Elie Naddaf, Thi Kim Oanh Nguyen, Jens O. Watzlawik, Huanyao Gao, Xu Hou, Fabienne C. Fiesel, Jay Mandrekar, Eileen Kokesh, William S. Harmsen, Ian R. Lanza, Wolfdieter Springer, Eugenia Trushina
BackgroundInclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM.MethodsThe study population consisted of 38 IBM patients and 22 age‐ and sex‐matched controls without a myopathy. Mean age was 62.9 years (SD = 9) in IBM group and 59.7 (10) in controls. Bulk RNA sequencing, Meso Scale Discovery electrochemiluminescence (ECL), western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants.ResultsWe demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome being the most upregulated pathway on RNA sequencing, along with increased expression of NLRP3 and ASC proteins in IBM group. <jats:italic>NLRP3</jats:italic> RNA levels most strongly correlated with <jats:italic>TLR7</jats:italic> (correlation coefficient <jats:italic>ρ</jats:italic> = 0.91) and complement activation‐related genes, and inversely correlated with several mitochondria‐related genes among others. On muscle histopathology, there was increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibres. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction—NLRP3 inflammasome activation. Herein, we showed altered mitophagy, as witnessed by the elevated levels of p‐S65‐Ubiquitin, a mitophagy marker, in muscle lysates from IBM patients compared to controls (median of 114.3 vs. 81.25 ECL units, <jats:italic>p</jats:italic> = 0.005). The p‐S65‐Ubiquitin levels were most significantly elevated in IBM males compared to male controls (136 vs. 83.5 ECL units; <jats:italic>p</jats:italic> = 0.013), whereas IBM females had milder nonsignificant elevation compared to female controls (97.25 vs. 69 ECL units, <jats:italic>p</jats:italic> = 0.31). On muscle histopathology, p‐S65‐Ubiquitin aggregates accumulated in muscle fibres that were mostly Type 2 and devoid of cytochrome‐c‐oxidase reactivity. <jats:italic>NLRP3 RNA</jats:italic> levels correlated with p‐S65‐Ubiquitin levels in both sexes (males: <jats:italic>ρ</jats:italic> = 0.48, females: <jats:italic>ρ</jats:italic> = 0.54) but with loss of muscle strength, as reflected by the manual motor test score, only in males (males: <jats:italic>ρ</jats:italic> = 0.62, females: <jats:italic>ρ</jats:italic> = −0.14). Lastly, we identified sex‐specific molecular pathways in IBM. Females had upregulation of pathways related to response to stress, which could conceivably offset some of the pathomechanisms of IBM, while males had upregulation of pathways related to cell adhesion and migration.ConclusionsThere is activation of the NLRP3 inflammasome in IBM, along with altered mitophagy, particularly in males, which is of potential therapeutic significance. T
{"title":"NLRP3 Inflammasome Activation and Altered Mitophagy Are Key Pathways in Inclusion Body Myositis","authors":"Elie Naddaf, Thi Kim Oanh Nguyen, Jens O. Watzlawik, Huanyao Gao, Xu Hou, Fabienne C. Fiesel, Jay Mandrekar, Eileen Kokesh, William S. Harmsen, Ian R. Lanza, Wolfdieter Springer, Eugenia Trushina","doi":"10.1002/jcsm.13672","DOIUrl":"https://doi.org/10.1002/jcsm.13672","url":null,"abstract":"BackgroundInclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM.MethodsThe study population consisted of 38 IBM patients and 22 age‐ and sex‐matched controls without a myopathy. Mean age was 62.9 years (SD = 9) in IBM group and 59.7 (10) in controls. Bulk RNA sequencing, Meso Scale Discovery electrochemiluminescence (ECL), western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants.ResultsWe demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome being the most upregulated pathway on RNA sequencing, along with increased expression of NLRP3 and ASC proteins in IBM group. <jats:italic>NLRP3</jats:italic> RNA levels most strongly correlated with <jats:italic>TLR7</jats:italic> (correlation coefficient <jats:italic>ρ</jats:italic> = 0.91) and complement activation‐related genes, and inversely correlated with several mitochondria‐related genes among others. On muscle histopathology, there was increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibres. