Journal of Cachexia Sarcopenia and Muscle最新文献_第3页

Factors associated with skeletal muscle mass in middle-aged men living with HIV 感染艾滋病毒的中年男性骨骼肌质量的相关因素。

IF 9.4 1区医学 Q1 GERIATRICS & GERONTOLOGY

Journal of Cachexia Sarcopenia and Muscle

Pub Date : 2024-07-17 DOI: 10.1002/jcsm.13545

Yide Xu, Dongdong Wang, Pei Chen, Bufeng Qi, Xiaoting Li, Chunfeng Xie, Jieshu Wu, Lin Li, Gu Gao, Shanshan Geng, Dandan Yang

Background

Despite extensive research on muscle loss in people living with HIV (PLWH), the prevalence and contributing factors specifically among middle-aged men remain unclear. This study aimed to determine the prevalence of low muscle mass within this demographic and to identify associated factors.

Methods

A total of 378 men living with HIV were enrolled in the study. They were classified into low muscle mass group if they displayed a skeletal muscle index (SMI) <7.00 kg/m² or fell within the lowest quintile of SMI based on the criteria established by the Asian Working Group for Sarcopenia 2019.

Results

Out of the 378 men living with HIV enrolled, 351 had normal muscle mass, while 27 (7.1%) had low muscle mass. Antiretroviral drugs Zidovudine (AZT) (OR = 0.246, P = 0.022) and higher serum albumin levels (OR = 0.899, P = 0.026) were found to be protective factors against low muscle mass according to quintile grouping. Strong positive associations between SMI and body mass index (BMI), nutritional risk index (NRI), oedema index and fat-free mass index (FFMI) (R > 0.5, P < 0.001) were observed. In addition, both BMI (sensitivity = 0.741, specificity = 0.906) and NRI (sensitivity = 0.963, specificity = 0.601) had high sensitivity and specificity in diagnosing low muscle mass, with critical values of 19.85 and 114.177 for BMI and NRI, respectively. The oedema index was the most effective measure of body composition in detecting abnormal fluid retention with high sensitivity (92.6%) and moderate specificity (71.8%) in identifying individuals with low muscle mass. Notably, PLWH with low muscle mass participants had a significantly higher prevalence (92.6%) of a high oedema index compared with those with normal muscle mass (28.2%). This observation indicates that individuals with HIV who experience reduced muscle mass is commonly accompanied with abnormal fluid retention within the body.

Conclusions

Antiretroviral medication types, specifically Zidovudine, BMI and NRI can be independent risk factors for low muscle mass in men with HIV. These factors, along with BMI, could be used conveniently to predict low muscle mass. Furthermore, the association between the oedema index and muscle mass suggests that observing signs of oedema may indicate a risk of low muscle mass in PLWH.

背景：尽管对艾滋病病毒感染者（PLWH）的肌肉流失进行了广泛的研究，但中年男性的发病率和诱发因素仍不清楚。本研究旨在确定低肌肉质量在这一人群中的流行率，并找出相关因素：方法：共有 378 名男性艾滋病病毒感染者参加了研究。根据亚洲肥胖症工作组 2019 年制定的标准，如果他们的骨骼肌指数（SMI）为 2 或属于 SMI 的最低五分位数，则被归入低肌肉质量组：在 378 名男性艾滋病感染者中，351 人的肌肉质量正常，27 人（7.1%）的肌肉质量较低。根据五分法分组发现，抗逆转录病毒药物齐多夫定（AZT）（OR = 0.246，P = 0.022）和较高的血清白蛋白水平（OR = 0.899，P = 0.026）是低肌肉质量的保护因素。SMI 与体重指数 (BMI)、营养风险指数 (NRI)、水肿指数和去脂体重指数 (FFMI) 之间存在很强的正相关性（R > 0.5，P 结论）：抗逆转录病毒药物类型（尤其是齐多夫定）、体重指数和营养风险指数可能是导致男性艾滋病患者肌肉质量低的独立风险因素。这些因素以及体重指数可用于预测低肌肉质量。此外，水肿指数与肌肉质量之间的关联表明，观察到水肿迹象可能预示着艾滋病毒感染者存在肌肉质量低的风险。

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引用次数: 0

Association between metabolic dysfunction-associated steatotic liver disease and myosteatosis measured by computed tomography 代谢功能障碍相关脂肪性肝病与计算机断层扫描测量的肌骨软化症之间的关系

IF 9.4 1区医学 Q1 GERIATRICS & GERONTOLOGY

Journal of Cachexia Sarcopenia and Muscle

Pub Date : 2024-07-16 DOI: 10.1002/jcsm.13543

Myung Jin Kim, Yun Kyung Cho, Eun Hee Kim, Min Jung Lee, Woo Je Lee, Hong-Kyu Kim, Chang Hee Jung

Background

In 2023, the concept of metabolic dysfunction-associated steatotic liver disease (MASLD) was introduced as an alternative to non-alcoholic fatty liver disease (NAFLD). We aimed to assess the quantity and quality of skeletal muscle using each of these diagnostic classifications.

Methods

This cross-sectional study included 18 154 participants (11 551 [63.6%] men and 6603 [36.4%] women, mean age 53.0 ± 8.8). The participants were classified into four categories: neither steatotic liver disease (SLD), NAFLD only, MASLD only or both SLDs. An appendicular skeletal muscle mass adjusted for body mass index of <0.789 for men and <0.512 for women was defined as sarcopenia. The total abdominal muscle area (TAMA) at the L3 vertebral level was segmented into normal-attenuation muscle area (NAMA), low-attenuation muscle area and intermuscular/intramuscular adipose tissue. Myosteatosis was defined by a T-score < −1.0 of the NAMA/TAMA index, which was calculated by dividing the NAMA by the TAMA and multiplying by 100.

