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Co-morbid sarcopenia and low bone mineral density in young paediatric cancer survivors 小儿癌症幸存者合并肌少症和骨矿物质密度低。
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-08-20 DOI: 10.1002/jcsm.13563
Andres Marmol-Perez, Esther Ubago-Guisado, Jose J. Gil-Cosano, Francisco J. Llorente-Cantarero, Juan Francisco Pascual-Gázquez, Manuel Muñoz-Torres, Vicente Martinez-Vizcaino, Kirsten K. Ness, Jonatan R. Ruiz, Luis Gracia-Marco
<div> <section> <h3> Background</h3> <p>Sarcopenia and low areal bone mineral density (aBMD) are prevalent musculoskeletal complications after paediatric cancer treatment. However, their relationship has not been examined in young paediatric cancers survivors. This study aimed to evaluate aBMD differences according to sarcopenia status and the risk of low aBMD <i>Z</i>-score in young paediatric cancer survivors with sarcopenia confirmed/probable.</p> </section> <section> <h3> Methods</h3> <p>This cross-sectional study included 116 paediatric cancer survivors (12.1 ± 3.3 years old; 42.2% female). Handgrip strength was used to assessed muscle strength. Dual-energy X-ray absorptiometry estimated aBMD (g/cm<sup>2</sup>) and appendicular lean mass index (ALMI, kg/m<sup>2</sup>). ‘No sarcopenia’ was defined when muscle strength was >decile 2. ‘Sarcopenia probable’ was defined when muscle strength was ≤ decile 2 and ALMI Z-score was > −1.5 standard deviation (SD). ‘Sarcopenia confirmed’ was defined when muscle strength was ≤ decile 2 and ALMI <i>Z</i>-score ≤ −1.5 SD. Analysis of covariance and logistic regression, adjusted for time from treatment completion, radiotherapy exposure, calcium intake, and physical activity, was used to evaluate aBMD and estimate the odds ratios (ORs) of low aBMD (aBMD <i>Z</i>-score < −1.0).</p> </section> <section> <h3> Results</h3> <p>Survivors with sarcopenia confirmed had significantly lower aBMD than those without sarcopenia at total body (−1.2 [95% CI: −1.5 to −0.8] vs. 0.2 [−0.2 to 0.6], <i>P</i> < 0.001), lumbar spine (−0.7 [−1.1 to −0.3] vs. 0.4 [0.0 to 0.8], <i>P</i> < 0.001), total hip (−0.5 [−0.9 to −0.2] vs. 0.4 [0.1 to 0.8], <i>P</i> < 0.001), and femoral neck (−1.0 [−1.4 to −0.6] vs. 0.1 [−0.3 to 0.4], <i>P</i> = 0.001). Compared with survivors with sarcopenia probable, survivors with sarcopenia confirmed had significantly lower aBMD <i>Z</i>-score at total body (−1.2 [−1.5 to −0.8] vs. −0.2 [−0.7 to 0.4], <i>P</i> = 0.009), total hip (−0.5 [−0.9 to −0.2] vs. 0.5 [−0.1 to 1.0], <i>P</i> = 0.010), and femoral neck (−1.0 [−1.4 to −0.6] vs. 0.1 [−0.5 to 0.7], <i>P</i> = 0.014). Survivors with sarcopenia confirmed were at higher risk of low aBMD <i>Z</i>-score at the total body (OR: 6.91, 95% CI: 2.31–24.15), total hip (OR: 2.98, 1.02–9.54), and femoral neck (OR: 4.72, 1.72–14.19), than those without sarcopenia. Survivors with sarcopenia probable were at higher risk of low aBMD <i>Z</i>-score at the total body (OR: 4.13, 1.04–17.60) than those without sarcopenia.</p> </section> <section> <h3> Conclusions</h3>
背景:骨质疏松症和低平均骨矿物质密度(aBMD)是儿科癌症治疗后常见的肌肉骨骼并发症。然而,在年轻的儿科癌症幸存者中,还没有人研究过它们之间的关系。本研究旨在评估肌肉疏松症状态下的骨密度差异,以及证实/可能患有肌肉疏松症的年轻儿科癌症幸存者的低骨密度 Z 值风险:这项横断面研究纳入了116名儿童癌症幸存者(12.1 ± 3.3岁;42.2%为女性)。手握力量用于评估肌肉力量。双能 X 射线吸收测量法估算了 aBMD(克/平方厘米)和阑尾瘦体重指数(ALMI,千克/平方米)。肌力大于第 2 分位时,定义为 "无肌肉疏松症"。当肌肉力量≤第 2 分位且 ALMI Z-score>-1.5 标准差(SD)时,则定义为 "可能患有肌肉疏松症"。当肌肉力量≤第2分位且ALMI Z-score≤-1.5标准差时,则定义为 "确诊肌少症"。采用协方差分析和逻辑回归,并对治疗结束时间、放疗暴露、钙摄入量和体力活动进行调整,以评估 aBMD,并估算低 aBMD(aBMD Z-score <-1.0)的几率比(ORs):结果:经证实患有肌肉疏松症的幸存者的全身 aBMD 明显低于未患肌肉疏松症的幸存者(-1.2 [95% CI:-1.5 至 -0.8]对 0.2 [-0.2 至 0.6],P 结论:患有肌肉疏松症的年轻儿科癌症幸存者出现低骨密度的风险较高。应在早期阶段实施以抗阻力训练为基础的干预措施,以减轻这类人群的骨肉疏松症。
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引用次数: 0
The maternal lifestyle in pregnancy: Implications for foetal skeletal muscle development 孕妇在孕期的生活方式:对胎儿骨骼肌发育的影响。
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-08-18 DOI: 10.1002/jcsm.13556
Haijun Sun, Meixia Chen, Jialong Liao, Linjuan He, Boyang Wan, Jingdong Yin, Xin Zhang

The world is facing a global nutrition crisis, as evidenced by the rising incidence of metabolic disorders such as obesity, insulin resistance and chronic inflammation. Skeletal muscle is the largest tissue in humans and plays an important role in movement and host metabolism. Muscle fibre formation occurs mainly during the embryonic stage. Therefore, maternal lifestyle, especially nutrition and exercise during pregnancy, has a critical influence on foetal skeletal muscle development and the subsequent metabolic health of the offspring. In this review, the influence of maternal obesity, malnutrition and micronutrient intake on foetal skeletal muscle development is systematically summarized. We also aim to describe how maternal exercise shapes foetal muscle development and metabolic health in the offspring. The role of maternal gut microbiota and its metabolites on foetal muscle development is further discussed, although this field is still in its ‘infancy’. This review will provide new insights to reduce the global crisis of metabolic disorders and highlight current gaps to promote further research.

