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}
Bram De Wel, Lotte Huysmans, Christophe E. Depuydt, Veerle Goosens, Ronald Peeters, Filipa P. Santos, Dietmar R. Thal, Patrick Dupont, Frederik Maes, Kristl G. Claeys
Background
Despite the widespread use of proton density fat fraction (PDFF) measurements with magnetic resonance imaging (MRI) to track disease progression in muscle disorders, it is still unclear how these findings relate to histopathological changes in muscle biopsies of patients with limb-girdle muscular dystrophy autosomal recessive type 12 (LGMDR12). Furthermore, although it is known that LGMDR12 leads to a selective muscle involvement distinct from other muscular dystrophies, the spatial distribution of fat replacement within these muscles is unknown.
Methods
We included 27 adult patients with LGMDR12 and 27 age-matched and sex-matched healthy controls and acquired 6-point Dixon images of the thighs and T1 and short tau inversion recovery (STIR) MR images of the whole body. In 16 patients and 15 controls, we performed three muscle biopsies, one in the semimembranosus, vastus lateralis, and rectus femoris muscles, which are severely, intermediately, and mildly affected in LGMDR12, respectively. We correlated the PDFF to the fat percentage measured on biopsies of the corresponding muscles, as well as to the Rochester histopathology grading scale.
Results
In patients, we demonstrated a strong correlation of PDFF on MRI and muscle biopsy fat percentage for the semimembranosus (r = 0.85, P < 0.001) and vastus lateralis (r = 0.68, P = 0.005). We found similar results for the correlation between PDFF and the Rochester histopathology grading scale. Out of the five patients with inflammatory changes on muscle biopsy, three showed STIR hyperintensities in the corresponding muscle on MRI. By modelling the PDFF on MRI for 18 thigh muscles from origin to insertion, we observed a significantly inhomogeneous proximo-distal distribution of fat replacement in all thigh muscles of patients with LGMDR12 (P < 0.001), and different patterns of fat replacement within each of the muscles.
Conclusions
We showed a strong correlation of fat fraction on MRI and fat percentage on muscle biopsy for diseased muscles and validated the use of Dixon fat fraction imaging as an outcome measure in LGMDR12. The inhomogeneous fat replacement within thigh muscles on imaging underlines the risk of analysing only samples of muscles instead of the entire muscles, which has important implications for clinical trials.
尽管磁共振成像(MRI)广泛使用质子密度脂肪含量(PDFF)测量来跟踪肌肉疾病的进展，但这些发现与肢体带状肌营养不良常染色体隐性12型(LGMDR12)患者肌肉活检的组织病理学变化之间的关系尚不清楚。此外，尽管已知LGMDR12导致与其他肌肉营养不良症不同的选择性肌肉受损伤，但这些肌肉中脂肪替代的空间分布尚不清楚。方法纳入27例LGMDR12成年患者和27例年龄和性别匹配的健康对照，获取大腿6点Dixon图像和全身T1和短tau反转恢复(STIR) MR图像。在16名患者和15名对照组中，我们进行了3次肌肉活检，分别是半膜肌、股外侧肌和股直肌，它们在LGMDR12中分别受到严重、中度和轻度影响。我们将PDFF与相应肌肉的活组织检查中测量的脂肪百分比以及罗切斯特组织病理学分级量表相关联。结果在患者中，我们发现MRI上的PDFF与半膜肌的肌肉活检脂肪百分比有很强的相关性(r = 0.85, P <0.001)和股外侧肌(r = 0.68, P = 0.005)。我们发现PDFF与罗切斯特组织病理学分级量表之间的相关性也有类似的结果。在5例肌肉活检有炎症改变的患者中，3例在MRI上显示相应肌肉的STIR高强度。通过在MRI上模拟18块大腿肌肉从起点到止点的PDFF，我们观察到LGMDR12患者所有大腿肌肉的脂肪置换近端到远端分布明显不均匀(P <0.001)，以及每块肌肉中不同的脂肪替代模式。我们发现MRI上的脂肪分数与患病肌肉的肌肉活检上的脂肪百分比有很强的相关性，并验证了Dixon脂肪分数成像作为LGMDR12结果测量的使用。在成像中，大腿肌肉内不均匀的脂肪替换强调了仅分析肌肉样本而不是整个肌肉的风险，这对临床试验具有重要意义。
{"title":"Histopathological correlations and fat replacement imaging patterns in recessive limb-girdle muscular dystrophy type 12","authors":"Bram De Wel, Lotte Huysmans, Christophe E. Depuydt, Veerle Goosens, Ronald Peeters, Filipa P. Santos, Dietmar R. Thal, Patrick Dupont, Frederik Maes, Kristl G. Claeys","doi":"10.1002/jcsm.13234","DOIUrl":"https://doi.org/10.1002/jcsm.13234","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Despite the widespread use of proton density fat fraction (PDFF) measurements with magnetic resonance imaging (MRI) to track disease progression in muscle disorders, it is still unclear how these findings relate to histopathological changes in muscle biopsies of patients with limb-girdle muscular dystrophy autosomal recessive type 12 (LGMDR12). Furthermore, although it is known that LGMDR12 leads to a selective muscle involvement distinct from other muscular dystrophies, the spatial distribution of fat replacement within these muscles is unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We included 27 adult patients with LGMDR12 and 27 age-matched and sex-matched healthy controls and acquired 6-point Dixon images of the thighs and T1 and short tau inversion recovery (STIR) MR images of the whole body. In 16 patients and 15 controls, we performed three muscle biopsies, one in the semimembranosus, vastus lateralis, and rectus femoris muscles, which are severely, intermediately, and mildly affected in LGMDR12, respectively. We correlated the PDFF to the fat percentage measured on biopsies of the corresponding muscles, as well as to the Rochester histopathology grading scale.