Results

Using subjects with neither SLD as a reference, the multivariable-adjusted odds ratios (ORs) for sarcopenia were significantly increased in those with MASLD, with adjusted ORs (95% confidence interval [CI]) of 2.62 (1.94–3.54) in the MASLD-only group and 2.33 (1.92–2.82) in the both SLDs group, while the association was insignificant in those with NAFLD only (adjusted OR [95% CI]: 2.16 [0.67–6.94]). The OR for myosteatosis was also elevated in the MASLD groups, with an OR (95% CI) of 1.75 (1.52–2.02) in subjects with MASLD only and 1.70 (1.57–1.84) in those with both SLDs, while it was slightly decreased in subjects with NAFLD only (0.52 [0.29–0.95]).

Conclusions

Employing the MASLD concept rather than that of the NAFLD proved to be more effective in distinguishing individuals with reduced muscle mass and compromised muscle quality.

背景：2023年，代谢功能障碍相关性脂肪性肝病（MASLD）的概念被引入，作为非酒精性脂肪肝（NAFLD）的替代方案。我们的目的是利用这些诊断分类评估骨骼肌的数量和质量：这项横断面研究包括 18 154 名参与者（男性 11 551 人[63.6%]，女性 6 603 人[36.4%]，平均年龄为 53.0 ± 8.8 岁）。参与者被分为四类：既无脂肪性肝病（SLD）、仅有非酒精性脂肪肝、仅有脂肪性肝病或同时患有脂肪性肝病。结果显示，根据体重指数调整后的阑尾骨骼肌质量为（0.0 ± 8.8）：以既无脂肪肝也无非酒精性脂肪肝的受试者为参照，经多变量调整后，患有肌肉疏松症的受试者患肌肉疏松症的几率比（ORs）显著增加，仅患有脂肪肝组的调整后几率比（95% 置信区间[CI]）为 2.62（1.94-3.54），同时患有两种脂肪肝组的调整后几率比（95% 置信区间[CI]）为 2.33（1.92-2.82），而仅患有非酒精性脂肪肝组的调整后几率比（95% 置信区间[CI]）为 2.16 [0.67-6.94]）微不足道。肌骨质疏松症的OR值在MASLD组中也有所升高，仅患有MASLD的受试者的OR值（95% CI）为1.75（1.52-2.02），患有两种SLD的受试者的OR值为1.70（1.57-1.84），而仅患有NAFLD的受试者的OR值略有下降（0.52 [0.29-0.95]）：结论：在区分肌肉质量下降和肌肉质量受损的个体时，采用 MASLD 概念比采用 NAFLD 概念更有效。

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引用次数: 0

Proteomic profiling of human plasma extracellular vesicles identifies PF4 and C1R as novel biomarker in sarcopenia 人体血浆细胞外囊泡的蛋白质组分析发现 PF4 和 C1R 是肌少症的新型生物标记物。

IF 9.4 1区医学 Q1 GERIATRICS & GERONTOLOGY

Journal of Cachexia Sarcopenia and Muscle

Pub Date : 2024-07-15 DOI: 10.1002/jcsm.13539

Paula Aparicio, David Navarrete-Villanueva, Alba Gómez-Cabello, Tresa López-Royo, Enrique Santamaría, Joaquín Fernández-Irigoyen, Karina Ausín, Manuel Arruebo, Victor Sebastian, Germán Vicente-Rodríguez, Rosario Osta, Raquel Manzano

<div> <section> <h3> Background</h3> <p>Sarcopenia, the gradual and generalized loss of muscle mass and function with ageing, is one of the major health problems in older adults, given its high prevalence and substantial socioeconomic implications. Despite the extensive efforts to reach consensus on definition and diagnostic tests and cut-offs for sarcopenia, there is an urgent and unmet need for non-invasive, specific and sensitive biomarkers for the disease. Extracellular vesicles (EVs) are present in different biofluids including plasma, whose cargo reflects cellular physiology. This work analysed EV proteome in sarcopenia and robust patients in the search for differentially contained proteins that can be used to diagnose the disease.</p> </section> <section> <h3> Methods</h3> <p>Plasma small EVs (sEVs) from a total of 29 robust controls (aged 73.4 ± 5.6 years; 11 men and 18 women) and 49 sarcopenic patients (aged 82.3 ± 5.4 years; 15 men and 34 women) aged 65 years and older were isolated and their cargo was analysed by proteomics. Proteins whose concentration in sEVs was different between sarcopenic and robust patients were further validated using ELISA. The concentration of these candidates was correlated to the EWGSOP2 sarcopenia tests for low muscle strength and low physical performance, and receiver operating characteristic (ROC) curve analyses were carried out to evaluate their diagnostic power, sensitivity and specificity.</p> </section> <section> <h3> Results</h3> <p>Proteomic analysis identified 157 sEVs proteins in both sarcopenic and robust samples. Among them, 48 proteins had never been reported in the ExoCarta nor Vesiclepedia databases. Statistical analysis revealed eight proteins whose concentration was significantly different between groups: PF4 (log2 FC = 4.806), OIT3 (log2 FC = −1.161), MMRN1 (log2 FC = −1.982), MASP1 (log2 FC = −0.627), C1R (log2 FC = 1.830), SVEP1 (log2 FC = 1.295), VCAN (FC = 0.937) and SPTB (log2 FC = 1.243). Among them, platelet factor 4 (PF4) showed the lowest concentration while Complement C1r subcomponent (C1R) increased the most in sarcopenic patients, being these results confirmed by ELISA (<i>P</i> = 1.07E-09 and <i>P</i> = 0.001287, respectively). The concentrations of candidate proteins significantly correlated with EWGSOP2 tests currently used. ROC curve analysis showed an area under the curve of 0.8921 and 0.7476 for PF4 and C1R, respectively. Choosing the optimal for PF4, 80% sensitivity and 85.71% specificity was reached while the optimal cut-off value of C1R would allow sarcopenia diagnosis with 75% sensitivity and 66.67% specificity.</p> </section> <se