肥胖、胰岛素抵抗和慢性炎症等新陈代谢疾病的发病率不断上升,证明世界正面临着全球性的营养危机。骨骼肌是人类最大的组织,在运动和宿主新陈代谢中发挥着重要作用。肌肉纤维的形成主要发生在胚胎阶段。因此,母体的生活方式,尤其是孕期的营养和运动,对胎儿骨骼肌的发育和后代的代谢健康有着至关重要的影响。本综述系统地总结了母体肥胖、营养不良和微量元素摄入对胎儿骨骼肌发育的影响。我们还将介绍母体运动如何影响胎儿肌肉发育和后代的代谢健康。我们还进一步讨论了母体肠道微生物群及其代谢物对胎儿肌肉发育的作用,尽管这一领域仍处于 "起步阶段"。这篇综述将为减少全球代谢紊乱危机提供新的见解,并强调目前存在的差距,以促进进一步的研究。
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引用次数: 0
Higher serum uric acid as a risk factor for frailty in older adults: A nationwide population-based study 较高的血清尿酸是导致老年人虚弱的风险因素:一项基于全国人口的研究。
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-08-18 DOI: 10.1002/jcsm.13561
Min-gu Kang, Ji Yeon Baek, Yunju Jo, Dongryeol Ryu, Il-Young Jang, Hee-Won Jung, Beom-Jun Kim
<div> <section> <h3> Background</h3> <p>Uric acid (UA), the terminal breakdown product of purine metabolism, possesses contradictory roles, functioning both as an inflammatory mediator and as an antioxidant. Its clinical relevance, particularly in geriatric populations, remains a topic of ongoing debate. Aiming to elucidate whether circulating UA is detrimental or beneficial to human health, we investigate the association between serum UA concentrations and the frailty index—a comprehensive measure of biological aging in a nationally representative cohort of community-dwelling older adults.</p> </section> <section> <h3> Methods</h3> <p>We conducted a population-based, cross-sectional study utilizing data from the Korea National Health and Nutrition Examination Survey. The sample included 4268 participants aged 65 years and above. A deficit accumulation frailty index (FI) was constructed using 38 items that assess physical, cognitive, psychological, and social domains. Based on the FI, participants were categorized into non-frail (FI ≤ 0.15), pre-frail (0.15 < FI ≤ 0.25), or frail (FI > 0.25). Serum UA levels were quantified through a colorimetric enzymatic assay.</p> </section> <section> <h3> Results</h3> <p>After controlling for confounders such as age, sex, socioeconomic status (including income and education level), lifestyle factors (smoking status), and medical history (hypertension, diabetes, dyslipidemia, stroke, cardiovascular diseases), and body mass index, serum UA levels were observed to be significantly higher in frail participants compared with their non-frail counterparts (<i>P</i> < 0.001). Furthermore, serum UA concentrations demonstrated a positive correlation with the FI (<i>P</i> < 0.001), and the odds ratio for frailty per 1 mg/dL increase in serum UA was 1.22 (<i>P</i> < 0.001). Additionally, older adults in the highest quartile of UA levels exhibited a significantly higher FI and 1.66-fold increased odds of frailty compared with those in the lowest quartile (<i>P</i> = 0.011 and <i>P</i> = 0.005, respectively).</p> </section> <section> <h3> Conclusions</h3> <p>These findings suggest that elevated circulating UA levels may act as a pro-aging factor rather than an anti-aging one in older adults, highlighting its potential role in accelerating biological aging. The data further support the utility of serum UA as a potential blood-based biomarker for frailty in this demographic, contributing to the expanding evidence on its significance in geriatric health assessments.</p> </section> </div
背景:尿酸(UA)是嘌呤代谢的终极分解产物,其作用相互矛盾,既是炎症介质,又是抗氧化剂。其临床相关性,尤其是在老年人群中的相关性,仍是一个争论不休的话题。为了弄清循环尿酸对人体健康是有害还是有益,我们研究了血清尿酸浓度与虚弱指数之间的关系--虚弱指数是对全国具有代表性的社区老年人生物衰老的综合衡量:我们利用韩国全国健康与营养调查的数据开展了一项基于人群的横断面研究。样本包括 4268 名 65 岁及以上的参与者。我们利用 38 个评估身体、认知、心理和社会领域的项目构建了赤字累积虚弱指数(FI)。根据 FI,参与者被分为非虚弱(FI ≤ 0.15)和前期虚弱(0.15 0.25)。血清尿酸水平通过比色酶法进行量化:结果:在控制了年龄、性别、社会经济地位(包括收入和教育水平)、生活方式因素(吸烟状况)、病史(高血压、糖尿病、血脂异常、中风、心血管疾病)和体重指数等混杂因素后,观察到体弱者的血清尿酸水平明显高于非体弱者(P 结论:这些研究结果表明,体弱者的血清尿酸水平明显高于非体弱者:这些研究结果表明,循环中尿酸水平的升高可能是促进老年人衰老的因素,而不是抗衰老的因素,突出了尿酸在加速生物衰老中的潜在作用。这些数据进一步支持了血清尿酸作为一种潜在的血液生物标志物在这一人群中的实用性,从而有助于不断扩大其在老年健康评估中的重要性。
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引用次数: 0
Change in physical activity and its association with decline in kidney function: A UK Biobank-based cohort study 体育锻炼的变化及其与肾功能下降的关系:一项基于英国生物库的队列研究。
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-08-18 DOI: 10.1002/jcsm.13551
Qiaoling Liu, Carlos Celis-Morales, Jennifer S. Lees, Naveed Sattar, Frederick K. Ho, Jill P. Pell, Patrick B. Mark, Paul Welsh

Background

Previous research on the association between physical activity (PA) and kidney function is inconsistent. The association between muscle mass and serum creatinine (SCr) may have implications for interpreting the effect of PA on estimated glomerular filtration rate (eGFR). Few studies have reported changes in physical activity and changes in kidney function.

Methods

A cohort study was constructed using the UK Biobank. Changes in physical activity were self-reported as metabolic equivalent task (MET) minutes/week. eGFR was calculated using SCr and cystatin C (CysC). Cox and nonlinear regressions with restricted cubic splines were applied to explore the association between changes in physical activity and rapid decline of kidney function (RDKF, eGFR annual decrease ≥3 mL/min/1.73 m2), and the annual change of eGFR. An exploratory analysis of cardiorespiratory fitness as the exposure was conducted.

Results

Among 11 757 participants, the median follow-up time was 4.4 years. Participants whose PA decreased by 1000 MET minutes/week at the follow-up assessment had a 2% reduction in risk of developing RDKFSCr (HR = 0.98, 95% CI: 0.96, 1.00). In contrast, a 1000 MET minutes/week increase in PA was associated with a 4% reduction in risk of developing RDKFCysC (HR = 0.96, 95% CI: 0.93, 0.99). A PA increase of 1000 MET minutes/week was associated with eGFRCysC annual increase of 0.04 mL/min/1.73 m2 (95% CI: 0.03, 0.06) but no significant changes in eGFRSCr.

Conclusions

In this general population study, there are differing associations between changes in PA and changes in kidney function depending on the kidney biomarker used. Increasing PA is modestly associated with improving annual eGFRCysC and reduced risk of RDKF.