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In patients, we demonstrated a strong correlation of PDFF on MRI and muscle biopsy fat percentage for the semimembranosus (<i>r</i> = 0.85, <i>P</i> < 0.001) and vastus lateralis (<i>r</i> = 0.68, <i>P</i> = 0.005). We found similar results for the correlation between PDFF and the Rochester histopathology grading scale. Out of the five patients with inflammatory changes on muscle biopsy, three showed STIR hyperintensities in the corresponding muscle on MRI. By modelling the PDFF on MRI for 18 thigh muscles from origin to insertion, we observed a significantly inhomogeneous proximo-distal distribution of fat replacement in all thigh muscles of patients with LGMDR12 (<i>P</i> < 0.001), and different patterns of fat replacement within each of the muscles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We showed a strong correlation of fat fraction on MRI and fat percentage on muscle biopsy for diseased muscles and validated the use of Dixon fat fraction imaging as an outcome measure in LGMDR12. The inhomogeneous fat replacement within thigh muscles on imaging underlines the risk of analysing only samples of muscles instead of the entire muscles, which has important implications for clinical trials.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1468-1481"},"PeriodicalIF":8.9,"publicationDate":"2023-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13234","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5944381","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}
Belle Yu-Hsuan Wang, Yi-Fan Chen, Allen Wei-Ting Hsiao, Wan-Jing Chen, Chien-Wei Lee, Oscar Kuang-Sheng Lee
Background
The progressive deterioration of tissue–tissue crosstalk with aging causes a striking impairment of tissue homeostasis and functionality, particularly in the musculoskeletal system. Rejuvenation of the systemic and local milieu via interventions such as heterochronic parabiosis and exercise has been reported to improve musculoskeletal homeostasis in aged organisms. We have shown that Ginkgolide B (GB), a small molecule from Ginkgo biloba, improves bone homeostasis in aged mice by restoring local and systemic communication, implying a potential for maintaining skeletal muscle homeostasis and enhancing regeneration. In this study, we investigated the therapeutic efficacy of GB on skeletal muscle regeneration in aged mice.
Methods
Muscle injury models were established by barium chloride induction into the hind limb of 20-month-old mice (aged mice) and into C2C12-derived myotubes. Therapeutic efficacy of daily administrated GB (12 mg/kg body weight) and osteocalcin (50 μg/kg body weight) on muscle regeneration was assessed by histochemical staining, gene expression, flow cytometry, ex vivo muscle function test and rotarod test. RNA sequencing was used to explore the mechanism of GB on muscle regeneration, with subsequent in vitro and in vivo experiments validating these findings.
Results
GB administration in aged mice improved muscle regeneration (muscle mass, P = 0.0374; myofiber number/field, P = 0.0001; centre nucleus, embryonic myosin heavy chain-positive myofiber area, P = 0.0144), facilitated the recovery of muscle contractile properties (tetanic force, P = 0.0002; twitch force, P = 0.0005) and exercise performance (rotarod performance, P = 0.002), and reduced muscular fibrosis (collagen deposition, P < 0.0001) and inflammation (macrophage infiltration, P = 0.03). GB reversed the aging-related decrease in the expression of osteocalcin (P < 0.0001), an osteoblast-specific hormone, to promote muscle regeneration. Exogenous osteocalcin supplementation was sufficient to improve muscle regeneration (muscle mass, P = 0.0029; myofiber number/field, P < 0.0001), functional recovery (tetanic force, P = 0.0059; twitch force, P = 0.07; rotarod performance, P < 0.0001) and fibrosis (collagen deposition, P = 0.0316) in aged mice, without an increased risk of heterotopic ossification.
