1 kg (−3.0, −1.2)]; P = 0.20. By 12 months, the risedronate group displayed no change in appendicular lean mass from baseline [−0.5 kg (−1.5, 0.6)]; however, the placebo group experienced significantly augmented loss [−2.9 kg (−3.6, −2.1)].

Conclusions

Pilot data indicate that risedronate treatment may mitigate appendicular lean mass loss following SG. Further study is warranted.

背景:尽管有显著的体重减轻和心脏代谢益处，但袖式胃切除术(SG)后的瘦体重减少会带来健康风险。双膦酸盐是维持瘦肉质量的潜在治疗剂。因此，我们的目的是探讨6个月的利塞膦酸钠(与安慰剂相比)对SG后一年双能x射线吸收测定(DXA)和计算机断层扫描(CT)衍生的瘦质量指标变化的影响。方法24例SG患者随机接受150 mg口服利塞膦酸酯或安慰剂胶囊(NCT03411902)治疗6个月。在基线和6个月时评估身体组成，并可选择12个月的随访，使用腰椎和大腿中部的全身DXA和CT。组治疗效果和95%置信区间(ci)由混合模型生成，使用6个月和12个月时的对比陈述，并根据基线值进行调整。结果入选的24名参与者[55.7±6.7岁(平均±SD)， 79%高加索人，83%女性，体重指数(BMI) 44.7±6.3 kg/m2]， 21人返回进行6个月的检测，14人返回进行12个月的检测。利塞膦酸钠组和安慰剂组6个月的体重减轻分别为- 16.3 kg(- 20.0， - 12.5)和- 20.9 kg (- 23.7， - 18.1) (P = 0.057)。6个月时的初步分析显示，与安慰剂相比，利塞酮组阑尾瘦质量无显著减少[- 1.2 kg(- 2.3， - 0.1)对- 2.1 kg (- 3.0， - 1.2)];p = 0.20。12个月时，利塞膦酸钠组阑尾瘦质量与基线相比没有变化[- 0.5 kg (- 1.5, 0.6)];然而，安慰剂组的体重损失显著增加[- 2.9 kg(- 3.6， - 2.1)]。结论初步数据表明，利塞膦酸钠治疗可减轻SG后阑尾瘦质量损失。值得进一步研究。
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引用次数: 0
Risedronate or Exercise for Lean Mass Preservation During Menopause: Secondary Analysis of a Randomized Controlled Trial. 利塞膦酸钠或运动对更年期瘦体重的保护作用：随机对照试验的二次分析。
JCSM rapid communications
Pub Date : 2022-07-01 Epub Date: 2022-03-09 DOI: 10.1002/rco2.59
Laura E Flores, Kevin Kupzyk, Nancy Waltman, Kristen M Beavers, Laura Bilek

Background: The menopause transition is marked by hormonal shifts leading to body composition changes, such as fat mass gain and lean mass loss. Weight-bearing and resistance exercise can help maintain lean mass during the menopause transition; however, uptake is low. Pre-clinical research points to bisphosphonates as also being effective in preventing loss of lean mass. Thus, we sought to investigate whether bisphosphonate therapy can mitigate loss of lean mass and outperform weight-bearing exercise in the years immediately following menopause.

Methods: Data come from the Heartland Osteoporosis Prevention Study (NCT02186600), where osteopenic, postmenopausal women were randomized to bisphosphonate (n=91), weight-bearing/resistance exercise (n=92), or control (n=93) conditions over a one-year period. Dual energy X-ray absorptiometry (DXA)-derived body composition measures (including total lean mass, total fat mass, lean mass index, and lean mass-to-fat mass ratio) were ascertained at baseline, six, and 12-months. Adherence to risedronate and weight-bearing exercise was defined as the percentage of dosages taken and exercise sessions attended. Intent-to-treat analysis using linear modeling was used to generate treatment effects on body composition. Secondary analysis utilized per-protocol analysis and included adjustment for weight change.

