Steffen H. Raun, Mona S. Ali, Xiuqing Han, Carlos Henríquez-Olguín, T.C. Phung Pham, Roberto Meneses-Valdés, Jonas R. Knudsen, Anna C.H. Willemsen, Steen Larsen, Thomas E. Jensen, Ramon Langen, Lykke Sylow
Background
Metabolic dysfunction and cachexia are associated with poor cancer prognosis. With no pharmacological treatments, it is crucial to define the molecular mechanisms causing cancer-induced metabolic dysfunction and cachexia. Adenosine monophosphate-activated protein kinase (AMPK) connects metabolic and muscle mass regulation. As AMPK could be a potential treatment target, it is important to determine the function for AMPK in cancer-associated metabolic dysfunction and cachexia. We therefore established AMPK's roles in cancer-associated metabolic dysfunction, insulin resistance and cachexia.
Methods
In vastus lateralis muscle biopsies from n = 26 patients with non-small cell lung cancer (NSCLC), AMPK signalling and protein content were examined by immunoblotting. To determine the role of muscle AMPK, male mice overexpressing a dominant-negative AMPKα2 (kinase-dead [KiDe]) specifically in striated muscle were inoculated with Lewis lung carcinoma (LLC) cells (wild type [WT]: n = 27, WT + LLC: n = 34, mAMPK-KiDe: n = 23, mAMPK-KiDe + LLC: n = 38). Moreover, male LLC-tumour-bearing mice were treated with (n = 10)/without (n = 9) 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK for 13 days. Littermate mice were used as controls. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose and insulin tolerance tests, tissue-specific 2-[3H]deoxy-d-glucose (2-DG) uptake and immunoblotting.
Results
Patients with NSCLC presented increased muscle protein content of AMPK subunits α1, α2, β2, γ1 and γ3 ranging from +27% to +79% compared with control subjects. In patients with NSCLC, AMPK subunit protein content correlated with weight loss (α1, α2, β2 and γ1), fat-free mass (α1, β2 and γ1) and fat mass (α1 and γ1). Tumour-bearing mAMPK-KiDe mice presented increased fat loss and glucose and insulin intolerance. LLC in mAMPK-KiDe mice displayed lower insulin-stimulated 2-DG uptake in skeletal muscle (quadriceps: −35%, soleus: −49%, extensor digitorum longus: −48%) and the heart (−29%) than that in non-tumour-bearing mice. In skeletal muscle, mAMPK-KiDe abrogated the tumour-induced increase in insulin-stimulated TBC1D4thr642 phosphorylation. The protein content of TBC1D4 (+26%), pyruvate dehydrogenase (PDH; +94%), PDH kinases (+45% to +100%) and glycogen synthase (+48%) was increased in skeletal muscle of tumour-bearing mice in an AMPK-dependent manner. Lastly, chronic AICAR treatment elevated hexokinase II protein co
背景:代谢功能障碍和恶病质与癌症预后不良有关。在没有药物治疗的情况下，确定引起癌症诱导的代谢功能障碍和恶病质的分子机制至关重要。腺苷单磷酸活化蛋白激酶(AMPK)连接代谢和肌肉质量调节。由于AMPK可能是一个潜在的治疗靶点，因此确定AMPK在癌症相关代谢功能障碍和恶病质中的功能非常重要。因此，我们确定了AMPK在癌症相关代谢功能障碍、胰岛素抵抗和恶病质中的作用。方法对26例非小细胞肺癌(NSCLC)患者行股外侧肌活检，采用免疫印迹法检测AMPK信号和蛋白含量。为了确定肌肉AMPK的作用，我们用Lewis肺癌(LLC)细胞(野生型[WT]: n = 27, WT + LLC: n = 34, mAMPK-KiDe: n = 23, mAMPK-KiDe + LLC: n = 38)接种横纹肌中特异性表达显性阴性AMPKα2(激酶死亡[KiDe])的雄性小鼠。此外，用(n = 10)/不(n = 9) 5-氨基咪唑-4-羧酰胺核糖核苷酸(AICAR)激活雄性llc -荷瘤小鼠13天。同窝小鼠作为对照。通过间接量热法、体成分分析、葡萄糖和胰岛素耐量试验、组织特异性2-[3H]脱氧-d-葡萄糖(2- dg)摄取和免疫印迹法对小鼠进行代谢表型分析。结果与对照组相比，NSCLC患者AMPK亚基α1、α2、β2、γ1和γ3的肌肉蛋白含量增加了27% ~ 79%。在NSCLC患者中，AMPK亚基蛋白含量与体重减轻(α1、α2、β2和γ1)、无脂质量(α1、β2和γ1)和脂肪质量(α1和γ1)相关。携带肿瘤的mAMPK-KiDe小鼠表现出增加的脂肪减少和葡萄糖和胰岛素不耐受。与非荷瘤小鼠相比，mAMPK-KiDe小鼠的LLC在骨骼肌(股四头肌:- 35%，比目鱼肌:- 49%，指长伸肌:- 48%)和心脏(- 29%)中显示出较低的胰岛素刺激2-DG摄取。在骨骼肌中，mAMPK-KiDe消除了肿瘤诱导的胰岛素刺激的TBC1D4thr642磷酸化的增加。TBC1D4蛋白含量(+26%)、丙酮酸脱氢酶(PDH;+94%)， PDH激酶(+45%至+100%)和糖原合成酶(+48%)在荷瘤小鼠骨骼肌中以ampk依赖的方式增加。最后，慢性AICAR治疗提高了己糖激酶II蛋白含量，并使p70S6Kthr389 (mTORC1底物)和ACCser212 (AMPK底物)的磷酸化正常化，挽救了癌症诱导的胰岛素不耐受。结论AMPK亚基蛋白含量在非小细胞肺癌骨骼肌中表达上调。AMPK激活似乎是通过AMPK缺陷小鼠在癌症反应中产生代谢功能障碍来推断的，包括对葡萄糖代谢至关重要的多种蛋白质的AMPK依赖性调节。这些观察结果强调了靶向AMPK对抗癌症相关代谢功能障碍和可能的恶病质的潜力。
{"title":"Adenosine monophosphate-activated protein kinase is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice","authors":"Steffen H. Raun, Mona S. Ali, Xiuqing Han, Carlos Henríquez-Olguín, T.C. Phung Pham, Roberto Meneses-Valdés, Jonas R. Knudsen, Anna C.H. Willemsen, Steen Larsen, Thomas E. Jensen, Ramon Langen, Lykke Sylow","doi":"10.1002/jcsm.13238","DOIUrl":"https://doi.org/10.1002/jcsm.13238","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Metabolic dysfunction and cachexia are associated with poor cancer prognosis. With no pharmacological treatments, it is crucial to define the molecular mechanisms causing cancer-induced metabolic dysfunction and cachexia. Adenosine monophosphate-activated protein kinase (AMPK) connects metabolic and muscle mass regulation. As AMPK could be a potential treatment target, it is important to determine the function for AMPK in cancer-associated metabolic dysfunction and cachexia. We therefore established AMPK's roles in cancer-associated metabolic dysfunction, insulin resistance and cachexia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In vastus lateralis muscle biopsies from <i>n</i> = 26 patients with non-small cell lung cancer (NSCLC), AMPK signalling and protein content were examined by immunoblotting. To determine the role of muscle AMPK, male mice overexpressing a dominant-negative AMPKα2 (kinase-dead [KiDe]) specifically in striated muscle were inoculated with Lewis lung carcinoma (LLC) cells (wild type [WT]: <i>n</i> = 27, WT + LLC: <i>n</i> = 34, mAMPK-KiDe: <i>n</i> = 23, mAMPK-KiDe + LLC: <i>n</i> = 38). Moreover, male LLC-tumour-bearing mice were treated with (<i>n</i> = 10)/without (<i>n</i> = 9) 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK for 13 days. Littermate mice were used as controls. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose and insulin tolerance tests, tissue-specific 2-[3H]deoxy-<span>d</span>-glucose (2-DG) uptake and immunoblotting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Patients with NSCLC presented increased muscle protein content of AMPK subunits α1, α2, β2, γ1 and γ3 ranging from +27% to +79% compared with control subjects. In patients with NSCLC, AMPK subunit protein content correlated with weight loss (α1, α2, β2 and γ1), fat-free mass (α1, β2 and γ1) and fat mass (α1 and γ1). Tumour-bearing mAMPK-KiDe mice presented increased fat loss and glucose and insulin intolerance. LLC in mAMPK-KiDe mice displayed lower insulin-stimulated 2-DG uptake in skeletal muscle (quadriceps: −35%, soleus: −49%, extensor digitorum longus: −48%) and the heart (−29%) than that in non-tumour-bearing mice. In skeletal muscle, mAMPK-KiDe abrogated the tumour-induced increase in insulin-stimulated TBC1D4<sup>thr642</sup> phosphorylation. The protein content of TBC1D4 (+26%), pyruvate dehydrogenase (PDH; +94%), PDH kinases (+45% to +100%) and glycogen synthase (+48%) was increased in skeletal muscle of tumour-bearing mice in an AMPK-dependent manner. Lastly, chronic AICAR treatment elevated hexokinase II protein co","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1631-1647"},"PeriodicalIF":8.9,"publicationDate":"2023-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13238","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5890001","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}
Rodrigo Xavier das Neves, Alex S. Yamashita, Daniela M.R. Riccardi, Julia K?hn-Gaone, Rodolfo G. Camargo, Nelson I. Neto, Daniela Caetano, Silvio P. Gomes, Felipe H. Santos, Joanna D.C.C. Lima, Miguel L. Batista Jr, José Cesar Rosa-Neto, Paulo Sérgio Martins De Alcantara, Linda F. Maximiano, José P. Otoch, Giorgio Trinchieri, Janina E.E. Tirnitz-Parker, Marília Seelaender
Background
