Chest computed tomography (CT) is a valuable tool for diagnosing and predicting the severity of coronavirus disease 2019 (COVID-19) and assessing extrapulmonary organs. Reduced muscle mass and visceral fat accumulation are important features of a body composition phenotype in which obesity and muscle loss coexist, but their relationship with COVID-19 outcomes remains unclear. In this study, we aimed to investigate the association between the erector spinae muscle (ESM) to epicardial adipose tissue (EAT) ratio (ESM/EAT) on chest CT and disease severity in patients with COVID-19.
Methods
We analysed data from 1074 COVID-19 patients enrolled in the Japan COVID-19 Task Force database. The primary outcome was the rate of critical outcomes (requiring high-flow oxygen therapy, invasive ventilator support or death). The incidence of critical outcomes was compared between patients with high and low ESM/EAT ratios.
Results
The low ESM/EAT group (n = 353) had a higher incidence of critical outcomes (13.3% vs. 5.13%, p < 0.001) and mortality (2.55% vs. 0.69%, p = 0.019) than the high ESM/EAT group (n = 721). In multivariable analysis, the low ESM/EAT ratio was associated with critical outcomes (adjusted odds ratio [aOR] 2.11, 95% confidence interval [CI] 1.22–3.66) independently of the known COVID-19 severity factors including age, sex, body mass index (BMI), smoking history, lifestyle-related comorbidities and pneumonia volume.
Conclusion
The low ESM/EAT ratio in COVID-19 patients can be obtained on chest CT and used to predict critical outcomes after disease onset, demonstrating the importance of detailed body composition assessments in COVID-19 practice.
{"title":"Erector Spinae Muscle to Epicardial Visceral Fat Ratio on Chest CT Predicts the Severity of Coronavirus Disease 2019","authors":"Takashi Shimada, Tomoki Maetani, Shotaro Chubachi, Naoya Tanabe, Takanori Asakura, Ho Namkoong, Hiromu Tanaka, Shuhei Azekawa, Shiro Otake, Kensuke Nakagawara, Takahiro Fukushima, Mayuko Watase, Yusuke Shiraishi, Hideki Terai, Mamoru Sasaki, Soichiro Ueda, Yukari Kato, Norihiro Harada, Shoji Suzuki, Shuichi Yoshida, Hiroki Tateno, Kaoruko Shimizu, Susumu Sato, Yoshitake Yamada, Masahiro Jinzaki, Toyohiro Hirai, Yukinori Okada, Ryuji Koike, Makoto Ishii, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga","doi":"10.1002/jcsm.13721","DOIUrl":"10.1002/jcsm.13721","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chest computed tomography (CT) is a valuable tool for diagnosing and predicting the severity of coronavirus disease 2019 (COVID-19) and assessing extrapulmonary organs. Reduced muscle mass and visceral fat accumulation are important features of a body composition phenotype in which obesity and muscle loss coexist, but their relationship with COVID-19 outcomes remains unclear. In this study, we aimed to investigate the association between the erector spinae muscle (ESM) to epicardial adipose tissue (EAT) ratio (ESM/EAT) on chest CT and disease severity in patients with COVID-19.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analysed data from 1074 COVID-19 patients enrolled in the Japan COVID-19 Task Force database. The primary outcome was the rate of critical outcomes (requiring high-flow oxygen therapy, invasive ventilator support or death). The incidence of critical outcomes was compared between patients with high and low ESM/EAT ratios.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The low ESM/EAT group (<i>n</i> = 353) had a higher incidence of critical outcomes (13.3% vs. 5.13%, <i>p</i> < 0.001) and mortality (2.55% vs. 0.69%, <i>p</i> = 0.019) than the high ESM/EAT group (<i>n</i> = 721). In multivariable analysis, the low ESM/EAT ratio was associated with critical outcomes (adjusted odds ratio [aOR] 2.11, 95% confidence interval [CI] 1.22–3.66) independently of the known COVID-19 severity factors including age, sex, body mass index (BMI), smoking history, lifestyle-related comorbidities and pneumonia volume.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The low ESM/EAT ratio in COVID-19 patients can be obtained on chest CT and used to predict critical outcomes after disease onset, demonstrating the importance of detailed body composition assessments in COVID-19 practice.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13721","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044706","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}
Salyan Bhattarai, Eva Kaufmann, Feng Liang, Yumin Zheng, Ekaterina Gusev, Qutayba Hamid, Jun Ding, Maziar Divangahi, Basil J. Petrof
<div> <section> <h3> Background</h3> <p>COVID-19 has been associated with both respiratory (diaphragm) and non-respiratory (limb) muscle atrophy. It is unclear if SARS-CoV-2 infection of skeletal muscle plays a role in these changes. This study sought to: 1) determine if cells comprising skeletal muscle tissue, particularly myofibres, express the molecular components required for SARS-CoV-2 infection; 2) assess the capacity for direct SARS-CoV-2 infection and its impact on atrophy pathway genes in myogenic cells; and 3) in an animal model of COVID-19, examine the relationship between viral infection of skeletal muscle and myofibre atrophy within the diaphragm and limb muscles.</p> </section> <section> <h3> Methods</h3> <p>We used in silico bioinformatics analysis of published human single cell RNA-seq datasets, as well as direct qPCR examination of human myotubes and diaphragm biopsies, to assess expression of key genes involved in SARS-CoV-2 cellular entry. In Vitro, we determined the ability of SARS-CoV-2 to directly infect myogenic cells and employed qPCR to assess the impact on muscle atrophy pathway genes (ubiquitin-proteasome, autophagy). In vivo, the diaphragm and quadriceps of Roborovski hamsters with SARS-CoV-2 respiratory infection were examined at day 3 post-inoculation to evaluate the relationship between atrophy pathway and SARS-CoV-2 transcripts by qPCR, as well as histological measurements of myofibre morphology.