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How can we design a proper trial for vitamin D treatment of diseases? Facts and numbers 我们如何设计一个适当的维生素D治疗疾病的试验?事实和数据
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-18 DOI: 10.1002/jcsm.13200
Shuang Zheng, Zhaohua Zhu, Changhai Ding

Vitamin D deficiency is a globally common situation and closely related with many chronic diseases. It is a hot topic to examine if vitamin D supplementation is effective for the treatment of diseases, and there have been dozens of clinical trials published in recent years. However, most studies have not proved the extra-skeletal benefits of vitamin D supplementation on these diseases. Some inherent shortcomings of these trials, such as inclusion with vitamin D-sufficient and obese participants, low response rate from participants and the insensitive changes in chosen outcomes over a shorter period, may be main reasons why most studies have yet to demonstrate effects of vitamin D supplementation. In this editorial, we aim to discuss the perspectives on how can we design a proper trial for vitamin D treatment of diseases based on the evidence-based practice framework PICOS (participants, intervention, control, outcomes and study design) in the future. First, right participants should be chosen, which is crucial for the success of vitamin D clinical trials. Participants with vitamin D sufficiency (e.g., baseline 25(OH)D of >50 nmol/L), obesity (e.g., body mass index > 30 kg/m2) and/or high vitamin D response index could be excluded from the trials. Second, intervention with vitamin D in right forms or dosages should be used. Vitamin D3 supplementation with appropriate dosages that keep 25(OH)D levels between 75 and 100 nmol/L is recommended. Third, ‘contamination’ in the control groups needs to pay attention. To diminish this, it is ideal to include participants less interfered by sun exposure (such as living in places at a high latitude) or with greater compliance (less interference by supplemental vitamin D-containing nutrients). Fourth, the outcome measures should be sensitive to change to avoid type II error. For outcomes such as bone density, radiographic osteoarthritis and cardiovascular diseases, follow-up period of 3–5 years may be required to observe the changes. Last, precision clinical trials may be the only way to prove the benefits of vitamin D supplementation.