Cachexia is a wasting syndrome associated with systemic inflammation and metabolic disruption. Detection of the early signs of the disease may contribute to the effective attenuation of associated symptoms. Despite playing a central role in the control of metabolism and inflammation, the liver has received little attention in cachexia. We previously described relevant disruption of metabolic pathways in the organ in an animal model of cachexia, and herein, we adopt the same model to investigate temporal onset of inflammation in the liver. The aim was thus to study inflammation in rodent liver in the well-characterized cachexia model of Walker 256 carcinosarcoma and, in addition, to describe inflammatory alterations in the liver of one cachectic colon cancer patient, as compared to one control and one weight-stable cancer patient.
Methods
Colon cancer patients (one weight stable [WSC] and one cachectic [CC]) and one patient undergoing surgery for cholelithiasis (control, n = 1) were enrolled in the study, after obtainment of fully informed consent. Eight-week-old male rats were subcutaneously inoculated with a Walker 256 carcinosarcoma cell suspension (2 × 107 cells in 1.0 mL; tumour-bearing [T]; or phosphate-buffered saline—controls [C]). The liver was excised on Days 0 (n = 5), 7 (n = 5) and 14 (n = 5) after tumour cell injection.
Results
In rodent cachexia, we found progressively higher numbers of CD68+ myeloid cells in the liver along cancer-cachexia development. Similar findings are described for CC, whose liver showed infiltration of the same cell type, compared with both WSC and control patient organs. In advanced rodent cachexia, hepatic phosphorylated c-Jun N-terminal kinase protein content and the inflammasome pathway protein expression were increased in relation to baseline (P < 0.05). These changes were accompanied by augmented expression of the active interleukin-1β (IL-1β) form (P < 0.05 for both circulating and hepatic content).
Conclusions
The results show that cancer cachexia is associated with an increase in the number of myeloid cells in rodent and human liver and with modulation of hepatic inflammasome pathway. The latter contributes to the aggravation of systemic inflammation, through increased release of IL-1β.
{"title":"Cachexia causes time-dependent activation of the inflammasome in the liver","authors":"Rodrigo Xavier das Neves, Alex S. Yamashita, Daniela M.R. Riccardi, Julia K?hn-Gaone, Rodolfo G. Camargo, Nelson I. Neto, Daniela Caetano, Silvio P. Gomes, Felipe H. Santos, Joanna D.C.C. Lima, Miguel L. Batista Jr, José Cesar Rosa-Neto, Paulo Sérgio Martins De Alcantara, Linda F. Maximiano, José P. Otoch, Giorgio Trinchieri, Janina E.E. Tirnitz-Parker, Marília Seelaender","doi":"10.1002/jcsm.13236","DOIUrl":"https://doi.org/10.1002/jcsm.13236","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cachexia is a wasting syndrome associated with systemic inflammation and metabolic disruption. Detection of the early signs of the disease may contribute to the effective attenuation of associated symptoms. Despite playing a central role in the control of metabolism and inflammation, the liver has received little attention in cachexia. We previously described relevant disruption of metabolic pathways in the organ in an animal model of cachexia, and herein, we adopt the same model to investigate temporal onset of inflammation in the liver. The aim was thus to study inflammation in rodent liver in the well-characterized cachexia model of Walker 256 carcinosarcoma and, in addition, to describe inflammatory alterations in the liver of one cachectic colon cancer patient, as compared to one control and one weight-stable cancer patient.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Colon cancer patients (one weight stable [WSC] and one cachectic [CC]) and one patient undergoing surgery for cholelithiasis (control, <i>n</i> = 1) were enrolled in the study, after obtainment of fully informed consent. Eight-week-old male rats were subcutaneously inoculated with a Walker 256 carcinosarcoma cell suspension (2 × 10<sup>7</sup> cells in 1.0 mL; tumour-bearing [T]; or phosphate-buffered saline—controls [C]). The liver was excised on Days 0 (<i>n</i> = 5), 7 (<i>n</i> = 5) and 14 (<i>n</i> = 5) after tumour cell injection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In rodent cachexia, we found progressively higher numbers of CD68<sup>+</sup> myeloid cells in the liver along cancer-cachexia development. Similar findings are described for CC, whose liver showed infiltration of the same cell type, compared with both WSC and control patient organs. In advanced rodent cachexia, hepatic phosphorylated c-Jun N-terminal kinase protein content and the inflammasome pathway protein expression were increased in relation to baseline (<i>P</i> < 0.05). These changes were accompanied by augmented expression of the active interleukin-1β (IL-1β) form (<i>P</i> < 0.05 for both circulating and hepatic content).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The results show that cancer cachexia is associated with an increase in the number of myeloid cells in rodent and human liver and with modulation of hepatic inflammasome pathway. The latter contributes to the aggravation of systemic inflammation, through increased release of IL-1β.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1621-1630"},"PeriodicalIF":8.9,"publicationDate":"2023-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13236","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6107268","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}
Charlotte Beaudart, Céline Demonceau, Jean-Yves Reginster, Médéa Locquet, Matteo Cesari, Alfonso J. Cruz Jentoft, Olivier Bruyère
The decrease of physical abilities and functional decline that can be caused by musculoskeletal conditions such as sarcopenia, can lead to higher levels of dependency and disability. Therefore, it may influence patient reported outcome measures (PROM), such as the health-related quality of life (HRQoL). The purpose of this systematic review and meta-analysis is to provide a comprehensive overview of the relationship between sarcopenia and HRQoL. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were followed throughout the whole process of this work. A protocol was previously published on PROSPERO. The electronic databases MEDLINE, Scopus, Allied and Complementary Medicine (AMED), EMB Review – ACP Journal Club, EBM Review - Cochrane Central of Register of Controlled Trials and APA PsychInfo were searched until October 2022 for observational studies reporting a HRQoL assessment in both sarcopenic and non-sarcopenic individuals. Study selection and data extraction were carried out by two independent researchers. Meta-analysis was performed using a random effect model, reporting an overall standardized mean difference (SMD) and its 95% confidence interval (CI) between sarcopenic and non-sarcopenic individuals. Study quality was measured using the Newcastle-Ottawa Scale and the strength of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. The search strategy identified 3725 references from which 43 observational studies were eligible and included in this meta-synthesis study. A significantly lower HRQoL was observed for sarcopenic individuals compared with non-sarcopenic ones (SMD −0.76; 95% CI −0.95; −0.57). Significant heterogeneity was associated with the model (I2 = 93%, Q test P-value <0.01). Subgroup analysis showed a higher effect size when using the specific questionnaire SarQoL compared with generic questionnaires (SMD −1.09; 95% CI −1.44; −0.74 with the SarQoL versus −0.49; 95% CI −0.63; −0.36 with generic tools; P-value for interaction <0.01). A greater difference of HRQoL between sarcopenic and non-sarcopenic was found for individuals residing in care homes compared with community-dwelling individuals (P-value for interaction <0.001). No differences were found between age groups, diagnostic techniques, and continents/regions. The level of evidence was rated as moderate using the GRADE assessment. This systematic review and meta-analysis combining 43 observational studies shows that HRQoL is significantly reduced in sarcopenic patients. The use of disease-specific HRQoL instruments may better discriminate sarcopenic patients with respect to their quality of life.