背景：肌肉疏松症是一种随着年龄增长而逐渐和普遍出现的肌肉质量和功能丧失的疾病，是老年人的主要健康问题之一，因为其发病率高，对社会经济有重大影响。尽管人们为肌少症的定义、诊断测试和临界值达成了广泛共识，但对该疾病的非侵入性、特异性和敏感性生物标志物的需求仍十分迫切。细胞外囊泡 (EV) 存在于包括血浆在内的不同生物流体中，其载体反映了细胞的生理机能。这项研究分析了肌肉疏松症和健壮患者体内的EV蛋白质组，以寻找可用于诊断该疾病的不同蛋白质：方法：分离了29名壮年对照组患者（年龄为73.4 ± 5.6岁，男性11人，女性18人）和49名65岁及以上的肌肉疏松症患者（年龄为82.3 ± 5.4岁，男性15人，女性34人）的血浆小EVs（sEVs），并通过蛋白质组学分析了它们的载体。使用 ELISA 方法进一步验证了肌肉疏松患者和健壮患者 sEV 中浓度不同的蛋白质。这些候选蛋白的浓度与 EWGSOP2 肌肉疏松症测试（低肌力和低体能）相关，并进行了接收器操作特征曲线（ROC）分析，以评估其诊断能力、灵敏度和特异性：蛋白质组分析在肌少症和健壮样本中发现了 157 个 sEVs 蛋白质。其中有 48 个蛋白质从未在 ExoCarta 或 Vesiclepedia 数据库中出现过。统计分析显示，有 8 种蛋白质的浓度在不同组间存在显著差异：PF4（log2 FC = 4.806）、OIT3（log2 FC =-1.161）、MMRN1（log2 FC =-1.982）、MASP1（log2 FC =-0.627）、C1R（log2 FC = 1.830）、SVEP1（log2 FC = 1.295）、VCAN（FC = 0.937）和SPTB（log2 FC = 1.243）。其中，血小板因子 4（PF4）的浓度最低，而补体 C1r 亚组分（C1R）在肌无力患者中的浓度增加最多，ELISA 证实了这些结果（P = 1.07E-09 和 P = 0.001287）。候选蛋白质的浓度与目前使用的 EWGSOP2 检测方法有明显的相关性。ROC 曲线分析显示，PF4 和 C1R 的曲线下面积分别为 0.8921 和 0.7476。选择 PF4 的最佳值，灵敏度为 80%，特异性为 85.71%，而选择 C1R 的最佳截断值，则可诊断肌肉疏松症，灵敏度为 75%，特异性为 66.67%：我们的研究结果支持将 EV PF4 和 C1R 确定为肌肉疏松症的血浆诊断生物标志物，并为研究这些囊泡内容物在疾病病因中的作用打开了大门。

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引用次数: 0

Mitochondrial bioenergetics are not associated with myofibrillar protein synthesis rates 线粒体生物能与肌纤维蛋白质合成率无关。

IF 9.4 1区医学 Q1 GERIATRICS & GERONTOLOGY

Journal of Cachexia Sarcopenia and Muscle

Pub Date : 2024-07-15 DOI: 10.1002/jcsm.13532

Andrew M. Holwerda, Marlou L. Dirks, Pierre-Andre Barbeau, Joy Goessens, Annemie Gijsen, Luc J.C. van Loon, Graham P. Holloway

Background

Mitochondria represent key organelles influencing cellular homeostasis and have been implicated in the signalling events regulating protein synthesis.

Methods

We examined whether mitochondrial bioenergetics (oxidative phosphorylation and reactive oxygen species (H₂O₂) emission, ROS) measured in vitro in permeabilized muscle fibres represent regulatory factors for integrated daily muscle protein synthesis rates and skeletal muscle mass changes across the spectrum of physical activity, including free-living and bed-rest conditions: n = 19 healthy, young men (26 ± 4 years, 23.4 ± 3.3 kg/m²) and following 12 weeks of resistance-type exercise training: n = 10 healthy older men (70 ± 3 years, 25.2 ± 2.1 kg/m²). Additionally, we evaluated the direct relationship between attenuated mitochondrial ROS emission and integrated daily myofibrillar and sarcoplasmic protein synthesis rates in genetically modified mice (mitochondrial-targeted catalase, MCAT).

Results

Neither oxidative phosphorylation nor H₂O₂ emission were associated with muscle protein synthesis rates in healthy young men under free-living conditions or following 1 week of bed rest (both P > 0.05). Greater increases in GSSG concentration were associated with greater skeletal muscle mass loss following bed rest (r = −0.49, P < 0.05). In older men, only submaximal mitochondrial oxidative phosphorylation (corrected for mitochondrial content) was positively associated with myofibrillar protein synthesis rates during exercise training (r = 0.72, P < 0.05). However, changes in oxidative phosphorylation and H₂O₂ emission were not associated with changes in skeletal muscle mass following training (both P > 0.05). Additionally, MCAT mice displayed no differences in myofibrillar (2.62 ± 0.22 vs. 2.75 ± 0.15%/day) and sarcoplasmic (3.68 ± 0.35 vs. 3.54 ± 0.35%/day) protein synthesis rates when compared with wild-type mice (both P > 0.05).

Conclusions

Mitochondrial oxidative phosphorylation and reactive oxygen emission do not seem to represent key factors regulating muscle protein synthesis or muscle mass regulation across the spectrum of physical activity.