维生素D缺乏症是一种全球普遍现象，与许多慢性疾病密切相关。研究补充维生素D是否对治疗疾病有效是一个热门话题，近年来已经发表了数十项临床试验。然而，大多数研究并没有证明补充维生素D对这些疾病的骨骼外益处。这些试验的一些固有缺陷，例如纳入了维生素D充足和肥胖的参与者，参与者的低反应率以及选择的结果在较短时间内的不敏感变化，可能是大多数研究尚未证明维生素D补充效果的主要原因。在这篇社论中，我们旨在讨论未来如何基于循证实践框架PICOS(参与者、干预、对照、结果和研究设计)设计维生素D治疗疾病的适当试验的观点。首先，应该选择正确的参与者，这对维生素D临床试验的成功至关重要。维生素D充足(例如，基线25(OH)D为50 nmol/L)，肥胖(例如，体重指数为50 nmol/L)的参与者30 kg/m2)和/或高维生素D反应指数可排除在试验之外。其次，应使用适当形式或剂量的维生素D进行干预。建议补充适当剂量的维生素D3，使25(OH)D水平保持在75至100 nmol/L之间。第三，控制组中的“污染”需要引起注意。为了减少这种情况，理想的做法是纳入受阳光照射干扰较少的参与者(如生活在高纬度地区)或更遵守规定的参与者(较少受补充维生素d的营养素的干扰)。第四，结局指标应对变化敏感，以避免II型误差。对于骨密度、x线骨关节炎和心血管疾病等结果，可能需要随访3-5年来观察变化。最后，精确的临床试验可能是证明补充维生素D益处的唯一途径。
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引用次数: 0
Direct electrical stimulation impacts on neuromuscular junction morphology on both stimulated and unstimulated contralateral soleus 直接电刺激对受刺激和未受刺激对侧比目鱼肌神经肌肉连接形态的影响
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-15 DOI: 10.1002/jcsm.13235
Young il Lee, Nicola Cacciani, Ya Wen, Xiang Zhang, Yvette Hedstr?m, Wesley Thompson, Lars Larsson
There is increasing evidence of crosstalk between organs. The neuromuscular junction (NMJ) is a peripheral chemical synapse whose function and morphology are sensitive to acetylcholine (ACh) release and muscle depolarization. In an attempt to improve our understanding of NMJ plasticity and muscle crosstalk, the effects of unilateral direct electrical stimulation of a hindlimb muscle on the NMJ were investigated in rats exposed long‐term post‐synaptic neuromuscular blockade.
越来越多的证据表明器官之间存在着串扰。神经肌肉连接(NMJ)是一种外周化学突触，其功能和形态对乙酰胆碱(ACh)释放和肌肉去极化敏感。为了提高我们对NMJ可塑性和肌肉串扰的理解，我们研究了长期突触后神经肌肉阻断大鼠后肢肌肉单侧直接电刺激对NMJ的影响。方法采用α-蛇毒全身给药并机械通气8 d，对Sprague Dawley大鼠进行突触后神经肌肉传递阻断，并与未治疗的假手术对照组和单侧慢性电刺激12 h/d，连续5、8 d进行比较。结果NMJs在突触后神经肌肉阻断反应中产生轴突和胶质芽(生长过程超出了由乙酰胆碱受体[achr]高密度聚集体定义的突触范围)，但在外周去神经支配或突触前阻断后较少报道。直接电刺激比目鱼肌可减少受刺激和未受刺激对侧比目鱼肌的末端雪旺细胞(tSC)和轴突萌发。8 d慢性刺激减少(P <0.001)，受刺激和未受刺激的比目鱼肌上的tSC芽数分别为6.7±0.5和6.9±0.5个，而受刺激的比目鱼肌上的tSC芽数为10.3±0.9个(P <0.001)，固定8天的大鼠无刺激比目鱼肌。轴突芽的类似减少(P <0.001)对侧受刺激和非受刺激比目鱼肌对慢性电刺激的反应。基于rnaseq的基因表达分析证实了对受刺激和未受刺激的对侧肌肉的恢复作用。这种交叉效应与受刺激和对侧未受刺激肌肉以及血浆中细胞因子/趋化因子水平的增加相平行。结论突触后神经肌肉阻断大鼠NMJs的运动轴突终末和末端雪旺细胞出现萌芽反应。这些轴突和神经胶质反应可能被一种肌肉来源的肌因子以活动依赖的方式释放，具有局部和全身效应。
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引用次数: 0
Exercise for sarcopenia in older people: A systematic review and network meta-analysis 运动治疗老年人肌肉减少症:一项系统综述和网络荟萃分析
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-14 DOI: 10.1002/jcsm.13225
Yanjiao Shen, Qingyang Shi, Kailei Nong, Sheyu Li, Jirong Yue, Jin Huang, Birong Dong, Marla Beauchamp, Qiukui Hao

Background

Sarcopenia is a serious public health concern among older adults worldwide. Exercise is the most common intervention for sarcopenia. This study aimed to compare the effectiveness of different exercise types for older adults with sarcopenia.

Methods

Randomized controlled trials (RCTs) that examined the effectiveness of exercise interventions on patient-important outcomes for older adults with sarcopenia were eligible. We systematically searched MEDLINE, Embase and Cochrane Central Register of Controlled Trials via Ovid until 3 June 2022. We used frequentist random-effects network meta-analyses to summarize the evidence and applied the Grading of Recommendations, Assessment, Development, and Evaluations framework to rate the certainty of evidence.

Results

Our search identified 5988 citations, of which 42 RCTs proved eligible with 3728 participants with sarcopenia (median age: 72.9 years, female: 73.3%) with a median follow-up of 12 weeks. We are interested in patient-important outcomes that include mortality, quality of life, muscle strength and physical function measures. High or moderate certainty evidence suggested that resistance exercise with or without nutrition and the combination of resistance exercise with aerobic and balance training were the most effective interventions for improving quality of life compared to usual care (standardized mean difference from 0.68 to 1.11). Moderate certainty evidence showed that resistance and balance exercise plus nutrition (mean difference [MD]: 4.19 kg) was the most effective for improving handgrip strength (minimally important difference [MID]: 5 kg). Resistance and balance exercise with or without nutrition (MD: 0.16 m/s, moderate) were the most effective for improving physical function measured by usual gait speed (MID: 0.1 m/s). Moderate certainty evidence showed that resistance and balance exercise (MD: 1.85 s) was intermediately effective for improving physical function measured by timed up and go test (MID: 2.1 s). High certainty evidence showed that resistance and aerobic, or resistance and balance, or resistance and aerobic exercise plus nutrition (MD from 1.72 to 2.28 s) were intermediately effective for improving physical function measured by the five-repetition chair stand test (MID: 2.3 s).