背景:以往关于体力活动(PA)与肾功能之间关系的研究并不一致。肌肉质量与血清肌酐(SCr)之间的关系可能会对解释体力活动对肾小球滤过率(eGFR)的影响产生影响。很少有研究报告了体育锻炼的变化和肾功能的变化:方法:利用英国生物库构建了一项队列研究。体力活动的变化以代谢当量任务(MET)分钟/周的形式进行自我报告。eGFR 使用 SCr 和胱抑素 C (CysC) 计算。采用限制性三次样条进行 Cox 回归和非线性回归,以探讨体力活动变化与肾功能快速下降(RDKF,eGFR 年下降率≥3 mL/min/1.73 m2)以及 eGFR 年变化之间的关系。对作为暴露因素的心肺功能进行了探索性分析:在 11 757 名参与者中,中位随访时间为 4.4 年。在随访评估中,如果参与者的业余爱好减少了 1000 MET 分钟/周,其罹患 RDKFSCr 的风险就会降低 2%(HR = 0.98,95% CI:0.96, 1.00)。相比之下,每周增加 1000 MET 分钟的 PA 与 RDKFCysC 患病风险降低 4% 相关(HR = 0.96,95% CI:0.93, 0.99)。PA每周增加1000 MET分钟与eGFRRCysC每年增加0.04 mL/min/1.73 m2(95% CI:0.03,0.06)有关,但eGFRSCr没有显著变化:在这项普通人群研究中,根据所使用的肾脏生物标志物,PA 的变化与肾功能的变化之间存在不同的关联。增加 PA 与改善每年的 eGFRCysC 和降低 RDKF 风险略有关联。
{"title":"Change in physical activity and its association with decline in kidney function: A UK Biobank-based cohort study","authors":"Qiaoling Liu,&nbsp;Carlos Celis-Morales,&nbsp;Jennifer S. Lees,&nbsp;Naveed Sattar,&nbsp;Frederick K. Ho,&nbsp;Jill P. Pell,&nbsp;Patrick B. Mark,&nbsp;Paul Welsh","doi":"10.1002/jcsm.13551","DOIUrl":"10.1002/jcsm.13551","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Previous research on the association between physical activity (PA) and kidney function is inconsistent. The association between muscle mass and serum creatinine (SCr) may have implications for interpreting the effect of PA on estimated glomerular filtration rate (eGFR). Few studies have reported changes in physical activity and changes in kidney function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A cohort study was constructed using the UK Biobank. Changes in physical activity were self-reported as metabolic equivalent task (MET) minutes/week. eGFR was calculated using SCr and cystatin C (CysC). Cox and nonlinear regressions with restricted cubic splines were applied to explore the association between changes in physical activity and rapid decline of kidney function (RDKF, eGFR annual decrease ≥3 mL/min/1.73 m<sup>2</sup>), and the annual change of eGFR. An exploratory analysis of cardiorespiratory fitness as the exposure was conducted.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 11 757 participants, the median follow-up time was 4.4 years. Participants whose PA decreased by 1000 MET minutes/week at the follow-up assessment had a 2% reduction in risk of developing RDKF<sub>SCr</sub> (HR = 0.98, 95% CI: 0.96, 1.00). In contrast, a 1000 MET minutes/week increase in PA was associated with a 4% reduction in risk of developing RDKF<sub>CysC</sub> (HR = 0.96, 95% CI: 0.93, 0.99). A PA increase of 1000 MET minutes/week was associated with eGFR<sub>CysC</sub> annual increase of 0.04 mL/min/1.73 m<sup>2</sup> (95% CI: 0.03, 0.06) but no significant changes in eGFR<sub>SCr</sub>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In this general population study, there are differing associations between changes in PA and changes in kidney function depending on the kidney biomarker used. Increasing PA is modestly associated with improving annual eGFR<sub>CysC</sub> and reduced risk of RDKF.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 5","pages":"2046-2055"},"PeriodicalIF":9.4,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999070","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
Regimen on Dnaja3 haploinsufficiency mediated sarcopenic obesity with imbalanced mitochondrial homeostasis and lipid metabolism 针对 Dnaja3 单倍体缺失介导的肌肉疏松性肥胖以及线粒体平衡和脂质代谢失衡的治疗方案。
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-08-12 DOI: 10.1002/jcsm.13549
Yu-Ning Fann, Wan-Huai Teo, Hsin-Chen Lee, Chen-Chung Liao, Yeou-Guang Tsay, Tung-Fu Huang, Jeng-Fan Lo
<div> <section> <h3> Background</h3> <p>Sarcopenic obesity is characterized by excess fat mass and diminished muscular mass/function. DNAJA3, a mitochondrial co-chaperone protein, plays a crucial role in skeletal muscle development. GMI, an immunomodulatory protein, promotes myogenic differentiation through DNAJA3 activation. This study aims to elucidate the physiological effects of muscular <i>Dnaja3</i> haploinsufficiency on mitochondrial dysfunction and dysregulated lipid metabolism and to assess the efficacy of GMI in rescuing sarcopenic obesity both <i>in vitro</i> and <i>in vivo</i>.</p> </section> <section> <h3> Methods</h3> <p>We generated mouse strain with <i>Dnaja3</i> heterozygosity (<i>HSA-Dnaja3</i><sup><i>f/+</i></sup>) specifically in skeletal muscle. The body weight, body composition, and locomotor activity of WT and <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> mice were examined. The isolated skeletal muscles and primary myoblasts from the WT and <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> mice, at young or old age, were utilized to study the molecular mechanisms, mitochondrial respiration and ROS level, mitochondrial proteomes, and serological analyses, respectively. To evaluate the therapeutic efficacy of GMI, both short-term and long-term GMI treatment were administrated intraperitoneally to the <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> young (4 weeks old) or adult (3 months old) mice for a duration of either 1 or 6 months, respectively.</p> </section> <section> <h3> Results</h3> <p>Muscular <i>Dnaja3</i> heterozygosity resulted in impaired locomotor activity (<i>P</i> < 0.05), reduced muscular cross-sectional area (<i>P</i> < 0.0001), and up-regulation of lipogenesis (ACC2) and pro-inflammation (STAT3) in skeletal muscles (<i>P</i> < 0.05). Primary myoblasts from the <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> mice displayed impaired mitochondrial respiration (<i>P</i> < 0.01) and imbalanced mitochondrial ROS levels. A systemic proteomic analysis of the purified mitochondria from the primary myoblasts was conducted to show the abnormalities in mitochondrial function and fatty acid metabolism (<i>P</i> < 0.0001). At age of 13 to 14 months, the <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> mice displayed increased body fat mass (<i>P</i> < 0.001), reduced fat-free mass (<i>P</i> < 0.01), and impaired glucose and insulin tolerance (<i>P</i> < 0.01). The short-term GMI treatment improved locomotor activity (<i>P</i> < 0.01) and down-regulated the protein levels of STAT3 (<i>P</i> < 0.05), ACC2, and mitochondrial respiratory complex III (UQCRC2) (<i>P</i> < 0.01) via DNAJA3 activation. The long-term GMI treatment ameliorated
背景:肌肉疏松性肥胖症的特征是脂肪量过多和肌肉质量/功能下降。DNAJA3是一种线粒体辅助伴侣蛋白,在骨骼肌发育过程中起着至关重要的作用。GMI是一种免疫调节蛋白,可通过激活DNAJA3促进肌肉分化。本研究旨在阐明肌肉 Dnaja3 单倍体缺失对线粒体功能障碍和脂质代谢失调的生理影响,并评估 GMI 在体外和体内拯救肌肉疏松性肥胖的功效:方法:我们产生了骨骼肌特异性 Dnaja3 杂合子小鼠品系(HSA-Dnaja3f/+)。我们检测了 WT 和 HSA-Dnaja3f/+ 小鼠的体重、身体成分和运动活性。研究人员利用 WT 小鼠和 HSA-Dnaja3f/+ 小鼠幼年或老年时分离的骨骼肌和原代肌母细胞,分别对其分子机制、线粒体呼吸和 ROS 水平、线粒体蛋白质组和血清学分析进行了研究。为了评估 GMI 的疗效,分别给 HSA-Dnaja3f/+ 幼鼠(4 周大)或成年鼠(3 个月大)腹腔注射短期和长期 GMI,疗程分别为 1 个月或 6 个月:结果:肌肉 Dnaja3 杂合子导致小鼠运动能力受损(P f/+ 小鼠线粒体呼吸能力受损(P f/+ 小鼠体脂量增加(P 结论:肌肉 Dnaja3 杂合子导致小鼠运动能力受损(P f/+ 小鼠线粒体呼吸能力受损(P f/+ 小鼠体脂量增加)):肌肉 Dnaja3 单倍体缺失会导致线粒体功能和脂质代谢失调,进而导致肌肉疏松性肥胖。通过激活 DNAJA3,GMI 成为治疗肌肉疏松性肥胖症的一种疗法。