背景：线粒体是影响细胞平衡的关键细胞器，与调节蛋白质合成的信号事件有关：我们研究了在体外透化肌纤维中测量的线粒体生物能（氧化磷酸化和活性氧（H2O2）释放，ROS）是否代表了肌肉蛋白质合成率和骨骼肌质量在各种体力活动（包括自由生活和卧床休息）中变化的调节因素：n = 19 名健康的年轻男性（26 ± 4 岁，23.4 ± 3.3 kg/m2）和 12 周阻力型运动训练后：n = 10 名健康老年男性（70 ± 3 岁，25.2 ± 2.1 kg/m2）。此外，我们还评估了线粒体 ROS 排放减少与转基因小鼠（线粒体靶向过氧化氢酶，MCAT）每日肌纤维和肌浆蛋白质合成率之间的直接关系：在自由生活条件下或卧床休息 1 周后，氧化磷酸化和 H2O2 排放均与健康年轻男性的肌肉蛋白质合成率无关（P 均 > 0.05）。GSSG浓度的增加与卧床休息后骨骼肌质量的减少有关（r = -0.49，P 2O2 排放与训练后骨骼肌质量的变化无关（均为 P > 0.05）。此外，与野生型小鼠相比，MCAT 小鼠的肌纤维（2.62 ± 0.22 vs. 2.75 ± 0.15%/天）和肌浆（3.68 ± 0.35 vs. 3.54 ± 0.35%/天）蛋白质合成率没有差异（均为 P > 0.05）：结论：线粒体氧化磷酸化和活性氧释放似乎并不是调节肌肉蛋白质合成或肌肉质量的关键因素。

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引用次数: 0

Association between myosteatosis and impaired glucose metabolism: A deep learning whole-body magnetic resonance imaging population phenotyping approach 骨质疏松症与糖代谢受损之间的关联：深度学习全身磁共振成像群体表型方法

IF 9.4 1区医学 Q1 GERIATRICS & GERONTOLOGY

Journal of Cachexia Sarcopenia and Muscle

Pub Date : 2024-07-15 DOI: 10.1002/jcsm.13527

Matthias Jung, Hanna Rieder, Marco Reisert, Susanne Rospleszcz, Johanna Nattenmueller, Annette Peters, Christopher L. Schlett, Fabian Bamberg, Jakob Weiss

<div> <section> <h3> Background</h3> <p>There is increasing evidence that myosteatosis, which is currently not assessed in clinical routine, plays an important role in risk estimation in individuals with impaired glucose metabolism, as it is associated with the progression of insulin resistance. With advances in artificial intelligence, automated and accurate algorithms have become feasible to fill this gap.</p> </section> <section> <h3> Methods</h3> <p>In this retrospective study, we developed and tested a fully automated deep learning model using data from two prospective cohort studies (German National Cohort [NAKO] and Cooperative Health Research in the Region of Augsburg [KORA]) to quantify myosteatosis on whole-body T1-weighted Dixon magnetic resonance imaging as (1) intramuscular adipose tissue (IMAT; the current standard) and (2) quantitative skeletal muscle (SM) fat fraction (SMFF). Subsequently, we investigated the two measures for their discrimination of and association with impaired glucose metabolism beyond baseline demographics (age, sex and body mass index [BMI]) and cardiometabolic risk factors (lipid panel, systolic blood pressure, smoking status and alcohol consumption) in asymptomatic individuals from the KORA study. Impaired glucose metabolism was defined as impaired fasting glucose or impaired glucose tolerance (140–200 mg/dL) or prevalent diabetes mellitus.</p> </section> <section> <h3> Results</h3> <p>Model performance was high, with Dice coefficients of ≥0.81 for IMAT and ≥0.91 for SM in the internal (NAKO) and external (KORA) testing sets. In the target population (380 KORA participants: mean age of 53.6 ± 9.2 years, BMI of 28.2 ± 4.9 kg/m<sup>2</sup>, 57.4% male), individuals with impaired glucose metabolism (<i>n</i> = 146; 38.4%) were older and more likely men and showed a higher cardiometabolic risk profile, higher IMAT (4.5 ± 2.2% vs. 3.9 ± 1.7%) and higher SMFF (22.0 ± 4.7% vs. 18.9 ± 3.9%) compared to normoglycaemic controls (all <i>P</i> ≤ 0.005). SMFF showed better discrimination for impaired glucose metabolism than IMAT (area under the receiver operating characteristic curve [AUC] 0.693 vs. 0.582, 95% confidence interval [CI] [0.06–0.16]; <i>P</i> < 0.001) but was not significantly different from BMI (AUC 0.733 vs. 0.693, 95% CI [−0.09 to 0.01]; <i>P</i> = 0.15). In univariable logistic regression, IMAT (odds ratio [OR] = 1.18, 95% CI [1.06–1.32]; <i>P</i> = 0.004) and SMFF (OR = 1.19, 95% CI [1.13–1.26]; <i>P</i> < 0.001) were associated with a higher risk of impaired glucose metabolism. This signal remained robust after multivariable adjustment for baseline demographics and cardiometabolic risk factors for