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction—NLRP3 inflammasome activation. Herein, we showed altered mitophagy, as witnessed by the elevated levels of p‐S65‐Ubiquitin, a mitophagy marker, in muscle lysates from IBM patients compared to controls (median of 114.3 vs. 81.25 ECL units, <jats:italic>p</jats:italic> = 0.005). The p‐S65‐Ubiquitin levels were most significantly elevated in IBM males compared to male controls (136 vs. 83.5 ECL units; <jats:italic>p</jats:italic> = 0.013), whereas IBM females had milder nonsignificant elevation compared to female controls (97.25 vs. 69 ECL units, <jats:italic>p</jats:italic> = 0.31). On muscle histopathology, p‐S65‐Ubiquitin aggregates accumulated in muscle fibres that were mostly Type 2 and devoid of cytochrome‐c‐oxidase reactivity. <jats:italic>NLRP3 RNA</jats:italic> levels correlated with p‐S65‐Ubiquitin levels in both sexes (males: <jats:italic>ρ</jats:italic> = 0.48, females: <jats:italic>ρ</jats:italic> = 0.54) but with loss of muscle strength, as reflected by the manual motor test score, only in males (males: <jats:italic>ρ</jats:italic> = 0.62, females: <jats:italic>ρ</jats:italic> = −0.14). Lastly, we identified sex‐specific molecular pathways in IBM. Females had upregulation of pathways related to response to stress, which could conceivably offset some of the pathomechanisms of IBM, while males had upregulation of pathways related to cell adhesion and migration.ConclusionsThere is activation of the NLRP3 inflammasome in IBM, along with altered mitophagy, particularly in males, which is of potential therapeutic significance. T","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"20 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wenjie Wang, Feijie Wang, Yihan Li, Yuwei Shi, Xiaoyan Wang, Xinyu Chen, Weifang Zheng, Julianna C. Hsing, Ying Lu, Yi‐Shuan Wu, Ann W. Hsing, Juntao Kan, Wei He, Shankuan Zhu
BackgroundNormal weight obesity (NWO) is characterized by excess body fat in individuals with normal body mass index (BMI). This study aimed to investigate gut microbiota alterations in NWO and their potential associations with cardiometabolic diseases (CMD) risk in two independent cohorts.MethodsOur NWO‐CMD mortality analysis included 168 099 adults with normal BMI from two large open‐access databases, while our NWO‐gut microbiota study involved 5467 adults with normal BMI from two independent cohorts: the WELL‐China cohort and the Lanxi cohort. NWO was defined as having a normal BMI (18.5–23.9 kg/m<jats:sup>2</jats:sup>) but an excess per cent body fat (PBF, ≥ 25% in men and ≥ 35% in women). Normal weight lean was defined as having a normal BMI and normal PBF. The 16S rRNA gene sequencing method was used to analyse gut microbiota data.ResultsThe study comprised 3620 (64.0% female, median age 58 years) and 1847 (64.3% female, median age 56 years) participants from the WELL‐China and Lanxi cohorts. In our meta‐analysis, NWO is associated with 26% (95% CI: 1.07–1.41) higher risk of CMD mortality. Gut microbial analyses indicated that the NWO group exhibited reduced levels of observed species (<jats:italic>p</jats:italic> = 0.009 and <jats:italic>p</jats:italic> = 0.013) and Chao 1 index (<jats:italic>p</jats:italic> = 0.002 and <jats:italic>p</jats:italic> = 0.002) and altered gut microbial compositions (<jats:italic>p</jats:italic> = 0.009 and <jats:italic>p</jats:italic> < 0.001) compared with the NWL group. Seven genera were consistently observed to be associated with NWO in both two cohorts (all Q < 0.25). Among them, five (<jats:italic>Fusobacterium</jats:italic>, <jats:italic><jats:styled-content style="fixed-case">Ruminococcus