{"title":"Ginkgolide B facilitates muscle regeneration via rejuvenating osteocalcin-mediated bone-to-muscle modulation in aged mice","authors":"Belle Yu-Hsuan Wang, Yi-Fan Chen, Allen Wei-Ting Hsiao, Wan-Jing Chen, Chien-Wei Lee, Oscar Kuang-Sheng Lee","doi":"10.1002/jcsm.13228","DOIUrl":"https://doi.org/10.1002/jcsm.13228","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The progressive deterioration of tissue–tissue crosstalk with aging causes a striking impairment of tissue homeostasis and functionality, particularly in the musculoskeletal system. Rejuvenation of the systemic and local milieu via interventions such as heterochronic parabiosis and exercise has been reported to improve musculoskeletal homeostasis in aged organisms. We have shown that Ginkgolide B (GB), a small molecule from <i>Ginkgo biloba</i>, improves bone homeostasis in aged mice by restoring local and systemic communication, implying a potential for maintaining skeletal muscle homeostasis and enhancing regeneration. In this study, we investigated the therapeutic efficacy of GB on skeletal muscle regeneration in aged mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Muscle injury models were established by barium chloride induction into the hind limb of 20-month-old mice (aged mice) and into C2C12-derived myotubes. Therapeutic efficacy of daily administrated GB (12 mg/kg body weight) and osteocalcin (50 μg/kg body weight) on muscle regeneration was assessed by histochemical staining, gene expression, flow cytometry, ex vivo muscle function test and rotarod test. RNA sequencing was used to explore the mechanism of GB on muscle regeneration, with subsequent in vitro and in vivo experiments validating these findings.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>GB administration in aged mice improved muscle regeneration (muscle mass, <i>P</i> = 0.0374; myofiber number/field, <i>P</i> = 0.0001; centre nucleus, embryonic myosin heavy chain-positive myofiber area, <i>P</i> = 0.0144), facilitated the recovery of muscle contractile properties (tetanic force, <i>P</i> = 0.0002; twitch force, <i>P</i> = 0.0005) and exercise performance (rotarod performance, <i>P</i> = 0.002), and reduced muscular fibrosis (collagen deposition, <i>P</i> < 0.0001) and inflammation (macrophage infiltration, <i>P</i> = 0.03). GB reversed the aging-related decrease in the expression of osteocalcin (<i>P</i> < 0.0001), an osteoblast-specific hormone, to promote muscle regeneration. Exogenous osteocalcin supplementation was sufficient to improve muscle regeneration (muscle mass, <i>P</i> = 0.0029; myofiber number/field, <i>P</i> < 0.0001), functional recovery (tetanic force, <i>P</i> = 0.0059; twitch force, <i>P</i> = 0.07; rotarod performance, <i>P</i> < 0.0001) and fibrosis (collagen deposition, <i>P</i> = 0.0316) in aged mice, without an increased risk of heterotopic ossification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 ","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1349-1364"},"PeriodicalIF":8.9,"publicationDate":"2023-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13228","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5754046","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}
Simone Radavelli-Bagatini, Helen Macpherson, David Scott, Robin M. Daly, Jonathan M. Hodgson, Simon M. Laws, Kun Zhu, Richard L. Prince, Joshua R. Lewis, Marc Sim
Background
Impaired muscle function has been identified as a risk factor for declining cognitive function and cardiovascular health, both of which are risk factors for late-life dementia (after 80 years of age). We examined whether hand grip strength and timed-up-and-go (TUG) performance, including their change over 5 years, were associated with late-life dementia events in older women and whether any associations provided independent information to Apolipoprotein E ℇ4 (APOEℇ4) genotype.
Methods
Grip strength and TUG were assessed in community-dwelling older women (mean ± SD; age 75.0 ± 2.6 years) at baseline (n = 1225) and 5 years (n = 1052). Incident 14.5-year late-life dementia events (dementia-related hospitalization/death) were obtained from linked health records. Cardiovascular risk factors (Framingham Risk Score), APOE genotyping, prevalent atherosclerotic vascular disease and cardiovascular-related medications were evaluated at baseline. These were included in multivariable-adjusted Cox-proportional hazards models assessing the relationship between muscle function measures and late-life-dementia events.