Conclusions

In older adults with sarcopenia, high or moderate certainty evidence showed that resistance exercise with or without nutrition and the combin

背景:骨骼肌减少症是全世界老年人中严重的公共卫生问题。运动是肌肉减少症最常见的干预措施。这项研究旨在比较不同运动类型对老年肌肉减少症患者的效果。方法随机对照试验(rct)检验了运动干预对老年肌肉减少症患者重要结果的有效性。我们通过Ovid系统检索MEDLINE、Embase和Cochrane Central Register of Controlled Trials，截止到2022年6月3日。我们使用频率随机效应网络荟萃分析来总结证据，并应用推荐、评估、发展和评估的分级框架来评估证据的确定性。结果:我们的检索确定了5988条引用，其中42项rct被证明符合条件，有3728名肌肉减少症患者(中位年龄:72.9岁，女性:73.3%)，中位随访时间为12周。我们感兴趣的是患者重要的结果，包括死亡率、生活质量、肌肉力量和身体功能测量。高或中等确定性证据表明，与常规护理相比，有营养或没有营养的阻力运动以及阻力运动与有氧和平衡训练相结合是改善生活质量的最有效干预措施(标准化平均差为0.68至1.11)。中等确定性证据表明，阻力和平衡运动加上营养(平均差值[MD]: 4.19 kg)对提高握力最有效(最小重要差值[MID]: 5 kg)。阻力和平衡运动(MD: 0.16 m/s，中等)对改善通常步态速度(MID: 0.1 m/s)测量的身体功能最有效。中等确定性证据表明，阻力和平衡运动(MD: 1.85 s)对计时起跑测试(MID: 2.1 s)测量的身体机能改善具有中等有效性。高确定性证据表明，阻力和有氧运动，或阻力和平衡运动，或阻力和有氧运动加营养运动(MD从1.72到2.28 s)对五次重复椅子站立测试(MID: 1)测量的身体机能改善具有中等有效性。结论在老年肌肉减少症患者中，高或中等确定性证据表明，有营养或无营养的阻力运动以及阻力运动与有氧和平衡训练相结合是改善生活质量的最有效干预措施。在锻炼中加入营养干预对握力的影响比单独锻炼更大，同时对其他身体机能的测量也显示出类似的效果。
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引用次数: 12
Effects of exercise habits in adolescence and older age on sarcopenia risk in older adults: the Bunkyo Health Study 青少年和老年运动习惯对老年人肌肉减少症风险的影响:文京健康研究
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-13 DOI: 10.1002/jcsm.13218
Hiroki Tabata, Hikaru Otsuka, Huicong Shi, Mari Sugimoto, Hideyoshi Kaga, Yuki Someya, Hitoshi Naito, Naoaki Ito, Abulaiti Abudurezake, Futaba Umemura, Mai Kiya, Tsubasa Tajima, Saori Kakehi, Yasuyo Yoshizawa, Ryuzo Kawamori, Hirotaka Watada, Yoshifumi Tamura

Background

Sarcopenia, defined as an age-associated loss of skeletal muscle mass and function, is a major risk factor for requiring long-term care. Because physical activity in adolescence and older age enhances peak muscle function in youth and prevents muscle function decline in older age, older adults with exercise habits during both periods may be at a lower risk for sarcopenia. We investigated the relationship between exercise habits in adolescence and older age and sarcopenia and its components in community-dwelling older Japanese adults.

Methods

This study included 1607 community-dwelling individuals (aged 65–84, medians 73 years, 679 men and 928 women) with complete health examinations, including measurements of skeletal muscle index, handgrip strength and gait speed, who were enrolled in the Bunkyo Health Study. We divided the participants into four groups according to exercise habits in adolescence and older age: no exercise in either period (none-none; NN), exercise only in adolescence (active-none; AN), exercise only in older age (none-active; NA) and exercise in both periods (active-active; AA). Multivariate-adjusted logistic regression models were used to estimate the odds ratios (ORs) and associated 95% confidence intervals (CIs) in each group for the prevalence of sarcopenia, defined as low muscle mass and low muscle performance, as compared with the NN group. Low muscle performance was defined as low muscle strength and/or low gait speed.