gnavus</jats:styled-content> group</jats:italic>, <jats:italic><jats:styled-content style="fixed-case">Ruminococcus torques</jats:styled-content> group</jats:italic>, <jats:italic>Coprococcus</jats:italic> and <jats:italic>Christensenellaceae_R7_group</jats:italic>) have been previously linked to obesity, while the other two (<jats:italic>Phascolarctobacterium</jats:italic> and <jats:italic>Clostridia_UCG‐014</jats:italic>) were minimally reported. We also found statistically significant differences in the microbial composition between the NWO group and the obesity group (<jats:italic>p</jats:italic> = 0.001 and <jats:italic>p</jats:italic> = 0.001). Furthermore, the NWO‐related gut microbiome was associated with an elevated risk of hypertension, dyslipidaemia and metabolic syndrome, the corresponding HR (95% CIs) were 1.11 (1.01–1.22), 1.19 (1.10–1.29) and 1.17 (1.05–1.30) in the WELL‐China cohort and 1.14 (1.02–1.27), 1.15 (1.02–1.29) and 1.16 (1.02–1.32) in the Lanxi cohort.ConclusionsThese two large cohorts provided reliable evidence that gut microbiota alterations in NWO resemble those found in obesity, yet also display unique aspects. This distinct microbiota profile may contribute to heightened cardiometa
{"title":"Distinct Gut Microbiota Profiles in Normal Weight Obesity and Their Association With Cardiometabolic Diseases: Results From Two Independent Cohort Studies","authors":"Wenjie Wang, Feijie Wang, Yihan Li, Yuwei Shi, Xiaoyan Wang, Xinyu Chen, Weifang Zheng, Julianna C. Hsing, Ying Lu, Yi‐Shuan Wu, Ann W. Hsing, Juntao Kan, Wei He, Shankuan Zhu","doi":"10.1002/jcsm.13644","DOIUrl":"https://doi.org/10.1002/jcsm.13644","url":null,"abstract":"BackgroundNormal weight obesity (NWO) is characterized by excess body fat in individuals with normal body mass index (BMI). This study aimed to investigate gut microbiota alterations in NWO and their potential associations with cardiometabolic diseases (CMD) risk in two independent cohorts.MethodsOur NWO‐CMD mortality analysis included 168 099 adults with normal BMI from two large open‐access databases, while our NWO‐gut microbiota study involved 5467 adults with normal BMI from two independent cohorts: the WELL‐China cohort and the Lanxi cohort. NWO was defined as having a normal BMI (18.5–23.9 kg/m<jats:sup>2</jats:sup>) but an excess per cent body fat (PBF, ≥ 25% in men and ≥ 35% in women). Normal weight lean was defined as having a normal BMI and normal PBF. The 16S rRNA gene sequencing method was used to analyse gut microbiota data.ResultsThe study comprised 3620 (64.0% female, median age 58 years) and 1847 (64.3% female, median age 56 years) participants from the WELL‐China and Lanxi cohorts. In our meta‐analysis, NWO is associated with 26% (95% CI: 1.07–1.41) higher risk of CMD mortality. Gut microbial analyses indicated that the NWO group exhibited reduced levels of observed species (<jats:italic>p</jats:italic> = 0.009 and <jats:italic>p</jats:italic> = 0.013) and Chao 1 index (<jats:italic>p</jats:italic> = 0.002 and <jats:italic>p</jats:italic> = 0.002) and altered gut microbial compositions (<jats:italic>p</jats:italic> = 0.009 and <jats:italic>p</jats:italic> < 0.001) compared with the NWL group. Seven genera were consistently observed to be associated with NWO in both two cohorts (all Q < 0.25). Among them, five (<jats:italic>Fusobacterium</jats:italic>, <jats:italic><jats:styled-content style=\"fixed-case\">Ruminococcus gnavus</jats:styled-content> group</jats:italic>, <jats:italic><jats:styled-content style=\"fixed-case\">Ruminococcus torques</jats:styled-content> group</jats:italic>, <jats:italic>Coprococcus</jats:italic> and <jats:italic>Christensenellaceae_R7_group</jats:italic>) have been previously linked to obesity, while the other two (<jats:italic>Phascolarctobacterium</jats:italic> and <jats:italic>Clostridia_UCG‐014</jats:italic>) were minimally reported. We