Valentina Tuninetti, Elisa Virano, Amedeo Calvo, Vittoria Carbone, Carmela Pisano, Monika Ducceschi, Giacinto Turitto, Giuseppa Scandurra, Maria Cristina Petrella, Valeria Forestieri, Massimo Petracchini, Alessandra Bianco, Raffaella Cioffi, Mara Mantiero, Eleonora Paluzzi, Maria Grazia Distefano, Olga Martelli, Sandro Pignata, Vincenzo Formica, Fotios Loupakis, Giorgio Valabrega
Background
A low fT3/fT4 ratio has been associated with poorer prognosis in several diseases. Inflammatory indexes (IIs) and the skeletal muscle index (SMI) are established prognostic factors in various cancer types. However, their interplay and individual contributions to the prognosis of cervical cancer remain unclear. This study aimed to evaluate the impact of these biomarkers on survival outcomes in cervical cancer patients treated with innovative immunotherapy.
Methods
This retrospective study included 101 patients with cervical cancer treated with cemiplimab at 12 Italian oncology centres. Patients with thyroid comorbidities or missing fT3/fT4 ratio data were excluded. The primary endpoint was overall survival (OS) in relation to the fT3/fT4 ratio. Secondary endpoints included progression-free survival (PFS) and correlations between the fT3/fT4 ratio, ECOG Performance Status, IIs and SMI.
Results
An optimal fT3/fT4 cutoff for OS prediction was identified at 0.29. Median OS was 10.9 months for patients with a low fT3/fT4 ratio, while it was not reached for those with high fT3/fT4 levels (HR = 2.70; 95% CI: 1.17–6.22; p = 0.02). Multivariate analysis confirmed that both the fT3/fT4 ratio and ECOG PS independently influenced OS. Among the IIs analysed, the systemic inflammatory index (SII) demonstrated the strongest correlation with fT3/fT4 levels (OR = 3.82; 95% CI: 1.39–10.50; p = 0.0092). Exploratory analysis also revealed significantly lower SMI values in patients with lower fT3/fT4 ratios (p = 0.034).
Conclusions
This study highlights the prognostic significance of the fT3/fT4 ratio, IIs, and SMI in cervical cancer patients treated with cemiplimab. Given the exploratory nature of these findings, further validation in larger, prospective cohorts is warranted to support their integration into clinical practice and the development of innovative prognostic tools.
背景：在一些疾病中，低fT3/fT4比率与较差的预后相关。炎症指数（IIs）和骨骼肌指数（SMI）是各种癌症类型的预后因素。然而，它们之间的相互作用和个体对宫颈癌预后的影响尚不清楚。本研究旨在评估这些生物标志物对接受创新免疫治疗的宫颈癌患者生存结果的影响。方法本回顾性研究纳入意大利12个肿瘤中心101例宫颈癌患者接受塞米单抗治疗。排除有甲状腺合并症或fT3/fT4比值缺失的患者。主要终点是与fT3/fT4比率相关的总生存期（OS）。次要终点包括无进展生存期（PFS）和fT3/fT4比率、ECOG性能状态、IIs和SMI之间的相关性。结果fT3/fT4预测OS的最佳临界值为0.29。fT3/fT4比值低的患者中位OS为10.9个月，而fT3/fT4比值高的患者中位OS未达到（HR = 2.70; 95% CI: 1.17-6.22; p = 0.02）。多因素分析证实fT3/fT4比值和ECOG PS独立影响OS。在所分析的i中，全身炎症指数（SII）与fT3/fT4水平相关性最强（OR = 3.82; 95% CI: 1.39-10.50; p = 0.0092）。探索性分析还显示，fT3/fT4比值较低的患者SMI值显著降低（p = 0.034）。结论本研究强调了fT3/fT4比值、IIs和SMI在宫颈癌患者接受塞米单抗治疗中的预后意义。鉴于这些发现的探索性，需要在更大的前瞻性队列中进行进一步验证，以支持其融入临床实践和开发创新的预后工具。
{"title":"Peripheral Thyroid Hormones, Inflammatory and Skeletal Muscle Indexes in Advanced Cervical Cancer Treated With Cemiplimab","authors":"Valentina Tuninetti, Elisa Virano, Amedeo Calvo, Vittoria Carbone, Carmela Pisano, Monika Ducceschi, Giacinto Turitto, Giuseppa Scandurra, Maria Cristina Petrella, Valeria Forestieri, Massimo Petracchini, Alessandra Bianco, Raffaella Cioffi, Mara Mantiero, Eleonora Paluzzi, Maria Grazia Distefano, Olga Martelli, Sandro Pignata, Vincenzo Formica, Fotios Loupakis, Giorgio Valabrega","doi":"10.1002/jcsm.70101","DOIUrl":"10.1002/jcsm.70101","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>A low fT3/fT4 ratio has been associated with poorer prognosis in several diseases. Inflammatory indexes (IIs) and the skeletal muscle index (SMI) are established prognostic factors in various cancer types. However, their interplay and individual contributions to the prognosis of cervical cancer remain unclear. This study aimed to evaluate the impact of these biomarkers on survival outcomes in cervical cancer patients treated with innovative immunotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This retrospective study included 101 patients with cervical cancer treated with cemiplimab at 12 Italian oncology centres. Patients with thyroid comorbidities or missing fT3/fT4 ratio data were excluded. The primary endpoint was overall survival (OS) in relation to the fT3/fT4 ratio. Secondary endpoints included progression-free survival (PFS) and correlations between the fT3/fT4 ratio, ECOG Performance Status, IIs and SMI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>An optimal fT3/fT4 cutoff for OS prediction was identified at 0.29. Median OS was 10.9 months for patients with a low fT3/fT4 ratio, while it was not reached for those with high fT3/fT4 levels (HR = 2.70; 95% CI: 1.17–6.22; <i>p</i> = 0.02). Multivariate analysis confirmed that both the fT3/fT4 ratio and ECOG PS independently influenced OS. Among the IIs analysed, the systemic inflammatory index (SII) demonstrated the strongest correlation with fT3/fT4 levels (OR = 3.82; 95% CI: 1.39–10.50; <i>p</i> = 0.0092). Exploratory analysis also revealed significantly lower SMI values in patients with lower fT3/fT4 ratios (<i>p</i> = 0.034).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study highlights the prognostic significance of the fT3/fT4 ratio, IIs, and SMI in cervical cancer patients treated with cemiplimab. Given the exploratory nature of these findings, further validation in larger, prospective cohorts is warranted to support their integration into clinical practice and the development of innovative prognostic tools.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 5","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277201","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}
Ning Li, Jida Hamati, Yi Li, Björn Brinschwitz, Mohamed Ghait, Elisa Martin, Dörte Lodka, Elke Hammer, Britta Fielitz, Uwe Völker, Gunnar Dittmar, Thomas Sommer, Friedrich C. Luft, Jens Fielitz
