Journal of Cachexia Sarcopenia and Muscle最新文献

{"title":"Chaperone Proteins: The Rising Players in Muscle Atrophy","authors":"Davide Acquarone,&nbsp;Alessandro Bertero,&nbsp;Mara Brancaccio,&nbsp;Matteo Sorge","doi":"10.1002/jcsm.13659","DOIUrl":"10.1002/jcsm.13659","url":null,"abstract":"<p>Despite significant progress in understanding the molecular aetiology of muscle atrophy, there is still a great need for new targets and drugs capable of counteracting muscle wasting. The role of an impaired proteostasis as the underlying causal mechanism of muscle atrophy is a well-established concept. From the earliest work on muscle atrophy and the identification of the first atrogenes, the hyper-activation of the proteolytic systems, such as autophagy and the ubiquitin proteasome system, has been recognized as the major driver of atrophy. However, the role of other key regulators of proteostasis, the chaperone proteins, has been largely overlooked. Chaperone proteins play a pivotal role in protein folding and in preventing the aggregation of misfolded proteins. Indeed, some chaperones, such as αB-crystallin and Hsp25, are involved in compensatory responses aimed at counteracting protein aggregation during sarcopenia. Chaperones also regulate different intracellular signalling pathways crucial for atrogene expression and the control of protein catabolism, such as the AKT and NF-kB pathways, which are regulated by Hsp70 and Hsp90. Furthermore, the downregulation of certain chaperones causes severe muscle wasting per se and experimental strategies aimed at preventing this downregulation have shown promising results in mitigating or reversing muscle atrophy. This highlights the therapeutic potential of targeting chaperones and confirms their crucial anti-atrophic functions. In this review, we summarize the most relevant data showing the modulation and the causative role of chaperone proteins in different types of skeletal muscle atrophies.</p>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13659","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867275","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}

{"title":"Lonafarnib Protects Against Muscle Atrophy Induced by Dexamethasone","authors":"Sanghoon Bae,&nbsp;Van-Hieu Mai,&nbsp;Seyoung Mun,&nbsp;Dalong Dong,&nbsp;Kyudong Han,&nbsp;Sunghyouk Park,&nbsp;Jung Keun Hyun","doi":"10.1002/jcsm.13665","DOIUrl":"10.1002/jcsm.13665","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Muscle atrophy, including glucocorticoid-induced muscle wasting from treatments such as dexamethasone (DEX), results in significant reductions in muscle mass, strength and function. This study investigates the potential of lonafarnib, a farnesyltransferase inhibitor, to counteract DEX-induced muscle atrophy by targeting key signalling pathways.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We utilized in vitro models with C2C12 myotubes treated with DEX and in vivo models with &lt;i&gt;Caenorhabditis elegans&lt;/i&gt; and DEX-treated Sprague–Dawley rats. Myotube morphology was assessed by measuring area, fusion index and diameter. Muscle function was evaluated by grip strength and compound muscle action potential (CMAP) in the gastrocnemius (GC) and tibialis anterior (TA) muscles. Molecular mechanisms were explored through RNA sequencing and Western blotting to assess changes in mitochondrial function and muscle signalling pathways.