背景：越来越多的证据表明，目前在临床常规中尚未评估的骨质疏松症在糖代谢受损患者的风险评估中起着重要作用，因为它与胰岛素抵抗的进展有关。随着人工智能技术的进步，自动化的精确算法已经可以填补这一空白：在这项回顾性研究中，我们利用两项前瞻性队列研究（德国国家队列[NAKO]和奥格斯堡地区合作健康研究[KORA]）的数据，开发并测试了一个全自动深度学习模型，将全身 T1 加权迪克森磁共振成像上的肌骨肥大症量化为（1）肌肉内脂肪组织（IMAT；现行标准）和（2）定量骨骼肌（SM）脂肪分数（SMFF）。随后，我们在 KORA 研究的无症状个体中研究了这两种测量方法对葡萄糖代谢受损的辨别力以及与之的关联，而不局限于基线人口统计学指标（年龄、性别和体重指数 [BMI]）和心血管代谢风险因素（血脂组合、收缩压、吸烟状况和饮酒量）。糖代谢受损被定义为空腹血糖受损或糖耐量受损（140-200 毫克/分升）或流行性糖尿病：模型性能很高，在内部（NAKO）和外部（KORA）测试集中，IMAT的Dice系数≥0.81，SM的Dice系数≥0.91。在目标人群（380 名 KORA 参与者：平均年龄为 53.6 ± 9.2 岁，体重指数为 28.2 ± 4.9 kg/m2，57.4% 为男性）中，糖代谢受损者（n = 146；38.与正常血糖对照组相比，糖代谢受损者（n = 146；38.4%）年龄更大，更可能是男性，并显示出更高的心脏代谢风险特征、更高的 IMAT（4.5 ± 2.2% vs. 3.9 ± 1.7%）和更高的 SMFF（22.0 ± 4.7% vs. 18.9 ± 3.9%）（所有 P 均≤0.005）。与 IMAT 相比，SMFF 对糖代谢受损的判别能力更强（接收器操作特征曲线下面积 [AUC] 0.693 vs. 0.582，95% 置信区间 [CI] [0.06-0.16]；P 结论：SMFF 比 IMAT 更能判别糖代谢受损：定量 SMFF（而非 IMAT）是糖代谢受损的独立预测指标，且与 BMI 的区分度无显著差异，使其有望替代现有方法。自动方法（如所提出的模型）可为肌骨质疏松症的机会性筛查提供一种可行的选择，从而提供一种低成本的个性化风险评估解决方案。

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引用次数: 0

Skeletal muscle p53-depletion uncovers a mechanism of fuel usage suppression that enables efficient energy conservation 骨骼肌 p53 损伤揭示了一种抑制燃料使用的机制，这种机制可实现高效的能量守恒。

IF 9.4 1区医学 Q1 GERIATRICS & GERONTOLOGY

Journal of Cachexia Sarcopenia and Muscle

Pub Date : 2024-07-15 DOI: 10.1002/jcsm.13529

Georgia Lenihan-Geels, Francisco Garcia Carrizo, Marina Leer, Sabrina Gohlke, Moritz Oster, Sophie Pöhle-Kronawitter, Christiane Ott, Alexandra Chadt, Isabel N. Reinisch, Markus Galhuber, Chen Li, Wenke Jonas, Markus Jähnert, Susanne Klaus, Hadi Al-Hasani, Tilman Grune, Annette Schürmann, Tobias Madl, Andreas Prokesch, Michael Schupp, Tim J. Schulz

<div> <section> <h3> Background</h3> <p>The ability of skeletal muscle to respond adequately to changes in nutrient availability, known as metabolic flexibility, is essential for the maintenance of metabolic health and loss of flexibility contributes to the development of diabetes and obesity. The tumour suppressor protein, p53, has been linked to the control of energy metabolism. We assessed its role in the acute control of nutrient allocation in skeletal muscle in the context of limited nutrient availability.</p> </section> <section> <h3> Methods</h3> <p>A mouse model with inducible deletion of the p53-encoding gene, <i>Trp53</i>, in skeletal muscle was generated using the Cre-loxP-system. A detailed analysis of nutrient metabolism in mice with control and knockout genotypes was performed under <i>ad libitum</i> fed and fasting conditions and in exercised mice.</p> </section> <section> <h3> Results</h3> <p>Acute deletion of p53 in myofibres of mice activated catabolic nutrient usage pathways even under <i>ad libitum</i> fed conditions, resulting in significantly increased overall energy expenditure (+10.6%; <i>P</i> = 0.0385) and a severe nutrient deficit in muscle characterized by depleted intramuscular glucose and glycogen levels (−62,0%; <i>P</i> < 0.0001 and −52.7%; <i>P</i> < 0.0001, respectively). This was accompanied by changes in marker gene expression patterns of circadian rhythmicity and hyperactivity (+57.4%; <i>P</i> = 0.0068). These metabolic changes occurred acutely, within 2–3 days after deletion of <i>Trp53</i> was initiated, suggesting a rapid adaptive response to loss of p53, which resulted in a transient increase in lactate release to the circulation (+46.6%; <i>P</i> = 0.0115) from non-exercised muscle as a result of elevated carbohydrate mobilization. Conversely, an impairment of proteostasis and amino acid metabolism was observed in knockout mice during fasting. During endurance exercise testing, mice with acute, muscle-specific <i>Trp53</i> inactivation displayed an early exhaustion phenotype with a premature shift in fuel usage and reductions in multiple performance parameters, including a significantly reduced running time and distance (−13.8%; <i>P</i> = 0.049 and −22.2%; <i>P</i> = 0.0384, respectively).</p> </section> <section> <h3> Conclusions</h3> <p>These findings suggest that efficient nutrient conservation is a key element of normal metabolic homeostasis that is sustained by p53. The homeostatic state in metabolic tissues is actively maintained to coordinate efficient energy conservation and metabolic flexib

背景：骨骼肌对营养供应变化做出适当反应的能力（称为代谢灵活性）对维持代谢健康至关重要，而失去灵活性则会导致糖尿病和肥胖症的发生。肿瘤抑制蛋白 p53 与能量代谢的控制有关。我们评估了它在有限营养供应情况下对骨骼肌营养分配的急性控制中的作用：方法：利用 Cre-loxP 系统在小鼠骨骼肌中诱导性缺失 p53 编码基因 Trp53。方法：利用 Cre-loxP 系统生成了骨骼肌中 p53 编码基因 Trp53 诱导性缺失的小鼠模型，在自由进食、禁食和运动条件下对对照组和基因敲除组小鼠的营养代谢进行了详细分析：结果：即使在自由进食条件下，小鼠肌纤维中p53的急性缺失也会激活分解代谢的营养物质利用途径，导致总体能量消耗显著增加（+10.6%；P = 0.0385），肌肉中的营养物质严重不足，表现为肌肉内葡萄糖和糖原水平的耗竭（-62.0%；P 结论：这些研究结果表明，有效的营养物质利用途径对小鼠肌肉的健康至关重要：这些发现表明，有效的营养保护是 p53 维持正常代谢平衡的关键因素。新陈代谢组织中的平衡状态是积极维持的，以协调有效的能量守恒和新陈代谢灵活性，从而应对营养压力。Trp53 的急性缺失会释放抑制营养物质分解途径活性的机制，导致肌肉内能量储存的大量损失，从而导致肌肉组织出现类似禁食的状态。总之，这些发现揭示了 p53 在短期调节骨骼肌营养代谢中的新功能，并表明 p53 有助于维持代谢平衡和有效的能量守恒。