<div> <section> <h3> Background</h3> <p>Muscle RING finger (MuRF) proteins are striated muscle-specific E3 ubiquitin ligases essential for muscle homeostasis. Whereas MuRF1 is well known for its role in muscle atrophy, MuRF2 and MuRF3 contribute to microtubule stabilization, influencing muscle differentiation and function. Their cooperative functions in regulating myogenesis are unclear. This study aimed to identify novel MuRF2 and MuRF3 interaction partners and investigate their function in myogenic differentiation.</p> </section> <section> <h3> Methods</h3> <p>Interaction partners of MuRF2 and MuRF3 were identified using stable isotope labelling with amino acids in cell culture (SILAC), followed by affinity purification and quantitative mass spectrometry (AP-MS). Mechanistic analyses included co-immunoprecipitation, domain mapping, ubiquitination assays, protein stability measurements and endosome isolation. Myogenic differentiation was evaluated by immunocytochemistry, qRT-PCR and western blotting. Functional effects were assessed using CRISPR-Cas9-mediated knockout and siRNA silencing.</p> </section> <section> <h3> Results</h3> <p>We identified sorting nexin 5 (SNX5), a BAR and PX domain-containing retromer component involved in retrograde vesicular transport, as a novel MuRF2 and MuRF3 binding partner. Both coiled-coil domains of MuRF3 were required for SNX5 binding, and the BAR domain of SNX5 mediated interaction with MuRF2 and MuRF3. Immunofluorescence staining demonstrated MuRF3–SNX5 interaction and colocalization on early endosomes along microtubules in myocytes. MuRF2 promoted ubiquitination of SNX5 at lysines 290 and 324, leading to proteasomal degradation, whereas MuRF3 counteracted this effect. Mass spectrometry revealed the protein kinase A regulatory subunit (PKA-RI-α) as cargo of SNX5-coated early endosomes in myocytes. SNX5 knockout (SNX5-KO) reduced RI-α stability in myocytes, enhanced PKA activity and increased HDAC5 degradation via the autophagy-lysosomal pathway, leading to MEF2-mediated upregulation of myostatin. SNX5-KO impaired myogenesis, with significant reductions in myogenin/<i>Myog</i> (<i>p</i> < 0.005), myomaker/<i>Mymk</i> (<i>p</i> < 0.01), myomerger/<i>Mymx</i> (<i>p</i> < 0.005) and MyHC isoforms <i>Myh2</i> and <i>Myh4</i> (<i>p</i> < 0.01). Myostatin treatment mimicked the SNX5-KO phenotype, reducing fast-twitch MyHC isoforms <i>Myh1</i>, <i>Myh2</i>, <i>Myh3</i> and <i>Myh4</i> (<i>p</i> < 0.05 for all) and significantly lowering Myomaker, Myomerger and MyHC expression throughout differentiation (<i>p</i> < 0.05 for all). Morphologically, myostatin-treated cells were shorter and thinner and ha
{"title":"The Novel MuRF2 Target SNX5 Regulates PKA Activity Through Stabilization of RI-α and Controls Myogenic Differentiation","authors":"Ning Li, Jida Hamati, Yi Li, Björn Brinschwitz, Mohamed Ghait, Elisa Martin, Dörte Lodka, Elke Hammer, Britta Fielitz, Uwe Völker, Gunnar Dittmar, Thomas Sommer, Friedrich C. Luft, Jens Fielitz","doi":"10.1002/jcsm.70103","DOIUrl":"10.1002/jcsm.70103","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Muscle RING finger (MuRF) proteins are striated muscle-specific E3 ubiquitin ligases essential for muscle homeostasis. Whereas MuRF1 is well known for its role in muscle atrophy, MuRF2 and MuRF3 contribute to microtubule stabilization, influencing muscle differentiation and function. Their cooperative functions in regulating myogenesis are unclear. This study aimed to identify novel MuRF2 and MuRF3 interaction partners and investigate their function in myogenic differentiation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Interaction partners of MuRF2 and MuRF3 were identified using stable isotope labelling with amino acids in cell culture (SILAC), followed by affinity purification and quantitative mass spectrometry (AP-MS). Mechanistic analyses included co-immunoprecipitation, domain mapping, ubiquitination assays, protein stability measurements and endosome isolation. Myogenic differentiation was evaluated by immunocytochemistry, qRT-PCR and western blotting. Functional effects were assessed using CRISPR-Cas9-mediated knockout and siRNA silencing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified sorting nexin 5 (SNX5), a BAR and PX domain-containing retromer component involved in retrograde vesicular transport, as a novel MuRF2 and MuRF3 binding partner. Both coiled-coil domains of MuRF3 were required for SNX5 binding, and the BAR domain of SNX5 mediated interaction with MuRF2 and MuRF3. Immunofluorescence staining demonstrated MuRF3–SNX5 interaction and colocalization on early endosomes along microtubules in myocytes. MuRF2 promoted ubiquitination of SNX5 at lysines 290 and 324, leading to proteasomal degradation, whereas MuRF3 counteracted this effect. Mass spectrometry revealed the protein kinase A regulatory subunit (PKA-RI-α) as cargo of SNX5-coated early endosomes in myocytes. SNX5 knockout (SNX5-KO) reduced RI-α stability in myocytes, enhanced PKA activity and increased HDAC5 degradation via the autophagy-lysosomal pathway, leading to MEF2-mediated upregulation of myostatin. SNX5-KO impaired myogenesis, with significant reductions in myogenin/<i>Myog</i> (<i>p</i> < 0.005), myomaker/<i>Mymk</i> (<i>p</i> < 0.01), myomerger/<i>Mymx</i> (<i>p</i> < 0.005) and MyHC isoforms <i>Myh2</i> and <i>Myh4</i> (<i>p</i> < 0.01). Myostatin treatment mimicked the SNX5-KO phenotype, reducing fast-twitch MyHC isoforms <i>Myh1</i>, <i>Myh2</i>, <i>Myh3</i> and <i>Myh4</i> (<i>p</i> < 0.05 for all) and significantly lowering Myomaker, Myomerger and MyHC expression throughout differentiation (<i>p</i> < 0.05 for all). Morphologically, myostatin-treated cells were shorter and thinner and ha","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 5","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145278593","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}
Pia Weinländer, Sara Hadzibegovic, Jan Porthun, Lucie Kretzler, Ruben Evertz, Alessia Lena, Laura-Carina Lück, Jonathan L. Hella, Ursula Wilkenshoff, Andrea Stroux, Kalliopi Keramida, Anne Letsch, Dominik Paul Modest, Lars Bullinger, Ulrich Keller, Mahir Karakas, Youssef S. Abdelwahed, Philipp Attanasio, Ursula Rauch, Carsten Skurk, Wolfram Doehner, Ulf Landmesser, Stephan von Haehling, Markus S. Anker
Background
Patients with advanced cancer frequently suffer from frailty associated with vulnerability and adverse outcomes. Our aim was to assess the prevalence of frailty and elucidate the utility of two commonly used frailty questionnaires in an advanced cancer population.
Methods
The Fried Frailty Phenotype (FFP) and Simple FRAIL Questionnaire (SFQ) were assessed in hospitalized patients with mostly advanced cancer. Patients were classified by both questionnaires as frail (3–5 points), pre-frail (1–2 points) and robust (0 points) and followed up for all-cause mortality. Utility was evaluated with correlation and survival analysis.