</p> </section> <section> <h3> Results</h3> <p>Angiotensin converting enzyme 2 (ACE2), the primary receptor for SARS-CoV-2, as well as cooperating proteases (furin, cathepsins B and L), are expressed by myofibres. ACE2 expression was increased 5-fold (<i>p</i> = 0.01) in the diaphragms of mechanically ventilated human subjects compared to controls. In Vitro, a time-dependent increase of SARS-CoV-2 transcript levels was observed in myotubes directly exposed to the virus (<i>p</i> = 0.002). This was associated with downregulation of the ubiquitin ligase MuRF1 (by 64%, <i>p</i> = 0.002) and the autophagy gene LC3B (by 31%, <i>p</i> = 0.009). In contrast, in vivo infection led to upregulation of MuRF1 in quadriceps (23-fold, <i>p</i> = 0.0007) and autophagy genes in both quadriceps (5.2-fold for Gabarapl1, <i>p</i> = 0.03; 7-fold for p62, <i>p</i> = 0.0002) and diaphragm (2.2-fold for Gabarapl1, <i>p</i> = 0.03; 2.3-fold for p62, <i>p</i> = 0.057). In infected hamsters the diaphragm lacked viral transcripts but exhibited atrophy (48% decrease in myofibre area; <i>p</i> = 0.02), whereas the quadriceps lacked myofibre atrophy despite elevated viral transcripts in the muscle.</p> </section> <s
{"title":"Characterization of SARS-CoV-2 Entry Genes in Skeletal Muscle and Impacts of In Vitro Versus In Vivo Infection","authors":"Salyan Bhattarai, Eva Kaufmann, Feng Liang, Yumin Zheng, Ekaterina Gusev, Qutayba Hamid, Jun Ding, Maziar Divangahi, Basil J. Petrof","doi":"10.1002/jcsm.13705","DOIUrl":"10.1002/jcsm.13705","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>COVID-19 has been associated with both respiratory (diaphragm) and non-respiratory (limb) muscle atrophy. It is unclear if SARS-CoV-2 infection of skeletal muscle plays a role in these changes. This study sought to: 1) determine if cells comprising skeletal muscle tissue, particularly myofibres, express the molecular components required for SARS-CoV-2 infection; 2) assess the capacity for direct SARS-CoV-2 infection and its impact on atrophy pathway genes in myogenic cells; and 3) in an animal model of COVID-19, examine the relationship between viral infection of skeletal muscle and myofibre atrophy within the diaphragm and limb muscles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used in silico bioinformatics analysis of published human single cell RNA-seq datasets, as well as direct qPCR examination of human myotubes and diaphragm biopsies, to assess expression of key genes involved in SARS-CoV-2 cellular entry. In Vitro, we determined the ability of SARS-CoV-2 to directly infect myogenic cells and employed qPCR to assess the impact on muscle atrophy pathway genes (ubiquitin-proteasome, autophagy). In vivo, the diaphragm and quadriceps of Roborovski hamsters with SARS-CoV-2 respiratory infection were examined at day 3 post-inoculation to evaluate the relationship between atrophy pathway and SARS-CoV-2 transcripts by qPCR, as well as histological measurements of myofibre morphology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Angiotensin converting enzyme 2 (ACE2), the primary receptor for SARS-CoV-2, as well as cooperating proteases (furin, cathepsins B and L), are expressed by myofibres. ACE2 expression was increased 5-fold (<i>p</i> = 0.01) in the diaphragms of mechanically ventilated human subjects compared to controls. In Vitro, a time-dependent increase of SARS-CoV-2 transcript levels was observed in myotubes directly exposed to the virus (<i>p</i> = 0.002). This was associated with downregulation of the ubiquitin ligase MuRF1 (by 64%, <i>p</i> = 0.002) and the autophagy gene LC3B (by 31%, <i>p</i> = 0.009). In contrast, in vivo infection led to upregulation of MuRF1 in quadriceps (23-fold, <i>p</i> = 0.0007) and autophagy genes in both quadriceps (5.2-fold for Gabarapl1, <i>p</i> = 0.03; 7-fold for p62, <i>p</i> = 0.0002) and diaphragm (2.2-fold for Gabarapl1, <i>p</i> = 0.03; 2.3-fold for p62, <i>p</i> = 0.057). In infected hamsters the diaphragm lacked viral transcripts but exhibited atrophy (48% decrease in myofibre area; <i>p</i> = 0.02), whereas the quadriceps lacked myofibre atrophy despite elevated viral transcripts in the muscle.</p>\u0000 </section>\u0000 \u0000 <s","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13705","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050807","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}
Viola Viola, Tagari Samanta, Maria Liza Duremdes Nava, Alessandra Celli, Reina Armamento-Villareal, Ngoc Ho Lam Nguyen, Georgia Colleluori, Yoann Barnouin, Nicola Napoli, Clifford Qualls, Benny Abraham Kaipparettu, Dennis T. Villareal
<div> <section> <h3> Background</h3> <p>Testosterone replacement therapy (TRT) added to lifestyle therapy can mitigate weight-loss–induced reduction of muscle mass and bone mineral density (BMD) in older men with obesity and hypogonadism.</p> </section> <section> <h3> Objective</h3> <p>To investigate the molecular mechanisms underlying the attenuation of muscle and BMD loss in response to TRT during intensive lifestyle intervention in this high-risk older population.</p> </section> <section> <h3> Methods</h3> <p>Among 83 older (≥ 65 years) men with obesity (BMI ≥ 30 kg/m<sup>2</sup>) and hypogonadism (early AM testosterone persistently < 300 ng/dL) associated with frailty (Modified Physical Performance Test score ≤ 31) randomized into 26-week lifestyle therapy plus testosterone (LT+TRT) or placebo (LT+Pbo) in the LITROS trial, 38 underwent serial muscle biopsies for the muscle transcriptomics substudy.