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Lonafarnib (2 μM) significantly improved myotube area (1.49 ± 0.14 × 10&lt;sup&gt;5&lt;/sup&gt; μm&lt;sup&gt;2&lt;/sup&gt; vs. 1.03 ± 0.49 × 10&lt;sup&gt;5&lt;/sup&gt; μm&lt;sup&gt;2&lt;/sup&gt; in DEX, &lt;i&gt;p&lt;/i&gt; &lt; 0.05), fusion index (18.73 ± 1.23% vs. 13.3 ± 1.56% in DEX, &lt;i&gt;p&lt;/i&gt; &lt; 0.05) and myotube diameter (31.89 ± 0.89 μm vs. 21.56 ± 1.01 μm in DEX, &lt;i&gt;p&lt;/i&gt; &lt; 0.05) in C2C12 myotubes. In &lt;i&gt;C. elegans&lt;/i&gt;, lonafarnib (100 μM) increased the pharyngeal pumping rate from 212 ± 7.21 contractions/min in controls to 308 ± 17.09 contractions/min at day 4 (&lt;i&gt;p&lt;/i&gt; &lt; 0.05), indicating enhanced neuromuscular function. In DEX-induced atrophic rats, lonafarnib improved maximal grip strength (DEX: 13.91 ± 0.78 N vs. 1 μM lonafarnib: 16.18 ± 0.84 N and 5 μM lonafarnib: 16.71 ± 0.83 N, &lt;i&gt;p&lt;/i&gt; &lt; 0.05), increased muscle weight in GC, and enhanced CMAP amplitudes in both GC and TA muscles. Western blot analysis showed that lonafarnib treatment upregulated UCP3 and ANGPTL4 and increased phosphorylation of mTOR and S6 ribosomal protein (&lt;i&gt;p&lt;/i&gt; &lt; 0.05), indicating enhanced mitochondrial function and protein synthesis. Knockdown models further demonstrated that lonafarnib could partially rescue muscle atrophy phenotypes, indicating its action through multiple molecular pathways.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Lonafarnib mitigates dexamethasone-induced muscle atrophy by enhancing mitochondrial function and activating anabolic pathways. These findings support further investigation of lonafarnib as a therapeutic agent for muscle atrophy in clinical settings.&lt;/p&gt;\u0000 ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13665","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832709","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}

{"title":"Acute Sarcopenia: Systematic Review and Meta-Analysis on Its Incidence and Muscle Parameter Shifts During Hospitalisation","authors":"Luke Aldrich,&nbsp;Theocharis Ispoglou,&nbsp;Konstantinos Prokopidis,&nbsp;Jasem Alqallaf,&nbsp;Oliver Wilson,&nbsp;Antonis Stavropoulos-Kalinoglou","doi":"10.1002/jcsm.13662","DOIUrl":"10.1002/jcsm.13662","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Acute sarcopenia is sarcopenia lasting less than 6 months, typically following acute illness or injury. It may impact patient recovery and quality of life, advancing to chronic sarcopenia. However, its development and assessment remain poorly understood, particularly during hospitalisation. This systematic review aimed to elucidate the incidence of acute sarcopenia and examine changes in muscle parameters during hospitalisation.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Eighty-eight papers were included in the narrative synthesis; 33 provided data for meta-analyses on the effects of hospitalisation on handgrip strength (HGS), rectus femoris cross-sectional area (RFCSA) and various muscle function tests. Meta-regressions were performed for length of hospital stay (LoS) and age for all meta-analyses; sex was also considered for HGS.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Acute sarcopenia development was assessed in four studies with a pooled incidence of 18% during hospitalisation. Incidence was highest among trauma patients in intensive care (59%), whereas it was lower among medical and surgical patients (15%–20%). Time of development ranged from 4 to 44 days. HGS remained stable during hospitalisation (SMD = 0.05, 95% CI = −0.18:0.28, &lt;i&gt;p&lt;/i&gt; = 0.67) as did knee extensor strength. LoS affected HGS performance (θ = 0.04, 95% CI = 0.001:0.09, &lt;i&gt;p&lt;/i&gt; = 0.045) but age (&lt;i&gt;p&lt;/i&gt; = 0.903) and sex (&lt;i&gt;p&lt;/i&gt; = 