肌肉骨骼疾病(如肌肉减少症)可能导致身体能力下降和功能衰退，从而导致更高程度的依赖和残疾。因此，它可能会影响患者报告的结果测量(PROM)，如与健康相关的生活质量(HRQoL)。本系统综述和荟萃分析的目的是提供肌肉减少症与HRQoL之间关系的全面概述。在整个研究过程中都遵循了系统评价和荟萃分析的首选报告项目(PRISMA)。先前在PROSPERO上发表了一份协议。电子数据库MEDLINE、Scopus、Allied and Complementary Medicine (AMED)、EMB Review - ACP Journal Club、EBM Review - Cochrane Central of Register of Controlled Trials和APA PsychInfo被检索到2022年10月，以寻找报告肌肉减少症和非肌肉减少症患者HRQoL评估的观察性研究。研究选择和数据提取由两名独立研究人员进行。使用随机效应模型进行meta分析，报告肌肉减少症和非肌肉减少症患者之间的总体标准化平均差(SMD)及其95%置信区间(CI)。使用纽卡斯尔-渥太华量表测量研究质量，使用建议评估、发展和评估分级(GRADE)工具评估证据的强度。检索策略确定了3725篇文献，其中43篇观察性研究符合条件，并纳入本综合研究。肌少症患者的HRQoL明显低于非肌少症患者(SMD - 0.76;95% ci−0.95;−0.57)。模型存在显著异质性(I2 = 93%， Q检验p值<0.01)。亚组分析显示，与通用问卷相比，使用特定问卷SarQoL具有更高的效应量(SMD为−1.09;95% ci−1.44;SarQoL为- 0.74,SarQoL为- 0.49;95% ci−0.63;−0.36使用通用工具;p值为相互作用<0.01)。与居住在社区的个体相比，居住在养老院的肌肉减少症患者和非肌肉减少症患者的HRQoL差异更大(相互作用的p值<0.001)。在年龄组、诊断技术和大洲/地区之间没有发现差异。使用GRADE评估将证据水平评定为中度。本系统综述和荟萃分析结合43项观察性研究表明，肌肉减少症患者的HRQoL显著降低。使用疾病特异性HRQoL仪器可以更好地区分肌肉减少症患者的生活质量。
{"title":"Sarcopenia and health-related quality of life: A systematic review and meta-analysis","authors":"Charlotte Beaudart, Céline Demonceau, Jean-Yves Reginster, Médéa Locquet, Matteo Cesari, Alfonso J. Cruz Jentoft, Olivier Bruyère","doi":"10.1002/jcsm.13243","DOIUrl":"https://doi.org/10.1002/jcsm.13243","url":null,"abstract":"<p>The decrease of physical abilities and functional decline that can be caused by musculoskeletal conditions such as sarcopenia, can lead to higher levels of dependency and disability. Therefore, it may influence patient reported outcome measures (PROM), such as the health-related quality of life (HRQoL). The purpose of this systematic review and meta-analysis is to provide a comprehensive overview of the relationship between sarcopenia and HRQoL. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were followed throughout the whole process of this work. A protocol was previously published on PROSPERO. The electronic databases MEDLINE, Scopus, Allied and Complementary Medicine (AMED), EMB Review – ACP Journal Club, EBM Review - Cochrane Central of Register of Controlled Trials and APA PsychInfo were searched until October 2022 for observational studies reporting a HRQoL assessment in both sarcopenic and non-sarcopenic individuals. Study selection and data extraction were carried out by two independent researchers. Meta-analysis was performed using a random effect model, reporting an overall standardized mean difference (SMD) and its 95% confidence interval (CI) between sarcopenic and non-sarcopenic individuals. Study quality was measured using the Newcastle-Ottawa Scale and the strength of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. The search strategy identified 3725 references from which 43 observational studies were eligible and included in this meta-synthesis study. A significantly lower HRQoL was observed for sarcopenic individuals compared with non-sarcopenic ones (SMD −0.76; 95% CI −0.95; −0.57). Significant heterogeneity was associated with the model (<i>I</i><sup>2</sup> = 93%, <i>Q</i> test <i>P</i>-value <0.01). Subgroup analysis showed a higher effect size when using the specific questionnaire SarQoL compared with generic questionnaires (SMD −1.09; 95% CI −1.44; −0.74 with the SarQoL versus −0.49; 95% CI −0.63; −0.36 with generic tools; <i>P</i>-value for interaction <0.01). A greater difference of HRQoL between sarcopenic and non-sarcopenic was found for individuals residing in care homes compared with community-dwelling individuals (<i>P</i>-value for interaction <0.001). No differences were found between age groups, diagnostic techniques, and continents/regions. The level of evidence was rated as moderate using the GRADE assessment. This systematic review and meta-analysis combining 43 observational studies shows that HRQoL is significantly reduced in sarcopenic patients. The use of disease-specific HRQoL instruments may better discriminate sarcopenic patients with respect to their quality of life.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1228-1243"},"PeriodicalIF":8.9,"publicationDate":"2023-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13243","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6123636","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}
Mary C. Stephenson, Jamie X.M. Ho, Eugenia Migliavacca, Maria Kalimeri, Neerja Karnani, Subhasis Banerji, John J. Totman, Jerome N. Feige, Reshma A. Merchant, Stacey K.H. Tay
Background
Mitochondrial dysfunction has been implicated in sarcopenia. 31P magnetic resonance spectroscopy (MRS) enables non-invasive measurement of adenosine triphosphate (ATP) synthesis rates to probe mitochondrial function. Here, we assessed muscle energetics in older sarcopenic and non-sarcopenic men and compared with muscle biopsy-derived markers of mitochondrial function.
Methods
Twenty Chinese men with sarcopenia (SARC, age = 73.1 ± 4.1 years) and 19 healthy aged and sex-matched controls (CON, age = 70.3 ± 4.2 years) underwent assessment of strength, physical performance, and magnetic resonance imaging. Concentrations of phosphocreatine (PCr), ATP and inorganic phosphate (Pi) as well as muscle pH were measured at rest and during an interleaved rest–exercise protocol to probe muscle mitochondrial function. Results were compared to biopsy-derived mitochondrial complex activity and expression to understand underlying metabolic perturbations.