</p> </section> <section> <h3> Results</h3> <p>Despite similar ~10% weight loss, lean body mass and thigh muscle volume decreased less in LT+TRT than LT+Pbo (−2% vs. −4%, respectively; <i>p</i> = 0.04). Hip BMD was preserved in LT+TRT compared with LT+Pbo (0.4% vs. −1.3%; <i>p</i> = 0.03). Muscle strength increased similarly in LT+TRT and LT+Pbo (23% vs. 24%; <i>p</i> = 0.95). Total testosterone increased more in LT+TRT than LT+Pbo (133% vs. 32%; <i>p</i> = 0.005). Based on Next Generation Sequencing, of the 39 160 and 39 115 genes detected in LT+TRT and LT+Pbo, respectively, 195 were differentially expressed in LT+TRT and 158 in LT+Pbo. Gene Ontology enrichment analyses revealed that in LT+TRT, just four muscle-related pathways (muscle organ development, muscle organ morphogenesis, regulation of skeletal muscle contraction, muscle atrophy) were downregulated and one pathway (muscle system process) was upregulated. In contrast, in LT+Pbo, nine muscle-related pathways (muscle system process, muscle tissue development, muscle organ development, skeletal muscle tissue development, skeletal muscle organ development, skeletal muscle cell differentiation, muscle organ morphogenesis, response to stimuli involved in regulation of muscle adaptation, muscle atrophy) and one pathway related to bone (bone mineralization involved in bone maturation) were downregulated. Muscle system process was upregulated in LT+TRT but downregulated in LT+Pbo. RT-PCR analyses showed that LT+TRT resulted in a higher expression of MYOD1 (<i>p</i> = 0.02) and WNT4 (<i>p</i> = 0.02), key genes involved in muscle and bone metabolism, respectively, compared with LT+Pbo. We also obse
{"title":"Testosterone Modulation of Muscle Transcriptomic Profile During Lifestyle Therapy in Older Men with Obesity and Hypogonadism","authors":"Viola Viola, Tagari Samanta, Maria Liza Duremdes Nava, Alessandra Celli, Reina Armamento-Villareal, Ngoc Ho Lam Nguyen, Georgia Colleluori, Yoann Barnouin, Nicola Napoli, Clifford Qualls, Benny Abraham Kaipparettu, Dennis T. Villareal","doi":"10.1002/jcsm.13697","DOIUrl":"10.1002/jcsm.13697","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Testosterone replacement therapy (TRT) added to lifestyle therapy can mitigate weight-loss–induced reduction of muscle mass and bone mineral density (BMD) in older men with obesity and hypogonadism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To investigate the molecular mechanisms underlying the attenuation of muscle and BMD loss in response to TRT during intensive lifestyle intervention in this high-risk older population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Among 83 older (≥ 65 years) men with obesity (BMI ≥ 30 kg/m<sup>2</sup>) and hypogonadism (early AM testosterone persistently < 300 ng/dL) associated with frailty (Modified Physical Performance Test score ≤ 31) randomized into 26-week lifestyle therapy plus testosterone (LT+TRT) or placebo (LT+Pbo) in the LITROS trial, 38 underwent serial muscle biopsies for the muscle transcriptomics substudy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Despite similar ~10% weight loss, lean body mass and thigh muscle volume decreased less in LT+TRT than LT+Pbo (−2% vs. −4%, respectively; <i>p</i> = 0.04). Hip BMD was preserved in LT+TRT compared with LT+Pbo (0.4% vs. −1.3%; <i>p</i> = 0.03). Muscle strength increased similarly in LT+TRT and LT+Pbo (23% vs. 24%; <i>p</i> = 0.95). Total testosterone increased more in LT+TRT than LT+Pbo (133% vs. 32%; <i>p</i> = 0.005). Based on Next Generation Sequencing, of the 39 160 and 39 115 genes detected in LT+TRT and LT+Pbo, respectively, 195 were differentially expressed in LT+TRT and 158 in LT+Pbo. Gene Ontology enrichment analyses revealed that in LT+TRT, just four muscle-related pathways (muscle organ development, muscle organ morphogenesis, regulation of skeletal muscle contraction, muscle atrophy) were downregulated and one pathway (muscle system process) was upregulated. In contrast, in LT+Pbo, nine muscle-related pathways (muscle system process, muscle tissue development, muscle organ development, skeletal muscle tissue development, skeletal muscle organ development, skeletal muscle cell differentiation, muscle organ morphogenesis, response to stimuli involved in regulation of muscle adaptation, muscle atrophy) and one pathway related to bone (bone mineralization involved in bone maturation) were downregulated. Muscle system process was upregulated in LT+TRT but downregulated in LT+Pbo. RT-PCR analyses showed that LT+TRT resulted in a higher expression of MYOD1 (<i>p</i> = 0.02) and WNT4 (<i>p</i> = 0.02), key genes involved in muscle and bone metabolism, respectively, compared with LT+Pbo. We also obse","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13697","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044274","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}
Georgios Kararigas, Mara C. Ebeling, Gengyun Le, Shaojuan Lai, Chunmei Cui, Qinghua Cui, Dawn A. Lowe
Background
With a decline of 17β-estradiol (E2) at menopause, E2 has been implicated in the accompanied loss of skeletal muscle mass and strength. We aimed at characterizing transcriptomic responses of skeletal muscle to E2 in female mice, testing the hypothesis that genes and pathways related to contraction and maintenance of mass are differentially expressed in ovariectomized mice with and without E2 treatment.
Methods
Soleus and tibialis anterior (TA) muscles from C57BL/6 ovariectomized mice treated with placebo (OVX) or E2 (OVX + E2) for 60 days, or from skeletal muscle-specific ERα knockout (skmERαKO) mice and wild-type littermates (skmERαWT), were used for genome-wide expression profiling, quantitative real-time PCR and immunoblotting. Computational detection of estrogen response elements (EREs) was performed with EREFINDER.
Results
We found 155 significantly regulated probe sets in response to E2 (p ≤ 0.001). Pathway analyses identified proteasome and ubiquitin-mediated proteolysis as two downregulated pathways in the E2 group. We confirmed downregulation (p ≤ 0.05) in levels of Fbxw7, Psmb6, Ube2h and Ubxn1, as well as pro-apoptotic Bnip3 and inflammatory factor Nfkbia. Computational analysis identified ERE in the promoter regions of Psmb6, Ube2h, Bnip3 and Nfkbia. The overall content of ubiquitinated proteins was modestly but significantly lower in TA muscles from OVX + E2 vs. OVX mice (p = 0.039). There were no differences between skmERαKO and skmERαWT mice or between skmERαKO/OVX and skmERαKO/OVX + E2 mice for any genes assessed, indicating that ERα is required for E2 regulation of those genes.
Conclusions
These results suggest that a mechanism whereby E2 protects against losses of skeletal muscle mass and strength is regulation of ubiquitin-proteasomal mediators.