Results
From 11/2017 to 02/2020, 251 mostly advanced cancer patients (61 ± 13 years, 53% men, BMI 25.3 ± 4.8 kg/m2, 78% cancer stage ≥ 3) were prospectively enrolled. In cancer patients, according to the FFP and SFQ, 17%/13% were frail, 52%/41% prefrail and 31%/47% robust. The correlation between both scores was strong (rs = 0.65, p < 0.001). Both scores were predictors of mortality of cancer patients in univariable and multivariable Cox proportional hazards analyses (multivariable adjusted: per 1 point: FFP: HR 1.36, 95% CI, 1.15–1.61, p < 0.001; SFQ: HR 1.29, 95% CI, 1.09–1.52, p = 0.003—adjustment for age, cancer stage/type, anti-cancer therapy naïve, sex, BMI, CKD and anaemia). The time-dependent multivariable adjusted area under the receiver operating characteristic curve for 6-/24-month survival follow-up for the FFP was 0.78 (95% CI, 0.70–0.86)/0.92 (95% CI, 0.87–0.98) and for the SFQ was 0.79 (95% CI, 0.69–0.88)/0.90 (95% CI, 0.83–0.97).
Conclusion
Frailty and pre-frailty as assessed by FFP and SFQ are commonly found in advanced stage cancer patients. Both questionnaires have a strong correlation and are associated with all-cause mortality in this population. Since the SFQ is easier and quicker to perform, it can be used remotely, and with untrained staff, it might facilitate earlier preventive measures and initiate further actions to mitigate its impact.
{"title":"The Prognostic Role of Frailty and Its Recognition With Simple FRAIL and Fried Frailty Questionnaires in Advanced Cancer Patients","authors":"Pia Weinländer, Sara Hadzibegovic, Jan Porthun, Lucie Kretzler, Ruben Evertz, Alessia Lena, Laura-Carina Lück, Jonathan L. Hella, Ursula Wilkenshoff, Andrea Stroux, Kalliopi Keramida, Anne Letsch, Dominik Paul Modest, Lars Bullinger, Ulrich Keller, Mahir Karakas, Youssef S. Abdelwahed, Philipp Attanasio, Ursula Rauch, Carsten Skurk, Wolfram Doehner, Ulf Landmesser, Stephan von Haehling, Markus S. Anker","doi":"10.1002/jcsm.70076","DOIUrl":"10.1002/jcsm.70076","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Patients with advanced cancer frequently suffer from frailty associated with vulnerability and adverse outcomes. Our aim was to assess the prevalence of frailty and elucidate the utility of two commonly used frailty questionnaires in an advanced cancer population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The Fried Frailty Phenotype (FFP) and Simple FRAIL Questionnaire (SFQ) were assessed in hospitalized patients with mostly advanced cancer. Patients were classified by both questionnaires as frail (3–5 points), pre-frail (1–2 points) and robust (0 points) and followed up for all-cause mortality. Utility was evaluated with correlation and survival analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>From 11/2017 to 02/2020, 251 mostly advanced cancer patients (61 ± 13 years, 53% men, BMI 25.3 ± 4.8 kg/m<sup>2</sup>, 78% cancer stage ≥ 3) were prospectively enrolled. In cancer patients, according to the FFP and SFQ, 17%/13% were frail, 52%/41% prefrail and 31%/47% robust. The correlation between both scores was strong (<i>r</i><sub><i>s</i></sub> = 0.65, <i>p</i> < 0.001). Both scores were predictors of mortality of cancer patients in univariable and multivariable Cox proportional hazards analyses (multivariable adjusted: per 1 point: FFP: HR 1.36, 95% CI, 1.15–1.61, <i>p</i> < 0.001; SFQ: HR 1.29, 95% CI, 1.09–1.52, <i>p</i> = 0.003—adjustment for age, cancer stage/type, anti-cancer therapy naïve, sex, BMI, CKD and anaemia). The time-dependent multivariable adjusted area under the receiver operating characteristic curve for 6-/24-month survival follow-up for the FFP was 0.78 (95% CI, 0.70–0.86)/0.92 (95% CI, 0.87–0.98) and for the SFQ was 0.79 (95% CI, 0.69–0.88)/0.90 (95% CI, 0.83–0.97).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Frailty and pre-frailty as assessed by FFP and SFQ are commonly found in advanced stage cancer patients. Both questionnaires have a strong correlation and are associated with all-cause mortality in this population. Since the SFQ is easier and quicker to perform, it can be used remotely, and with untrained staff, it might facilitate earlier preventive measures and initiate further actions to mitigate its impact.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 5","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70076","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277206","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}
Lotte Huysmans, Louise Iterbeke, Bram De Wel, Matthias Opsomer, Kristl G. Claeys, Frederik Maes
Background
Neuromuscular diseases (NMDs) are diagnosed using a combination of clinical evaluation, electromyography, nerve conduction studies, blood tests, muscle biopsy, and genetic testing. In addition, muscle magnetic resonance imaging (MRI) is used to visualise affected areas and allows the identification of fatty replacement of muscle tissue, muscle atrophy and oedema. The distinct muscle involvement patterns can be used to help in the diagnosis of NMDs. Our aim was to develop an automatic approach with interpretations that explain the model's decision to classify NMDs based on symptomatic MRI scans of the upper leg.
Methods
We used 109 Dixon muscle MRI scans of the upper legs of four different NMDs: limb–girdle muscular dystrophy type R12 (LGMDR12), Becker muscular dystrophy (BMD), myotonic dystrophy type 1 (DM1), Charcot–Marie–Tooth neuropathy type 1A (CMT1A) and healthy controls (HC). A U-Net was trained to segment all 18 muscles in the upper leg from which the fat fractions are calculated and used as input to a random forest classification model. SHapley Additive exPlanations (SHAP) are used to get an understanding of the reasoning of the model and are compared with muscle involvement patterns previously described in the medical literature.
Results
The baseline models demonstrate strong performance in distinguishing between different classes, as evidenced by an overall accuracy of 89% and high area under the receiver operating characteristic curve (AUC) values for every class: 0.972, 0.983, 0.960, 0.990 and 0.997 for respectively LGMDR12, BMD, DM1, CMT1A and HC. In addition, we demonstrated that no significant difference could be observed with models trained on features calculated from ground truth segmentations, features calculated from a limited field of view or Mercuri score features. SHAP explanations help understand the decision of the models and can be linked to muscle patterns described in the medical literature.
Conclusion
A fully automated method was developed that is effective in distinguishing between four NMDs and healthy controls.