Results
Despite matched muscle contractile power (strength/cross-sectional area), the ATP contractile cost was higher in SARC compared with CON (low-intensity exercise: 1.06 ± 0.59 vs. 0.57 ± 0.22, moderate: 0.93 ± 0.43 vs. 0.58 ± 0.68, high: 0.70 ± 0.57 vs. 0.43 ± 0.51 mmol L−1 min−1 bar−1 cm−2, P = 0.003, <0.0001 and <0.0001, respectively). Post-exercise mitochondrial oxidative synthesis rates (a marker of mitochondrial function) tended to be longer in SARC but did not reach significance (17.3 ± 6.4 vs. 14.6 ± 6.5 mmol L−1 min−1, P = 0.2). However, relative increases in end-exercise ADP in SARC (31.8 ± 9.9 vs. 24.0 ± 7.3 mmol L−1, P = 0.008) may have been a compensatory mechanism. Mitochondrial complex activity was found to be associated with exercise-induced drops in PCr [citrate synthetase activity (CS), Spearman correlation rho = −0.42, P = 0.03] and end-exercise ADP (complex III, rho = −0.52, P = 0.01; CS rho = −0.45, P = 0.02; SDH rho = −0.45, P = 0.03), with CS also being strongly associated with the PCr recovery rate following low intensity exercise (rho = −0.47, P = 0.02), and the cost of contraction at high intensity (rho = −0.54, P = 0.02). Interestingly, at high intensity, the fractional contribution of oxidative phosphorylation to exercise was correlated with activity in complex II (rho = 0.5, P = 0.03), CS (rho = 0.47, P = 0.02) and SDH (rho = 0.46, P = 0.03), linking increased mitochondrial complex activity with
线粒体功能障碍与肌肉减少症有关。31P磁共振波谱(MRS)可以无创测量三磷酸腺苷(ATP)合成速率，以探测线粒体功能。在这里，我们评估了老年肌肉减少症和非肌肉减少症男性的肌肉能量学，并与肌肉活检衍生的线粒体功能标志物进行了比较。方法20例中国男性肌肉减少症患者(SARC，年龄= 73.1±4.1岁)和19例健康老年人和性别匹配的对照组(CON，年龄= 70.3±4.2岁)进行力量、体能表现和磁共振成像评估。在休息和交叉休息-运动方案中测量磷酸肌酸(PCr)、ATP和无机磷酸盐(Pi)的浓度以及肌肉pH，以探测肌肉线粒体功能。将结果与活检衍生的线粒体复合物活性和表达进行比较，以了解潜在的代谢扰动。结果尽管肌肉收缩能力(强度/截面积)相匹配，但SARC组的ATP收缩成本高于CON组(低强度运动:1.06±0.59 vs. 0.57±0.22，中等强度运动:0.93±0.43 vs. 0.58±0.68，高强度运动:0.70±0.57 vs. 0.43±0.51 mmol L−1 min−1 bar−1 cm−2,P = 0.003， <0.0001和<0.0001)。运动后线粒体氧化合成速率(线粒体功能的标志)在SARC中有延长的趋势，但没有达到显著性(17.3±6.4 vs. 14.6±6.5 mmol L−1 min−1,P = 0.2)。然而，SARC运动末期ADP的相对增加(31.8±9.9 vs. 24.0±7.3 mmol L−1,P = 0.008)可能是代偿机制。线粒体复合物活性与运动诱导的PCr[柠檬酸合成酶活性(CS)， Spearman相关rho = - 0.42, P = 0.03]和运动末期ADP(复合物III, rho = - 0.52, P = 0.01;CS rho = - 0.45, P = 0.02;SDH rho = - 0.45, P = 0.03)， CS也与低强度运动后的PCr回收率(rho = - 0.47, P = 0.02)和高强度运动时的收缩成本(rho = - 0.54, P = 0.02)密切相关。有趣的是，在高强度下，氧化磷酸化对运动的部分贡献与复合体II (rho = 0.5, P = 0.03)、CS (rho = 0.47, P = 0.02)和SDH (rho = 0.46, P = 0.03)的活性相关，这将线粒体复合体活性的增加与通过氧化途径产生能量的能力的增强联系起来。结论:本研究利用31P MRS评估肌少症肌肉的ATP利用和再合成，发现运动时能量消耗异常增加，恢复时线粒体能量紊乱。线粒体复合物活性与运动中能量需求的部分贡献之间的关联表明，线粒体复合物活性较好的人氧化产生能量的能力增强。
{"title":"Evidence for inefficient contraction and abnormal mitochondrial activity in sarcopenia using magnetic resonance spectroscopy","authors":"Mary C. Stephenson, Jamie X.M. Ho, Eugenia Migliavacca, Maria Kalimeri, Neerja Karnani, Subhasis Banerji, John J. Totman, Jerome N. Feige, Reshma A. Merchant, Stacey K.H. Tay","doi":"10.1002/jcsm.13220","DOIUrl":"https://doi.org/10.1002/jcsm.13220","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Mitochondrial dysfunction has been implicated in sarcopenia. <sup>31</sup>P magnetic resonance spectroscopy (MRS) enables non-invasive measurement of adenosine triphosphate (ATP) synthesis rates to probe mitochondrial function. Here, we assessed muscle energetics in older sarcopenic and non-sarcopenic men and compared with muscle biopsy-derived markers of mitochondrial function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Twenty Chinese men with sarcopenia (SARC, age = 73.1 ± 4.1 years) and 19 healthy aged and sex-matched controls (CON, age = 70.3 ± 4.2 years) underwent assessment of strength, physical performance, and magnetic resonance imaging. Concentrations of phosphocreatine (PCr), ATP and inorganic phosphate (Pi) as well as muscle pH were measured at rest and during an interleaved rest–exercise protocol to probe muscle mitochondrial function. Results were compared to biopsy-derived mitochondrial complex activity and expression to understand underlying metabolic perturbations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Despite matched muscle contractile power (strength/cross-sectional area), the ATP contractile cost was higher in SARC compared with CON (low-intensity exercise: 1.06 ± 0.59 vs. 0.57 ± 0.22, moderate: 0.93 ± 0.43 vs. 0.58 ± 0.68, high: 0.70 ± 0.57 vs. 0.43 ± 0.51 mmol L<sup>−1</sup> min<sup>−1</sup> bar<sup>−1</sup> cm<sup>−2</sup>, <i>P</i> = 0.003, <0.0001 and <0.0001, respectively). Post-exercise mitochondrial oxidative synthesis rates (a marker of mitochondrial function) tended to be longer in SARC but did not reach significance (17.3 ± 6.4 vs. 14.6 ± 6.5 mmol L<sup>−1</sup> min<sup>−1</sup>, <i>P</i> = 0.2). However, relative increases in end-exercise ADP in SARC (31.8 ± 9.9 vs. 24.0 ± 7.3 mmol L<sup>−1</sup>, <i>P</i> = 0.008) may have been a compensatory mechanism. Mitochondrial complex activity was found to be associated with exercise-induced drops in PCr [citrate synthetase activity (CS), Spearman correlation rho = −0.42, <i>P</i> = 0.03] and end-exercise ADP (complex III, rho = −0.52, <i>P</i> = 0.01; CS rho = −0.45, <i>P</i> = 0.02; SDH rho = −0.45, <i>P</i> = 0.03), with CS also being strongly associated with the PCr recovery rate following low intensity exercise (rho = −0.47, <i>P</i> = 0.02), and the cost of contraction at high intensity (rho = −0.54, <i>P</i> = 0.02). Interestingly, at high intensity, the fractional contribution of oxidative phosphorylation to exercise was correlated with activity in complex II (rho = 0.5, <i>P</i> = 0.03), CS (rho = 0.47, <i>P</i> = 0.02) and SDH (rho = 0.46, <i>P</i> = 0.03), linking increased mitochondrial complex activity with ","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1482-1494"},"PeriodicalIF":8.9,"publicationDate":"2023-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6092273","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}
Sarcopenic obesity, a combination of sarcopenia and obesity, is a pathological feature of type 2 diabetes. Several human studies have shown that milk is useful in the prevention of sarcopenia. This study was aimed at clarifying the effect of milk on the prevention of sarcopenic obesity in db/db mice.
Methods
A randomized and investigator-blinded study was conducted using male db/db mice. Eight-week-old db/db mice were housed for 8 weeks and fed milk (100 μL/day) using a sonde. The faecal microbiota transplantation (FMT) group received antibiotics for 2 weeks, starting at 6 weeks of age, followed by FMT twice a week until 16 weeks of age.