{"title":"Regimen on Dnaja3 haploinsufficiency mediated sarcopenic obesity with imbalanced mitochondrial homeostasis and lipid metabolism","authors":"Yu-Ning Fann,&nbsp;Wan-Huai Teo,&nbsp;Hsin-Chen Lee,&nbsp;Chen-Chung Liao,&nbsp;Yeou-Guang Tsay,&nbsp;Tung-Fu Huang,&nbsp;Jeng-Fan Lo","doi":"10.1002/jcsm.13549","DOIUrl":"10.1002/jcsm.13549","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;Sarcopenic obesity is characterized by excess fat mass and diminished muscular mass/function. DNAJA3, a mitochondrial co-chaperone protein, plays a crucial role in skeletal muscle development. GMI, an immunomodulatory protein, promotes myogenic differentiation through DNAJA3 activation. This study aims to elucidate the physiological effects of muscular &lt;i&gt;Dnaja3&lt;/i&gt; haploinsufficiency on mitochondrial dysfunction and dysregulated lipid metabolism and to assess the efficacy of GMI in rescuing sarcopenic obesity both &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&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;We generated mouse strain with &lt;i&gt;Dnaja3&lt;/i&gt; heterozygosity (&lt;i&gt;HSA-Dnaja3&lt;/i&gt;&lt;sup&gt;&lt;i&gt;f/+&lt;/i&gt;&lt;/sup&gt;) specifically in skeletal muscle. The body weight, body composition, and locomotor activity of WT and &lt;i&gt;HSA-Dnaja3&lt;/i&gt;&lt;sup&gt;&lt;i&gt;f/+&lt;/i&gt;&lt;/sup&gt; mice were examined. The isolated skeletal muscles and primary myoblasts from the WT and &lt;i&gt;HSA-Dnaja3&lt;/i&gt;&lt;sup&gt;&lt;i&gt;f/+&lt;/i&gt;&lt;/sup&gt; mice, at young or old age, were utilized to study the molecular mechanisms, mitochondrial respiration and ROS level, mitochondrial proteomes, and serological analyses, respectively. To evaluate the therapeutic efficacy of GMI, both short-term and long-term GMI treatment were administrated intraperitoneally to the &lt;i&gt;HSA-Dnaja3&lt;/i&gt;&lt;sup&gt;&lt;i&gt;f/+&lt;/i&gt;&lt;/sup&gt; young (4 weeks old) or adult (3 months old) mice for a duration of either 1 or 6 months, respectively.&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;Muscular &lt;i&gt;Dnaja3&lt;/i&gt; heterozygosity resulted in impaired locomotor activity (&lt;i&gt;P&lt;/i&gt; &lt; 0.05), reduced muscular cross-sectional area (&lt;i&gt;P&lt;/i&gt; &lt; 0.0001), and up-regulation of lipogenesis (ACC2) and pro-inflammation (STAT3) in skeletal muscles (&lt;i&gt;P&lt;/i&gt; &lt; 0.05). Primary myoblasts from the &lt;i&gt;HSA-Dnaja3&lt;/i&gt;&lt;sup&gt;&lt;i&gt;f/+&lt;/i&gt;&lt;/sup&gt; mice displayed impaired mitochondrial respiration (&lt;i&gt;P&lt;/i&gt; &lt; 0.01) and imbalanced mitochondrial ROS levels. A systemic proteomic analysis of the purified mitochondria from the primary myoblasts was conducted to show the abnormalities in mitochondrial function and fatty acid metabolism (&lt;i&gt;P&lt;/i&gt; &lt; 0.0001). At age of 13 to 14 months, the &lt;i&gt;HSA-Dnaja3&lt;/i&gt;&lt;sup&gt;&lt;i&gt;f/+&lt;/i&gt;&lt;/sup&gt; mice displayed increased body fat mass (&lt;i&gt;P&lt;/i&gt; &lt; 0.001), reduced fat-free mass (&lt;i&gt;P&lt;/i&gt; &lt; 0.01), and impaired glucose and insulin tolerance (&lt;i&gt;P&lt;/i&gt; &lt; 0.01). The short-term GMI treatment improved locomotor activity (&lt;i&gt;P&lt;/i&gt; &lt; 0.01) and down-regulated the protein levels of STAT3 (&lt;i&gt;P&lt;/i&gt; &lt; 0.05), ACC2, and mitochondrial respiratory complex III (UQCRC2) (&lt;i&gt;P&lt;/i&gt; &lt; 0.01) via DNAJA3 activation. The long-term GMI treatment ameliorated ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 5","pages":"2013-2029"},"PeriodicalIF":9.4,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915606","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
Different outcomes of endurance and resistance exercise in skeletal muscles of Oculopharyngeal muscular dystrophy 眼咽肌营养不良症患者骨骼肌耐力运动和阻力运动的不同结果。
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-08-07 DOI: 10.1002/jcsm.13546
Alexis Boulinguiez, Jamila Dhiab, Barbara Crisol, Laura Muraine, Ludovic Gaut, Corentin Rouxel, Justine Flaire, Hadidja-Rose Mouigni, Mégane Lemaitre, Benoit Giroux, Lucie Audoux, Benjamin SaintPierre, Arnaud Ferry, Vincent Mouly, Gillian Butler-Browne, Elisa Negroni, Alberto Malerba, Capucine Trollet
<div> <section> <h3> Background</h3> <p>Exercise is widely considered to have beneficial impact on skeletal muscle aging. In addition, there are also several studies demonstrating a positive effect of exercise on muscular dystrophies. Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant inherited neuromuscular disorder caused by mutations in the <i>PAPBN1</i> gene. These mutations consist in short (1-8) and meiotically stable GCN trinucleotide repeat expansions in its coding region responsible for the formation of PAPBN1 intranuclear aggregates. This study aims to characterize the effects of two types of chronic exercise, resistance and endurance, on the OPMD skeletal muscle phenotype using a relevant murine model of OPMD.</p> </section> <section> <h3> Methods</h3> <p>In this study, we tested two protocols of exercise. In the first, based on endurance exercise, FvB (wild-type) and A17 (OPMD) mice underwent a 6-week-long motorized treadmill protocol consisting in three sessions per week of running 20 cm/s for 20 min. In the second protocol, based on resistance exercise generated by chronic mechanical overload (OVL), surgical removal of <i>gastrocnemius</i> and <i>soleus</i> muscles was performed, inducing hypertrophy of the <i>plantaris</i> muscle. In both types of exercise, muscles of A17 and FvB mice were compared with those of respective sedentary mice. For all the groups, force measurement, muscle histology, and molecular analyses were conducted.</p> </section> <section> <h3> Results</h3> <p>Following the endurance exercise protocol, we did not observe any major changes in the muscle physiological parameters, but an increase in the number of PABPN1 intranuclear aggregates in both <i>tibialis anterior</i> (+24%, **<i>P</i> = 0.0026) and <i>gastrocnemius</i> (+18%, ****<i>P</i> < 0.0001) as well as enhanced collagen deposition (+20%, **<i>P</i> = 0.0064 in the <i>tibialis anterior</i>; +35%, **<i>P</i> = 0.0042 in the <i>gastrocnemius</i>) in the exercised A17 OPMD mice. In the supraphysiological resistance overload protocol, we also observed an increased collagen deposition (×2, ****<i>P</i> < 0.0001) in the <i>plantaris</i> muscle of A17 OPMD mice which was associated with larger muscle mass (×2, ****<i>P</i> < 0.0001) and fibre cross sectional area (×2, ***<i>P</i> = 0.0007) and increased absolute maximal force (×2, ****<i>P</i> < 0.0001) as well as a reduction in PABPN1 aggregate number (−16%, ****<i>P</i> < 0.0001).</p> </section> <section> <h3> Conclusions</h3> <p>Running exercise and mechanical overloa