{"title":"Automated Classification of Neuromuscular Diseases Using Thigh Muscle MRI With Model Interpretations","authors":"Lotte Huysmans, Louise Iterbeke, Bram De Wel, Matthias Opsomer, Kristl G. Claeys, Frederik Maes","doi":"10.1002/jcsm.70102","DOIUrl":"10.1002/jcsm.70102","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Neuromuscular diseases (NMDs) are diagnosed using a combination of clinical evaluation, electromyography, nerve conduction studies, blood tests, muscle biopsy, and genetic testing. In addition, muscle magnetic resonance imaging (MRI) is used to visualise affected areas and allows the identification of fatty replacement of muscle tissue, muscle atrophy and oedema. The distinct muscle involvement patterns can be used to help in the diagnosis of NMDs. Our aim was to develop an automatic approach with interpretations that explain the model's decision to classify NMDs based on symptomatic MRI scans of the upper leg.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used 109 Dixon muscle MRI scans of the upper legs of four different NMDs: limb–girdle muscular dystrophy type R12 (LGMDR12), Becker muscular dystrophy (BMD), myotonic dystrophy type 1 (DM1), Charcot–Marie–Tooth neuropathy type 1A (CMT1A) and healthy controls (HC). A U-Net was trained to segment all 18 muscles in the upper leg from which the fat fractions are calculated and used as input to a random forest classification model. SHapley Additive exPlanations (SHAP) are used to get an understanding of the reasoning of the model and are compared with muscle involvement patterns previously described in the medical literature.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The baseline models demonstrate strong performance in distinguishing between different classes, as evidenced by an overall accuracy of 89% and high area under the receiver operating characteristic curve (AUC) values for every class: 0.972, 0.983, 0.960, 0.990 and 0.997 for respectively LGMDR12, BMD, DM1, CMT1A and HC. In addition, we demonstrated that no significant difference could be observed with models trained on features calculated from ground truth segmentations, features calculated from a limited field of view or Mercuri score features. SHAP explanations help understand the decision of the models and can be linked to muscle patterns described in the medical literature.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>A fully automated method was developed that is effective in distinguishing between four NMDs and healthy controls.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 5","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70102","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261389","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}
Amirhossein Abazarikia, Wonmi So, Yi Luan, Chandramohan Kattamuri, Thomas B. Thompson, So-Youn Kim
<div> <section> <h3> Background</h3> <p>Cancer-associated cachexia (CAC) is a severe metabolic disorder characterized by involuntary weight loss, skeletal muscle atrophy and adipose tissue depletion. It is a major contributor to morbidity and mortality in the advanced stages of various cancers. However, the impact of CAC on the pancreas remains largely unexplored.</p> </section> <section> <h3> Methods</h3> <p>We used mice with constitutively active <i>PI3K</i> in oocytes, generated through a Cre-inducible <i>Pik3ca*</i> knock-in allele driven by <i>Gdf9</i>-icre and performed histological and molecular analyses of the pancreas during cachexia development. Additionally, we examined pancreatic changes following ovariectomy and administration of Follistatin 288 (FST288).</p> </section> <section> <h3> Results</h3> <p>Mice that developed cachexia symptoms associated with granulosa cell tumour (GCT) growth exhibited significant pancreatic atrophy compared to controls (Cre+ vs. Cre− at PD83, <i>p</i> < 0.0001), including reduced size of individual acinar cells (102.99 ± 12.19 μm<sup>2</sup> vs. 207.94 ± 24.85 μm<sup>2</sup> at PD83, <i>p</i> < 0.0001) and acinar units (346.41 ± 169.22 μm<sup>2</sup> vs. 1193.59 ± 136.01 μm<sup>2</sup> at PD83, <i>p</i> < 0.0001), despite comparable food intake between groups. Acinar cells exhibited a decrease in zymogen granules, reduced amylase expression and diminished amylase activity in both serum (0.29 ± 0.08 vs. 1.41 ± 0.40, <i>p</i> < 0.001) and tissue (0.37 ± 0.14 vs. 1.05 ± 0.29, <i>p</i> < 0.01). In contrast, pancreatic islets remained intact, as evidenced by histological analysis and preserved insulin expression. The pancreas of PD83 Cre+ mice also developed fibrosis and acinar cell death, characterized by elevated expression of collagen IV and α-SMA, and TUNEL-positive signals in acinar cells, respectively. Ovariectomy preserved body weight (2.66 ± 1.30 g for Cre+/OVX vs. 1.60 ± 0.97 g for Cre−) compared to Cre+ mice (−3.66 g) and maintained pancreatic function, suggesting that tumour-derived factors from GCT contribute to the severity of cachexia. Acinar cells showed high expression of ACVR2B, leading to activation of downstream p-SMAD3 signalling. Accordingly, activin A directly induced acinar cell atrophy in both ex vivo cultured pancreas (79.27 ± 19.03 μm<sup>2</sup> vs. 171.14 ± 27.01 μm<sup>2</sup>, <i>p</i> < 0.0001) and 266-6 acinar cells, as evidenced by reduced acinar cell size and decreased amylase production. Injection of FST288, an activin A inhibitor, rescued pancreatic acinar atrophy (252.95 ± 11.59 μm<sup>2</sup> in Cre+/FST288 vs. 97.25 ± 12.37 μm<sup>2</sup> in Cre+, <i>p</i
{"title":"Pancreatic Damage in Ovarian Cancer–Associated Cachexia Is Driven by Activin A Signalling","authors":"Amirhossein Abazarikia, Wonmi So, Yi Luan, Chandramohan Kattamuri, Thomas B. Thompson, So-Youn Kim","doi":"10.1002/jcsm.70096","DOIUrl":"10.1002/jcsm.70096","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cancer-associated cachexia (CAC) is a severe metabolic disorder characterized by involuntary weight loss, skeletal muscle atrophy and adipose tissue depletion. It is a major contributor to morbidity and mortality in the advanced stages of various cancers. However, the impact of CAC on the pancreas remains largely unexplored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used mice with constitutively active <i>PI3K</i> in oocytes, generated through a Cre-inducible <i>Pik3ca*</i> knock-in allele driven by <i>Gdf9</i>-icre and performed histological and molecular analyses of the pancreas during cachexia development. Additionally, we examined pancreatic changes following ovariectomy and administration of Follistatin 288 (FST288).