{"title":"Transcriptomic Profiling Reveals 17β-Estradiol Treatment Represses Ubiquitin-Proteasomal Mediators in Skeletal Muscle of Ovariectomized Mice","authors":"Georgios Kararigas, Mara C. Ebeling, Gengyun Le, Shaojuan Lai, Chunmei Cui, Qinghua Cui, Dawn A. Lowe","doi":"10.1002/jcsm.13698","DOIUrl":"10.1002/jcsm.13698","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>With a decline of 17β-estradiol (E2) at menopause, E2 has been implicated in the accompanied loss of skeletal muscle mass and strength. We aimed at characterizing transcriptomic responses of skeletal muscle to E2 in female mice, testing the hypothesis that genes and pathways related to contraction and maintenance of mass are differentially expressed in ovariectomized mice with and without E2 treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Soleus and tibialis anterior (TA) muscles from C57BL/6 ovariectomized mice treated with placebo (OVX) or E2 (OVX + E2) for 60 days, or from skeletal muscle-specific ERα knockout (skmERαKO) mice and wild-type littermates (skmERαWT), were used for genome-wide expression profiling, quantitative real-time PCR and immunoblotting. Computational detection of estrogen response elements (EREs) was performed with EREFINDER.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found 155 significantly regulated probe sets in response to E2 (<i>p</i> ≤ 0.001). Pathway analyses identified proteasome and ubiquitin-mediated proteolysis as two downregulated pathways in the E2 group. We confirmed downregulation (<i>p</i> ≤ 0.05) in levels of <i>Fbxw7</i>, <i>Psmb6</i>, <i>Ube2h</i> and <i>Ubxn1</i>, as well as pro-apoptotic <i>Bnip3</i> and inflammatory factor <i>Nfkbia</i>. Computational analysis identified ERE in the promoter regions of <i>Psmb6</i>, <i>Ube2h</i>, <i>Bnip3</i> and <i>Nfkbia</i>. The overall content of ubiquitinated proteins was modestly but significantly lower in TA muscles from OVX + E2 vs. OVX mice (<i>p</i> = 0.039). There were no differences between skmERαKO and skmERαWT mice or between skmERαKO/OVX and skmERαKO/OVX + E2 mice for any genes assessed, indicating that ERα is required for E2 regulation of those genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These results suggest that a mechanism whereby E2 protects against losses of skeletal muscle mass and strength is regulation of ubiquitin-proteasomal mediators.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13698","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030925","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}
Diaphragm thickness is a potential marker of sarcopenia in addition to muscle mass and strength at extremities. We aimed to clarify the descriptive epidemiology and prognostic significance of diaphragm thickness in the general population.
Methods
The study participants were 3324 community residents (mean age: 61.4 ± 12.8 years) who participated in a longitudinal cohort study. Clinical parameters were obtained during the follow-up survey of the study population. Diaphragm thickness was measured from B-mode ultrasound images obtained in a supine position. Clinical and physical factors independently associated with diaphragm thickness were assessed by a linear regression model and a causal mediation analysis. All-cause mortality was determined by reviewing residential registry records. Prognostic significance of diaphragm thickness for all-cause mortality was examined using a Cox proportional hazard model analysis.
Results
Diaphragm thickness was greater in men than women (end-expiration, β = 0.161, p < 0.001; end-inspiration, β = 0.156, p < 0.001) and associated with waist circumference (end-expiration, β = 0.259, p < 0.001; end-inspiration, β = 0.128, p < 0.001). Handgrip strength, smoking habit, insulin resistance and exercise habit were not associated with diaphragm thickness. Skeletal muscle mass index showed apparent association with diaphragm thickness, though this association was not observed after adjusting for waist circumference. Over a mean follow-up of 1686 days (15 358 person-years), there were 56 cases of all-cause mortality. Weak handgrip strength (hazard ratio = 0.95, p = 0.044) and low forced vital capacity (hazard ratio = 0.57, p = 0.045) were associated with all-cause mortality, though none of the diaphragm thickness parameters showed a significant association (thickness at end-expiration, p = 0.722; thickness at end-inspiration, p = 0.277; thickening fraction, p = 0.219).
Conclusions
Waist circumference but not parameters of sarcopenia was independently associated with diaphragm thickness. Diaphragm thickness was not associated with all-cause mortality. Diaphragm thickness may not be a marker of systemic sarcopenia.
{"title":"Descriptive Epidemiology and Prognostic Significance of Diaphragm Thickness in the General Population: The Nagahama Study","authors":"Yasuharu Tabara, Takeshi Matsumoto, Kimihiko Murase, Takahisa Kawaguchi, Kazuya Setoh, Tomoko Wakamura, Toyohiro Hirai, Kazuo Chin, Fumihiko Matsuda","doi":"10.1002/jcsm.13690","DOIUrl":"10.1002/jcsm.13690","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Diaphragm thickness is a potential marker of sarcopenia in addition to muscle mass and strength at extremities. We aimed to clarify the descriptive epidemiology and prognostic significance of diaphragm thickness in the general population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The study participants were 3324 community residents (mean age: 61.4 ± 12.8 years) who participated in a longitudinal cohort study. Clinical parameters were obtained during the follow-up survey of the study population. Diaphragm thickness was measured from B-mode ultrasound images obtained in a supine position. Clinical and physical factors independently associated with diaphragm thickness were assessed by a linear regression model and a causal mediation analysis. All-cause mortality was determined by reviewing residential registry records. Prognostic significance of diaphragm thickness for all-cause mortality was examined using a Cox proportional hazard model analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Diaphragm thickness was greater in men than women (end-expiration, β = 0.161, <i>p</i> < 0.001; end-inspiration, β = 0.156, <i>p</i> < 0.001) and associated with waist circumference (end-expiration, β = 0.259, <i>p</i> < 0.001; end-inspiration, β = 0.128, <i>p</i> < 0.001). Handgrip strength, smoking habit, insulin resistance and exercise habit were not associated with diaphragm thickness. Skeletal muscle mass index showed apparent association with diaphragm thickness, though this association was not observed after adjusting for waist circumference. Over a mean follow-up of 1686 days (15 358 person-years), there were 56 cases of all-cause mortality. Weak handgrip strength (hazard ratio = 0.95, <i>p</i> = 0.044) and low forced vital capacity (hazard ratio = 0.57, <i>p</i> = 0.045) were associated with all-cause mortality, though none of the diaphragm thickness parameters showed a significant association (thickness at end-expiration, <i>p</i> = 0.722; thickness at end-inspiration, <i>p</i> = 0.277; thickening fraction, <i>p</i> = 0.219).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Waist circumference but not parameters of sarcopenia was independently associated with diaphragm thickness. Diaphragm thickness was not associated with all-cause mortality. Diaphragm thickness may not be a marker of systemic sarcopenia.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13690","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030924","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}
Mitja Lainscak, Tina Zupanic, Daniel Omersa, Ivan Erzen, Jerneja Farkas
Background
Cachexia is a frequent companion of chronic diseases and a well-established predictor of poor patient performance and outcome. Since cachexia as a discharge diagnosis is not much investigated, we aimed to investigate prevalence of cachexia in hospitalised patients and their outcome.