Results

The total prevalence of sarcopenia was 6.6% (45/679) in men and 1.7% (16/928) in women, the total prevalence of low muscle mass was 14.3% (97/679) in men and 5.2% (48/928) in women, and the total prevalence of low muscle performance was 25.6% (174/679) in men and 19.6% (182/928) in women. In men, the ORs (95% CIs) for sarcopenia, low muscle mass and low muscle performance were significantly lower in the AA group (sarcopenia: 0.29 [0.09–0.95], P = 0.041; low muscle mass: 0.21 [0.09–0.52], P = 0.001; and low muscle performance: 0.52 [0.28–0.97], P = 0.038). In women, the OR (95% CI) for low muscle performance was significantly lower in the AA group than in the other groups (0.48 [0.27–0.84], P = 0.010), whereas none of the ORs for sarcopenia and low muscle mass were significant.

Conclusions

Older men with exercise habits in both adolescence and older age were at a lower risk of sarcopenia, low muscle mass and low muscle per

骨骼肌减少症被定义为与年龄相关的骨骼肌质量和功能的丧失，是需要长期护理的主要危险因素。由于青少年和老年时期的体育锻炼可以提高青年时期肌肉功能的峰值，并防止老年时期肌肉功能的下降，因此在这两个时期都有锻炼习惯的老年人患肌肉减少症的风险较低。我们调查了日本社区老年人青少年和老年运动习惯与肌肉减少症及其组成部分之间的关系。方法本研究纳入了1607名社区居民(年龄65-84岁，中位年龄73岁，男性679名，女性928名)，他们进行了完整的健康检查，包括骨骼肌指数、握力和步态速度，这些人都参加了Bunkyo健康研究。我们根据参与者在青少年时期和老年时期的运动习惯将他们分为四组:两组都没有运动(没有-没有;NN)，只在青春期锻炼(主动-无;AN)，老年人只运动(不运动;NA)和锻炼(active-active;AA)。与神经网络组相比，使用多变量调整的逻辑回归模型来估计每组肌肉减少症患病率的比值比(ORs)和相关的95%置信区间(CIs)，肌肉减少症定义为低肌肉质量和低肌肉表现。低肌肉表现被定义为低肌肉力量和/或低步态速度。结果男性肌肉减少症总患病率为6.6%(45/679)，女性为1.7%(16/928);男性低肌量总患病率为14.3%(97/679)，女性低肌量总患病率为5.2%(48/928);男性低肌性能总患病率为25.6%(174/679)，女性低肌性能总患病率为19.6%(182/928)。在男性中，AA组肌肉减少症、低肌肉量和低肌肉表现的or (95% ci)显著低于AA组(肌肉减少症:0.29 [0.09-0.95]，P = 0.041;低肌肉质量:0.21 [0.09-0.52]，P = 0.001;低肌肉性能:0.52 [0.28-0.97]，P = 0.038)。在女性中，AA组低肌肉表现的OR (95% CI)显著低于其他组(0.48 [0.27-0.84]，P = 0.010)，而肌肉减少症和低肌肉量的OR均不显著。结论:在青春期和老年时期都有运动习惯的老年男性患肌肉减少症、低肌肉量和低肌肉表现的风险较低，而在这两个时期都有运动习惯的老年女性患低肌肉表现的风险较低。
{"title":"Effects of exercise habits in adolescence and older age on sarcopenia risk in older adults: the Bunkyo Health Study","authors":"Hiroki Tabata,&nbsp;Hikaru Otsuka,&nbsp;Huicong Shi,&nbsp;Mari Sugimoto,&nbsp;Hideyoshi Kaga,&nbsp;Yuki Someya,&nbsp;Hitoshi Naito,&nbsp;Naoaki Ito,&nbsp;Abulaiti Abudurezake,&nbsp;Futaba Umemura,&nbsp;Mai Kiya,&nbsp;Tsubasa Tajima,&nbsp;Saori Kakehi,&nbsp;Yasuyo Yoshizawa,&nbsp;Ryuzo Kawamori,&nbsp;Hirotaka Watada,&nbsp;Yoshifumi Tamura","doi":"10.1002/jcsm.13218","DOIUrl":"https://doi.org/10.1002/jcsm.13218","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sarcopenia, defined as an age-associated loss of skeletal muscle mass and function, is a major risk factor for requiring long-term care. Because physical activity in adolescence and older age enhances peak muscle function in youth and prevents muscle function decline in older age, older