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Mice that developed cachexia symptoms associated with granulosa cell tumour (GCT) growth exhibited significant pancreatic atrophy compared to controls (Cre+ vs. Cre− at PD83, <i>p</i> < 0.0001), including reduced size of individual acinar cells (102.99 ± 12.19 μm<sup>2</sup> vs. 207.94 ± 24.85 μm<sup>2</sup> at PD83, <i>p</i> < 0.0001) and acinar units (346.41 ± 169.22 μm<sup>2</sup> vs. 1193.59 ± 136.01 μm<sup>2</sup> at PD83, <i>p</i> < 0.0001), despite comparable food intake between groups. Acinar cells exhibited a decrease in zymogen granules, reduced amylase expression and diminished amylase activity in both serum (0.29 ± 0.08 vs. 1.41 ± 0.40, <i>p</i> < 0.001) and tissue (0.37 ± 0.14 vs. 1.05 ± 0.29, <i>p</i> < 0.01). In contrast, pancreatic islets remained intact, as evidenced by histological analysis and preserved insulin expression. The pancreas of PD83 Cre+ mice also developed fibrosis and acinar cell death, characterized by elevated expression of collagen IV and α-SMA, and TUNEL-positive signals in acinar cells, respectively. Ovariectomy preserved body weight (2.66 ± 1.30 g for Cre+/OVX vs. 1.60 ± 0.97 g for Cre−) compared to Cre+ mice (−3.66 g) and maintained pancreatic function, suggesting that tumour-derived factors from GCT contribute to the severity of cachexia. Acinar cells showed high expression of ACVR2B, leading to activation of downstream p-SMAD3 signalling. Accordingly, activin A directly induced acinar cell atrophy in both ex vivo cultured pancreas (79.27 ± 19.03 μm<sup>2</sup> vs. 171.14 ± 27.01 μm<sup>2</sup>, <i>p</i> < 0.0001) and 266-6 acinar cells, as evidenced by reduced acinar cell size and decreased amylase production. Injection of FST288, an activin A inhibitor, rescued pancreatic acinar atrophy (252.95 ± 11.59 μm<sup>2</sup> in Cre+/FST288 vs. 97.25 ± 12.37 μm<sup>2</sup> in Cre+, <i>p</i","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 5","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70096","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145255322","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}
Alice Sabatino, Alessandro Guerra, Kenia Mara Baiocchi de Carvalho, Lilian Cuppari, Juan Jesus Carrero, Peter Stenvinkel, Bengt Lindholm, Carla Maria Avesani
<div> <section> <h3> Background</h3> <p>Loss of muscle mass, muscle weakness and the combination of the two are commonly observed in patients on dialysis and may have a negative impact on their survival. In this systematic review and meta-analysis (MA), we evaluated the consistency and strength of the association between mortality risk and the presence of low muscle mass with adequate muscle strength, low muscle strength with adequate muscle mass and sarcopenia (low muscle mass and strength combined) in patients on dialysis. Ultimately, we aimed to grade which of these three conditions had the strongest association with increased mortality risk in this vulnerable group of patients.</p> </section> <section> <h3> Methods</h3> <p>We searched for studies published until 31 January 2024 that evaluated sarcopenia and its individual components in patients aged > 18 years on dialysis (haemodialysis and peritoneal dialysis) and that had a mean follow-up for mortality for ≥ 12 months. Included studies had to enable the evaluation of sarcopenia traits to identify patients with low muscle mass and adequate muscle strength, low muscle strength with adequate muscle mass, and sarcopenia. A systematic search was conducted in MEDLINE (by PubMed), Embase, Web of Science, Lilacs and grey literature (i.e., Google Scholar and ProQuest). We estimated consistency in the association between sarcopenia traits and death using random effects MA and reporting hazard ratio (HR) with a 95% confidence interval (95% CI).</p> </section> <section> <h3> Results</h3> <p>The electronic search retrieved 5712 records. After removing duplicated records and those that did not meet the eligibility criteria, 19 studies were included in the qualitative synthesis (4281 participants) and 17 studies (4024 participants) with extractable data for the MA. The MA showed low heterogeneity in the association between muscle parameters and sarcopenia with the risk of death: <i>low muscle mass with adequate muscle strength,</i> HR: 1.49; 95% CI: 1.04 to 2.13; <i>I</i><sup>2</sup> = 0%; <i>low muscle strength with adequate muscle mass,</i> HR: 1.82; 95% CI: 1.38 to 2.41; <i>I</i><sup>2</sup> = 0%; and <i>sarcopenia,</i> HR: 2.02; 95% CI: 1.61 to 2.54; <i>I</i><sup>2</sup> = 40%.</p> </section> <section> <h3> Conclusion</h3> <p>Although being statistically significant, the association between low muscle mass and mortality seems to be less strong than the association between low muscle strength and mortality in patients on dialysis. Those presenting with a combination of the two traits, that is, sarcope
{"title":"Sarcopenia and Its Individual Traits Independently Predict Mortality in Patients on Dialysis: A Systematic Review and Meta-Analysis","authors":"Alice Sabatino, Alessandro Guerra, Kenia Mara Baiocchi de Carvalho, Lilian Cuppari, Juan Jesus Carrero, Peter Stenvinkel, Bengt Lindholm, Carla Maria Avesani","doi":"10.1002/jcsm.70089","DOIUrl":"10.1002/jcsm.70089","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Loss of muscle mass, muscle weakness and the combination of the two are commonly observed in patients on dialysis and may have a negative impact on their survival. In this systematic review and meta-analysis (MA), we evaluated the consistency and strength of the association between mortality risk and the presence of low muscle mass with adequate muscle strength, low muscle strength with adequate muscle mass and sarcopenia (low muscle mass and strength combined) in patients on dialysis. Ultimately, we aimed to grade which of these three conditions had the strongest association with increased mortality risk in this vulnerable group of patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We searched for studies published until 31 January 2024 that evaluated sarcopenia and its individual components in patients aged > 18 years on dialysis (haemodialysis and peritoneal dialysis) and that had a mean follow-up for mortality for ≥ 12 months. Included studies had to enable the evaluation of sarcopenia traits to identify patients with low muscle mass and adequate muscle strength, low muscle strength with adequate muscle mass, and sarcopenia. A systematic search was conducted in MEDLINE (by PubMed), Embase, Web of Science, Lilacs and grey literature (i.e., Google Scholar and ProQuest). We estimated consistency in the association between sarcopenia traits and death using random effects MA and reporting hazard ratio (HR) with a 95% confidence interval (95% CI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The electronic search retrieved 5712 records. After removing duplicated records and those that did not meet the eligibility criteria, 19 studies were included in the qualitative synthesis (4281 participants) and 17 studies (4024 participants) with extractable data for the MA. The MA showed low heterogeneity in the association between muscle parameters and sarcopenia with the risk of death: <i>low muscle mass with adequate muscle strength,</i> HR: 1.49; 95% CI: 1.04 to 2.13; <i>I</i><sup>2</sup> = 0%; <i>low muscle strength with adequate muscle mass,</i> HR: 1.82; 95% CI: 1.38 to 2.41; <i>I</i><sup>2</sup> = 0%; and <i>sarcopenia,</i> HR: 2.02; 95% CI: 1.61 to 2.54; <i>I</i><sup>2</sup> = 40%.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Although being statistically significant, the association between low muscle mass and mortality seems to be less strong than the association between low muscle strength and mortality in patients on dialysis. Those presenting with a combination of the two traits, that is, sarcope","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 5","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254781","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}
Takuya Karasawa, Ran Hee Choi, Cesar A. Meza, Shinya Watanabe, J. Alan Maschek, Linda S. Nikolova, James E. Cox, Katsuhiko Funai