Methods
We conducted a retrospective analysis of the National Hospital Health Care Statistics Database using the 10th revision of the International Classification of Diseases codes. During period 2004–2019, patients with cachexia were identified, as well as patients with cancer, heart failure, chronic obstructive pulmonary disease and chronic kidney disease. The primary endpoint was the discharge code of cachexia; secondary endpoints were length of hospital stay, in-hospital and post discharge all-cause mortality.
Results
In period 2004–2019, 5 484 103 hospitalisations were screened; cachexia was coded 19 348 times (0.35%) in 14 089 patients (67 ± 13 years, 42% women). From 2004 to 2019, prevalence of cachexia increased steadily from 1.2% to 1.9%, which was most prominent for cancer and chronic obstructive pulmonary disease. At one year post discharge, 49% patients with cachexia were dead as compared to 26% in patients without cachexia. In Cox multivariate analysis, cachexia predicted post-discharge death in any of chronic diseases (hazard ratio of 1.28 in heart failure to 1.47 in chronic kidney disease).
Conclusions
In our report from a National Hospital Health Care Statistics Database, we found that cachexia was underreported as ICD-10 coded discharge diagnosis in patients with chronic diseases. When diagnosed, it was associated with higher hazard of post discharge mortality.
{"title":"Prevalence of Cachexia and Outcomes in Patients With Chronic Diseases: A National Database Analysis of 5 484 103 Hospitalisations","authors":"Mitja Lainscak, Tina Zupanic, Daniel Omersa, Ivan Erzen, Jerneja Farkas","doi":"10.1002/jcsm.13688","DOIUrl":"10.1002/jcsm.13688","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cachexia is a frequent companion of chronic diseases and a well-established predictor of poor patient performance and outcome. Since cachexia as a discharge diagnosis is not much investigated, we aimed to investigate prevalence of cachexia in hospitalised patients and their outcome.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a retrospective analysis of the National Hospital Health Care Statistics Database using the 10th revision of the International Classification of Diseases codes. During period 2004–2019, patients with cachexia were identified, as well as patients with cancer, heart failure, chronic obstructive pulmonary disease and chronic kidney disease. The primary endpoint was the discharge code of cachexia; secondary endpoints were length of hospital stay, in-hospital and post discharge all-cause mortality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In period 2004–2019, 5 484 103 hospitalisations were screened; cachexia was coded 19 348 times (0.35%) in 14 089 patients (67 ± 13 years, 42% women). From 2004 to 2019, prevalence of cachexia increased steadily from 1.2% to 1.9%, which was most prominent for cancer and chronic obstructive pulmonary disease. At one year post discharge, 49% patients with cachexia were dead as compared to 26% in patients without cachexia. In Cox multivariate analysis, cachexia predicted post-discharge death in any of chronic diseases (hazard ratio of 1.28 in heart failure to 1.47 in chronic kidney disease).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In our report from a National Hospital Health Care Statistics Database, we found that cachexia was underreported as ICD-10 coded discharge diagnosis in patients with chronic diseases. When diagnosed, it was associated with higher hazard of post discharge mortality.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13688","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990556","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}
Pauline Parent, Frédéric Pigneur, Marc Hilmi, Aurélien Carnot, Marie-Line Garcia Larnicol, Dewi Vernerey, Alain Luciani, Pascal Hammel, Julie Henriques, Cindy Neuzillet, Anthony Turpin
<div> <section> <h3> Background</h3> <p>Advanced pancreatic ductal adenocarcinoma (aPDAC) is often accompanied by significant muscle mass loss, contributing to poor prognosis. SarcAPACaP, an ancillary study of the GERCOR-APACaP phase III trial, evaluated the role of adapted physical activity (APA) in aPDAC Western patients receiving first-line chemotherapy. The study aimed to assess (1) the potential impact of computed tomography (CT)–quantified muscle mass before and during treatments on health-related quality of life (HRQoL) and overall survival (OS) and (2) the role of APA in mitigating muscle mass loss.</p> </section> <section> <h3> Methods</h3> <p>In the APACaP trial, aPDAC patients with ECOG performance status (PS) 0–2 were randomized 1:1 to usual care including first-line chemotherapy or usual care plus a 16-week home-based APA program. In the SarcAPACaP study, the surface muscular index (SMI) was determined from L3 CT scan slices. Two patient populations were analysed: those with CT scan available at baseline (modified[m] intent-to-treat [ITT]1-W0) and those with CT scans available at both W0 and W16 (mITT2 W0–W16). Low muscle mass was defined by low SMI with SMI < 41 cm<sup>2</sup>/m<sup>2</sup> for women and < 43 and < 53 cm<sup>2</sup>/m<sup>2</sup> for men with body max index < 25.0 and ≥ 25.0 kg/m<sup>2</sup>, respectively. Muscle loss was defined by the relative difference of SMI between W0 and W16 (100*[SMI W16–SMI W0]/SMI W0). In mITT2 W0–W16, patients were stratified into three groups based on the severity of muscle loss: none, moderate (0%–10%) and high (≥ 10%). Associations between muscle mass loss and OS, time until definitive deterioration (TUDD) of HRQoL and the effect of APA on loss of muscle mass were assessed.</p> </section> <section> <h3> Results</h3> <p>Between October 2014 and May 2020, 313 patients were prospectively enrolled, with 225 in mITT1 W0 and 128 in mITT2 W0–W16, with 65 assigned to the APA arm. Both groups had similar baseline characteristics with comparable OS and TUDD. A low SMI at W0 was not associated with OS and TUDD of HRQoL in either group. Among mITT2 W0–W16 patients, high muscle mass loss (<i>n</i> = 27) independently predicted OS (<i>p</i> = 0.012) and showed a trend toward negatively affecting TUDD of HRQoL. Notably, APA did not mitigate muscle loss in our study population.</p> </section> <section> <h3> Conclusions</h3> <p>Longitudinal muscle mass loss emerged as a predictive factor for both OS and HRQoL in aPDAC patients undergoing chemotherapy, while a low SMI at diagnosis did not prov