背景:运动被广泛认为对骨骼肌老化有好处。此外,也有一些研究表明运动对肌肉萎缩症有积极影响。眼咽肌营养不良症(OPMD)是一种晚发型常染色体显性遗传神经肌肉疾病,由 PAPBN1 基因突变引起。这些突变包括其编码区中短的(1-8)和减数分裂稳定的 GCN 三核苷酸重复扩增,导致 PAPBN1 核内聚集体的形成。本研究旨在利用一个相关的 OPMD 小鼠模型,描述两种类型的慢性运动(阻力运动和耐力运动)对 OPMD 骨骼肌表型的影响:在这项研究中,我们测试了两种运动方案。第一种方案以耐力运动为基础,FvB(野生型)和A17(OPMD)小鼠接受了为期6周的电动跑步机方案,每周三次,每次20厘米/秒,每次20分钟。第二个方案基于慢性机械过载(OVL)产生的阻力运动,通过手术切除腓肠肌和比目鱼肌,诱导跖肌肥大。在这两种类型的运动中,A17 和 FvB 小鼠的肌肉与各自的静止小鼠的肌肉进行了比较。对所有组别进行了力量测量、肌肉组织学和分子分析:结果:耐力锻炼后,我们没有观察到肌肉生理参数发生任何重大变化,但胫骨前肌(+24%,**P = 0.0026)和腓肠肌(+18%,****P)核内PABPN1聚集体的数量增加了:跑步运动和机械过载对 A17 小鼠骨骼肌的影响截然不同。两种类型的运动都会促进胶原蛋白沉积,但跑步会增加聚集体,而 OVL 则会减少聚集体。更重要的是,OVL 逆转了 A17 小鼠的肌肉萎缩和最大力量。我们在相关模型中进行的研究表明了不同类型的运动对 OPMD 肌肉的影响,应在人体中进行进一步评估,以便作为 OPMD 患者未来生活方式的一部分提出建议。
{"title":"Different outcomes of endurance and resistance exercise in skeletal muscles of Oculopharyngeal muscular dystrophy","authors":"Alexis Boulinguiez,&nbsp;Jamila Dhiab,&nbsp;Barbara Crisol,&nbsp;Laura Muraine,&nbsp;Ludovic Gaut,&nbsp;Corentin Rouxel,&nbsp;Justine Flaire,&nbsp;Hadidja-Rose Mouigni,&nbsp;Mégane Lemaitre,&nbsp;Benoit Giroux,&nbsp;Lucie Audoux,&nbsp;Benjamin SaintPierre,&nbsp;Arnaud Ferry,&nbsp;Vincent Mouly,&nbsp;Gillian Butler-Browne,&nbsp;Elisa Negroni,&nbsp;Alberto Malerba,&nbsp;Capucine Trollet","doi":"10.1002/jcsm.13546","DOIUrl":"10.1002/jcsm.13546","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;Exercise is widely considered to have beneficial impact on skeletal muscle aging. In addition, there are also several studies demonstrating a positive effect of exercise on muscular dystrophies. Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant inherited neuromuscular disorder caused by mutations in the &lt;i&gt;PAPBN1&lt;/i&gt; gene. These mutations consist in short (1-8) and meiotically stable GCN trinucleotide repeat expansions in its coding region responsible for the formation of PAPBN1 intranuclear aggregates. This study aims to characterize the effects of two types of chronic exercise, resistance and endurance, on the OPMD skeletal muscle phenotype using a relevant murine model of OPMD.&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, we tested two protocols of exercise. In the first, based on endurance exercise, FvB (wild-type) and A17 (OPMD) mice underwent a 6-week-long motorized treadmill protocol consisting in three sessions per week of running 20 cm/s for 20 min. In the second protocol, based on resistance exercise generated by chronic mechanical overload (OVL), surgical removal of &lt;i&gt;gastrocnemius&lt;/i&gt; and &lt;i&gt;soleus&lt;/i&gt; muscles was performed, inducing hypertrophy of the &lt;i&gt;plantaris&lt;/i&gt; muscle. In both types of exercise, muscles of A17 and FvB mice were compared with those of respective sedentary mice. For all the groups, force measurement, muscle histology, and molecular analyses were conducted.&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;Following the endurance exercise protocol, we did not observe any major changes in the muscle physiological parameters, but an increase in the number of PABPN1 intranuclear aggregates in both &lt;i&gt;tibialis anterior&lt;/i&gt; (+24%, **&lt;i&gt;P&lt;/i&gt; = 0.0026) and &lt;i&gt;gastrocnemius&lt;/i&gt; (+18%, ****&lt;i&gt;P&lt;/i&gt; &lt; 0.0001) as well as enhanced collagen deposition (+20%, **&lt;i&gt;P&lt;/i&gt; = 0.0064 in the &lt;i&gt;tibialis anterior&lt;/i&gt;; +35%, **&lt;i&gt;P&lt;/i&gt; = 0.0042 in the &lt;i&gt;gastrocnemius&lt;/i&gt;) in the exercised A17 OPMD mice. In the supraphysiological resistance overload protocol, we also observed an increased collagen deposition (×2, ****&lt;i&gt;P&lt;/i&gt; &lt; 0.0001) in the &lt;i&gt;plantaris&lt;/i&gt; muscle of A17 OPMD mice which was associated with larger muscle mass (×2, ****&lt;i&gt;P&lt;/i&gt; &lt; 0.0001) and fibre cross sectional area (×2, ***&lt;i&gt;P&lt;/i&gt; = 0.0007) and increased absolute maximal force (×2, ****&lt;i&gt;P&lt;/i&gt; &lt; 0.0001) as well as a reduction in PABPN1 aggregate number (−16%, ****&lt;i&gt;P&lt;/i&gt; &lt; 0.0001).&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;Running exercise and mechanical overloa","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 5","pages":"1976-1988"},"PeriodicalIF":9.4,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900293","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
l-Carnitine relieves cachexia-related skeletal muscle fibrosis by inducing deltex E3 ubiquitin ligase 3L to negatively regulate the Runx2/COL1A1 axis 左旋肉碱通过诱导 deltex E3 泛素连接酶 3L 负向调节 Runx2/COL1A1 轴,缓解与恶病质相关的骨骼肌纤维化。
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-08-02 DOI: 10.1002/jcsm.13544
Zongliang Lu, Li Wang, Zhenyu Huo, Na Li, Ning Tong, Feifei Chong, Jie Liu, Yaowen Zhang, Hongxia Xu
<div> <section> <h3> Background</h3> <p>Cancer cachexia-induced skeletal muscle fibrosis (SMF) impairs muscle regeneration, alters the muscle structure and function, reduces the efficacy of anticancer drugs, diminishes the patient's quality of life and shortens overall survival. RUNX family transcription factor 2 (Runx2), a transcription factor, and collagen type I alpha 1 chain (COL1A1), the principal constituent of SMF, have been linked previously, with Runx2 shown to directly modulate COL1A1 mRNA levels. <span>l</span>-Carnitine, a marker of cancer cachexia, can alleviate fibrosis in liver and kidney models; however, its role in cancer cachexia-associated fibrosis and the involvement of Runx2 in the process remain unexplored.</p> </section> <section> <h3> Methods</h3> <p>Female C57 mice (48 weeks old) were inoculated subcutaneously with MC38 cells to establish a cancer cachexia model. A 5 mg/kg dose of <span>l</span>-carnitine or an equivalent volume of water was administered for 14 days via oral gavage, followed by assessments of muscle function (grip strength) and fibrosis. To elucidate the interplay between the deltex E3 ubiquitin ligase 3L(DTX3L)/Runx2/COL1A1 axis and fibrosis in transforming growth factor beta 1-stimulated NIH/3T3 cells, a suite of molecular techniques, including quantitative real-time PCR, western blot analysis, co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays, were used. The relevance of the DTX3L/Runx2/COL1A1 axis in the gastrocnemius was also explored in the in vivo model.</p> </section> <section> <h3> Results</h3> <p><span>l</span>-Carnitine supplementation reduced cancer cachexia-induced declines in grip strength (>88.2%, <i>P</i> < 0.05) and the collagen fibre area within the gastrocnemius (>57.9%, <i>P</i> < 0.05). At the 5 mg/kg dose, <span>l</span>-carnitine also suppressed COL1A1 and alpha-smooth muscle actin (α-SMA) protein expression, which are markers of SMF and myofibroblasts. Analyses of the TRRUST database indicated that Runx2 regulates both COL1A1 and COL1A2. In vitro, <span>l</span>-carnitine diminished Runx2 protein levels and promoted its ubiquitination. Overexpression of Runx2 abolished the effects of <span>l</span>-carnitine on COL1A1 and α-SMA. Co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays confirmed an interaction between DTX3L and Runx2, with <span>l</span>-carnitine enhancing this interaction to promote Runx2 ubiquitination. <span>l</span>-Carnitine supplementation restored DTX3L levels to those observed under non-cachectic conditions, both in vitro and in vivo. Knockdown of DTX3L abolished the effects of <span>l</span>-