<div> <section> <h3> Background</h3> <p>The coupling of oxygen consumption to ATP synthesis via oxidative phosphorylation (OXPHOS) is central for cellular energy homeostasis. Some studies suggest exercise training increases the efficiency of ATP synthesis, but the molecular mechanisms are unclear. We have previously shown that exercise remodels the lipid composition of mitochondrial membranes, and some of these changes in mitochondrial lipids might influence OXPHOS efficiency (ATP produced per O<sub>2</sub> consumed, referred to as P/O). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional co-activator that coordinately regulates exercise-induced adaptations, including mitochondria. We hypothesized that increased PGC-1α activity might remodel mitochondrial membrane lipids and promote energy efficiency.</p> </section> <section> <h3> Methods</h3> <p>Mice with skeletal muscle-specific overexpression of PGC-1α (MCK-PGC-1α) and their wildtype littermates were used for this study. Lipid mass spectrometry and quantitative PCR were used to assess muscle mitochondrial lipid composition and their biosynthesis pathway. The abundance of OXPHOS enzymes was determined by Western blotting. High-resolution respirometry and fluorometry analyses were performed to characterize mitochondrial bioenergetics (ATP production, O<sub>2</sub> consumption and P/O) for permeabilized fibres and isolated mitochondria. Respiratory supercomplexes were assessed by blue native PAGE.</p> </section> <section> <h3> Results</h3> <p>Lipidomic analyses of skeletal muscle mitochondria from wildtype and MCK-PGC-1α mice revealed that PGC-1α increases the concentrations of cone-shaped lipids such as phosphatidylethanolamine (PE; +25%, <i>p</i> < 0.0001), cardiolipin (CL; +184%, <i>p</i> < 0.0001) and lysophospholipids (+34%–94%, all <i>p</i> < 0.01), while decreasing the concentrations of phosphatidylcholine (PC; −4%, <i>p</i> = 0.0020), phosphatidylinositol (PI; −17%, <i>p</i> < 0.0001) and phosphatidic acid (PA; −35%, <i>p</i> < 0.0001). However, while PGC-1α overexpression increased the abundance of OXPHOS enzymes (two- to fourfold, <i>p</i> < 0.0001), the rate of O<sub>2</sub> consumption (1.5-fold, <i>p</i> = 0.0030), or the respiratory supercomplexes (~1.5-fold, <i>p</i> < 0.01), P/O values were unaffected by PGC-1α overexpression in permeabilized fibres or isolated mitochondria.</p> </section> <section> <h3> Conclusions</h3> <p>Collectively, overexpression of PGC-1α promotes the biosynthesis of mitochondrial PE and CL,
{"title":"Skeletal Muscle PGC-1α Remodels Mitochondrial Phospholipidome but Does Not Alter Energy Efficiency for ATP Synthesis","authors":"Takuya Karasawa, Ran Hee Choi, Cesar A. Meza, Shinya Watanabe, J. Alan Maschek, Linda S. Nikolova, James E. Cox, Katsuhiko Funai","doi":"10.1002/jcsm.70090","DOIUrl":"10.1002/jcsm.70090","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The coupling of oxygen consumption to ATP synthesis via oxidative phosphorylation (OXPHOS) is central for cellular energy homeostasis. Some studies suggest exercise training increases the efficiency of ATP synthesis, but the molecular mechanisms are unclear. We have previously shown that exercise remodels the lipid composition of mitochondrial membranes, and some of these changes in mitochondrial lipids might influence OXPHOS efficiency (ATP produced per O<sub>2</sub> consumed, referred to as P/O). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional co-activator that coordinately regulates exercise-induced adaptations, including mitochondria. We hypothesized that increased PGC-1α activity might remodel mitochondrial membrane lipids and promote energy efficiency.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Mice with skeletal muscle-specific overexpression of PGC-1α (MCK-PGC-1α) and their wildtype littermates were used for this study. Lipid mass spectrometry and quantitative PCR were used to assess muscle mitochondrial lipid composition and their biosynthesis pathway. The abundance of OXPHOS enzymes was determined by Western blotting. High-resolution respirometry and fluorometry analyses were performed to characterize mitochondrial bioenergetics (ATP production, O<sub>2</sub> consumption and P/O) for permeabilized fibres and isolated mitochondria. Respiratory supercomplexes were assessed by blue native PAGE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Lipidomic analyses of skeletal muscle mitochondria from wildtype and MCK-PGC-1α mice revealed that PGC-1α increases the concentrations of cone-shaped lipids such as phosphatidylethanolamine (PE; +25%, <i>p</i> < 0.0001), cardiolipin (CL; +184%, <i>p</i> < 0.0001) and lysophospholipids (+34%–94%, all <i>p</i> < 0.01), while decreasing the concentrations of phosphatidylcholine (PC; −4%, <i>p</i> = 0.0020), phosphatidylinositol (PI; −17%, <i>p</i> < 0.0001) and phosphatidic acid (PA; −35%, <i>p</i> < 0.0001). However, while PGC-1α overexpression increased the abundance of OXPHOS enzymes (two- to fourfold, <i>p</i> < 0.0001), the rate of O<sub>2</sub> consumption (1.5-fold, <i>p</i> = 0.0030), or the respiratory supercomplexes (~1.5-fold, <i>p</i> < 0.01), P/O values were unaffected by PGC-1α overexpression in permeabilized fibres or isolated mitochondria.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Collectively, overexpression of PGC-1α promotes the biosynthesis of mitochondrial PE and CL, ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 5","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145255327","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}
Chongyang Chen, Bingge Zhang, Chao Yang, Jing Wang, Ye He, Haitao Yu, Jianjun Liu, Yongmei Xie, Xifei Yang, Gong-Ping Liu
<div> <section> <h3> Background</h3> <p>Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle weakness, with inflammation and fibrosis contributing to its pathogenesis. Despite advancements in genetic disease-modifying treatment, there is currently no effective pharmacological treatment for DMD.</p> </section> <section> <h3> Methods</h3> <p>New compound ARC-18, a derivative of Arctigenin known for its anti-inflammatory activity, was designed and synthesized in our lab and administered prophylactically to 2-month-old mdx mice for 60 days. The motor performance was investigated by rotarod test, climbing-pole test, grip strength test, hanging endurance test, treadmill endurance test and gait analysis. Afterwards, molecular biological experiments, including proteomics, immunohistochemistry, immunofluorescence, western blots, gene transfection and immunoprecipitation, were employed to investigate the molecular mechanism of ARC-18 in the treatment of mdx.</p> </section> <section> <h3> Results</h3> <p>ARC-18 significantly ameliorated the motor performance of DMD mice (rotating time +65.9%, <i>p</i> < 0.01; hanging time +59.7%, <i>p</i> < 0.05; grip strength +32.1%, <i>p</i> < 0.0001; climbing time −29.0%, <i>p</i> < 0.0001; numbers of electric shocks −69.3%, <i>p</i> < 0.01) by up-regulating the expression of dystrophin-associated proteins (dystrophin, <i>p</i> < 0.01; α-dystroglycan, <i>p</i> < 0.01) and down-regulating the expression of muscle satellite/stem cell proteins (Pax7, <i>p</i> < 0.05; Myod, <i>p</i> < 0.05; Myog, <i>p</i> < 0.05; α-SMA, <i>p</i> < 0.01; fibronectin, <i>p</i> < 0.001; collagen I, <i>p</i> < 0.05). ARC-18 prevented the progression of muscle fibrosis, reduced inflammatory factors transforming growth factor (TGF) β1 (<i>p</i> < 0.05), IL-1β (<i>p</i> < 0.05) and TNF-α (<i>p</i> < 0.05) levels, and promoted the structural integrity of gastrocnemius and triceps muscles. Proteomics analysis demonstrated that ARC-18 treatment reversed the protein expression pattern of DMD model mice, with ATP-citrate synthase (ACLY) enriched in the TCA cycle pathway, showing a significant correlation with DMD expression levels (<i>R</i> = −0.72, <i>p</i> = 0.00031). Further investigations revealed that ARC-18 directly bound with ACLY (EC<sub>50</sub> = 120.2 nM) to promote its degradation by the proteasome system and suppressed the ACLY-mediated acetylation of Smad2/3 (<i>p</i> < 0.01) to reduce its nuclear localization (<i>p</i> < 0.05) to inhibit fibrosis.</p> </section> <section> <h3> Co