{"title":"Muscle Loss During First-Line Chemotherapy Impairs Survival in Advanced Pancreatic Cancer Despite Adapted Physical Activity","authors":"Pauline Parent, Frédéric Pigneur, Marc Hilmi, Aurélien Carnot, Marie-Line Garcia Larnicol, Dewi Vernerey, Alain Luciani, Pascal Hammel, Julie Henriques, Cindy Neuzillet, Anthony Turpin","doi":"10.1002/jcsm.13595","DOIUrl":"10.1002/jcsm.13595","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Advanced pancreatic ductal adenocarcinoma (aPDAC) is often accompanied by significant muscle mass loss, contributing to poor prognosis. SarcAPACaP, an ancillary study of the GERCOR-APACaP phase III trial, evaluated the role of adapted physical activity (APA) in aPDAC Western patients receiving first-line chemotherapy. The study aimed to assess (1) the potential impact of computed tomography (CT)–quantified muscle mass before and during treatments on health-related quality of life (HRQoL) and overall survival (OS) and (2) the role of APA in mitigating muscle mass loss.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In the APACaP trial, aPDAC patients with ECOG performance status (PS) 0–2 were randomized 1:1 to usual care including first-line chemotherapy or usual care plus a 16-week home-based APA program. In the SarcAPACaP study, the surface muscular index (SMI) was determined from L3 CT scan slices. Two patient populations were analysed: those with CT scan available at baseline (modified[m] intent-to-treat [ITT]1-W0) and those with CT scans available at both W0 and W16 (mITT2 W0–W16). Low muscle mass was defined by low SMI with SMI < 41 cm<sup>2</sup>/m<sup>2</sup> for women and < 43 and < 53 cm<sup>2</sup>/m<sup>2</sup> for men with body max index < 25.0 and ≥ 25.0 kg/m<sup>2</sup>, respectively. Muscle loss was defined by the relative difference of SMI between W0 and W16 (100*[SMI W16–SMI W0]/SMI W0). In mITT2 W0–W16, patients were stratified into three groups based on the severity of muscle loss: none, moderate (0%–10%) and high (≥ 10%). Associations between muscle mass loss and OS, time until definitive deterioration (TUDD) of HRQoL and the effect of APA on loss of muscle mass were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Between October 2014 and May 2020, 313 patients were prospectively enrolled, with 225 in mITT1 W0 and 128 in mITT2 W0–W16, with 65 assigned to the APA arm. Both groups had similar baseline characteristics with comparable OS and TUDD. A low SMI at W0 was not associated with OS and TUDD of HRQoL in either group. Among mITT2 W0–W16 patients, high muscle mass loss (<i>n</i> = 27) independently predicted OS (<i>p</i> = 0.012) and showed a trend toward negatively affecting TUDD of HRQoL. Notably, APA did not mitigate muscle loss in our study population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Longitudinal muscle mass loss emerged as a predictive factor for both OS and HRQoL in aPDAC patients undergoing chemotherapy, while a low SMI at diagnosis did not prov","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13595","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988834","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}
Victoria J. Old, Melanie J. Davies, Dimitris Papamargaritis, Pratik Choudhary, Emma L. Watson
<div> <section> <h3> Background</h3> <p>Obesity is a chronic disease associated with increased risk of multiple metabolic and mental health–related comorbidities. Recent advances in obesity pharmacotherapy, particularly with glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), have the potential to transform obesity and type 2 diabetes mellitus (T2DM) care by promoting marked weight loss, improving glycaemic control and addressing multiple obesity-related comorbidities, with added cardio-renal benefits. Dual agonists combining GLP-1 with other enteropancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP) have also been developed in recent years, leading to greater weight loss than using GLP-1 RAs alone. However, up to 40% of the weight lost with GLP-1 RAs comes from lean body mass, raising concerns about potential adverse effects on skeletal muscle function. Mitochondrial dysfunction, characterized by reduced mitochondrial size and activity, is prevalent in individuals with obesity and T2DM and is a known contributor to muscle wasting in ageing and some chronic diseases. This systematic review investigates the impact of GLP-1-based therapies on skeletal muscle mitochondrial function in individuals with obesity and T2DM or in related animal and cell models.</p> </section> <section> <h3> Methods</h3> <p>A comprehensive search of MEDLINE, Scopus, CINAHL and clinicaltrials.gov was conducted. Inclusion criteria included randomized controlled trials, randomized crossover trials, cluster randomized control trials and basic science studies involving any GLP-1 RA or GLP-1/GIP dual agonist. Outcomes of interest were skeletal muscle respiratory function either in the form of measurements of mass, number, content, oxidative capacity/respiratory function, mitochondrial dynamics, mitochondrial biogenesis and mitophagy.</p> </section> <section> <h3> Results</h3> <p>Eight studies were eligible for analysis; no human studies were identified. All of the included studies used GLP-1 RAs (single agonists) as intervention. The emerging evidence suggests that GLP-1 RAs increase mitochondrial area, number and morphology (i.e., reduces swelling). Data are conflicting on the effect of GLP-1 RAs upon mitochondrial mass, respiration and the expression of uncoupling proteins and PGC-1α. Data also demonstrate muscle specific (i.e., soleus vs. extensor digitorum longus) responses to GLP-1 RAs.</p> </section> <section> <h3> Conclusion</h3> <p>GLP-1 RAs appear to have a positive effect upon mitochondria area, number and morphology, but effects upon other
{"title":"The Effects of Glucagon-Like Peptide-1 Receptor Agonists on Mitochondrial Function Within Skeletal Muscle: A Systematic Review","authors":"Victoria J. Old, Melanie J. Davies, Dimitris Papamargaritis, Pratik Choudhary, Emma L. Watson","doi":"10.1002/jcsm.13677","DOIUrl":"10.1002/jcsm.13677","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Obesity is a chronic disease associated with increased risk of multiple metabolic and mental health–related comorbidities. Recent advances in obesity pharmacotherapy, particularly with glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), have the potential to transform obesity and type 2 diabetes mellitus (T2DM) care by promoting marked weight loss, improving glycaemic control and addressing multiple obesity-related comorbidities, with added cardio-renal benefits. Dual agonists combining GLP-1 with other enteropancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP) have also been developed in recent years, leading to greater weight loss than using GLP-1 RAs alone. However, up to 40% of