Results
Milk administration to db/db mice increased grip strength (Milk−: 164.2 ± 4.7 g, Milk+: 230.2 ± 56.0 g, P = 0.017), muscle mass (soleus muscle, Milk−: 164.2 ± 4.7 mg, Milk+: 230.2 ± 56.0 mg, P < 0.001; plantaris muscle, Milk−: 13.3 ± 1.2 mg, Milk+: 16.0 ± 1.7 mg, P < 0.001) and decreased visceral fat mass (Milk−: 2.39 ± 0.08 g, Milk+: 1.98 ± 0.04 mg, P < 0.001), resulting in a significant increase in physical activity (light: P = 0.013, dark: P = 0.034). FMT from mice fed milk not only improved sarcopenic obesity but also significantly improved glucose intolerance. Microarray analysis of gene expression in the small intestine revealed that the expression of amino acid absorption transporter genes, namely, SIc7a5 (P = 0.010), SIc7a1 (P = 0.015), Ppp1r15a (P = 0.041) and SIc7a11 (P = 0.029), was elevated in mice fed milk. In 16S rRNA sequencing of gut microbiota, the genus Akkermansia was increased in both the mice fed milk and the FMT group from the mice fed milk.
Conclusions
The findings of this study suggest that besides increasing the intake of nutrients, such as amino acids, milk consumption also changes the intestinal environment, which might contribute to the mechanism of milk-induced improvement of sarcopenic obesity.
{"title":"Milk protects against sarcopenic obesity due to increase in the genus Akkermansia in faeces of db/db mice","authors":"Takuro Okamura, Masahide Hamaguchi, Hanako Nakajima, Nobuko Kitagawa, Saori Majima, Takafumi Senmaru, Hiroshi Okada, Emi Ushigome, Naoko Nakanishi, Ryoichi Sasano, Michiaki Fukui","doi":"10.1002/jcsm.13245","DOIUrl":"https://doi.org/10.1002/jcsm.13245","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sarcopenic obesity, a combination of sarcopenia and obesity, is a pathological feature of type 2 diabetes. Several human studies have shown that milk is useful in the prevention of sarcopenia. This study was aimed at clarifying the effect of milk on the prevention of sarcopenic obesity in <i>db/db</i> mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A randomized and investigator-blinded study was conducted using male <i>db/db</i> mice. Eight-week-old <i>db/db</i> mice were housed for 8 weeks and fed milk (100 μL/day) using a sonde. The faecal microbiota transplantation (FMT) group received antibiotics for 2 weeks, starting at 6 weeks of age, followed by FMT twice a week until 16 weeks of age.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Milk administration to <i>db/db</i> mice increased grip strength (Milk−: 164.2 ± 4.7 g, Milk+: 230.2 ± 56.0 g, <i>P</i> = 0.017), muscle mass (soleus muscle, Milk−: 164.2 ± 4.7 mg, Milk+: 230.2 ± 56.0 mg, <i>P</i> < 0.001; plantaris muscle, Milk−: 13.3 ± 1.2 mg, Milk+: 16.0 ± 1.7 mg, <i>P</i> < 0.001) and decreased visceral fat mass (Milk−: 2.39 ± 0.08 g, Milk+: 1.98 ± 0.04 mg, <i>P</i> < 0.001), resulting in a significant increase in physical activity (light: <i>P</i> = 0.013, dark: <i>P</i> = 0.034). FMT from mice fed milk not only improved sarcopenic obesity but also significantly improved glucose intolerance. Microarray analysis of gene expression in the small intestine revealed that the expression of amino acid absorption transporter genes, namely, <i>SIc7a5</i> (<i>P</i> = 0.010), <i>SIc7a1</i> (<i>P</i> = 0.015), <i>Ppp1r15a</i> (<i>P</i> = 0.041) and <i>SIc7a11</i> (<i>P</i> = 0.029), was elevated in mice fed milk. In 16S rRNA sequencing of gut microbiota, the genus <i>Akkermansia</i> was increased in both the mice fed milk and the FMT group from the mice fed milk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The findings of this study suggest that besides increasing the intake of nutrients, such as amino acids, milk consumption also changes the intestinal environment, which might contribute to the mechanism of milk-induced improvement of sarcopenic obesity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1395-1409"},"PeriodicalIF":8.9,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13245","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6064465","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}
Jochen Springer, Queralt Jové, Edson Alves de Lima Junior, Natalia álvarez Ladrón, Francisco Javier López-Soriano, Silvia Busquets, Josep M. Argiles, Daniel L. Marks
Background
It is known that S-pindolol attenuates muscle loss in animal models of cancer cachexia and sarcopenia. In cancer cachexia, it also significantly reduced mortality and improved cardiac function, which is strongly compromised in cachectic animals.
Methods
Here, we tested 3 mg/kg/day of S-pindolol in two murine cancer cachexia models: pancreatic cancer cachexia (KPC) and Lewis lung carcinoma (LLC).
Results
Treatment of mice with 3 mg/kg/day of S-pindolol in KPC or LLC cancer cachexia models significantly attenuated the loss of body weight, including lean mass and muscle weights, leading to improved grip strength compared with placebo-treated mice. In the KPC model, treated mice lost less than half of the total weight lost by placebo (−0.9 ± 1.0 vs. −2.2 ± 1.4 g for S-pindolol and placebo, respectively, P < 0.05) and around a third of the lean mass lost by tumour-bearing controls (−0.4 ± 1.0 vs. −1.5 ± 1.5 g for S-pindolol and placebo, respectively, P < 0.05), whereas loss of fat mass was similar. In the LLC model, the gastrocnemius weight was higher in sham (108 ± 16 mg) and S-pindolol tumour-bearing (94 ± 15 mg) mice than that in placebo (83 ± 12 mg), whereas the soleus weight was only significantly higher in the S-pindolol-treated group (7.9 ± 1.7 mg) than that in placebo (6.5 ± 0.9). Grip strength was significantly improved by S-pindolol treatment (110.8 ± 16.2 vs. 93.9 ± 17.1 g for S-pindolol and placebo, respectively). A higher grip strength was observed in all groups; whereas S-pindolol-treated mice improved by 32.7 ± 18.5 g, tumour-bearing mice only show minimal improvements (7.3 ± 19.4 g, P < 0.01).
Conclusions
S-pindolol is an important candidate for clinical development in the treatment of cancer cachexia that strongly attenuates loss of body weight and lean body mass. This was also seen in the weight of individual muscles and resulted in higher grip strength.
{"title":"Effects of S-pindolol in mouse pancreatic and lung cancer cachexia models","authors":"Jochen Springer, Queralt Jové, Edson Alves de Lima Junior, Natalia álvarez Ladrón, Francisco Javier López-Soriano, Silvia Busquets, Josep M. Argiles, Daniel L. Marks","doi":"10.1002/jcsm.13249","DOIUrl":"https://doi.org/10.1002/jcsm.13249","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>It is known that S-pindolol attenuates muscle loss in animal models of cancer cachexia and sarcopenia. In cancer cachexia, it also significantly reduced mortality and improved cardiac function, which is strongly compromised in cachectic animals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we tested 3 mg/kg/day of S-pindolol in two murine cancer cachexia models: pancreatic cancer cachexia (KPC) and Lewis lung carcinoma (LLC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Treatment of mice with 3 mg/kg/day of S-pindolol in KPC or LLC cancer cachexia models significantly attenuated the loss of body weight, including lean mass and muscle weights, leading to improved grip strength compared with placebo-treated mice. In the KPC model, treated mice lost less than half of the total weight lost by placebo (−0.9 ± 1.0 vs. −2.2 ± 1.4 g for S-pindolol and placebo, respectively, <i>P</i> < 0.05) and around a third of the lean mass lost by tumour-bearing controls (−0.4 ± 1.0 vs. −1.5 ± 1.5 g for S-pindolol and placebo, respectively, <i>P</i> < 0.05), whereas loss of fat mass was similar. In the LLC model, the gastrocnemius weight was higher in sham (108 ± 16 mg) and S-pindolol tumour-bearing (94 ± 15 mg) mice than that in placebo (83 ± 12 mg), whereas the soleus weight was only significantly higher in the S-pindolol-treated group (7.9 ± 1.7 mg) than that in placebo (6.5 ± 0.9). Grip strength was significantly improved by S-pindolol treatment (110.8 ± 16.2 vs. 93.9 ± 17.1 g for S-pindolol and placebo, respectively). A higher grip strength was observed in all groups; whereas S-pindolol-treated mice improved by 32.7 ± 18.5 g, tumour-bearing mice only show minimal improvements (7.3 ± 19.4 g, <i>P</i> < 0.01).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>S-pindolol is an important candidate for clinical development in the treatment of cancer cachexia that strongly attenuates loss of body weight and lean body mass. This was also seen in the weight of individual muscles and resulted in higher grip strength.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1244-1248"},"PeriodicalIF":8.9,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13249","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6061103","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}
Ye An Kim, Seung Hun Lee, Jung-Min Koh, Seung-hyun Kwon, Young Lee, Han Jin Cho, Hanjun Kim, Su Jung Kim, Ji Hyun Lee, Hyun Ju Yoo, Je Hyun Seo
Background
Sarcopenia is characterized by a progressive decrease in skeletal muscle mass and function with age. Given that sarcopenia is associated with various metabolic disorders, effective metabolic biomarkers for its early detection are required. We aimed to investigate the metabolic biomarkers related to sarcopenia in elderly men and perform experimental studies using metabolomics.