also found statistically significant differences in the microbial composition between the NWO group and the obesity group (<jats:italic>p</jats:italic> = 0.001 and <jats:italic>p</jats:italic> = 0.001). Furthermore, the NWO‐related gut microbiome was associated with an elevated risk of hypertension, dyslipidaemia and metabolic syndrome, the corresponding HR (95% CIs) were 1.11 (1.01–1.22), 1.19 (1.10–1.29) and 1.17 (1.05–1.30) in the WELL‐China cohort and 1.14 (1.02–1.27), 1.15 (1.02–1.29) and 1.16 (1.02–1.32) in the Lanxi cohort.ConclusionsThese two large cohorts provided reliable evidence that gut microbiota alterations in NWO resemble those found in obesity, yet also display unique aspects. This distinct microbiota profile may contribute to heightened cardiometa","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"299 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leo R. Brown, Maria Soupashi, Michael S. Yule, Danielle R. Clyde, Ellen Gardner, Charlotte Smith, Ahmed Dhaif, Barry J. A. Laird, Stephen J. Wigmore, Richard J. E. Skipworth
BackgroundSingle‐slice computed tomography (CT) body composition has been studied extensively for prognostication in patients with cancer. New software packages can also provide multi‐slice volumetric measurements, but the clinical utility of these remains under explored. This study aimed to evaluate the agreement between single‐ and multi‐slice body composition analyses in patients with oesophagogastric cancer and to explore the association between these measures and overall survival.MethodsConsecutive patients with newly diagnosed oesophagogastric (OG) cancer were identified through the prospectively maintained regional database of the South East Scotland Cancer Network across a 2‐year study period. CT body composition analyses were undertaken using scans collected during routine clinical care. Single‐slice (cross‐sectional area at mid L3) and multi‐slice (volume between T12 and L4) measurements were compared for skeletal muscle (SKM), subcutaneous adipose (SAT), visceral adipose (VAT) and intermuscular adipose (IMAT). Agreement between sex‐stratified z‐scores was quantified using Pearson correlation coefficients and Bland–Altman analyses. Cox proportional hazard modelling was used to estimate the effect of these measures on overall survival.ResultsOverall, 504 patients (67.9% male, median 72 years) were newly diagnosed with OG cancer during the study period. Single‐ and multi‐slice (mean: 169 slices) measurements correlated highly for SKM (R: 0.97, p < 0.001), SAT (R: 0.98, p < 0.001), VAT (R: 0.97, p < 0.001), SKM radiodensity (R: 0.93, p < 0.001) and IMAT (R: 0.88, p < 0.001). Bias on Bland–Altman analysis was 0.00 for all tissue measurements. Limits of agreement (LoA) were narrowest for SAT (±0.43), VAT (±0.46) and SKM (±0.48), but slightly wider for SKM radiodensity (±0.73) and IMAT (±0.96). Adipose tissue ‘outliers’ (those where agreement between single‐ and multi‐slice z‐scores was outside the LoA) had a higher median weight and body mass index (BMI), suggestive of poorer agreement in patients with obesity. Sensitivity analysis, excluding those with BMI > 30, narrowed the LoA for SKM, VAT, SAT and IMAT. Direction and magnitudes of observed effect sizes for overall survival were all highly comparable, with hazard ratios for each tissue type varying by ≤ 0.04 between single‐ and multi‐slice adjusted estimates.ConclusionsSingle‐slice and multi‐slice CT assessments provide highly correlated tissue measurements amongst patients with OG cancer. Associations between these measurements and overall survival were also comparable across both types of body composition analysis. Agreement between single‐ and multi‐slice measurements of adiposity is worse in patients with obesity, suggesting single‐slice analyses may less accurately reflect the quantity or distribution of adipose tissue in this patient group.