Results
Over follow-up, 207 (16.9%) women had a late-life dementia event. Compared with women with the highest grip strength (Quartile [Q] 4, 25.8 kg), those with the lowest grip strength (Q1, 16.0 kg) had greater hazard for a late-life dementia event (HR 2.27 95% CI 1.54–3.35, P < 0.001). For TUG, the slowest women (Q4, 12.4 vs. Q1, 7.4 s) also recorded a greater hazard for a late-life dementia event (HR 2.10 95% CI 1.42–3.10, P = 002). Weak hand grip (<22 kg) or slow TUG (>10.2 s) provided independent information to the presence of an APOEℇ4 allele (n = 280, 22.9%). Compared with women with no weakness and no APOEℇ4 allele, those with weakness and APOEℇ4 allele had a greater hazard (HR 3.19 95% CI 2.09–4.88, P < 0.001) for a late-life dementia event. Women presenting with slowness and the APOEℇ4 allele also recorded a greater hazard for a late-life dementia event (HR 2.59 95% CI 1.64–4.09, P < 0.001). For 5-year muscle function changes, compared with women with the lowest performance decrement (Q1), those with the largest decrement (Q4) had higher hazards for a late-life dementia event (grip strength HR 1.94 95% CI 1.22–3.08, P = 0.006; TUG HR 2.52 95% CI 1.59–3.98, P < 0.001) over the next 9.5 years.
肌肉功能受损已被确定为认知功能和心血管健康下降的危险因素，这两者都是老年痴呆(80岁以后)的危险因素。我们研究了握力和随动随动(TUG)表现(包括它们在5年内的变化)是否与老年妇女的晚年痴呆事件有关，以及是否有任何关联为载脂蛋白Eℇ4 (APOEℇ4)基因型提供了独立信息。方法对社区老年妇女的握力和TUG进行评估(mean±SD;基线年龄75.0±2.6岁(n = 1225)和5岁(n = 1052)。14.5年的老年痴呆事件(与痴呆相关的住院/死亡)从相关的健康记录中获得。在基线时评估心血管危险因素(Framingham风险评分)、APOE基因分型、流行的动脉粥样硬化性血管疾病和心血管相关药物。这些被纳入多变量校正cox比例风险模型，评估肌肉功能测量与晚年痴呆事件之间的关系。结果随访期间，207名(16.9%)女性出现老年痴呆事件。与握力最高的女性(四分位数[Q] 4, 25.8 kg)相比，握力最低的女性(Q1, 16.0 kg)患老年痴呆的风险更高(HR 2.27, 95% CI 1.54-3.35, P <0.001)。对于拖船来说，最慢的女性(Q4, 12.4 vs. Q1, 7.4 s)也记录了更大的晚年痴呆事件风险(HR 2.10 95% CI 1.42-3.10, P = 002)。握力弱(22公斤)或拖拽慢(10.2秒)提供了APOEℇ4等位基因存在的独立信息(n = 280, 22.9%)。与无虚弱和无APOEℇ4等位基因的女性相比，虚弱和APOEℇ4等位基因的女性有更大的风险(HR 3.19 95% CI 2.09-4.88, P <0.001)的老年痴呆事件。表现迟缓和APOEℇ4等位基因的女性患老年痴呆的风险也更高(HR 2.59 95% CI 1.64-4.09, P <0.001)。对于5年肌肉功能变化，与表现下降最小(Q1)的女性相比，下降最大(Q4)的女性晚年痴呆事件的风险更高(握力HR 1.94 95% CI 1.22-3.08, P = 0.006;TUG HR 2.52 95% CI 1.59-3.98, P <0.001)。结论握力较弱、TUG速度较慢，且在5年内下降幅度较大，是社区老年妇女发生老年痴呆的重要危险因素，与生活方式和遗传风险因素无关。将肌肉功能测量作为痴呆症筛查的一部分似乎有助于识别可能从初级预防规划中受益的高危人群。
{"title":"Impaired muscle function, including its decline, is related to greater long-term late-life dementia risk in older women","authors":"Simone Radavelli-Bagatini, Helen Macpherson, David Scott, Robin M. Daly, Jonathan M. Hodgson, Simon M. Laws, Kun Zhu, Richard L. Prince, Joshua R. Lewis, Marc Sim","doi":"10.1002/jcsm.13227","DOIUrl":"https://doi.org/10.1002/jcsm.13227","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Impaired muscle function has been identified as a risk factor for declining cognitive function and cardiovascular health, both of which are risk factors for late-life dementia (after 80 years of age). We examined whether hand grip strength and timed-up-and-go (TUG) performance, including their change over 5 years, were associated with late-life dementia events in older women and whether any associations provided independent information to Apolipoprotein E <sub>ℇ</sub>4 (<i>APOE</i> <sub>ℇ</sub>4) genotype.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Grip strength and TUG were assessed in community-dwelling older women (mean ± SD; age 75.0 ± 2.6 years) at baseline (<i>n</i> = 1225) and 5 years (<i>n</i> = 1052). Incident 14.5-year late-life dementia events (dementia-related hospitalization/death) were obtained from linked health records. Cardiovascular risk factors (Framingham Risk Score), <i>APOE</i> genotyping, prevalent atherosclerotic vascular disease and cardiovascular-related medications were evaluated at baseline. These were included in multivariable-adjusted Cox-proportional hazards models assessing the relationship between muscle function measures and late-life-dementia events.