Methods
Plasma metabolites from 142 elderly men, comprising a sarcopenia group and an age-matched control group, were measured using global metabolome profiling. Muscle and plasma samples from an aging mouse model of sarcopenia, as well as cell media and cell lysates during myoblast differentiation, were analysed based on targeted metabolome profiling. Based on these experimental results, fatty acid amides were quantified from human plasma as well as human muscle tissues. The association of fatty acid amide levels with sarcopenia parameters was evaluated.
Results
Global metabolome profiling showed that fatty acid amide levels were significantly different in the plasma of elderly men with sarcopenia (all Ps < 0.01). Consistent with these results in human plasma, targeted metabolome profiling in an aging mouse model of sarcopenia showed decreased levels of fatty acid amides in plasma but not in muscle tissue. In addition, the levels of fatty acid amides increased in cell lysates during muscle cell differentiation. Targeted metabolome profiling in men showed decreased docosahexaenoic acid ethanolamide (DHA EA) levels in the plasma (P = 0.016) but not in the muscle of men with sarcopenia. DHA EA level was positively correlated with sarcopenia parameters such as skeletal muscle mass index (SMI) and handgrip strength (HGS) (P = 0.001, P = 0.001, respectively). The area under the receiver-operating characteristic curve (AUC) for DHA EA level ≤ 4.60 fmol/μL for sarcopenia was 0.618 (95% confidence interval [CI]: 0.532–0.698). DHA EA level ≤ 4.60 fmol/μL was associated with a significantly greater likelihood of sarcopenia (odds ratio [OR]: 2.11, 95% CI: 1.03–4.30), independent of HGS. The addition of DHA EA level to age and HGS significantly improved the AUC from 0.620 to 0.691 (P = 0.0497).
Conclusions
Our study demonstrated that fatty acid amides are potential circulating biomarkers in elderly men with sarcopenia. DHA EA, in particular, strongly related to muscle mass and strength, can be a key
{"title":"Fatty acid amides as potential circulating biomarkers for sarcopenia","authors":"Ye An Kim, Seung Hun Lee, Jung-Min Koh, Seung-hyun Kwon, Young Lee, Han Jin Cho, Hanjun Kim, Su Jung Kim, Ji Hyun Lee, Hyun Ju Yoo, Je Hyun Seo","doi":"10.1002/jcsm.13244","DOIUrl":"https://doi.org/10.1002/jcsm.13244","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sarcopenia is characterized by a progressive decrease in skeletal muscle mass and function with age. Given that sarcopenia is associated with various metabolic disorders, effective metabolic biomarkers for its early detection are required. We aimed to investigate the metabolic biomarkers related to sarcopenia in elderly men and perform experimental studies using metabolomics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Plasma metabolites from 142 elderly men, comprising a sarcopenia group and an age-matched control group, were measured using global metabolome profiling. Muscle and plasma samples from an aging mouse model of sarcopenia, as well as cell media and cell lysates during myoblast differentiation, were analysed based on targeted metabolome profiling. Based on these experimental results, fatty acid amides were quantified from human plasma as well as human muscle tissues. The association of fatty acid amide levels with sarcopenia parameters was evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Global metabolome profiling showed that fatty acid amide levels were significantly different in the plasma of elderly men with sarcopenia (all <i>P</i>s < 0.01). Consistent with these results in human plasma, targeted metabolome profiling in an aging mouse model of sarcopenia showed decreased levels of fatty acid amides in plasma but not in muscle tissue. In addition, the levels of fatty acid amides increased in cell lysates during muscle cell differentiation. Targeted metabolome profiling in men showed decreased docosahexaenoic acid ethanolamide (DHA EA) levels in the plasma (<i>P</i> = 0.016) but not in the muscle of men with sarcopenia. DHA EA level was positively correlated with sarcopenia parameters such as skeletal muscle mass index (SMI) and handgrip strength (HGS) (<i>P</i> = 0.001, <i>P</i> = 0.001, respectively). The area under the receiver-operating characteristic curve (AUC) for DHA EA level ≤ 4.60 fmol/μL for sarcopenia was 0.618 (95% confidence interval [CI]: 0.532–0.698). DHA EA level ≤ 4.60 fmol/μL was associated with a significantly greater likelihood of sarcopenia (odds ratio [OR]: 2.11, 95% CI: 1.03–4.30), independent of HGS. The addition of DHA EA level to age and HGS significantly improved the AUC from 0.620 to 0.691 (<i>P</i> = 0.0497).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study demonstrated that fatty acid amides are potential circulating biomarkers in elderly men with sarcopenia. DHA EA, in particular, strongly related to muscle mass and strength, can be a key ","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1558-1568"},"PeriodicalIF":8.9,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13244","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6028409","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}
Adeline Dolly, Sarah A. P?tgens, Morgane M. Thibaut, Audrey M. Neyrinck, Gabriela S. de Castro, Chloé Galbert, Camille Lefevre, Elisabeth Wyart, Silvio P. Gomes, Daniela C. Gon?alves, Nicolas Lanthier, Pamela Baldin, Joshua R. Huot, Andrea Bonetto, Marília Seelaender, Nathalie M. Delzenne, Harry Sokol, Laure B. Bindels
Background
The aryl hydrocarbon receptor (AHR) is expressed in the intestine and liver, where it has pleiotropic functions and target genes. This study aims to explore the potential implication of AHR in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. Specifically, we tested the hypothesis that targeting AHR can alleviate cachectic features, particularly through the gut–liver axis.
Methods
AHR pathways were explored in multiple tissues from four experimental mouse models of cancer cachexia (C26, BaF3, MC38 and APCMin/+) and from non-cachectic mice (sham-injected mice and non-cachexia-inducing [NC26] tumour-bearing mice), as well as in liver biopsies from cancer patients. Cachectic mice were treated with an AHR agonist (6-formylindolo(3,2-b)carbazole [FICZ]) or an antibody neutralizing interleukin-6 (IL-6). Key mechanisms were validated in vitro on HepG2 cells.