0.434) did not. RFCSA, reduced by 16.5% over 3–21 days (SMD = −0.67, 95% CI = −0.92:−0.43, &lt;i&gt;p&lt;/i&gt; &lt; 0.001); LoS or time between scans did significantly predict the reduction (θ = −0.04, 95% CI = −0.077:−0.011, &lt;i&gt;p&lt;/i&gt; = 0.012). Indices of muscle quality also reduced. Muscle function improved when assessed by the short physical performance battery (SMD = 0.86, 95% CI = 0.03:1.69, &lt;i&gt;p&lt;/i&gt; = 0.046); there was no change in 6-min walk (&lt;i&gt;p&lt;/i&gt; = 0.22), timed up-and-go (&lt;i&gt;p&lt;/i&gt; = 0.46) or gait speed tests (&lt;i&gt;p&lt;/i&gt; = 0.98). The only significant predictor of timed up-and-go performance was age (θ = −0.11, 95% CI = −0.018:−0.005, &lt;i&gt;p&lt;/i&gt; = 0.009).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Assessment and understanding of acute sarcopenia in clinical settings are limited. Incidence varies between clinical conditions, and muscle parameters are affected differently. HGS and muscle function tests may not be sensitive enough to identify acute changes during hospitalisation. Currently, muscle health deterioration may be underdiagnosed impacting recovery, quality of life and overall health follo","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13662","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841431","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}

{"title":"Low Skeletal Muscle Radiodensity Predicts Response to CDK4/6 Inhibitors Plus Aromatase Inhibitors in Advanced Breast Cancer","authors":"Hyunwook Kim,&nbsp;Seungjin Baek,&nbsp;Sookyeong Han,&nbsp;Gun Min Kim,&nbsp;Joohyuk Sohn,&nbsp;Yumie Rhee,&nbsp;Namki Hong,&nbsp;Min Hwan Kim","doi":"10.1002/jcsm.13666","DOIUrl":"10.1002/jcsm.13666","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Recent evidence indicates that a dysregulated host metabolism influences treatment outcomes in patients with breast cancer. We investigated the association of computed tomography (CT)-derived body composition indices with therapeutic responses in patients with hormone receptor-positive, HER2-negative advanced breast cancer (ABC) on endocrine plus CDK4/6 inhibitor (CDK4/6i) treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The study involved a retrospective cohort of patients with ABC at the Yonsei Cancer Center who received CDK4/6i and aromatase inhibitors as first-line therapy between January 2017 and October 2020. Body composition parameters were estimated from the non-enhanced CT images of the third lumbar spine by commercialized deep learning software. Patients with low skeletal muscle radiodensity (SMD) were defined as patients with SMD of low tertile (≤ 28.7 Hounsfield Units). The primary outcome was progression-free survival (PFS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among the 247 female participants (median age, 53 years; mean body mass index [BMI], 23.7 kg/m²), 45.7% had disease progression or death during a median follow-up of 36.4 months. After adjusting for age and visceral metastasis, SMD was the only independent predictor among body composition parameters for worse PFS (adjusted hazard ratio [HR] = 1.20 per standard deviation decrement, 95% CI: 1.01–1.42, <i>p</i> = 0.041), whereas BMI, muscle area, and fat area were not. Participants with low SMD had a higher risk of progression than those without (PFS, 27.2 vs. 51.1 months, <i>p</i> = 0.009; adjusted HR 1.84, 95% CI: 1.22–2.76, <i>p</i> = 0.003). Strong associations between low SMD and poor PFS were observed in groups with pre-menopause status (HR, 3.04 vs. 1.19 in post-menopause; 95% CI: 1.54–5.99, <i>p</i> for interaction &lt; 0.05) and without visceral metastases (HR, 2.95 vs. 1.19 in with visceral metastases; 95% CI: 1.59–5.49, <i>p</i> for interaction &lt; 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>CT-defined low SMD predicts poor treatment outcomes in patients with ABC undergoing first-line treatment with aromatase inhibitors and CDK4/6i.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13666","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832697","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}