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Over follow-up, 207 (16.9%) women had a late-life dementia event. Compared with women with the highest grip strength (Quartile [Q] 4, 25.8 kg), those with the lowest grip strength (Q1, 16.0 kg) had greater hazard for a late-life dementia event (HR 2.27 95% CI 1.54–3.35, <i>P</i> < 0.001). For TUG, the slowest women (Q4, 12.4 vs. Q1, 7.4 s) also recorded a greater hazard for a late-life dementia event (HR 2.10 95% CI 1.42–3.10, <i>P</i> = 002). Weak hand grip (<22 kg) or slow TUG (>10.2 s) provided independent information to the presence of an <i>APOE</i> <sub>ℇ</sub>4 allele (<i>n</i> = 280, 22.9%). Compared with women with no weakness and no <i>APOE</i> <sub>ℇ</sub>4 allele, those with weakness and <i>APOE</i> <sub>ℇ</sub>4 allele had a greater hazard (HR 3.19 95% CI 2.09–4.88, <i>P</i> < 0.001) for a late-life dementia event. Women presenting with slowness and the <i>APOE</i> <sub>ℇ</sub>4 allele also recorded a greater hazard for a late-life dementia event (HR 2.59 95% CI 1.64–4.09, <i>P</i> < 0.001). For 5-year muscle function changes, compared with women with the lowest performance decrement (Q1), those with the largest decrement (Q4) had higher hazards for a late-life dementia event (grip strength HR 1.94 95% CI 1.22–3.08, <i>P</i> = 0.006; TUG HR 2.52 95% CI 1.59–3.98, <i>P</i> < 0.001) over the next 9.5 years.</p>\u0000 </section>\u0000 \u0000 ","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1508-1519"},"PeriodicalIF":8.9,"publicationDate":"2023-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13227","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5698467","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}
Vitamin D deficiency is a globally common situation and closely related with many chronic diseases. It is a hot topic to examine if vitamin D supplementation is effective for the treatment of diseases, and there have been dozens of clinical trials published in recent years. However, most studies have not proved the extra-skeletal benefits of vitamin D supplementation on these diseases. Some inherent shortcomings of these trials, such as inclusion with vitamin D-sufficient and obese participants, low response rate from participants and the insensitive changes in chosen outcomes over a shorter period, may be main reasons why most studies have yet to demonstrate effects of vitamin D supplementation. In this editorial, we aim to discuss the perspectives on how can we design a proper trial for vitamin D treatment of diseases based on the evidence-based practice framework PICOS (participants, intervention, control, outcomes and study design) in the future. First, right participants should be chosen, which is crucial for the success of vitamin D clinical trials. Participants with vitamin D sufficiency (e.g., baseline 25(OH)D of >50 nmol/L), obesity (e.g., body mass index > 30 kg/m2) and/or high vitamin D response index could be excluded from the trials. Second, intervention with vitamin D in right forms or dosages should be used. Vitamin D3 supplementation with appropriate dosages that keep 25(OH)D levels between 75 and 100 nmol/L is recommended. Third, ‘contamination’ in the control groups needs to pay attention. To diminish this, it is ideal to include participants less interfered by sun exposure (such as living in places at a high latitude) or with greater compliance (less interference by supplemental vitamin D-containing nutrients). Fourth, the outcome measures should be sensitive to change to avoid type II error. For outcomes such as bone density, radiographic osteoarthritis and cardiovascular diseases, follow-up period of 3–5 years may be required to observe the changes. Last, precision clinical trials may be the only way to prove the benefits of vitamin D supplementation.