Results
AHR activation, reflected by the expression of Cyp1a1 and Cyp1a2, two major AHR target genes, was deeply reduced in all models (C26 and BaF3, P < 0.001; MC38 and APCMin/+, P < 0.05) independently of anorexia. This reduction occurred early in the liver (P < 0.001; before the onset of cachexia), compared to the ileum and skeletal muscle (P < 0.01; pre-cachexia stage), and was intrinsically related to cachexia (C26 vs. NC26, P < 0.001). We demonstrate a differential modulation of AHR activation in the liver (through the IL-6/hypoxia-inducing factor 1α pathway) compared to the ileum (attributed to the decreased levels of indolic AHR ligands, P < 0.001), and the muscle. In cachectic mice, FICZ treatment reduced hepatic inflammation: expression of cytokines (Ccl2, P = 0.005; Cxcl2, P = 0.018; Il1b, P = 0.088) with similar trends at the protein levels, expression of genes involved in the acute-phase response (Apcs, P = 0.040; Saa1, P = 0.002; Saa2, P = 0.039; Alb, P = 0.003), macrophage activation (Cd68, P = 0.038) and extracellular matrix remodelling (Fga, P = 0.008; Pcolce, P = 0.025; Timp1, P = 0.003). We observed a decrease in blood glucose in cachectic mice (P < 0.0001), which was also improved by FICZ treatment (P = 0.026) through hepatic transcriptional promotion of a key marker of gluconeogenesis, namely, G6pc (C26 vs. C26 + FICZ, P = 0.029). Strikingly, these
芳烃受体(aryl hydrocarbon receptor, AHR)在肠道和肝脏中表达，具有多效性和靶基因。本研究旨在探讨AHR在癌症恶病质(一种导致癌症死亡的炎症和代谢综合征)中的潜在意义。具体来说，我们验证了靶向AHR可以减轻病质特征的假设，特别是通过肠-肝轴。方法在4种癌症恶病质模型小鼠(C26、BaF3、MC38和APCMin/+)和非恶病质小鼠(假注射小鼠和非恶病质诱导[NC26]的载瘤小鼠)的多种组织以及肿瘤患者肝脏活检中探索AHR通路。恶病质小鼠用AHR激动剂(6-甲酰基林多洛(3,2-b)咔唑[FICZ])或抗体中和白介素-6 (IL-6)治疗。在HepG2细胞上验证了关键机制。结果AHR的两个主要靶基因Cyp1a1和Cyp1a2的表达显著降低了AHR的活性(C26和BaF3, P <0.001;MC38和APCMin/+， P <0.05)与厌食症无关。这种减少发生在肝脏早期(P <0.001;与回肠和骨骼肌相比(P <0.01;恶病质前期)，且与恶病质有内在关系(C26 vs. NC26, P <0.001)。我们证明了与回肠相比，肝脏中AHR激活的不同调节(通过IL-6/缺氧诱导因子1α途径)(归因于吲哚AHR配体水平的降低，P <0.001)，肌肉。在恶病质小鼠中，FICZ治疗降低了肝脏炎症:细胞因子的表达(Ccl2, P = 0.005;Cxcl2, P = 0.018;il - 1b, P = 0.088)在蛋白水平上具有相似的趋势，参与急性期反应的基因表达(Apcs, P = 0.040;Saa1, P = 0.002;Saa2, P = 0.039;Alb, P = 0.003)，巨噬细胞活化(Cd68, P = 0.038)和细胞外基质重塑(Fga, P = 0.008;Pcolce, P = 0.025;Timp1, P = 0.003)。我们观察到恶病质小鼠的血糖下降(P <0.0001)， FICZ处理也通过肝脏转录促进糖异生关键标志物G6pc (C26 vs C26 + FICZ, P = 0.029)改善了这一情况(P = 0.026)。引人注目的是，这些对血糖紊乱的益处独立于肠道屏障功能障碍的改善而发生。在肿瘤患者中，G6pc的肝脏表达与Cyp1a1 (Spearman’s ρ = 0.52, P = 0.089)和Cyp1a2 (Spearman’s ρ = 0.67, P = 0.020)相关。通过这组研究，我们证明了AHR信号的损伤有助于癌症恶病质特征的肝脏炎症和代谢紊乱，为这方面的创新治疗策略铺平了道路。
{"title":"Impairment of aryl hydrocarbon receptor signalling promotes hepatic disorders in cancer cachexia","authors":"Adeline Dolly, Sarah A. P?tgens, Morgane M. Thibaut, Audrey M. Neyrinck, Gabriela S. de Castro, Chloé Galbert, Camille Lefevre, Elisabeth Wyart, Silvio P. Gomes, Daniela C. Gon?alves, Nicolas Lanthier, Pamela Baldin, Joshua R. Huot, Andrea Bonetto, Marília Seelaender, Nathalie M. Delzenne, Harry Sokol, Laure B. Bindels","doi":"10.1002/jcsm.13246","DOIUrl":"https://doi.org/10.1002/jcsm.13246","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The aryl hydrocarbon receptor (AHR) is expressed in the intestine and liver, where it has pleiotropic functions and target genes. This study aims to explore the potential implication of AHR in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. Specifically, we tested the hypothesis that targeting AHR can alleviate cachectic features, particularly through the gut–liver axis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>AHR pathways were explored in multiple tissues from four experimental mouse models of cancer cachexia (C26, BaF3, MC38 and APC<sup>Min/+</sup>) and from non-cachectic mice (sham-injected mice and non-cachexia-inducing [NC26] tumour-bearing mice), as well as in liver biopsies from cancer patients. Cachectic mice were treated with an AHR agonist (6-formylindolo(3,2-<i>b</i>)carbazole [FICZ]) or an antibody neutralizing interleukin-6 (IL-6). Key mechanisms were validated in vitro on HepG2 cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>AHR activation, reflected by the expression of <i>Cyp1a1</i> and <i>Cyp1a2</i>, two major AHR target genes, was deeply reduced in all models (C26 and BaF3, <i>P</i> < 0.001; MC38 and APC<sup>Min/+</sup>, <i>P</i> < 0.05) independently of anorexia. This reduction occurred early in the liver (<i>P</i> < 0.001; before the onset of cachexia), compared to the ileum and skeletal muscle (<i>P</i> < 0.01; pre-cachexia stage), and was intrinsically related to cachexia (C26 vs. NC26, <i>P</i> < 0.001). We demonstrate a differential modulation of AHR activation in the liver (through the IL-6/hypoxia-inducing factor 1α pathway) compared to the ileum (attributed to the decreased levels of indolic AHR ligands, <i>P</i> < 0.001), and the muscle. In cachectic mice, FICZ treatment reduced hepatic inflammation: expression of cytokines (<i>Ccl2</i>, <i>P</i> = 0.005; <i>Cxcl2</i>, <i>P</i> = 0.018; <i>Il1b</i>, <i>P</i> = 0.088) with similar trends at the protein levels, expression of genes involved in the acute-phase response (<i>Apcs</i>, <i>P</i> = 0.040; <i>Saa1</i>, <i>P</i> = 0.002; <i>Saa2</i>, <i>P</i> = 0.039; <i>Alb</i>, <i>P</i> = 0.003), macrophage activation (<i>Cd68</i>, <i>P</i> = 0.038) and extracellular matrix remodelling (<i>Fga</i>, <i>P</i> = 0.008; <i>Pcolce</i>, <i>P</i> = 0.025; <i>Timp1</i>, <i>P</i> = 0.003). We observed a decrease in blood glucose in cachectic mice (<i>P</i> < 0.0001), which was also improved by FICZ treatment (<i>P</i> = 0.026) through hepatic transcriptional promotion of a key marker of gluconeogenesis, namely, <i>G6pc</i> (C26 vs. C26 + FICZ, <i>P</i> = 0.029). Strikingly, these ","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1569-1582"},"PeriodicalIF":8.9,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6077986","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}
Donnie Cameron, Tooba Abbassi-Daloii, Laura G.M. Heezen, Nienke M. van de Velde, Za?da Koeks, Thom T.J. Veeger, Melissa T. Hooijmans, Salma el Abdellaoui, Sjoerd G. van Duinen, Jan J.G.M. Verschuuren, Maaike van Putten, Annemieke Aartsma-Rus, Vered Raz, Pietro Spitali, Erik H. Niks, Hermien E. Kan
Background
Becker muscular dystrophy (BMD) is an X-linked disorder characterized by slow, progressive muscle damage and muscle weakness. Hallmarks include fibre-size variation and replacement of skeletal muscle with fibrous and adipose tissues, after repeated cycles of regeneration. Muscle histology can detect these features, but the required biopsies are invasive, are difficult to repeat and capture only small muscle volumes. Diffusion-tensor magnetic resonance imaging (DT-MRI) is a potential non-invasive alternative that can calculate muscle fibre diameters when applied with the novel random permeable barrier model (RPBM). In this study, we assessed muscle fibre diameters using DT-MRI in BMD patients and healthy controls and compared these with histology.