the weight lost with GLP-1 RAs comes from lean body mass, raising concerns about potential adverse effects on skeletal muscle function. Mitochondrial dysfunction, characterized by reduced mitochondrial size and activity, is prevalent in individuals with obesity and T2DM and is a known contributor to muscle wasting in ageing and some chronic diseases. This systematic review investigates the impact of GLP-1-based therapies on skeletal muscle mitochondrial function in individuals with obesity and T2DM or in related animal and cell models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A comprehensive search of MEDLINE, Scopus, CINAHL and clinicaltrials.gov was conducted. Inclusion criteria included randomized controlled trials, randomized crossover trials, cluster randomized control trials and basic science studies involving any GLP-1 RA or GLP-1/GIP dual agonist. Outcomes of interest were skeletal muscle respiratory function either in the form of measurements of mass, number, content, oxidative capacity/respiratory function, mitochondrial dynamics, mitochondrial biogenesis and mitophagy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Eight studies were eligible for analysis; no human studies were identified. All of the included studies used GLP-1 RAs (single agonists) as intervention. The emerging evidence suggests that GLP-1 RAs increase mitochondrial area, number and morphology (i.e., reduces swelling). Data are conflicting on the effect of GLP-1 RAs upon mitochondrial mass, respiration and the expression of uncoupling proteins and PGC-1α. Data also demonstrate muscle specific (i.e., soleus vs. extensor digitorum longus) responses to GLP-1 RAs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>GLP-1 RAs appear to have a positive effect upon mitochondria area, number and morphology, but effects upon other","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13677","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986196","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}
Steven D. Tran, Noah J. Forrest, Vijeeth Guggilla, Geovanni M. Perottino, Jodi L. Johnson, Jeffrey Sosman, Ishan Roy, Theresa L. Walunas
<div> <section> <h3> Background</h3> <p>Cancer-associated cachexia can inhibit immune checkpoint inhibitor (ICI) therapy efficacy. Cachexia's effect on ICI therapy has not been studied in large cohorts of cancer patients aside from lung cancer. We studied associations between real-world routinely collected clinical cachexia markers and disability-free, hospitalization-free and overall survival of cancer patients.</p> </section> <section> <h3> Methods</h3> <p>A retrospective study was conducted of electronic health records (EHR) of patients with lung, renal cell, melanoma and other cancers treated with ICI therapy at Northwestern Medicine of Chicago, IL, United States, between March 2011 and January 2022. Weight, body mass index, absolute neutrophil and lymphocyte counts, albumin and C-reactive protein (CRP) measures were analysed to calculate the Fearon consensus criteria for cachexia, weight loss grading system (WLGS) score, neutrophil-lymphocyte ratio (NLR), Prognostic Nutritional Index (PNI) and modified Glasgow Prognostic Score (mGPS) at ICI therapy initiation. Kaplan–Meier and Cox proportional hazards analyses were used to determine associations between these metrics and disability-free, hospitalization-free and overall survival.</p> </section> <section> <h3> Results</h3> <p>EHR analysis uncovered 3285 cancer patients on ICI therapy (54% > 65 years of age, 50.7% male, 77.7% White). At ICI therapy initiation, 1282 (39.0%) patients had cachexia (consensus criteria), 1641 (50.0%) had a WLGS score ≥ 2, 1806 (55.0%) had an NLR > 3, 1087 (33.1%) had albumin < 3.5 g/dL and 1318 (40.1%) had a PNI < 44. Missing measurements included CRP missing for 98.2% and mGPS missing for 98.6% of patients. Disability-free (<i>n</i> = 1373), hospitalization-free (<i>n</i> = 2374) and overall survival (<i>n</i> = 1599) events were analysed with 1-year rates of 65% (64%–67%), 35% (34%–37%) and 65% (63%–66%), respectively. Multivariate Cox model analyses showed hazard ratios (HR) for cachexia at 1.58 (95% CI 1.38–1.80), 1.47 (95% CI 1.33–1.63) and 1.97 (95% CI 1.75–2.23) for disability, hospitalization and death, respectively. HRs for WLGS ≥ 2 were 1.45 (95% CI 1.28–1.66), 1.37 (95% CI 1.24–1.51) and 1.91 (95% CI 1.69–2.17). HRs for NLR > 3 were 1.57 (95% CI 1.35–1.83), 1.40 (95% CI 1.25–1.58) and 1.95 (95% CI 1.67–2.27). HRs for albumin < 3.5 g/dL were 1.33 (95% CI 1.15–1.54), 1.67 (95% CI 1.50–1.86) and 2.09 (95% CI 1.84–2.36). HRs for PNI < 44 were 1.60 (95% CI 1.39–1.84), 1.46 (95% CI 1.31–1.63) and 2.07 (95% CI 1.80–2.37).</p> </section> <section> <h3> Conclusions</h3>
{"title":"Weight and Blood-Based Markers of Cachexia Predict Disability, Hospitalization and Worse Survival in Cancer Immunotherapy Patients","authors":"Steven D. Tran, Noah J. Forrest, Vijeeth Guggilla, Geovanni M. Perottino, Jodi L. Johnson, Jeffrey Sosman, Ishan Roy, Theresa L. Walunas","doi":"10.1002/jcsm.13685","DOIUrl":"10.1002/jcsm.13685","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cancer-associated cachexia can inhibit immune checkpoint inhibitor (ICI) therapy efficacy. Cachexia's effect on ICI therapy has not been studied in large cohorts of cancer patients aside from lung cancer. We studied associations between real-world routinely collected clinical cachexia markers and disability-free, hospitalization-free and overall survival of cancer patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A retrospective study was conducted of electronic health records (EHR) of patients with lung, renal cell, melanoma and other cancers treated with ICI therapy at Northwestern Medicine of Chicago, IL, United States, between March 2011 and January 2022. Weight, body mass index, absolute neutrophil and lymphocyte counts, albumin and C-reactive protein (CRP) measures were analysed to calculate the Fearon consensus criteria for cachexia, weight loss grading system (WLGS) score, neutrophil-lymphocyte ratio (NLR), Prognostic Nutritional Index (PNI) and modified Glasgow Prognostic Score (mGPS) at ICI therapy initiation. Kaplan–Meier and Cox proportional hazards analyses were used to determine associations between these metrics and disability-free, hospitalization-free and overall survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>EHR analysis uncovered 3285 cancer patients on ICI therapy (54% > 65 years of age, 50.7% male, 77.7% White). At ICI therapy initiation, 1282 (39.0%) patients had cachexia (consensus criteria), 1641 (50.0%) had a WLGS score ≥ 2, 1806 (55.0%) had an NLR > 3, 1087 (33.1%) had albumin < 3.5 g/dL and 1318 (40.1%) had a PNI < 44. Missing measurements included CRP missing for 98.2% and mGPS missing for 98.6% of patients. Disability-free (<i>n</i> = 1373), hospitalization-free (<i>n</i> = 2374) and overall survival (<i>n</i> = 1599) events were analysed with 1-year rates of 65% (64%–67%), 35% (34%–37%) and 65% (63%–66%), respectively. Multivariate Cox model analyses showed hazard ratios (HR) for cachexia at 1.58 (95% CI 1.38–1.80), 1.47 (95% CI 1.33–1.63) and 1.97 (95% CI 1.75–2.23) for disability, hospitalization and death, respectively. HRs for WLGS ≥ 2 were 1.45 (95% CI 1.28–1.66), 1.37 (95% CI 1.24–1.51) and 1.91 (95% CI 1.69–2.17). HRs for NLR > 3 were 1.57 (95% CI 1.35–1.83), 1.40 (95% CI 1.25–1.58) and 1.95 (95% CI 1.67–2.27). HRs for albumin < 3.5 g/dL were 1.33 (95% CI 1.15–1.54), 1.67 (95% CI 1.50–1.86) and 2.09 (95% CI 1.84–2.36). HRs for PNI < 44 were 1.60 (95% CI 1.39–1.84), 1.46 (95% CI 1.31–1.63) and 2.07 (95% CI 1.80–2.37).