{"title":"ARC-18 Improved Motor Performance Through Inhibiting ACLY-Mediated Smad2/3 Acetylation in a Model of Duchenne Muscular Dystrophy","authors":"Chongyang Chen, Bingge Zhang, Chao Yang, Jing Wang, Ye He, Haitao Yu, Jianjun Liu, Yongmei Xie, Xifei Yang, Gong-Ping Liu","doi":"10.1002/jcsm.70081","DOIUrl":"10.1002/jcsm.70081","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle weakness, with inflammation and fibrosis contributing to its pathogenesis. Despite advancements in genetic disease-modifying treatment, there is currently no effective pharmacological treatment for DMD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>New compound ARC-18, a derivative of Arctigenin known for its anti-inflammatory activity, was designed and synthesized in our lab and administered prophylactically to 2-month-old mdx mice for 60 days. The motor performance was investigated by rotarod test, climbing-pole test, grip strength test, hanging endurance test, treadmill endurance test and gait analysis. Afterwards, molecular biological experiments, including proteomics, immunohistochemistry, immunofluorescence, western blots, gene transfection and immunoprecipitation, were employed to investigate the molecular mechanism of ARC-18 in the treatment of mdx.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ARC-18 significantly ameliorated the motor performance of DMD mice (rotating time +65.9%, <i>p</i> < 0.01; hanging time +59.7%, <i>p</i> < 0.05; grip strength +32.1%, <i>p</i> < 0.0001; climbing time −29.0%, <i>p</i> < 0.0001; numbers of electric shocks −69.3%, <i>p</i> < 0.01) by up-regulating the expression of dystrophin-associated proteins (dystrophin, <i>p</i> < 0.01; α-dystroglycan, <i>p</i> < 0.01) and down-regulating the expression of muscle satellite/stem cell proteins (Pax7, <i>p</i> < 0.05; Myod, <i>p</i> < 0.05; Myog, <i>p</i> < 0.05; α-SMA, <i>p</i> < 0.01; fibronectin, <i>p</i> < 0.001; collagen I, <i>p</i> < 0.05). ARC-18 prevented the progression of muscle fibrosis, reduced inflammatory factors transforming growth factor (TGF) β1 (<i>p</i> < 0.05), IL-1β (<i>p</i> < 0.05) and TNF-α (<i>p</i> < 0.05) levels, and promoted the structural integrity of gastrocnemius and triceps muscles. Proteomics analysis demonstrated that ARC-18 treatment reversed the protein expression pattern of DMD model mice, with ATP-citrate synthase (ACLY) enriched in the TCA cycle pathway, showing a significant correlation with DMD expression levels (<i>R</i> = −0.72, <i>p</i> = 0.00031). Further investigations revealed that ARC-18 directly bound with ACLY (EC<sub>50</sub> = 120.2 nM) to promote its degradation by the proteasome system and suppressed the ACLY-mediated acetylation of Smad2/3 (<i>p</i> < 0.01) to reduce its nuclear localization (<i>p</i> < 0.05) to inhibit fibrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Co","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 5","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235367","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}
Diego Marcos-Perez, Adrián Hernandez-Vicente, Sara Cruces-Salguero, Jon Landa, Michelle Bonvini, German Vicente-Rodríguez, Esther Pueyo, Leocadio Rodriguez-Mañas, Pedro Abizanda, David Otaegui, Nuria Garatachea, Ander Matheu
<div> <section> <h3> Background</h3> <p>Centenarians comprise an age group characterized by exceptional longevity and low age-associated pathologies. However, they still experience physiological decline, and different studies have linked frailty to this population. Exercise interventions reverse frailty and improve functional capacity, but no studies have addressed the effect of an intervention in centenarians. In this study, we assessed the impact of a 12-week resistance exercise intervention in a group of centenarians and characterized their functional capacity as well as the expression of several molecular biomarkers associated with frailty.</p> </section> <section> <h3> Methods</h3> <p>A total of 19 centenarians were enrolled, but 7 of them did not complete the study. The remaining 12 centenarians were randomly assigned to the control or intervention group, which was a 12-week resistance exercise intervention. Molecular biomarkers were measured by qRT-PCR and ELISA.</p> </section> <section> <h3> Results</h3> <p>The intervention group improved their functional capacity measured by Short Physical Performance Battery (SPPB) (post 5.0 vs 2.3 in pre) and Physical Performance and Mobility Examination (PPME) (6.5 vs 3.8), as well as in frailty status studied by Fried Frailty Phenotype (3.0 vs 3.8) and Frailty Trait Scale 5 (FTS5) (post 30.7 vs 34.0 in pre) scales. ANCOVA revealed that the resistance training led to significant improvements in functional capacity scales SPPB (<i>p</i> = 0.01) and PPME (<i>p</i> < 0.001), as well as Fried Frailty Phenotype (<i>p</i> = 0.001) and FTS5 (<i>p</i> = 0.05). Biomarkers related to frailty <i>(EGR1</i>, <i>miR194-5p, miR125b-5p</i> and <i>miR454-3p)</i> and inflammation (<i>IL-</i>6 and <i>IL-1β)</i> showed different expression patterns in centenarians (<i>n</i> = 19) compared to both old (<i>n</i> = 44, average of 79 years old) and young adults (<i>n</i> = 34, average of 29 years old) groups. Notably, the intervention was associated with improvements in frailty and inflammation biomarkers expression. Finally, correlation analyses showed significant associations between all functional and frailty variables, with SPPB correlating with <i>miR454-3p (ρ = 0.73)</i> and FTS5 correlating with <i>miR454-3p (ρ = −0.83), IL-6 (ρ = 0.60)</i> and <i>miR125b-5p (ρ = −0.55)</i>.</p> </section> <section> <h3> Conclusions</h3> <p>Our results revealed that resistance exercise intervention enhances functional status and reduces frailty in centenarians, and this is associated with improvements in frailty and inflammation biom
{"title":"Resistance Exercise Intervention Restores Functional Capacity and Improves Frailty Biomarkers in Centenarians","authors":"Diego Marcos-Perez, Adrián Hernandez-Vicente, Sara Cruces-Salguero, Jon Landa, Michelle Bonvini, German Vicente-Rodríguez, Esther Pueyo, Leocadio Rodriguez-Mañas, Pedro Abizanda, David Otaegui, Nuria Garatachea, Ander Matheu","doi":"10.1002/jcsm.70079","DOIUrl":"10.1002/jcsm.70079","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Centenarians comprise an age group characterized by exceptional longevity and low age-associated pathologies. However, they still experience physiological decline, and different studies have linked frailty to this population. Exercise interventions reverse frailty and improve functional capacity, but no studies have addressed the effect of an intervention in centenarians. In this study, we assessed the impact of a 12-week resistance exercise intervention in a group of centenarians and characterized their functional capacity as well as the expression of several molecular biomarkers associated with frailty.