Results: 276 women (age: 54.5 years; 83.3% Caucasian; BMI: 25.7 kg/m2) were included in the analyses. 12-month adherence to the risedronate and exercise interventions was 89% and 64%, respectively. Group-by-time interactions were observed for lean mass, revealing exercise (0.43±1.49kg) and risedronate groups (0.31±1.68 kg) gained significantly more lean mass than control (-0.15±1.27 kg) over 12-months. However, after controlling for weight change in secondary analysis, the difference in lean mass change between control and risedronate became non-significant (p=0.059).

Conclusions: Results suggest both 12 months of oral risedronate and 12 months of weight-bearing exercise may diminish lean mass loss experienced during the menopause transition as compared to control. The lean mass sparing effect for risedronate may be driven by overall weight change.

背景：绝经过渡期的特点是荷尔蒙变化导致身体成分发生变化，如脂肪量增加和瘦肉量减少。负重和阻力运动有助于在更年期过渡期间保持瘦体重；然而，这种运动的吸收率很低。临床前研究表明，双膦酸盐也能有效防止瘦体重的减少。因此，我们试图研究双膦酸盐疗法是否能在绝经后的几年内减轻瘦体重的流失，并优于负重运动：方法：数据来自心脏地带骨质疏松症预防研究（NCT02186600），在该研究中，骨质疏松的绝经后妇女被随机分配到双膦酸盐（91 人）、负重/阻力运动（92 人）或对照组（93 人），为期一年。在基线、6 个月和 12 个月期间，对双能 X 射线吸收测定法（DXA）得出的身体成分测量结果（包括总瘦肉质量、总脂肪质量、瘦肉质量指数和瘦肉质量与脂肪质量比）进行确认。利塞膦酸盐和负重锻炼的依从性定义为服用剂量和参加锻炼次数的百分比。采用线性建模的意向治疗分析产生了对身体成分的治疗效果。结果：276 名女性（年龄：54.5 岁；83.3% 白种人；体重指数：25.7 kg/m2）被纳入分析。利塞膦酸盐和运动干预12个月的坚持率分别为89%和64%。在瘦体重方面观察到了组间时间交互作用，显示运动组（0.43±1.49 千克）和利塞膦酸钠组（0.31±1.68 千克）在 12 个月内增加的瘦体重明显高于对照组（-0.15±1.27 千克）。然而，在二次分析中控制体重变化后，对照组和利塞膦酸钠组的瘦体重变化差异变得不显著（P=0.059）：结果表明，与对照组相比，口服利塞膦酸钠 12 个月和负重锻炼 12 个月可减少绝经过渡期的瘦体重减轻。利塞膦酸钠的瘦体重减少效应可能是由整体体重变化驱动的。
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引用次数: 0
Identification of circulating plasma ceramides as a potential sexually dimorphic biomarker of pancreatic cancer-induced cachexia. 循环血浆神经酰胺作为胰腺癌诱导恶病质的潜在性二型生物标志物的鉴定。
JCSM rapid communications
Pub Date : 2022-07-01 Epub Date: 2022-06-20 DOI: 10.1002/rco2.68
Jeffery M Chakedis, Mary E Dillhoff, Carl R Schmidt, Priyani V Rajasekera, David C Evans, Terence M Williams, Denis C Guttridge, Erin E Talbert

Background: Cancer patients who exhibit cachexia lose weight and have low treatment tolerance and poor outcomes compared to cancer patients without weight loss. Despite the clear increased risk for patients, diagnosing cachexia still often relies on self-reported weight loss. A reliable biomarker to identify patients with cancer cachexia would be a valuable tool to improve clinical decision making and identification of patients at risk of adverse outcomes.

Methods: Targeted metabolomics, that included panels of amino acids, tricarboxylic acids, fatty acids, acylcarnitines, and sphingolipids, were conducted on plasma samples from patients with confirmed pancreatic ductal adenocarcinoma (PDAC) with and without cachexia and control patients without cancer (n=10/group, equally divided by sex). Additional patient samples were analyzed (total n=95) and Receiver Operating Characteristic (ROC) analyses were performed to establish if any metabolite could effectively serve as a biomarker of cachexia.

Results: Targeted profiling revealed that cachectic patients had decreased circulating levels of three sphingolipids compared to either non-cachectic PDAC patients or patients without cancer. The ratio of C18-ceramide to C24-ceramide (C18:C24) outperformed a number of other previously proposed biomarkers of cachexia (area under ROC = 0.810). It was notable that some biomarkers, including C18:C24, were only altered in cachectic males.