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13685","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987122","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}
Daria Neyroud, Andrew C. D'Lugos, Enrique J. Trevino, Chandler S. Callaway, Jacqueline Lamm, Orlando Laitano, Brittney Poole, Michael R. Deyhle, Justina Brantley, Lam Le, Andrew R. Judge, Sarah M. Judge
<div> <section> <h3> Background</h3> <p>Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer-related deaths, with deterioration of respiratory muscles suspected to be a key contributor to cachexia-associated morbidity and mortality. In recent studies, we identified fibrotic remodelling of respiratory accessory muscles as a key feature of human PDAC cachexia.</p> </section> <section> <h3> Methods</h3> <p>To gain insight into mechanisms driving respiratory muscle wasting and fibrotic remodelling in response to PDAC, we conducted temporal histological and transcriptomic analyses on diaphragm muscles harvested from mice-bearing orthotopic murine pancreatic (KPC) tumours at time points reflective of precachexia (D8 and D10), mild–moderate cachexia (D12 and D14) and advanced cachexia (endpoint).</p> </section> <section> <h3> Results</h3> <p>During the precachexia phase, diaphragms showed significant leukocyte infiltration (+3-fold to +13-fold; D8—endpoint vs. Sham, <i>p</i> < 0.05) and transcriptomic enrichment of inflammatory processes associated with tissue injury that remained increased through endpoint. Diaphragm inflammation was followed by increases in PDGFR-ɑ<sup>+</sup> fibroadipogenic progenitors (+2.5 to +3.8-fold; D10—endpoint vs. Sham, <i>p</i> < 0.05), fibre atrophy (−16% to −24%, D12 to endpoint vs. Sham, <i>p</i> < 0.05), ECM expansion (+1.5 to +1.8-fold; D14—endpoint vs. Sham, <i>p</i> < 0.05), collagen accumulation (+3.8-fold; endpoint vs. Sham, <i>p</i> = 0.0013) and reductions in breathing frequency (−55%, <i>p</i> = 0.0074) and diaphragm excursion (−43%, <i>p</i> = 0.0006). These biological processes were supported by changes in the diaphragm transcriptome. Ingenuity pathway analysis predicted factors involved in inflammatory responses to tissue injury, including TGF-β1, angiotensin and PDGF BB, as top upstream regulators activated in diaphragms prior to and throughout cachexia progression, while PGC-1α and the insulin receptor were among the top upstream regulators predicted to be suppressed. The transcriptomic dataset further revealed progressive disturbances to networks involved in lipid, glucose and oxidative metabolism, activation of the unfolded protein response and neuromuscular junction remodelling associated with denervation.</p> </section> <section> <h3> Conclusions</h3> <p>In summary, our data support leukocyte infiltration and expansion of P
{"title":"Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer","authors":"Daria Neyroud, Andrew C. D'Lugos, Enrique J. Trevino, Chandler S. Callaway, Jacqueline Lamm, Orlando Laitano, Brittney Poole, Michael R. Deyhle, Justina Brantley, Lam Le, Andrew R. Judge, Sarah M. Judge","doi":"10.1002/jcsm.13668","DOIUrl":"10.1002/jcsm.13668","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer-related deaths, with deterioration of respiratory muscles suspected to be a key contributor to cachexia-associated morbidity and mortality. In recent studies, we identified fibrotic remodelling of respiratory accessory muscles as a key feature of human PDAC cachexia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To gain insight into mechanisms driving respiratory muscle wasting and fibrotic remodelling in response to PDAC, we conducted temporal histological and transcriptomic analyses on diaphragm muscles harvested from mice-bearing orthotopic murine pancreatic (KPC) tumours at time points reflective of precachexia (D8 and D10), mild–moderate cachexia (D12 and D14) and advanced cachexia (endpoint).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>During the precachexia phase, diaphragms showed significant leukocyte infiltration (+3-fold to +13-fold; D8—endpoint vs. Sham, <i>p</i> < 0.05) and transcriptomic enrichment of inflammatory processes associated with tissue injury that remained increased through endpoint. Diaphragm inflammation was followed by increases in PDGFR-ɑ<sup>+</sup> fibroadipogenic progenitors (+2.5 to +3.8-fold; D10—endpoint vs. Sham, <i>p</i> < 0.05), fibre atrophy (−16% to −24%, D12 to endpoint vs. Sham, <i>p</i> < 0.05), ECM expansion (+1.5 to +1.8-fold; D14—endpoint vs. Sham, <i>p</i> < 0.05), collagen accumulation (+3.8-fold; endpoint vs. Sham, <i>p</i> = 0.0013) and reductions in breathing frequency (−55%, <i>p</i> = 0.0074) and diaphragm excursion (−43%, <i>p</i> = 0.0006). These biological processes were supported by changes in the diaphragm transcriptome. Ingenuity pathway analysis predicted factors involved in inflammatory responses to tissue injury, including TGF-β1, angiotensin and PDGF BB, as top upstream regulators activated in diaphragms prior to and throughout cachexia progression, while PGC-1α and the insulin receptor were among the top upstream regulators predicted to be suppressed. The transcriptomic dataset further revealed progressive disturbances to networks involved in lipid, glucose and oxidative metabolism, activation of the unfolded protein response and neuromuscular junction remodelling associated with denervation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In summary, our data support leukocyte infiltration and expansion of P","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13668","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981659","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号