{"title":"Muscle Mass Index Decline as a Predictor of Lung Function Reduction in the General Population","authors":"Joon Young Choi,&nbsp;Chin Kook Rhee,&nbsp;Sang Hyuk Kim,&nbsp;Yong Suk Jo","doi":"10.1002/jcsm.13663","DOIUrl":"10.1002/jcsm.13663","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>This study explores the link between muscle mass decline and lung function deterioration, which can worsen respiratory health by reducing exercise capacity and quality of life. The relationship between muscle mass index (MMI) changes and lung function in the general population remains unclear, especially as muscle mass fluctuates with aging. We aimed to clarify this dynamic relationship by examining how changes in muscle mass impact pulmonary function and the development of respiratory symptoms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We utilized the Ansan and Ansung Cohort Study of the Korean Genome and Epidemiology Study (KoGES) database, a large-scale prospective cohort, enrolling participants aged 40 to 69 years with lung function and body composition measurements. Over 12 years, data were collected biannually. The study assessed associations between changes in MMI and lung function trends, with cT1-T3 calculated using the linear regression coefficient and stratified by tertile. Survival analysis was then performed to examine differences in time to first airflow obstruction (AFO) and exacerbation among the tertiles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 2956 participants were enrolled in this study. At baseline, participants with higher MMI tended to be younger, had fewer co-morbidities and exhibited better lung function. Those with a steeper MMI decline rate exhibited a more rapid forced expiratory volume in 1 s (FEV₁) decline over a 12-year follow-up (cT1: 43.3 mL/year, cT2: 38.4 mL/year, cT3: 33.2 mL/year, <i>p</i> &lt; 0.001). Forced vital capacity (FVC) decline were more pronounced in groups with greater MMI decline rates (cT1: 38.5 mL/year, cT2: 32.8 mL/year, cT3: 26.0 mL/year, <i>p</i> &lt; 0.001). Although, the time to first AFO did not differ significantly among T1-T3 groups, the time to first exacerbation related to wheezing event was significantly lower in cT3 group than in cT1 group (HR: 0.786, 95% CI: 0.629, 0.982).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>A faster decline in MMI was associated with more rapid decline of both FEV₁ and FVC and a higher risk of developing exacerbations of respiratory symptom. Although AFO was not associated with changes in MMI, further research is needed to explore the long-term relationships between muscle mass and the effects of preventive interventions aimed at maintaining muscle mass and respiratory health.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13663","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832700","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}