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引用次数: 0

A multi-omics approach to overeating and inactivity-induced muscle atrophy in db/db mice 暴饮暴食和非活动诱导 db/db 小鼠肌肉萎缩的多组学方法

IF 9.4 1区医学 Q1 GERIATRICS & GERONTOLOGY

Journal of Cachexia Sarcopenia and Muscle

Pub Date : 2024-07-13 DOI: 10.1002/jcsm.13550

Takuro Okamura, Masahide Hamaguchi, Genki Kobayashi, Takahiro Ichikawa, Yuka Hasegawa, Tomoki Miyoshi, Takafumi Senmaru, Naoko Nakanishi, Ryoichi Sasano, Michiaki Fukui

Background

Overeating and inactivity are associated with type 2 diabetes. This study aimed to investigate its pathological basis using integrated omics and db/db/mice, a model representing this condition.

Methods

The study involved housing 8-week-old db/m and db/db mice for 8 weeks. Various analyses were conducted, including gene expression in skeletal muscle and small intestine using next-generation sequencing; cytokine arrays of serum; assessment of metabolites in skeletal muscle, stool, and serum; and analysis of the gut microbiota. Histone modifications in small intestinal epithelial cells were profiled using CUT&Tag.

Results

Compared with db/m mice, db/db mice had 22.4% lower grip strength and approximately five times the visceral fat weight (P < 0.0001). Serum cytokine arrays showed a 2.8-fold relative concentration of VEGF-A in db/db mice (P < 0.0001) and lower concentrations of several other cytokines. mRNA sequencing revealed downregulation of Myh expression in skeletal muscle, upregulation of lipid and glucose transporters, and downregulation of amino acid transporters in the small intestine of db/db/mice. The concentrations of saturated fatty acids in skeletal muscle were significantly higher, and the levels of essential amino acids were lower in db/db mice. Analysis of the gut microbiota, 16S rRNA sequencing, revealed lower levels of the phylum Bacteroidetes (59.7% vs. 44.9%) and higher levels of the phylum Firmicutes (20.9% vs. 31.4%) in db/db mice (P = 0.003). The integrated signal of histone modifications of lipid and glucose transporters was higher, while the integrated signal of histone modifications of amino acid transporters was lower in the db/db mice.

Conclusions

The multi-omics approach provided insights into the epigenomic alterations in the small intestine, suggesting their involvement in the pathogenesis of inactivity-induced muscle atrophy in obese mice.

暴饮暴食和缺乏运动与 2 型糖尿病有关。本研究旨在利用综合全息技术和代表该病症的模型 db/db/mice 研究其病理基础。

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引用次数: 0

Tumour-induced alterations in single-nucleus transcriptome of atrophying muscles indicate enhanced protein degradation and reduced oxidative metabolism 肿瘤诱导的萎缩肌肉单核转录组变化表明蛋白质降解增强，氧化代谢降低。

IF 9.4 1区医学 Q1 GERIATRICS & GERONTOLOGY

Journal of Cachexia Sarcopenia and Muscle

Pub Date : 2024-07-13 DOI: 10.1002/jcsm.13540

Samet Agca, Aylin Domaniku-Waraich, Sevval Nur Bilgic, Melis Sucuoglu, Meric Dag, Sukru Anil Dogan, Serkan Kir

<div> <section> <h3> Background</h3> <p>Tumour-induced skeletal muscle wasting in the context of cancer cachexia is a condition with profound implications for patient survival. The loss of muscle mass is a significant clinical obstacle and is linked to reduced tolerance to chemotherapy and increased frailty. Understanding the molecular mechanisms driving muscle atrophy is crucial for the design of new therapeutics.</p> </section> <section> <h3> Methods</h3> <p>Lewis lung carcinoma tumours were utilized to induce cachexia and muscle atrophy in mice. Single-nucleus libraries of the tibialis anterior (TA) muscle from tumour-bearing mice and their non-tumour-bearing controls were constructed using 10X Genomics applications following the manufacturer's guidelines. RNA sequencing results were analysed with Cell Ranger software and the Seurat R package. Oxygen consumption of mitochondria isolated from TA muscle was measured using an Oroboros O2k-FluoRespirometer. Mouse primary myotubes were treated with a recombinant ectodysplasin A2 (EDA-A2) protein to activate EDA-A2 receptor (EDA2R) signalling and study changes in gene expression and oxygen consumption.</p> </section> <section> <h3> Results</h3> <p>Tumour-bearing mice were sacrificed while exhibiting moderate cachexia. Average TA muscle weight was reduced by 11% (<i>P</i> = 0.0207) in these mice. A total of 12 335 nuclei, comprising 6422 nuclei from the control group and 5892 nuclei from atrophying muscles, were studied. The analysis of single-nucleus transcriptomes identified distinct myonuclear gene signatures and a shift towards type IIb myonuclei. Muscle atrophy-related genes, including <i>Atrogin1</i>, <i>MuRF1</i> and <i>Eda2r</i>, were upregulated in these myonuclei, emphasizing their crucial roles in muscle wasting. Gene set enrichment analysis demonstrated that EDA2R activation and tumour inoculation led to similar expression patterns in muscle cells, including the stimulation of nuclear factor-kappa B, Janus kinase–signal transducer and activator of transcription and transforming growth factor-beta pathways and the suppression of myogenesis and oxidative phosphorylation. Muscle oxidative metabolism was suppressed by both tumours and EDA2R activation.</p> </section> <section> <h3> Conclusions</h3> <p>This study identified tumour-induced transcriptional changes in muscle tissue at single-nucleus resolution and highlighted the negative impact of tumours on oxidative metabolism. These findings contribute to a deeper understanding of the molecular mechanisms underlying muscle wasting.</p>