Conclusions: Our findings identify C18:C24 as a potentially new biomarker of PDAC-induced cachexia that also highlight a previously unappreciated sexual dimorphism in cancer cachexia.

背景：与没有体重减轻的癌症患者相比，表现出恶病质的癌症患者体重减轻，治疗耐受性低，预后差。尽管患者的风险明显增加，但恶病质的诊断仍然经常依赖于自我报告的体重减轻。识别癌症恶病质患者的可靠生物标志物将是改善临床决策和识别有不良后果风险的患者的有价值工具。方法：对确诊患有和不患有恶病质的胰腺导管腺癌（PDAC）患者和未患有癌症的对照患者的血浆样本进行靶向代谢组学研究，包括氨基酸、三羧酸、脂肪酸、酰基肉碱和鞘脂。分析了额外的患者样本（总n=95），并进行了受试者操作特征（ROC）分析，以确定是否有任何代谢物可以有效地作为恶病质的生物标志物。结果：靶向分析显示，与非恶病质PDAC患者或无癌症患者相比，恶病质患者的三种鞘脂循环水平降低。C18神经酰胺与C24神经酰胺的比例（C18:C24）优于其他一些先前提出的恶病质生物标志物（ROC=0.810）。值得注意的是，包括C18:C24在内的一些生物标志物仅在恶病质男性中发生改变。结论：我们的研究结果将C18:C24确定为PDAC诱导的恶病质的潜在新生物标志物，这也突出了癌症恶病质中先前未被重视的性别二型。
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引用次数: 0
MRI thigh measurements predict whole‐body skeletal muscle mass in patients with type 2 diabetes: a comparison with DXA MRI大腿测量预测2型糖尿病患者全身骨骼肌质量：与DXA的比较
JCSM rapid communications
Pub Date : 2022-07-01 DOI: 10.1002/rco2.70
E. Brown, A. Williams, O. Hakim, M. Wilton, J. Harrold, David Hughes, G. Kemp, J. Wilding, L. Goff, D. Cuthbertson
Sarcopenia is an age‐related loss of skeletal muscle mass (SMM) and function, associated with falls, frailty, and functional decline. It is more prevalent and often accelerated in people with Type 2 diabetes (T2D), especially when co‐existing with obesity (sarcopenic obesity). Accurate whole‐body SMM measurement, feasible using dual‐energy X‐ray absorptiometry (DXA) or magnetic resonance imaging (MRI), has utility both in clinical practice and in epidemiological and mechanistic research, considering the dual mechanical and metabolic function of skeletal muscle. Compared with MRI, DXA may underestimate age‐related muscle mass by up to 30%, and so direct comparison of DXA/MRI‐derived SMM measurements may be invalid in patients with obesity and T2D, who have potentially even more pronounced sarcopenia/sarcopenic obesity. We aimed to validate single‐slice or multiple‐slice measures of SMM, using MRI, with whole‐body SMM measures derived from DXA scans of appendicular lean soft tissue, specifically in patients with obesity and T2D.
肌萎缩是一种与年龄相关的骨骼肌质量（SMM）和功能丧失，与跌倒、虚弱和功能下降有关。它在2型糖尿病（T2D）患者中更为普遍，并且经常加速，尤其是当与肥胖（肌萎缩性肥胖）共存时。考虑到骨骼肌的双重机械和代谢功能，使用双能X射线吸收仪（DXA）或磁共振成像（MRI）进行准确的全身SMM测量是可行的，在临床实践以及流行病学和机制研究中都有实用性。与MRI相比，DXA可能低估了高达30%的与年龄相关的肌肉质量，因此直接比较DXA/MRI衍生的SMM测量结果在肥胖和T2D患者中可能无效，因为他们可能有更明显的少肌症/少肌性肥胖。我们的目的是使用MRI验证SMM的单层或多层测量，以及来自阑尾瘦软组织DXA扫描的全身SMM测量，特别是在肥胖和T2D患者中。
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引用次数: 0
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