{"title":"How can we design a proper trial for vitamin D treatment of diseases? Facts and numbers","authors":"Shuang Zheng, Zhaohua Zhu, Changhai Ding","doi":"10.1002/jcsm.13200","DOIUrl":"https://doi.org/10.1002/jcsm.13200","url":null,"abstract":"<p>Vitamin D deficiency is a globally common situation and closely related with many chronic diseases. It is a hot topic to examine if vitamin D supplementation is effective for the treatment of diseases, and there have been dozens of clinical trials published in recent years. However, most studies have not proved the extra-skeletal benefits of vitamin D supplementation on these diseases. Some inherent shortcomings of these trials, such as inclusion with vitamin D-sufficient and obese participants, low response rate from participants and the insensitive changes in chosen outcomes over a shorter period, may be main reasons why most studies have yet to demonstrate effects of vitamin D supplementation. In this editorial, we aim to discuss the perspectives on how can we design a proper trial for vitamin D treatment of diseases based on the evidence-based practice framework PICOS (participants, intervention, control, outcomes and study design) in the future. First, right participants should be chosen, which is crucial for the success of vitamin D clinical trials. Participants with vitamin D sufficiency (e.g., baseline 25(OH)D of >50 nmol/L), obesity (e.g., body mass index > 30 kg/m<sup>2</sup>) and/or high vitamin D response index could be excluded from the trials. Second, intervention with vitamin D in right forms or dosages should be used. Vitamin D<sub>3</sub> supplementation with appropriate dosages that keep 25(OH)D levels between 75 and 100 nmol/L is recommended. Third, ‘contamination’ in the control groups needs to pay attention. To diminish this, it is ideal to include participants less interfered by sun exposure (such as living in places at a high latitude) or with greater compliance (less interference by supplemental vitamin D-containing nutrients). Fourth, the outcome measures should be sensitive to change to avoid type II error. For outcomes such as bone density, radiographic osteoarthritis and cardiovascular diseases, follow-up period of 3–5 years may be required to observe the changes. Last, precision clinical trials may be the only way to prove the benefits of vitamin D supplementation.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1146-1149"},"PeriodicalIF":8.9,"publicationDate":"2023-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13200","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5708524","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}
Young il Lee, Nicola Cacciani, Ya Wen, Xiang Zhang, Yvette Hedstr?m, Wesley Thompson, Lars Larsson
There is increasing evidence of crosstalk between organs. The neuromuscular junction (NMJ) is a peripheral chemical synapse whose function and morphology are sensitive to acetylcholine (ACh) release and muscle depolarization. In an attempt to improve our understanding of NMJ plasticity and muscle crosstalk, the effects of unilateral direct electrical stimulation of a hindlimb muscle on the NMJ were investigated in rats exposed long‐term post‐synaptic neuromuscular blockade.
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Sarcopenia is a serious public health concern among older adults worldwide. Exercise is the most common intervention for sarcopenia. This study aimed to compare the effectiveness of different exercise types for older adults with sarcopenia.
Methods
Randomized controlled trials (RCTs) that examined the effectiveness of exercise interventions on patient-important outcomes for older adults with sarcopenia were eligible. We systematically searched MEDLINE, Embase and Cochrane Central Register of Controlled Trials via Ovid until 3 June 2022. We used frequentist random-effects network meta-analyses to summarize the evidence and applied the Grading of Recommendations, Assessment, Development, and Evaluations framework to rate the certainty of evidence.
Results
Our search identified 5988 citations, of which 42 RCTs proved eligible with 3728 participants with sarcopenia (median age: 72.9 years, female: 73.3%) with a median follow-up of 12 weeks. We are interested in patient-important outcomes that include mortality, quality of life, muscle strength and physical function measures. High or moderate certainty evidence suggested that resistance exercise with or without nutrition and the combination of resistance exercise with aerobic and balance training were the most effective interventions for improving quality of life compared to usual care (standardized mean difference from 0.68 to 1.11). Moderate certainty evidence showed that resistance and balance exercise plus nutrition (mean difference [MD]: 4.19 kg) was the most effective for improving handgrip strength (minimally important difference [MID]: 5 kg). Resistance and balance exercise with or without nutrition (MD: 0.16 m/s, moderate) were the most effective for improving physical function measured by usual gait speed (MID: 0.1 m/s). Moderate certainty evidence showed that resistance and balance exercise (MD: 1.85 s) was intermediately effective for improving physical function measured by timed up and go test (MID: 2.1 s). High certainty evidence showed that resistance and aerobic, or resistance and balance, or resistance and aerobic exercise plus nutrition (MD from 1.72 to 2.28 s) were intermediately effective for improving physical function measured by the five-repetition chair stand test (MID: 2.3 s).