背景:癌症恶病质诱发的骨骼肌纤维化(SMF)会影响肌肉再生、改变肌肉结构和功能、降低抗癌药物的疗效、降低患者的生活质量并缩短总生存期。RUNX家族转录因子2(Runx2)是一种转录因子,它与SMF的主要成分I型胶原蛋白α1链(COL1A1)有关联,Runx2可直接调节COL1A1 mRNA水平:雌性 C57 小鼠(48 周大)皮下接种 MC38 细胞,建立癌症恶病质模型。连续14天通过口服灌胃给药5毫克/千克剂量的左旋肉碱或同等体积的水,然后评估肌肉功能(握力)和纤维化。为了阐明Deltex E3泛素连接酶3L(DTX3L)/Runx2/COL1A1轴与转化生长因子β1刺激的NIH/3T3细胞纤维化之间的相互作用,研究人员使用了一系列分子技术,包括定量实时PCR、Western印迹分析、共免疫沉淀、分子对接、免疫荧光和Duolink检测。结果:补充左旋肉碱可减少癌症恶病质诱发的握力下降(>88.2%,P 57.9%,P 结论:该研究揭示了一种以前未被认识的新的腓肠肌肌酸激酶--DTX3L/Runx2/COL1A1轴:这项研究揭示了Runx2和DTX3L在SMF中的联系,并证明了左旋肉碱对癌症恶病质相关SMF有显著的治疗作用,这可能是通过上调DTX3L实现的。
{"title":"l-Carnitine relieves cachexia-related skeletal muscle fibrosis by inducing deltex E3 ubiquitin ligase 3L to negatively regulate the Runx2/COL1A1 axis","authors":"Zongliang Lu,&nbsp;Li Wang,&nbsp;Zhenyu Huo,&nbsp;Na Li,&nbsp;Ning Tong,&nbsp;Feifei Chong,&nbsp;Jie Liu,&nbsp;Yaowen Zhang,&nbsp;Hongxia Xu","doi":"10.1002/jcsm.13544","DOIUrl":"10.1002/jcsm.13544","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-induced skeletal muscle fibrosis (SMF) impairs muscle regeneration, alters the muscle structure and function, reduces the efficacy of anticancer drugs, diminishes the patient's quality of life and shortens overall survival. RUNX family transcription factor 2 (Runx2), a transcription factor, and collagen type I alpha 1 chain (COL1A1), the principal constituent of SMF, have been linked previously, with Runx2 shown to directly modulate COL1A1 mRNA levels. &lt;span&gt;l&lt;/span&gt;-Carnitine, a marker of cancer cachexia, can alleviate fibrosis in liver and kidney models; however, its role in cancer cachexia-associated fibrosis and the involvement of Runx2 in the process remain unexplored.&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;Female C57 mice (48 weeks old) were inoculated subcutaneously with MC38 cells to establish a cancer cachexia model. A 5 mg/kg dose of &lt;span&gt;l&lt;/span&gt;-carnitine or an equivalent volume of water was administered for 14 days via oral gavage, followed by assessments of muscle function (grip strength) and fibrosis. To elucidate the interplay between the deltex E3 ubiquitin ligase 3L(DTX3L)/Runx2/COL1A1 axis and fibrosis in transforming growth factor beta 1-stimulated NIH/3T3 cells, a suite of molecular techniques, including quantitative real-time PCR, western blot analysis, co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays, were used. The relevance of the DTX3L/Runx2/COL1A1 axis in the gastrocnemius was also explored in the in vivo model.&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;&lt;span&gt;l&lt;/span&gt;-Carnitine supplementation reduced cancer cachexia-induced declines in grip strength (&gt;88.2%, &lt;i&gt;P&lt;/i&gt; &lt; 0.05) and the collagen fibre area within the gastrocnemius (&gt;57.9%, &lt;i&gt;P&lt;/i&gt; &lt; 0.05). At the 5 mg/kg dose, &lt;span&gt;l&lt;/span&gt;-carnitine also suppressed COL1A1 and alpha-smooth muscle actin (α-SMA) protein expression, which are markers of SMF and myofibroblasts. Analyses of the TRRUST database indicated that Runx2 regulates both COL1A1 and COL1A2. In vitro, &lt;span&gt;l&lt;/span&gt;-carnitine diminished Runx2 protein levels and promoted its ubiquitination. Overexpression of Runx2 abolished the effects of &lt;span&gt;l&lt;/span&gt;-carnitine on COL1A1 and α-SMA. Co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays confirmed an interaction between DTX3L and Runx2, with &lt;span&gt;l&lt;/span&gt;-carnitine enhancing this interaction to promote Runx2 ubiquitination. &lt;span&gt;l&lt;/span&gt;-Carnitine supplementation restored DTX3L levels to those observed under non-cachectic conditions, both in vitro and in vivo. Knockdown of DTX3L abolished the effects of &lt;span&gt;l&lt;/span&gt;-","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 5","pages":"1953-1964"},"PeriodicalIF":9.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873688","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
The mortality burden of cachexia or weight loss in patients with colorectal or pancreatic cancer: A systematic literature review 结直肠癌或胰腺癌患者恶病质或体重减轻对死亡率造成的负担:系统性文献综述。
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-08-02 DOI: 10.1002/jcsm.13510
Richard F. Dunne, Jeffrey Crawford, Karen E. Smoyer, Thomas D. McRae, Michelle I. Rossulek, James H. Revkin, Lisa C. Tarasenko, Philip D. Bonomi

Cancer-associated cachexia is a multifactorial wasting disorder characterized by anorexia, unintentional weight loss (skeletal muscle mass with or without loss of fat mass), progressive functional impairment, and poor prognosis. This systematic literature review (SLR) examined the relationship between cachexia and survival in patients with colorectal or pancreatic cancer in recent literature. The SLR was conducted following PRISMA guidelines. Embase® and PubMed were searched to identify articles published in English between 1 January 2016 and 10 October 2021 reporting survival in adults with cancer and cachexia or at risk of cachexia, defined by international consensus (IC) diagnostic criteria or a broader definition of any weight loss. Included publications were studies in ≥100 patients with colorectal or pancreatic cancer. Thirteen publications in patients with colorectal cancer and 13 with pancreatic cancer met eligibility criteria. Included studies were observational and primarily from Europe and the United States. Eleven studies (42%) reported cachexia using IC criteria and 15 (58%) reported any weight loss. An association between survival and cachexia or weight loss was assessed across studies using multivariate (n = 23) or univariate (n = 3) analyses and within each study across multiple weight loss categories. Cachexia/weight loss was associated with a statistically significantly poorer survival in at least one weight loss category in 16 of 23 studies that used multivariate analyses and in 1 of 3 studies (33%) that used univariate analyses. Of the 17 studies demonstrating a significant association, 9 were in patients with colorectal cancer and 8 were in patients with pancreatic cancer. Cachexia or weight loss was associated with significantly poorer survival in patients with colorectal or pancreatic cancer in nearly two-thirds of the studies. The classification of weight loss varied across and within studies (multiple categories were evaluated) and may have contributed to variability. Nonetheless, awareness of cachexia and routine assessment of weight change in clinical practice in patients with colorectal or pancreatic cancer could help inform prognosis and influence early disease management strategies.