adults with exercise habits during both periods may be at a lower risk for sarcopenia. We investigated the relationship between exercise habits in adolescence and older age and sarcopenia and its components in community-dwelling older Japanese adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study included 1607 community-dwelling individuals (aged 65–84, medians 73 years, 679 men and 928 women) with complete health examinations, including measurements of skeletal muscle index, handgrip strength and gait speed, who were enrolled in the Bunkyo Health Study. We divided the participants into four groups according to exercise habits in adolescence and older age: no exercise in either period (none-none; NN), exercise only in adolescence (active-none; AN), exercise only in older age (none-active; NA) and exercise in both periods (active-active; AA). Multivariate-adjusted logistic regression models were used to estimate the odds ratios (ORs) and associated 95% confidence intervals (CIs) in each group for the prevalence of sarcopenia, defined as low muscle mass and low muscle performance, as compared with the NN group. Low muscle performance was defined as low muscle strength and/or low gait speed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The total prevalence of sarcopenia was 6.6% (45/679) in men and 1.7% (16/928) in women, the total prevalence of low muscle mass was 14.3% (97/679) in men and 5.2% (48/928) in women, and the total prevalence of low muscle performance was 25.6% (174/679) in men and 19.6% (182/928) in women. In men, the ORs (95% CIs) for sarcopenia, low muscle mass and low muscle performance were significantly lower in the AA group (sarcopenia: 0.29 [0.09–0.95], <i>P</i> = 0.041; low muscle mass: 0.21 [0.09–0.52], <i>P</i> = 0.001; and low muscle performance: 0.52 [0.28–0.97], <i>P</i> = 0.038). In women, the OR (95% CI) for low muscle performance was significantly lower in the AA group than in the other groups (0.48 [0.27–0.84], <i>P</i> = 0.010), whereas none of the ORs for sarcopenia and low muscle mass were significant.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Older men with exercise habits in both adolescence and older age were at a lower risk of sarcopenia, low muscle mass and low muscle per","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1299-1311"},"PeriodicalIF":8.9,"publicationDate":"2023-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5828740","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
Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle 肝脏和肌肉脂肪变性氨基酸传感器Ubr1的鉴定
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-13 DOI: 10.1002/jcsm.13233
Wanni Zhao, Yansong Zhang, Siyuan Lin, Yajuan Li, Alan Jian Zhu, Hanping Shi, Min Liu