{"title":"Risk of Sarcopenia Following Long-Term Statin Use in Community-Dwelling Middle-Aged and Older Adults in Japan","authors":"Shih-Tsung Huang,&nbsp;Rei Otsuka,&nbsp;Yukiko Nishita,&nbsp;Lin-Chieh Meng,&nbsp;Fei-Yuan Hsiao,&nbsp;Hiroshi Shimokata,&nbsp;Liang-Kung Chen,&nbsp;Hidenori Arai","doi":"10.1002/jcsm.13660","DOIUrl":"10.1002/jcsm.13660","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Inconsistent results have been reported concerning the association between statin administration and muscle health, specifically its potential to increase the risk of sarcopenia. Given the widespread long-term use of statins among the elderly population, the exploration of this association remains a crucial yet insufficiently examined matter. This study aimed to assess the association between the prolonged administration of statins and the risk of sarcopenia, diminished muscle strength, reduced skeletal muscle mass and impaired physical performance.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This population-based cohort study was conducted in Japan utilizing data derived from the National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA). The study participants, enlisted from the 2nd to the 6th waves (spanning from April 2000 to July 2010) of NILS-LSA, were those who aged 40 years or older and had initiated statin therapy (&lt;i&gt;n&lt;/i&gt; = 348, age: 64.1 years, female: 63.5%). Individuals who were not administered statins (&lt;i&gt;n&lt;/i&gt; = 2559, age: 55.5 years, female: 48.4%) were arbitrarily chosen using a combined approach of propensity score (PS) matching and risk set sampling to form the control group (with a 1:4 matching ratio). The primary outcome of this study was the occurrence of sarcopenia, as defined by the 2019 consensus of the Asian Working Group for Sarcopenia (AWGS). The secondary outcomes included low muscle mass (&lt; 7.0 kg/m&lt;sup&gt;2&lt;/sup&gt; for men and below 5.4 kg/m&lt;sup&gt;2&lt;/sup&gt; for women by DXA), reduced skeletal muscle strength (handgrip strength &lt; 28 kg in men and &lt; 18 kg in women) and subpar physical performance (6-min walking speed &lt; 1.0 m/s). The relationship between the use of statins and the outcomes was estimated using a Cox proportional hazard model with time-varying covariates, which included the status of statin use and other variables (two-tailed &lt;i&gt;p&lt;/i&gt; &lt; 0.05 was considered statistically significant). Stratification based on age and sex, along with five sensitivity analyses—including propensity score overlap weighting and a negative control—was conducted.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;After applying PS matching, we identified 342 statin initiators and 1294 non-statin users, with well-balanced baseline characteristics between the groups. The use of statins was not associated with an increased risk of incident sarcopenia (adjusted hazard ratio [aHR], 1.43 [95% CI, 0.86, 2.36]), diminished muscle strength (aHR, 1.11 [95% CI, 0.80, 1.54]), reduced muscle mass (aHR, 1.09 [95% CI, 0.66, 1.82]) or impaired physical performance (aHR, 0.73 [95% C","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13660","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825131","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}