癌症相关恶病质是一种多因素消瘦性疾病,其特征是厌食、无意中体重减轻(骨骼肌质量下降,伴有或不伴有脂肪质量下降)、进行性功能障碍和预后不良。本系统性文献综述(SLR)研究了近期文献中结直肠癌或胰腺癌患者恶病质与生存之间的关系。SLR遵循PRISMA指南进行。对 Embase® 和 PubMed 进行了检索,以确定 2016 年 1 月 1 日至 2021 年 10 月 10 日期间发表的、报道成人癌症患者生存率和恶病质或有恶病质风险(根据国际共识 (IC) 诊断标准或任何体重减轻的更广泛定义)的英文文章。纳入的文献均为对≥100 名结直肠癌或胰腺癌患者进行的研究。有 13 篇针对结直肠癌患者和 13 篇针对胰腺癌患者的研究符合资格标准。纳入的研究均为观察性研究,主要来自欧洲和美国。11项研究(42%)采用IC标准报告了恶病质,15项研究(58%)报告了体重减轻。通过多变量分析(n = 23)或单变量分析(n = 3)评估了不同研究中生存率与恶病质或体重减轻之间的关系,并在每项研究中评估了多个体重减轻类别。在采用多变量分析的 23 项研究中,有 16 项研究的至少一个体重减轻类别与恶病质/体重减轻相关,而在采用单变量分析的 3 项研究中,有 1 项研究(33%)的至少一个体重减轻类别与较差的存活率相关。在 17 项有显著相关性的研究中,9 项针对结直肠癌患者,8 项针对胰腺癌患者。在近三分之二的研究中,痛风或体重减轻与结直肠癌或胰腺癌患者生存率明显降低有关。不同研究和研究内部对体重减轻的分类各不相同(评估了多个类别),这可能是造成差异的原因之一。不过,在结直肠癌或胰腺癌患者的临床实践中,对恶病质的认识和对体重变化的常规评估有助于为预后提供信息并影响早期疾病管理策略。
{"title":"The mortality burden of cachexia or weight loss in patients with colorectal or pancreatic cancer: A systematic literature review","authors":"Richard F. Dunne,&nbsp;Jeffrey Crawford,&nbsp;Karen E. Smoyer,&nbsp;Thomas D. McRae,&nbsp;Michelle I. Rossulek,&nbsp;James H. Revkin,&nbsp;Lisa C. Tarasenko,&nbsp;Philip D. Bonomi","doi":"10.1002/jcsm.13510","DOIUrl":"10.1002/jcsm.13510","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Cancer-associated cachexia is a multifactorial wasting disorder characterized by anorexia, unintentional weight loss (skeletal muscle mass with or without loss of fat mass), progressive functional impairment, and poor prognosis. This systematic literature review (SLR) examined the relationship between cachexia and survival in patients with colorectal or pancreatic cancer in recent literature. The SLR was conducted following PRISMA guidelines. Embase<sup>®</sup> and PubMed were searched to identify articles published in English between 1 January 2016 and 10 October 2021 reporting survival in adults with cancer and cachexia or at risk of cachexia, defined by international consensus (IC) diagnostic criteria or a broader definition of any weight loss. Included publications were studies in ≥100 patients with colorectal or pancreatic cancer. Thirteen publications in patients with colorectal cancer and 13 with pancreatic cancer met eligibility criteria. Included studies were observational and primarily from Europe and the United States. Eleven studies (42%) reported cachexia using IC criteria and 15 (58%) reported any weight loss. An association between survival and cachexia or weight loss was assessed across studies using multivariate (<i>n</i> = 23) or univariate (<i>n</i> = 3) analyses and within each study across multiple weight loss categories. Cachexia/weight loss was associated with a statistically significantly poorer survival in at least one weight loss category in 16 of 23 studies that used multivariate analyses and in 1 of 3 studies (33%) that used univariate analyses. Of the 17 studies demonstrating a significant association, 9 were in patients with colorectal cancer and 8 were in patients with pancreatic cancer. Cachexia or weight loss was associated with significantly poorer survival in patients with colorectal or pancreatic cancer in nearly two-thirds of the studies. The classification of weight loss varied across and within studies (multiple categories were evaluated) and may have contributed to variability. Nonetheless, awareness of cachexia and routine assessment of weight change in clinical practice in patients with colorectal or pancreatic cancer could help inform prognosis and influence early disease management strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 5","pages":"1628-1640"},"PeriodicalIF":9.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877942","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
Sex similarities and divergences in systemic and muscle iron metabolism adaptations to extreme physical inactivity in rats 大鼠全身和肌肉铁代谢对极端缺乏运动的适应性的性别相似性和差异性
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-07-24 DOI: 10.1002/jcsm.13547
Mathieu Horeau, Melissa Delalande, Martine Ropert, Patricia Leroyer, Brice Martin, Luz Orfila, Olivier Loréal, Frédéric Derbré
<div> <section> <h3> Background</h3> <p>Previous data in humans suggest that extreme physical inactivity (EPI) affects iron metabolism differently between sexes. Our objective was to deepen the underlying mechanisms by studying rats of both sexes exposed to hindlimb unloading (HU), the reference experimental model mimicking EPI.</p> </section> <section> <h3> Methods</h3> <p>Eight-week-old male and female Wistar rats were assigned to control (CTL) or hindlimb unloading (HU) conditions (<i>n</i> = 12/group). After 7 days of HU, serum, liver, spleen, and soleus muscle were removed. Iron parameters were measured in serum samples, and ICP-MS was used to quantify iron in tissues. Iron metabolism genes and proteins were analysed by RT-qPCR and Western blot.</p> </section> <section> <h3> Results</h3> <p>Compared with control males, control females exhibited higher iron concentrations in serum (+43.3%, <i>p</i> < 0.001), liver (LIC; +198%, <i>P</i> < 0.001), spleen (SIC; +76.1%, <i>P</i> < 0.001), and transferrin saturation (TS) in serum (+53.3%, <i>P</i> < 0.001), contrasting with previous observations in humans. HU rat males, but not females, exhibited an increase of LIC (+54% <i>P</i> < 0.001) and SIC (+30.1%, <i>P</i> = 0.023), along with a rise of H-ferritin protein levels (+60.9% and +134%, respectively, in liver and spleen; <i>P</i> < 0.05) and a decrease of TFRC protein levels (−36%; −50%, respectively, <i>P</i> < 0.05). HU males also exhibited an increase of splenic <i>HO-1</i> and <i>NRF2</i> mRNA levels, (<i>p</i> < 0.001), as well as HU females (<i>P</i> < 0.001). Concomitantly to muscle atrophy observed in HU animals, the iron concentration increased in soleus in females (+26.7, <i>P</i> = 0.004) while only a trend is observed in males (+17.5%, <i>P</i> = 0.088). In addition, the H-ferritin and myoglobin protein levels in soleus were increased in males (+748%, <i>P</i> < 0.001, +22%, <i>P</i> = 0.011, respectively) and in females (+369%, <i>P</i> < 0.001, +21.9%, <i>P</i> = 0.007, respectively), whereas TFRC and ferroportin (FPN) protein levels were reduced in males (−68.9%, <i>P</i> < 0.001, −76.8%, <i>P</i> < 0.001, respectively) and females (−75.9%, <i>P</i> < 0.001, −62.9%, <i>P</i> < 0.001, respectively). Interestingly, in both sexes, heme exporter FLVCR1 mRNA increased in soleus, while protein levels decreased (−39.9% for males <i>P</i> = 0.010 and −49.1% for females <i>P</i> < 0.001).</p> </section> <section> <h3> Conclusions</h3> <p>Taken together, these data support that, in rats (1) extr
以前的人类数据表明,极端缺乏体力活动(EPI)对铁代谢的影响在性别上有所不同。我们的目的是通过研究暴露于后肢卸载(HU)(模拟 EPI 的参考实验模型)的雌雄大鼠来深入研究其潜在机制。
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引用次数: 0
Roles of programmed death-1 and muscle innate lymphoid cell-derived interleukin 13 in sepsis-induced intensive care unit-acquired weakness 程序性死亡-1和肌肉先天性淋巴细胞衍生白细胞介素13在败血症诱发的重症监护室获得性虚弱中的作用。
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-07-17 DOI: 10.1002/jcsm.13548