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 19 centenarians were enrolled, but 7 of them did not complete the study. The remaining 12 centenarians were randomly assigned to the control or intervention group, which was a 12-week resistance exercise intervention. Molecular biomarkers were measured by qRT-PCR and ELISA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The intervention group improved their functional capacity measured by Short Physical Performance Battery (SPPB) (post 5.0 vs 2.3 in pre) and Physical Performance and Mobility Examination (PPME) (6.5 vs 3.8), as well as in frailty status studied by Fried Frailty Phenotype (3.0 vs 3.8) and Frailty Trait Scale 5 (FTS5) (post 30.7 vs 34.0 in pre) scales. ANCOVA revealed that the resistance training led to significant improvements in functional capacity scales SPPB (<i>p</i> = 0.01) and PPME (<i>p</i> < 0.001), as well as Fried Frailty Phenotype (<i>p</i> = 0.001) and FTS5 (<i>p</i> = 0.05). Biomarkers related to frailty <i>(EGR1</i>, <i>miR194-5p, miR125b-5p</i> and <i>miR454-3p)</i> and inflammation (<i>IL-</i>6 and <i>IL-1β)</i> showed different expression patterns in centenarians (<i>n</i> = 19) compared to both old (<i>n</i> = 44, average of 79 years old) and young adults (<i>n</i> = 34, average of 29 years old) groups. Notably, the intervention was associated with improvements in frailty and inflammation biomarkers expression. Finally, correlation analyses showed significant associations between all functional and frailty variables, with SPPB correlating with <i>miR454-3p (ρ = 0.73)</i> and FTS5 correlating with <i>miR454-3p (ρ = −0.83), IL-6 (ρ = 0.60)</i> and <i>miR125b-5p (ρ = −0.55)</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our results revealed that resistance exercise intervention enhances functional status and reduces frailty in centenarians, and this is associated with improvements in frailty and inflammation biom","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 5","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203206","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}
Felix N. von Brackel, Robert Munzinger, Mikolaj Bartosik, Alexander Simon, Florian Barvencik, Ralf Oheim, Michael Amling
<div> <section> <h3> Background</h3> <p>Relative energy deficiency in sport (REDs) is associated with impaired performance and compromised bone health in elite athletes. While reduced bone mineral density (BMD) and increased risk for bone stress injuries are well documented, the underlying metabolic mechanisms remain poorly understood. This study investigates the bone metabolism in athletes with REDs and its impact on BMD and bone microstructure.</p> </section> <section> <h3> Methods</h3> <p>We retrospectively analysed data from 82 elite athletes (30.5% females, age 23.4 ± 7.6 years) who presented to our outpatient clinic. The diagnosis of REDs was made according to the International Olympic Committee REDs Clinical Assessment Tool Version 2 (IOC REDs CAT2), and athletes were categorised into strength-based vs. endurance-based sports. Laboratory assessment of calcium and bone metabolism included bone turnover markers such as osteocalcin, procollagen type 1 N-terminal propeptide (P1NP) and urinary deoxypyridinoline (DPD). Areal BMD with corresponding <i>Z</i>-score was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and hip. Volumetric BMD and bone microstructure were assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and tibia.</p> </section> <section> <h3> Results</h3> <p>REDs was diagnosed in 24% of the athletes, and stress fractures were observed more frequently in athletes with REDs compared with those without REDs (70% vs. 25%, <i>p</i> < 0.001). Athletes with REDs showed significantly lower haemoglobin and haematocrit levels (<i>p</i> < 0.05). Osteocalcin and P1NP were reduced in REDs compared with athletes of strength-based disciplines (<i>p</i> < 0.01), while urinary DPD/creatinine and calcium excretion were elevated (<i>p</i> < 0.05), indicating suppressed bone formation and increased bone resorption, respectively. Athletes with REDs exhibited significantly reduced <i>Z</i>-scores at the lumbar spine and hip compared with strength and endurance athletes without REDs (<i>p</i> < 0.05). HR-pQCT revealed significantly lower bone volume to tissue volume and trabecular BMD at the distal radius and tibia, with more pronounced effects at the load-bearing tibia (<i>p</i> < 0.01). Similarly, trabecular number and cortical thickness were reduced in REDs, while no differences were observed in trabecular thickness.</p> </section> <section> <h3> Conclusion</h3> <p>Athletes with REDs are characterised by a catabolic bone metabolism, marked by reduced bone formati
{"title":"Impact of Relative Energy Deficiency in Sport (REDs) on Bone Health in Elite Athletes: A Retrospective Analysis","authors":"Felix N. von Brackel, Robert Munzinger, Mikolaj Bartosik, Alexander Simon, Florian Barvencik, Ralf Oheim, Michael Amling","doi":"10.1002/jcsm.70082","DOIUrl":"10.1002/jcsm.70082","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Relative energy deficiency in sport (REDs) is associated with impaired performance and compromised bone health in elite athletes. While reduced bone mineral density (BMD) and increased risk for bone stress injuries are well documented, the underlying metabolic mechanisms remain poorly understood. This study investigates the bone metabolism in athletes with REDs and its impact on BMD and bone microstructure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We retrospectively analysed data from 82 elite athletes (30.5% females, age 23.4 ± 7.6 years) who presented to our outpatient clinic. The diagnosis of REDs was made according to the International Olympic Committee REDs Clinical Assessment Tool Version 2 (IOC REDs CAT2), and athletes were categorised into strength-based vs. endurance-based sports. Laboratory assessment of calcium and bone metabolism included bone turnover markers such as osteocalcin, procollagen type 1 N-terminal propeptide (P1NP) and urinary deoxypyridinoline (DPD). Areal BMD with corresponding <i>Z</i>-score was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and hip. Volumetric BMD and bone microstructure were assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and tibia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>REDs was diagnosed in 24% of the athletes, and stress fractures were observed more frequently in athletes with REDs compared with those without REDs (70% vs. 25%, <i>p</i> < 0.001). Athletes with REDs showed significantly lower haemoglobin and haematocrit levels (<i>p</i> < 0.05). Osteocalcin and P1NP were reduced in REDs compared with athletes of strength-based disciplines (<i>p</i> < 0.01), while urinary DPD/creatinine and calcium excretion were elevated (<i>p</i> < 0.05), indicating suppressed bone formation and increased bone resorption, respectively. Athletes with REDs exhibited significantly reduced <i>Z</i>-scores at the lumbar spine and hip compared with strength and endurance athletes without REDs (<i>p</i> < 0.05). HR-pQCT revealed significantly lower bone volume to tissue volume and trabecular BMD at the distal radius and tibia, with more pronounced effects at the load-bearing tibia (<i>p</i> < 0.01). Similarly, trabecular number and cortical thickness were reduced in REDs, while no differences were observed in trabecular thickness.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Athletes with REDs are characterised by a catabolic bone metabolism, marked by reduced bone formati","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 5","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194642","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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