{"title":"Pharmacokinetics, Pharmacodynamics and Bioavailability of ACM-001.1 (S-Pindolol Benzoate) in Healthy Volunteers","authors":"Frank Misselwitz,&nbsp;Dennis Henderson,&nbsp;Somasekhara R. Menakuru,&nbsp;Elaine Morten,&nbsp;Chris Roe,&nbsp;Gareth Whitaker,&nbsp;Stefan Wohlfeil,&nbsp;John McDermott","doi":"10.1002/jcsm.13651","DOIUrl":"10.1002/jcsm.13651","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;&lt;i&gt;S&lt;/i&gt;-pindolol has metabolic effects of potential benefit in cancer cachexia: reduced catabolism through nonselective β-blockade; increased anabolism through partial β2 receptor agonism; and increased appetite and reduced fatigue through central 5-hydroxytryptamine/serotonin receptor activity. A Phase 2a clinical trial demonstrated that &lt;i&gt;S&lt;/i&gt;-pindolol can reverse weight loss and improve fat-free mass in patients with cancer-related weight loss. A comparative phase I bioavailability study of &lt;i&gt;S&lt;/i&gt;-pindolol and racemic pindolol was performed to support the development of &lt;i&gt;S&lt;/i&gt;-pindolol in cancer cachexia.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This two-part study assessed the comparative bioavailability and pharmacokinetics of single doses of &lt;i&gt;S&lt;/i&gt;-pindolol benzoate (ACM-001.1) or pindolol (Part 1) and the steady-state pharmacokinetics and pharmacodynamics of multiple doses of ACM-001.1 and pindolol (Part 2) in healthy volunteers (NCT06028321). ACM-001.1 5, 10 and 15 mg and pindolol 15, 20 and 30 mg were tested. In Part 1, subjects were randomised to ACM-001.1 15 mg followed after a 48-h washout period by pindolol 30 mg, or the reverse sequence; another group received pindolol 15 mg. Subjects in Part 2 were randomised to pindolol 20 mg twice-daily or ACM-001.1 5, 10 or 15 mg twice-daily for 4 days. Bioavailability, pharmacokinetics, pharmacodynamics, potential for and extent of stereoconversion, and tolerability were assessed.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Parts 1 and 2 included 24 and 27 healthy volunteers, respectively. ACM-001.1 had predictable pharmacokinetics up to a dose of 15 mg twice daily, with low intersubject variability, after single and multiple doses (&lt;i&gt;T&lt;/i&gt;&lt;sub&gt;max&lt;/sub&gt; 1 vs. 1.5 h; &lt;i&gt;C&lt;/i&gt;&lt;sub&gt;max&lt;/sub&gt; 74 vs. 73.6 ng/mL; AUC&lt;sub&gt;(0−&lt;i&gt;t&lt;/i&gt;)&lt;/sub&gt; 440 vs. 414 ng·h/mL; &lt;i&gt;t&lt;/i&gt;&lt;sub&gt;1/2&lt;/sub&gt; 4.042 vs. 3.566 h). The bioavailability of &lt;i&gt;S&lt;/i&gt;-pindolol after equivalent doses of pindolol (20 mg) and ACM-001.1 (10 mg) was comparable, and formal bioequivalence margins were met (90% CI for &lt;i&gt;C&lt;/i&gt;&lt;sub&gt;max&lt;/sub&gt;, AUC&lt;sub&gt;(0−&lt;i&gt;t&lt;/i&gt;)&lt;/sub&gt; and AUC&lt;sub&gt;(0–inf)&lt;/sub&gt; within 80%–125% bioequivalence acceptance criteria). No evidence of stereoconversion of the &lt;i&gt;S&lt;/i&gt;-enantiomer into the &lt;i&gt;R&lt;/i&gt;-enantiomer, no accumulation, dose linearity and dose proportionality of &lt;i&gt;S&lt;/i&gt;-pindolol over a range of doses were demonstrated; we also show indirectly that there was no food effect. ACM-001.1 was generally well tolerated, with no apparent relationship of side effects to dose, no serious adverse events, severe treatment-emergent adverse events (TEAEs) or deaths, and s","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13651","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142810077","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}

{"title":"With Appreciation","authors":"","doi":"10.1002/jcsm.13686","DOIUrl":"10.1002/jcsm.13686","url":null,"abstract":"&lt;p&gt;We thank the following individuals who served as manuscript reviewers for The Journal of Cachexia, Sarcopenia and Muscle (JCSM) in 2024.&lt;/p&gt;&lt;p&gt;We highly appreciate their efforts.&lt;/p&gt;&lt;p&gt;Fair, conscientious and timely peer reviews contribute to the success of JCSM.&lt;/p&gt;&lt;p&gt;The Editors.