Yuichi Akama, Eun Jeong Park, Naoko Satoh-Takayama, Atsushi Ito, Eiji Kawamoto, Arong Gaowa, Eri Matsuo, Satoshi Oikawa, Masafumi Saito, Shigeaki Inoue, Takayuki Akimoto, Kei Suzuki, Motomu Shimaoka
<div> <section> <h3> Background</h3> <p>Intensive care unit-acquired weakness (ICU-AW) is a syndrome characterized by a long-term muscle weakness often observed in sepsis-surviving patients during the chronic phase. Although ICU-AW is independently associated with increased mortality, effective therapies have yet to be established. Programmed death-1 (PD-1) inhibitors have attracted attention as potential treatments for reversing immune exhaustion in sepsis; however, its impact on ICU-AW remains to be elucidated. Here, we study how PD-1 deficiency affects sepsis-induced skeletal muscle dysfunction in a preclinical sepsis model.</p> </section> <section> <h3> Methods</h3> <p>Chronic sepsis model was developed by treating wild-type (WT) and PD-1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15–17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL-13) and PD-1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow-twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). In an <i>in vitro</i> study, C2C12 myotubes were treated with lipopolysaccharide (LPS) and recombinant IL-13 followed by gene expression measurements.</p> </section> <section> <h3> Results</h3> <p>WT septic mice exhibited decreased muscle weight (quadriceps, <i>P</i> < 0.01; gastrocnemius, <i>P</i> < 0.05; and tibialis anterior, <i>P</i> < 0.01) and long-term muscle weakness (<i>P</i> < 0.0001), whereas PD-1 KO septic mice did not exhibit any reduction in muscle weights and strengths. Slow-twitch specific mRNAs, including myoglobin (<i>Mb</i>), troponin I type 1 (<i>Tnni1</i>), and myosin heavy chain 7 (<i>Myh7</i>) were decreased in WT skeletal muscle (<i>Mb</i>, <i>P</i> < 0.0001; <i>Tnni1</i>, <i>P</i> < 0.05; and <i>Myh7</i>, <i>P</i> < 0.05) after sepsis induction, but mRNA expressions of Tnni1 and Myh7 were increased in PD-1 KO septic mice (<i>Mb</i>, not significant; <i>Tnni1</i>, <i>P</i> < 0.0001; and <i>Myh7</i>, <i>P</i> < 0.05). Treatment of C2C12 myotube cells with LPS decreased the expression of slow-twitch mRNAs, which was restored by IL-13 (<i>Mb</i>, <i>P</i> < 0.0001; <i>Tnni1</i>, <i>P</i> < 0.001; and <i>Myh7</i>, <i>P</i> < 0.05). IL-13 production was significantly higher in ILC2s compared to T cells in skeletal muscle (<i>P</i> < 0.05). IL-13-producing ILC2s in skeletal muscle were examined and found to increase in PD-1 KO septic mice, compared with WT septic mice (<i>P</i> < 0.05). ILC2-derived IL-13 was increased by PD-1 KO se
背景:重症监护室获得性肌无力(ICU-AW)是一种综合征,其特点是脓毒症存活患者在慢性期经常出现长期肌无力。虽然 ICU-AW 与死亡率的增加有独立关联,但有效的治疗方法尚未确立。程序性死亡-1(PD-1)抑制剂作为逆转脓毒症免疫衰竭的潜在治疗方法引起了人们的关注;然而,它对 ICU-AW 的影响仍有待阐明。在此,我们研究了在临床前脓毒症模型中,PD-1缺陷如何影响脓毒症诱发的骨骼肌功能障碍:方法:用粪便处理野生型(WT)和 PD-1 基因敲除(KO)小鼠,然后用抗生素和生理盐水复苏,建立慢性败血症模型。小鼠在第15-17天安乐死。测量体重、肌肉重量和四肢肌肉力量。通过流式细胞术检测白细胞介素 13 (IL-13) 和 PD-1 的表达。通过逆转录和定量聚合酶链反应(RT-qPCR)测定了慢肌的信使 RNA(mRNA)表达。在体外研究中,用脂多糖(LPS)和重组 IL-13 处理 C2C12 肌管,然后测量基因表达:结果:WT 败血症小鼠的肌肉重量减轻(股四头肌、PPD-1 KO 小鼠在实验性 ICU-AW 中的长期肌无力症状得到了改善。PD-1 KO 小鼠骨骼肌中 ILC2 衍生的 IL-13 生成增加,从而表明 IL-13 可缓解败血症期间的肌肉无力。这项研究证明了 PD-1 阻断可通过增加 ILC2 衍生的 IL-13 来保护脓毒症期间的肌肉力量,这可能是脓毒症引起的 ICU-AW 的一个有吸引力的治疗靶点。
{"title":"Roles of programmed death-1 and muscle innate lymphoid cell-derived interleukin 13 in sepsis-induced intensive care unit-acquired weakness","authors":"Yuichi Akama,&nbsp;Eun Jeong Park,&nbsp;Naoko Satoh-Takayama,&nbsp;Atsushi Ito,&nbsp;Eiji Kawamoto,&nbsp;Arong Gaowa,&nbsp;Eri Matsuo,&nbsp;Satoshi Oikawa,&nbsp;Masafumi Saito,&nbsp;Shigeaki Inoue,&nbsp;Takayuki Akimoto,&nbsp;Kei Suzuki,&nbsp;Motomu Shimaoka","doi":"10.1002/jcsm.13548","DOIUrl":"10.1002/jcsm.13548","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;Intensive care unit-acquired weakness (ICU-AW) is a syndrome characterized by a long-term muscle weakness often observed in sepsis-surviving patients during the chronic phase. Although ICU-AW is independently associated with increased mortality, effective therapies have yet to be established. Programmed death-1 (PD-1) inhibitors have attracted attention as potential treatments for reversing immune exhaustion in sepsis; however, its impact on ICU-AW remains to be elucidated. Here, we study how PD-1 deficiency affects sepsis-induced skeletal muscle dysfunction in a preclinical sepsis model.&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;Chronic sepsis model was developed by treating wild-type (WT) and PD-1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15–17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL-13) and PD-1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow-twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). In an &lt;i&gt;in vitro&lt;/i&gt; study, C2C12 myotubes were treated with lipopolysaccharide (LPS) and recombinant IL-13 followed by gene expression measurements.&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;WT septic mice exhibited decreased muscle weight (quadriceps, &lt;i&gt;P&lt;/i&gt; &lt; 0.01; gastrocnemius, &lt;i&gt;P&lt;/i&gt; &lt; 0.05; and tibialis anterior, &lt;i&gt;P&lt;/i&gt; &lt; 0.01) and long-term muscle weakness (&lt;i&gt;P&lt;/i&gt; &lt; 0.0001), whereas PD-1 KO septic mice did not exhibit any reduction in muscle weights and strengths. Slow-twitch specific mRNAs, including myoglobin (&lt;i&gt;Mb&lt;/i&gt;), troponin I type 1 (&lt;i&gt;Tnni1&lt;/i&gt;), and myosin heavy chain 7 (&lt;i&gt;Myh7&lt;/i&gt;) were decreased in WT skeletal muscle (&lt;i&gt;Mb&lt;/i&gt;, &lt;i&gt;P&lt;/i&gt; &lt; 0.0001; &lt;i&gt;Tnni1&lt;/i&gt;, &lt;i&gt;P&lt;/i&gt; &lt; 0.05; and &lt;i&gt;Myh7&lt;/i&gt;, &lt;i&gt;P&lt;/i&gt; &lt; 0.05) after sepsis induction, but mRNA expressions of Tnni1 and Myh7 were increased in PD-1 KO septic mice (&lt;i&gt;Mb&lt;/i&gt;, not significant; &lt;i&gt;Tnni1&lt;/i&gt;, &lt;i&gt;P&lt;/i&gt; &lt; 0.0001; and &lt;i&gt;Myh7&lt;/i&gt;, &lt;i&gt;P&lt;/i&gt; &lt; 0.05). Treatment of C2C12 myotube cells with LPS decreased the expression of slow-twitch mRNAs, which was restored by IL-13 (&lt;i&gt;Mb&lt;/i&gt;, &lt;i&gt;P&lt;/i&gt; &lt; 0.0001; &lt;i&gt;Tnni1&lt;/i&gt;, &lt;i&gt;P&lt;/i&gt; &lt; 0.001; and &lt;i&gt;Myh7&lt;/i&gt;, &lt;i&gt;P&lt;/i&gt; &lt; 0.05). IL-13 production was significantly higher in ILC2s compared to T cells in skeletal muscle (&lt;i&gt;P&lt;/i&gt; &lt; 0.05). IL-13-producing ILC2s in skeletal muscle were examined and found to increase in PD-1 KO septic mice, compared with WT septic mice (&lt;i&gt;P&lt;/i&gt; &lt; 0.05). ILC2-derived IL-13 was increased by PD-1 KO se","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 5","pages":"1999-2012"},"PeriodicalIF":9.4,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141625523","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}
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Journal of Cachexia Sarcopenia and Muscle
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