Conclusions
In older adults with sarcopenia, high or moderate certainty evidence showed that resistance exercise with or without nutrition and the combin
背景:骨骼肌减少症是全世界老年人中严重的公共卫生问题。运动是肌肉减少症最常见的干预措施。这项研究旨在比较不同运动类型对老年肌肉减少症患者的效果。方法随机对照试验(rct)检验了运动干预对老年肌肉减少症患者重要结果的有效性。我们通过Ovid系统检索MEDLINE、Embase和Cochrane Central Register of Controlled Trials，截止到2022年6月3日。我们使用频率随机效应网络荟萃分析来总结证据，并应用推荐、评估、发展和评估的分级框架来评估证据的确定性。结果:我们的检索确定了5988条引用，其中42项rct被证明符合条件，有3728名肌肉减少症患者(中位年龄:72.9岁，女性:73.3%)，中位随访时间为12周。我们感兴趣的是患者重要的结果，包括死亡率、生活质量、肌肉力量和身体功能测量。高或中等确定性证据表明，与常规护理相比，有营养或没有营养的阻力运动以及阻力运动与有氧和平衡训练相结合是改善生活质量的最有效干预措施(标准化平均差为0.68至1.11)。中等确定性证据表明，阻力和平衡运动加上营养(平均差值[MD]: 4.19 kg)对提高握力最有效(最小重要差值[MID]: 5 kg)。阻力和平衡运动(MD: 0.16 m/s，中等)对改善通常步态速度(MID: 0.1 m/s)测量的身体功能最有效。中等确定性证据表明，阻力和平衡运动(MD: 1.85 s)对计时起跑测试(MID: 2.1 s)测量的身体机能改善具有中等有效性。高确定性证据表明，阻力和有氧运动，或阻力和平衡运动，或阻力和有氧运动加营养运动(MD从1.72到2.28 s)对五次重复椅子站立测试(MID: 1)测量的身体机能改善具有中等有效性。结论在老年肌肉减少症患者中，高或中等确定性证据表明，有营养或无营养的阻力运动以及阻力运动与有氧和平衡训练相结合是改善生活质量的最有效干预措施。在锻炼中加入营养干预对握力的影响比单独锻炼更大，同时对其他身体机能的测量也显示出类似的效果。
{"title":"Exercise for sarcopenia in older people: A systematic review and network meta-analysis","authors":"Yanjiao Shen, Qingyang Shi, Kailei Nong, Sheyu Li, Jirong Yue, Jin Huang, Birong Dong, Marla Beauchamp, Qiukui Hao","doi":"10.1002/jcsm.13225","DOIUrl":"https://doi.org/10.1002/jcsm.13225","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sarcopenia is a serious public health concern among older adults worldwide. Exercise is the most common intervention for sarcopenia. This study aimed to compare the effectiveness of different exercise types for older adults with sarcopenia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Randomized controlled trials (RCTs) that examined the effectiveness of exercise interventions on patient-important outcomes for older adults with sarcopenia were eligible. We systematically searched MEDLINE, Embase and Cochrane Central Register of Controlled Trials via Ovid until 3 June 2022. We used frequentist random-effects network meta-analyses to summarize the evidence and applied the Grading of Recommendations, Assessment, Development, and Evaluations framework to rate the certainty of evidence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our search identified 5988 citations, of which 42 RCTs proved eligible with 3728 participants with sarcopenia (median age: 72.9 years, female: 73.3%) with a median follow-up of 12 weeks. We are interested in patient-important outcomes that include mortality, quality of life, muscle strength and physical function measures. High or moderate certainty evidence suggested that resistance exercise with or without nutrition and the combination of resistance exercise with aerobic and balance training were the most effective interventions for improving quality of life compared to usual care (standardized mean difference from 0.68 to 1.11). Moderate certainty evidence showed that resistance and balance exercise plus nutrition (mean difference [MD]: 4.19 kg) was the most effective for improving handgrip strength (minimally important difference [MID]: 5 kg). Resistance and balance exercise with or without nutrition (MD: 0.16 m/s, moderate) were the most effective for improving physical function measured by usual gait speed (MID: 0.1 m/s). Moderate certainty evidence showed that resistance and balance exercise (MD: 1.85 s) was intermediately effective for improving physical function measured by timed up and go test (MID: 2.1 s). High certainty evidence showed that resistance and aerobic, or resistance and balance, or resistance and aerobic exercise plus nutrition (MD from 1.72 to 2.28 s) were intermediately effective for improving physical function measured by the five-repetition chair stand test (MID: 2.3 s).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In older adults with sarcopenia, high or moderate certainty evidence showed that resistance exercise with or without nutrition and the combin","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1199-1211"},"PeriodicalIF":8.9,"publicationDate":"2023-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6126821","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}
Sarcopenia, defined as an age-associated loss of skeletal muscle mass and function, is a major risk factor for requiring long-term care. Because physical activity in adolescence and older age enhances peak muscle function in youth and prevents muscle function decline in older age, older adults with exercise habits during both periods may be at a lower risk for sarcopenia. We investigated the relationship between exercise habits in adolescence and older age and sarcopenia and its components in community-dwelling older Japanese adults.