背景：在癌症恶病质的背景下，肿瘤引起的骨骼肌萎缩对患者的生存有着深远的影响。肌肉质量的丧失是一个重要的临床障碍，与化疗耐受性降低和虚弱程度增加有关。了解肌肉萎缩的分子机制对于设计新疗法至关重要：方法：利用路易斯肺癌肿瘤诱导小鼠出现恶病质和肌肉萎缩。方法：利用路易斯肺癌肿瘤诱导小鼠出现恶病质和肌肉萎缩。按照制造商的指导原则，使用 10X Genomics 应用程序构建了肿瘤小鼠及其非肿瘤对照组胫骨前肌（TA）的单核文库。使用 Cell Ranger 软件和 Seurat R 软件包分析 RNA 测序结果。使用 Oroboros O2k-FluoRespirometer 测量从 TA 肌肉分离的线粒体的耗氧量。用重组外胚层蛋白 A2（EDA-A2）蛋白处理小鼠原代肌管，以激活 EDA-A2 受体（EDA2R）信号，并研究基因表达和耗氧量的变化：结果：肿瘤小鼠在出现中度恶病质时被处死。这些小鼠的平均 TA 肌肉重量减少了 11%（P = 0.0207）。共研究了 12 335 个细胞核，包括来自对照组的 6422 个细胞核和来自萎缩肌肉的 5892 个细胞核。对单核转录组的分析发现了不同的肌核基因特征，以及向 IIb 型肌核的转变。肌肉萎缩相关基因（包括 Atrogin1、MuRF1 和 Eda2r）在这些肌核中上调，强调了它们在肌肉萎缩中的关键作用。基因组富集分析表明，EDA2R激活和肿瘤接种会导致肌肉细胞中出现类似的表达模式，包括刺激核因子-卡巴B、Janus激酶-信号转导和转录激活因子以及转化生长因子-β通路，抑制肌生成和氧化磷酸化。肿瘤和EDA2R激活都抑制了肌肉氧化代谢：这项研究以单核分辨率确定了肿瘤诱导的肌肉组织转录变化，并强调了肿瘤对氧化代谢的负面影响。这些发现有助于深入了解肌肉萎缩的分子机制。

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引用次数: 0

A new computed tomography-based approach to quantify swallowing muscle volume by measuring tongue muscle area in a single slice 基于计算机断层扫描的新方法，通过单片测量舌肌面积量化吞咽肌体积。

IF 9.4 1区医学 Q1 GERIATRICS & GERONTOLOGY

Journal of Cachexia Sarcopenia and Muscle

Pub Date : 2024-07-12 DOI: 10.1002/jcsm.13537

Javier Hurtado-Oliva, Aniek T. Zwart, Jeroen Vister, Anouk van der Hoorn, Roel J.H.M. Steenbakkers, Inge Wegner, Gyorgy B. Halmos

<div> <section> <h3> Background</h3> <p>Measuring the swallowing muscle mass with volume measurements is complex and time intensive; therefore, it is not used in clinical practice. However, it can be clinically relevant, for instance, in the case of sarcopenic dysphagia. The aim of the study was to develop a feasible and clinically applicable method to measure swallowing muscle mass.</p> </section> <section> <h3> Methods</h3> <p>Data from 10 head and neck cancer patients were collected from the Oncological Life Study data-biobank of the University Medical Center Groningen. The pharyngeal constrictor, genioglossus, mylohyoid and geniohyoid complex muscles, as well as the tongue complex muscles, were delineated manually on routinely performed head and neck computed tomography scans. Axial and sagittal planes were used for volume and area measurements, respectively. Muscle density measurements were performed with and without Hounsfield unit thresholding. Correlations were assessed by Pearson correlation coefficients, and interobserver reliability was measured using intra-class correlation coefficients (ICCs).</p> </section> <section> <h3> Results</h3> <p>Significant differences were observed between sagittal area measurements with and without Hounsfield unit thresholds for pharyngeal constrictor, tongue complex and the sum of the swallowing muscles (<i>t</i> > 6; <i>P</i>-value < 0.001). Stronger correlations emerged without Hounsfield unit thresholding. Strong positive and significant correlations were found between the total swallowing muscle mass volume and the sagittal area of the tongue complex muscles (<i>r</i> = 0.87, <i>P</i>-value < 0.05) and the sum of the sagittal areas of the pharyngeal constrictor and tongue complex muscles (<i>r</i> = 0.85, <i>P</i>-value < 0.05). The use of the Hounsfield unit threshold weakened correlations. Interobserver reliability was assessed and found to be fair to good for the pharyngeal constrictor muscle (ICC = 0.68, <i>P</i>-value < 0.05), excellent for the tongue complex muscles (ICC = 0.98, <i>P</i>-value < 0.05) and excellent for the total swallowing muscle area (ICC = 0.96, <i>P</i>-value < 0.05).</p> </section> <section> <h3> Conclusions</h3> <p>Single-slice delineation of the sagittal area of tongue complex muscle and pharyngeal constrictor muscle is a promising, fast, simple and clinically applicable method for measuring the total volume of the swallowing muscle mass in head and neck cancer patients without Hounsfield unit thresholding. These advancements and findings would help in