{"title":"Comparison Between Single‐ and Multi‐slice Computed Tomography Body Composition Analysis in Patients With Oesophagogastric Cancer","authors":"Leo R. Brown, Maria Soupashi, Michael S. Yule, Danielle R. Clyde, Ellen Gardner, Charlotte Smith, Ahmed Dhaif, Barry J. A. Laird, Stephen J. Wigmore, Richard J. E. Skipworth","doi":"10.1002/jcsm.13673","DOIUrl":"https://doi.org/10.1002/jcsm.13673","url":null,"abstract":"BackgroundSingle‐slice computed tomography (CT) body composition has been studied extensively for prognostication in patients with cancer. New software packages can also provide multi‐slice volumetric measurements, but the clinical utility of these remains under explored. This study aimed to evaluate the agreement between single‐ and multi‐slice body composition analyses in patients with oesophagogastric cancer and to explore the association between these measures and overall survival.MethodsConsecutive patients with newly diagnosed oesophagogastric (OG) cancer were identified through the prospectively maintained regional database of the South East Scotland Cancer Network across a 2‐year study period. CT body composition analyses were undertaken using scans collected during routine clinical care. Single‐slice (cross‐sectional area at mid L3) and multi‐slice (volume between T12 and L4) measurements were compared for skeletal muscle (SKM), subcutaneous adipose (SAT), visceral adipose (VAT) and intermuscular adipose (IMAT). Agreement between sex‐stratified z‐scores was quantified using Pearson correlation coefficients and Bland–Altman analyses. Cox proportional hazard modelling was used to estimate the effect of these measures on overall survival.ResultsOverall, 504 patients (67.9% male, median 72 years) were newly diagnosed with OG cancer during the study period. Single‐ and multi‐slice (mean: 169 slices) measurements correlated highly for SKM (R: 0.97, <jats:italic>p</jats:italic> < 0.001), SAT (R: 0.98, <jats:italic>p</jats:italic> < 0.001), VAT (R: 0.97, <jats:italic>p</jats:italic> < 0.001), SKM radiodensity (R: 0.93, <jats:italic>p</jats:italic> < 0.001) and IMAT (R: 0.88, p < 0.001). Bias on Bland–Altman analysis was 0.00 for all tissue measurements. Limits of agreement (LoA) were narrowest for SAT (±0.43), VAT (±0.46) and SKM (±0.48), but slightly wider for SKM radiodensity (±0.73) and IMAT (±0.96). Adipose tissue ‘outliers’ (those where agreement between single‐ and multi‐slice z‐scores was outside the LoA) had a higher median weight and body mass index (BMI), suggestive of poorer agreement in patients with obesity. Sensitivity analysis, excluding those with BMI > 30, narrowed the LoA for SKM, VAT, SAT and IMAT. Direction and magnitudes of observed effect sizes for overall survival were all highly comparable, with hazard ratios for each tissue type varying by ≤ 0.04 between single‐ and multi‐slice adjusted estimates.ConclusionsSingle‐slice and multi‐slice CT assessments provide highly correlated tissue measurements amongst patients with OG cancer. Associations between these measurements and overall survival were also comparable across both types of body composition analysis. Agreement between single‐ and multi‐slice measurements of adiposity is worse in patients with obesity, suggesting single‐slice analyses may less accurately reflect the quantity or distribution of adipose tissue in this patient group.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"32 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brandon Stretton, Joshua Kovoor, Aashray Gupta, Stephen Bacchi
{"title":"Anorexia of Ageing, an Underappreciated Perioperative Concern?","authors":"Brandon Stretton, Joshua Kovoor, Aashray Gupta, Stephen Bacchi","doi":"10.1002/jcsm.13683","DOIUrl":"https://doi.org/10.1002/jcsm.13683","url":null,"abstract":"","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"22 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rachana Mehta, Ashok Kumar Balaraman, Muhammed Shabil, Sanjit Sah
<p>We read with great interest the article titled ‘Association of computed tomography-derived body composition and complications after colorectal cancer surgery A systematic review and meta-analysis’ and commend the authors for their rigorous and insightful systematic review and meta-analysis on body composition measurements using computed tomography (CT) scans as predictors of complications following colorectal cancer surgery [<span>1</span>]. This research addresses a highly relevant clinical issue, providing valuable information to guide surgical decision-making. While the article provides important findings, we believe there are some additional aspects that could further strengthen its impact and provide readers with an even more comprehensive understanding.</p>