Methods
This study included 1607 community-dwelling individuals (aged 65–84, medians 73 years, 679 men and 928 women) with complete health examinations, including measurements of skeletal muscle index, handgrip strength and gait speed, who were enrolled in the Bunkyo Health Study. We divided the participants into four groups according to exercise habits in adolescence and older age: no exercise in either period (none-none; NN), exercise only in adolescence (active-none; AN), exercise only in older age (none-active; NA) and exercise in both periods (active-active; AA). Multivariate-adjusted logistic regression models were used to estimate the odds ratios (ORs) and associated 95% confidence intervals (CIs) in each group for the prevalence of sarcopenia, defined as low muscle mass and low muscle performance, as compared with the NN group. Low muscle performance was defined as low muscle strength and/or low gait speed.
Results
The total prevalence of sarcopenia was 6.6% (45/679) in men and 1.7% (16/928) in women, the total prevalence of low muscle mass was 14.3% (97/679) in men and 5.2% (48/928) in women, and the total prevalence of low muscle performance was 25.6% (174/679) in men and 19.6% (182/928) in women. In men, the ORs (95% CIs) for sarcopenia, low muscle mass and low muscle performance were significantly lower in the AA group (sarcopenia: 0.29 [0.09–0.95], P = 0.041; low muscle mass: 0.21 [0.09–0.52], P = 0.001; and low muscle performance: 0.52 [0.28–0.97], P = 0.038). In women, the OR (95% CI) for low muscle performance was significantly lower in the AA group than in the other groups (0.48 [0.27–0.84], P = 0.010), whereas none of the ORs for sarcopenia and low muscle mass were significant.
Conclusions
Older men with exercise habits in both adolescence and older age were at a lower risk of sarcopenia, low muscle mass and low muscle per
{"title":"Effects of exercise habits in adolescence and older age on sarcopenia risk in older adults: the Bunkyo Health Study","authors":"Hiroki Tabata, Hikaru Otsuka, Huicong Shi, Mari Sugimoto, Hideyoshi Kaga, Yuki Someya, Hitoshi Naito, Naoaki Ito, Abulaiti Abudurezake, Futaba Umemura, Mai Kiya, Tsubasa Tajima, Saori Kakehi, Yasuyo Yoshizawa, Ryuzo Kawamori, Hirotaka Watada, Yoshifumi Tamura","doi":"10.1002/jcsm.13218","DOIUrl":"https://doi.org/10.1002/jcsm.13218","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sarcopenia, defined as an age-associated loss of skeletal muscle mass and function, is a major risk factor for requiring long-term care. Because physical activity in adolescence and older age enhances peak muscle function in youth and prevents muscle function decline in older age, older adults with exercise habits during both periods may be at a lower risk for sarcopenia. We investigated the relationship between exercise habits in adolescence and older age and sarcopenia and its components in community-dwelling older Japanese adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study included 1607 community-dwelling individuals (aged 65–84, medians 73 years, 679 men and 928 women) with complete health examinations, including measurements of skeletal muscle index, handgrip strength and gait speed, who were enrolled in the Bunkyo Health Study. We divided the participants into four groups according to exercise habits in adolescence and older age: no exercise in either period (none-none; NN), exercise only in adolescence (active-none; AN), exercise only in older age (none-active; NA) and exercise in both periods (active-active; AA). Multivariate-adjusted logistic regression models were used to estimate the odds ratios (ORs) and associated 95% confidence intervals (CIs) in each group for the prevalence of sarcopenia, defined as low muscle mass and low muscle performance, as compared with the NN group. Low muscle performance was defined as low muscle strength and/or low gait speed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The total prevalence of sarcopenia was 6.6% (45/679) in men and 1.7% (16/928) in women, the total prevalence of low muscle mass was 14.3% (97/679) in men and 5.2% (48/928) in women, and the total prevalence of low muscle performance was 25.6% (174/679) in men and 19.6% (182/928) in women. In men, the ORs (95% CIs) for sarcopenia, low muscle mass and low muscle performance were significantly lower in the AA group (sarcopenia: 0.29 [0.09–0.95], <i>P</i> = 0.041; low muscle mass: 0.21 [0.09–0.52], <i>P</i> = 0.001; and low muscle performance: 0.52 [0.28–0.97], <i>P</i> = 0.038). In women, the OR (95% CI) for low muscle performance was significantly lower in the AA group than in the other groups (0.48 [0.27–0.84], <i>P</i> = 0.010), whereas none of the ORs for sarcopenia and low muscle mass were significant.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Older men with exercise habits in both adolescence and older age were at a lower risk of sarcopenia, low muscle mass and low muscle per","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1299-1311"},"PeriodicalIF":8.9,"publicationDate":"2023-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5828740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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