背景：用容积测量吞咽肌肉质量既复杂又费时，因此在临床实践中并不常用。然而，它可能与临床相关，例如在肌肉疏松性吞咽困难的情况下。本研究旨在开发一种可行且适用于临床的方法来测量吞咽肌肉质量：方法：从格罗宁根大学医学中心的肿瘤生命研究数据库中收集了 10 名头颈部癌症患者的数据。咽部收缩肌、舌根肌、舌肌和舌根复合肌以及舌复合肌是在常规头颈部计算机断层扫描中人工划定的。轴向和矢状面分别用于测量体积和面积。肌肉密度测定采用或不采用 Hounsfield 单位阈值。相关性通过皮尔逊相关系数进行评估，观察者之间的可靠性通过类内相关系数（ICC）进行测量：对咽收缩肌、舌复合体和吞咽肌总和进行矢状面面积测量时，采用 Hounsfield 单位阈值与不采用 Hounsfield 单位阈值之间存在显著差异（t > 6；P 值单片划定舌复合肌和咽收缩肌的矢状面面积是一种前景广阔、快速、简单且适用于临床的方法，无需 Hounsfield 单位阈值即可测量头颈部癌症患者吞咽肌群的总体积。这些进展和发现将有助于早期准确诊断明确的肌肉萎缩性吞咽困难。

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引用次数: 0

Differential impacts of fat and muscle mass on cardiovascular and non-cardiovascular mortality in individuals with type 2 diabetes 脂肪和肌肉质量对 2 型糖尿病患者心血管和非心血管死亡率的不同影响。

IF 9.4 1区医学 Q1 GERIATRICS & GERONTOLOGY

Journal of Cachexia Sarcopenia and Muscle

Pub Date : 2024-07-12 DOI: 10.1002/jcsm.13542

Jie Guo, Yuxia Wei, Emerald G. Heiland, Anna Marseglia

Background

The distribution of fat and muscle mass in different regions of the body can reflect different pathways to mortality in individuals with diabetes. Therefore, we investigated the associations between whole-body and regional body fat and muscle mass with cardiovascular disease (CVD) and non-CVD mortality in type 2 diabetes (T2D).

Methods

Within the National Health and Nutrition Examination Survey 1999–2006, 1417 adults aged ≥50 years with T2D were selected. Dual-energy X-ray absorptiometry was used to derive whole-body, trunk, arm, and leg fat mass and muscle mass indices (FMI and MMI). Mortality data until 31 December 2019 were retrieved from the National Death Index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models.

Results

A total of 1417 participants were included in this study (weighted mean age [standard error]: 63.7 [0.3] years; 50.5% female). Over a median follow-up of 13.6 years, 797 deaths were recorded (371 CVD-related and 426 non-CVD deaths). Higher FMI in the arm was associated with increased risk of non-CVD mortality (fourth quartile [Q4] vs. first quartile [Q1]: HR 1.82 [95% CI 1.13–2.94]), whereas higher FMI in the trunk or leg was not significantly associated with CVD or non-CVD mortality. Conversely, higher arm MMI was associated with a lower risk of both CVD (Q4 vs. Q1: HR 0.51 [95% CI 0.33–0.81]) and non-CVD (Q4 vs. Q1: HR 0.56 [95% CI 0.33–0.94]) mortality. There was a significant interaction between smoking status and arm FMI on non-CVD mortality (P for interaction = 0.007). Higher arm FMI was associated with a higher risk of non-CVD mortality among current or former smokers (Q4 vs. Q1: HR 2.67 [95% CI 1.46–4.88]) but not non-smokers (Q4 vs. Q1: HR 0.85 [95% CI 0.49–1.47]).

Conclusions

Fat mass and muscle mass, especially in the arm, are differently associated with CVD and non-CVD mortality in people with T2D. Our findings underscore the predictive value of body compositions in the arm in forecasting mortality among older adults with T2D.

背景：脂肪和肌肉质量在身体不同区域的分布可反映糖尿病患者死亡的不同途径。因此，我们研究了2型糖尿病（T2D）患者全身及各区域脂肪和肌肉质量与心血管疾病（CVD）和非CVD死亡率之间的关系：方法：在1999-2006年全国健康与营养调查中，选取了1417名年龄≥50岁的2型糖尿病成人。采用双能 X 射线吸收测量法得出全身、躯干、手臂和腿部脂肪量和肌肉量指数（FMI 和 MMI）。截至 2019 年 12 月 31 日的死亡率数据来自国家死亡指数。根据 Cox 比例危险模型估算出危险比（HRs）和 95% 置信区间（CIs）：本研究共纳入 1417 名参与者（加权平均年龄 [标准误差]：63.7 [0.3] 岁；50.5% 为女性）。中位随访时间为 13.6 年，共记录了 797 例死亡（371 例心血管疾病相关死亡和 426 例非心血管疾病相关死亡）。手臂的 FMI 值越高，非心血管疾病死亡风险越高（第四四分位数 [Q4] 与第一四分位数 [Q1]：HR 1.82 [95% CI 1.13-2.94]），而躯干或腿部的 FMI 值越高，与心血管疾病或非心血管疾病死亡的关系不大。相反，手臂MMI越高，心血管疾病（Q4 vs. Q1：HR 0.51 [95% CI 0.33-0.81]）和非心血管疾病（Q4 vs. Q1：HR 0.56 [95% CI 0.33-0.94]）死亡风险越低。吸烟状况和臂部 FMI 对非心血管疾病死亡率有明显的交互作用（交互作用的 P = 0.007）。在目前或曾经吸烟者中，较高的手臂FMI与较高的非心血管疾病死亡风险相关（Q4 vs. Q1：HR 2.67 [95% CI 1.46-4.88]），但与非吸烟者无关（Q4 vs. Q1：HR 0.85 [95% CI 0.49-1.47]）：结论：脂肪量和肌肉量（尤其是手臂肌肉量）与 T2D 患者的心血管疾病和非心血管疾病死亡率的相关性不同。我们的发现强调了手臂的身体成分在预测患有 T2D 的老年人死亡率方面的预测价值。

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