Methods
We included 13 BMD patients and 9 age-matched controls, who underwent water-fat MRI and DT-MRI at multiple diffusion times, allowing RPBM parameter estimation in the lower leg muscles. Tibialis anterior muscle biopsies were taken from the contralateral leg in 6 BMD patients who underwent DT-MRI and from an additional 32 BMD patients and 15 healthy controls. Laminin and Sirius-red stainings were performed to evaluate muscle fibre morphology and fibrosis. Twelve ambulant patients from the MRI cohort underwent the North Star ambulatory assessment, and 6-min walk, rise-from-floor and 10-m run/walk functional tests.
Results
RPBM fibre diameter was significantly larger in BMD patients (P = 0.015): mean (SD) = 68.0 (25.3) μm versus 59.4 (19.2) μm in controls. Inter-muscle differences were also observed (P ≤ 0.002). Both inter- and intra-individual RPBM fibre diameter variability were similar between groups. Laminin staining agreed with the RPBM, showing larger median fibre diameters in patients than in controls: 72.5 (7.9) versus 63.2 (6.9) μm, P = 0.006. However, despite showing similar inter-individual variation, patients showed more intra-individual fibre diameter variability than controls—mean variance (SD) = 34.2 (7.9) versus 21.4 (6.9) μm, P < 0.001—and larger fibrosis areas: median (interquartile range) = 21.7 (5.6)% versus 14.9 (3.4)%, P < 0.001. Despite good overall agreement of RPBM and laminin fibre diameters, they were not associated in patients who underwent DT-MRI and muscle biopsy, perhaps due to lack of colocalization of DT-MRI with biopsy samples.
{"title":"Diffusion-tensor magnetic resonance imaging captures increased skeletal muscle fibre diameters in Becker muscular dystrophy","authors":"Donnie Cameron, Tooba Abbassi-Daloii, Laura G.M. Heezen, Nienke M. van de Velde, Za?da Koeks, Thom T.J. Veeger, Melissa T. Hooijmans, Salma el Abdellaoui, Sjoerd G. van Duinen, Jan J.G.M. Verschuuren, Maaike van Putten, Annemieke Aartsma-Rus, Vered Raz, Pietro Spitali, Erik H. Niks, Hermien E. Kan","doi":"10.1002/jcsm.13242","DOIUrl":"https://doi.org/10.1002/jcsm.13242","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Becker muscular dystrophy (BMD) is an X-linked disorder characterized by slow, progressive muscle damage and muscle weakness. Hallmarks include fibre-size variation and replacement of skeletal muscle with fibrous and adipose tissues, after repeated cycles of regeneration. Muscle histology can detect these features, but the required biopsies are invasive, are difficult to repeat and capture only small muscle volumes. Diffusion-tensor magnetic resonance imaging (DT-MRI) is a potential non-invasive alternative that can calculate muscle fibre diameters when applied with the novel random permeable barrier model (RPBM). In this study, we assessed muscle fibre diameters using DT-MRI in BMD patients and healthy controls and compared these with histology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We included 13 BMD patients and 9 age-matched controls, who underwent water-fat MRI and DT-MRI at multiple diffusion times, allowing RPBM parameter estimation in the lower leg muscles. Tibialis anterior muscle biopsies were taken from the contralateral leg in 6 BMD patients who underwent DT-MRI and from an additional 32 BMD patients and 15 healthy controls. Laminin and Sirius-red stainings were performed to evaluate muscle fibre morphology and fibrosis. Twelve ambulant patients from the MRI cohort underwent the North Star ambulatory assessment, and 6-min walk, rise-from-floor and 10-m run/walk functional tests.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>RPBM fibre diameter was significantly larger in BMD patients (<i>P</i> = 0.015): mean (SD) = 68.0 (25.3) μm versus 59.4 (19.2) μm in controls. Inter-muscle differences were also observed (<i>P</i> ≤ 0.002). Both inter- and intra-individual RPBM fibre diameter variability were similar between groups. Laminin staining agreed with the RPBM, showing larger median fibre diameters in patients than in controls: 72.5 (7.9) versus 63.2 (6.9) μm, <i>P</i> = 0.006. However, despite showing similar inter-individual variation, patients showed more intra-individual fibre diameter variability than controls—mean variance (SD) = 34.2 (7.9) versus 21.4 (6.9) μm, <i>P</i> < 0.001—and larger fibrosis areas: median (interquartile range) = 21.7 (5.6)% versus 14.9 (3.4)%, <i>P</i> < 0.001. Despite good overall agreement of RPBM and laminin fibre diameters, they were not associated in patients who underwent DT-MRI and muscle biopsy, perhaps due to lack of colocalization of DT-MRI with biopsy samples.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>DT-MRI RPBM metrics agree with histolo","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1546-1557"},"PeriodicalIF":8.9,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13242","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6043239","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}
Qian Zhong, Kun Zheng, Wanmeng Li, Kang An, Yu Liu, Xina Xiao, Shan Hai, Biao Dong, Shuangqing Li, Zhenmei An, Lunzhi Dai
Skeletal muscle makes up 30–40% of the total body mass. It is of great significance in maintaining digestion, inhaling and exhaling, sustaining body posture, exercising, protecting joints and many other aspects. Moreover, muscle is also an important metabolic organ that helps to maintain the balance of sugar and fat. Defective skeletal muscle function not only limits the daily activities of the elderly but also increases the risk of disability, hospitalization and death, placing a huge burden on society and the healthcare system. Sarcopenia is a progressive decline in muscle mass, muscle strength and muscle function with age caused by environmental and genetic factors, such as the abnormal regulation of protein post-translational modifications (PTMs). To date, many studies have shown that numerous PTMs, such as phosphorylation, acetylation, ubiquitination, SUMOylation, glycosylation, glycation, methylation, S-nitrosylation, carbonylation and S-glutathionylation, are involved in the regulation of muscle health and diseases. This article systematically summarizes the post-translational regulation of muscle growth and muscle atrophy and helps to understand the pathophysiology of muscle aging and develop effective strategies for diagnosing, preventing and treating sarcopenia.
{"title":"Post-translational regulation of muscle growth, muscle aging and sarcopenia","authors":"Qian Zhong, Kun Zheng, Wanmeng Li, Kang An, Yu Liu, Xina Xiao, Shan Hai, Biao Dong, Shuangqing Li, Zhenmei An, Lunzhi Dai","doi":"10.1002/jcsm.13241","DOIUrl":"https://doi.org/10.1002/jcsm.13241","url":null,"abstract":"<p>Skeletal muscle makes up 30–40% of the total body mass. It is of great significance in maintaining digestion, inhaling and exhaling, sustaining body posture, exercising, protecting joints and many other aspects. Moreover, muscle is also an important metabolic organ that helps to maintain the balance of sugar and fat. Defective skeletal muscle function not only limits the daily activities of the elderly but also increases the risk of disability, hospitalization and death, placing a huge burden on society and the healthcare system. Sarcopenia is a progressive decline in muscle mass, muscle strength and muscle function with age caused by environmental and genetic factors, such as the abnormal regulation of protein post-translational modifications (PTMs). To date, many studies have shown that numerous PTMs, such as phosphorylation, acetylation, ubiquitination, SUMOylation, glycosylation, glycation, methylation, S-nitrosylation, carbonylation and S-glutathionylation, are involved in the regulation of muscle health and diseases. This article systematically summarizes the post-translational regulation of muscle growth and muscle atrophy and helps to understand the pathophysiology of muscle aging and develop effective strategies for diagnosing, preventing and treating sarcopenia.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1212-1227"},"PeriodicalIF":8.9,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13241","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6028418","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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