Background

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

Methods

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

Results

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

Conclusions

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

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

Background

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

Methods

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

Results

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

Conclusions

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

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

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

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

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

Introduction

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

Methods

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

Results

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

癌症恶病质在肺癌中非常普遍，是一种以骨骼肌质量不自主丧失为特征的衰弱综合征，与临床预后差、生存率降低和对肿瘤治疗的负面影响相关。各种肺肿瘤动物模型被用来探索癌症恶病质的潜在机制。然而，这些模型并不能模拟肺癌和相关肌肉萎缩的解剖学和免疫学特征。克服这些缺点对于将实验结果转化为临床至关重要。因此，我们评估了同基因的原位肺癌小鼠模型是否复制了与人类肺癌恶病质相关的全身和肌肉特异性改变。方法选取11周龄具有免疫功能的雄性129S2/Sv小鼠，随机分为(1)假对照组和(2)荷瘤组。同基因肺上皮源性腺癌细胞(K-rasG12D;p53R172HΔG)接种于小鼠左肺叶肺内。每天测量体重和食物摄入量。在基线和术后每周，测量握力，并使用微锥束CT成像评估肿瘤生长和肌肉体积。在达到预定的替代生存终点后，对动物实施安乐死，并收集下后肢骨骼肌进行生化分析。结果三分之二的荷瘤小鼠根据预先设定的标准发生恶病质。最终体重(−13.7±5.7%;P & lt;0.01)，肌肉质量(−13.8±8.1%;P & lt;0.01)和肌力(−25.5±10.5%;P & lt;0.001)，术后中位生存时间为33.5天。与对照组相比，病毒症小鼠骨骼肌中蛋白水解标志物，泛素蛋白酶体系统(Fbxo32和Trim63)和自噬-溶酶体途径(Gabarapl1和Bnip3)均显著上调，而蛋白合成标志物(Akt、S6和4E-BP1的相对磷酸化)显著降低。恶病质小鼠表现出戊素-2 (P <0.001)和CXCL1/KC (P <0.01)表达水平升高，IκBα mRNA表达升高(P <0.05)，提示存在全身性炎症。引人注目的是，小鼠骨骼肌的RNA测序、途径富集和miRNA表达分析强烈反映了肺癌恶病质患者肌肉活检中观察到的改变。结论建立了免疫正常小鼠肺癌恶病质原位模型。由于该模型模拟了肺癌患者恶病质特异性的关键方面，因此非常适合进一步研究肺癌恶病质的潜在机制，并测试新的干预策略的效果。
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引用次数: 1
Specific miRNAs are associated with human cancer cachexia in an organ-specific manner 特异性mirna以器官特异性的方式与人类癌症恶病质相关
IF 8.9 1区 医学
Journal of Cachexia, Sarcopenia and Muscle
Pub Date : 2023-04-06 DOI: 10.1002/jcsm.13224
Tanja Krauss, Simone Heisz, Julius Honecker, Olga Prokopchuk, Marc Martignoni, Klaus-Peter Janssen, Melina Claussnitzer, Hans Hauner, Claudine Seeliger

Background

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

Methods

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

Results

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

癌症恶病质(CCx)是一种复杂的多器官消耗综合征，以体重减轻和预后差为特征。提高对癌症恶病质发生和发展的机制的理解是必要的。microRNAs如何促进CCx的临床表现和进展仍然是一个谜。本研究的目的是鉴定与器官特异性CCx相关的特异性mirna，并探索它们在人类中的功能作用。方法分析体重稳定(N≤12)和病毒质(N≤23)胃肠道肿瘤患者血清及恶病质靶器官(肝脏、肌肉和脂肪组织)的miRNA谱。作为第一步，在汇集的血清样本中进行miRNA阵列(158个miRNA)。在血清和相应的组织样本中验证鉴定的mirna。利用计算机预测，对相关基因进行了鉴定和评价。通过体外人内脏前脂肪细胞和C2C12成肌细胞siRNA敲除实验和连续基因表达分析，证实了这一发现。验证该阵列的结果，miR-122-5p下调2倍(P = 0.0396)， miR-194-5p下调4.5倍(P <与健康对照相比，CCx患者血清中有0.0001)。只有miR-122-5p与体重减轻和CCx状态相关(P = 0.0367)。分析了相应的组织，鉴定了6个肌肉和8个内脏脂肪组织(VAT)恶病质相关的mirna。miR-27b-3p、miR-375和miR-424-5p是CCx患者组织中受影响最一致的mirna，与体重减轻严重程度呈负相关(P = 0.0386、P = 0.0112和P = 0.0075)。我们确定了许多与肌肉萎缩和脂肪分解途径相关的mirna的假定靶基因。在C2C12成肌细胞中进行敲除实验，发现miR-27b-3p与计算机预测的萎缩相关靶基因IL-15和TRIM63存在关联。两者在miR-27b-3p敲除细胞中均上调(P <0.05)。同时，在CCx个体的肌肉组织中，IL-15 (P = 0.0237)和TRIM63 (P = 0.0442)的表达水平显著升高。发现miR-424-5p调节脂肪酶基因的表达。人内脏前脂肪细胞的敲除实验显示，miR-424-5p与其预测的靶基因LIPE、PNPLA2、MGLL和LPL呈负相关(P <0.01)。鉴定出的mirna，特别是miR-122-5p、miR-27b-3p、miR-375和miR-424-5p，代表了人类CCx的特征，并可能通过调节分解代谢信号参与组织损耗和骨骼肌萎缩。需要进一步的研究来探索鉴定的mirna作为早期检测癌症恶病质的筛选工具的潜力。
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引用次数: 0
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