&lt;/p&gt;&lt;p&gt;Olasunkanmi Adegoke&lt;/p&gt;&lt;p&gt;Jiyun Ahn&lt;/p&gt;&lt;p&gt;Amy Attaway&lt;/p&gt;&lt;p&gt;Vickie Baracos&lt;/p&gt;&lt;p&gt;Patricia Batista&lt;/p&gt;&lt;p&gt;Catherine Bellissimo&lt;/p&gt;&lt;p&gt;Philip Bonomi&lt;/p&gt;&lt;p&gt;Leo Brown&lt;/p&gt;&lt;p&gt;Liang-Kung Chen&lt;/p&gt;&lt;p&gt;Xian Wu Cheng&lt;/p&gt;&lt;p&gt;Wai Cheung&lt;/p&gt;&lt;p&gt;Jeffrey Crawford&lt;/p&gt;&lt;p&gt;Rafaela Espírito Santo&lt;/p&gt;&lt;p&gt;Jens Fielitz&lt;/p&gt;&lt;p&gt;Denis Guttridge&lt;/p&gt;&lt;p&gt;Yoshitaka Hashimoto&lt;/p&gt;&lt;p&gt;Satoshi Ikeda&lt;/p&gt;&lt;p&gt;Hee-Won Jung&lt;/p&gt;&lt;p&gt;Serkan Kir&lt;/p&gt;&lt;p&gt;Masaaki Konishi&lt;/p&gt;&lt;p&gt;Barry Laird&lt;/p&gt;&lt;p&gt;Ning Li&lt;/p&gt;&lt;p&gt;Ryan McGrath&lt;/p&gt;&lt;p&gt;Tateaki Naito&lt;/p&gt;&lt;p&gt;Gopal Nambi&lt;/p&gt;&lt;p&gt;Miguel Naveira&lt;/p&gt;&lt;p&gt;Amirabbas Nikkhah&lt;/p&gt;&lt;p&gt;Mats Nilsson&lt;/p&gt;&lt;p&gt;Masatsugu Okamura&lt;/p&gt;&lt;p&gt;Luciana Pereira&lt;/p&gt;&lt;p&gt;Ishan Roy&lt;/p&gt;&lt;p&gt;Guo-Tian Ruan&lt;/p&gt;&lt;p&gt;Kunihiro Sakuma&lt;/p&gt;&lt;p&gt;Hiroshi Shamoto&lt;/p&gt;&lt;p&gt;Mitsuhiro Shimura&lt;/p&gt;&lt;p&gt;Liz Simon Peter&lt;/p&gt;&lt;p&gt;Vanessa Stadlbauer&lt;/p&gt;&lt;p&gt;Ming Yang&lt;/p&gt;&lt;p&gt;Yoshihiro Yoshimura&lt;/p&gt;&lt;p&gt;Belgin Akan&lt;/p&gt;&lt;p&gt;Eva Alves&lt;/p&gt;&lt;p&gt;Elia Angelino&lt;/p&gt;&lt;p&gt;Nile Banks&lt;/p&gt;&lt;p&gt;Jing-Fu Bao&lt;/p&gt;&lt;p&gt;Jose Barreto Carvalheira&lt;/p&gt;&lt;p&gt;Linda Beenet&lt;/p&gt;&lt;p&gt;Laure B. Bindels&lt;/p&gt;&lt;p&gt;Richard Bohannon&lt;/p&gt;&lt;p&gt;Miguel Borda&lt;/p&gt;&lt;p&gt;Arben Boshnjaku&lt;/p&gt;&lt;p&gt;Marina Bouche&lt;/p&gt;&lt;p&gt;Jeffrey Brault&lt;/p&gt;&lt;p&gt;Danna Breen&lt;/p&gt;&lt;p&gt;Dean Campelj&lt;/p&gt;&lt;p&gt;An-Chih Chang&lt;/p&gt;&lt;p&gt;Wei Chen&lt;/p&gt;&lt;p&gt;Zi Chen&lt;/p&gt;&lt;p&gt;Paola Costelli&lt;/p&gt;&lt;p&gt;Brittany Counts&lt;/p&gt;&lt;p&gt;Adeline Dolly&lt;/p&gt;&lt;p&gt;Richard Ehman&lt;/p&gt;&lt;p&gt;Mert Eşme&lt;/p&gt;&lt;p&gt;Susanne Fleig&lt;/p&gt;&lt;p&gt;Wie Gao&lt;/p&gt;&lt;p&gt;Nicholas Greene&lt;/p&gt;&lt;p&gt;Daniel Ham&lt;/p&gt;&lt;p&gt;Tewfik Hamidi&lt;/p&gt;&lt;p&gt;Sabah Hussain&lt;/p&gt;&lt;p&gt;Krystian Josiak&lt;/p&gt;&lt;p&gt;Nicole Kiss&lt;/p&gt;&lt;p&gt;Adam Kuchnia&lt;/p&gt;&lt;p&gt;Wei-Ju Lee&lt;/p&gt;&lt;p&gt;Daniel Marks&lt;/p&gt;&lt;p&gt;Radmila Matijevic&lt;/p&gt;&lt;p&gt;Alexandra Mayhew&lt;/p&gt;&lt;p&gt;Chris McGlory&lt;/p&gt;&lt;p&gt;Benjamin Miller&lt;/p&gt;&lt;p&gt;Yusuke Nishimura&lt;/p&gt;&lt;p&gt;Mario Perez-Zepeda&lt;/p&gt;&lt;p&gt;Christopher Perry&lt;/p&gt;&lt;p&gt;Carla Prado&lt;/p&gt;&lt;p&gt;Andrea David Re Cecconi&lt;/p&gt;&lt;p&gt;Vanina Romanello&lt;/p&gt;&lt;p&gt;Megan Rosa-Caldwell&lt;/p&gt;&lt;p&gt;Akihiro Sakuyama&lt;/p&gt;&lt;p&gt;Rengfei Shi&lt;/p&gt;&lt;p&gt;Ng Shyh-Chang&lt;/p&gt;&lt;p&gt;Brandon VanderVeen&lt;/p&gt;&lt;p&gt;Noah Weisleder&lt;/p&gt;&lt;p&gt;Leo Westbury&lt;/p&gt;&lt;p&gt;Sandra Zampieri&lt;/p&gt;&lt;p&gt;Silke Zimmermann&lt;/p&gt;&lt;p&gt;Ece Acar&lt;/p&gt;&lt;p&gt;Hiroaki Adachi&lt;/p&gt;&lt;p&gt;Volker Adams&lt;/p&gt;&lt;p&gt;Bumsoo Ahn&lt;/p&gt;&lt;p&gt;Takeru Akabane&lt;/p&gt;&lt;p&gt;Naoki Akazawa&lt;/p&gt;&lt;p&gt;Julian Alcazar&lt;/p&gt;&lt;p&gt;Matthew Alexander&lt;/p&gt;&lt;p&gt;Tiago Alexandre&lt;/p&gt;&lt;p&gt;Hazim Alhiti&lt;/p&gt;&lt;p&gt;Hamed Alizadeh pahlavani&lt;/p&gt;&lt;p&gt;Stephen Alway&lt;/p&gt;&lt;p&gt;Hilman Amin&lt;/p&gt;&lt;p&gt;Ethan Anderson&lt;/p&gt;&lt;p&gt;Hidenori Arai&lt;/p&gt;&lt;p&gt;Amelia Aranega&lt;/p&gt;&lt;p&gt;Gopalakrishnan Aneeshkumar Arimbasseri&lt;/p&gt;&lt;p&gt;Paige Arneson-Wissink&lt;/p&gt;&lt;p&gt;Christopher Axelrod&lt;/p&gt;&lt;p&gt;Martin Bahls&lt;/p&gt;&lt;p&gt;Luke Baker&lt;/p&gt;&lt;p&gt;Omar Baritello&lt;/p&gt;&lt;p&gt;Elisabeth Barton&lt;/p&gt;&lt;p&gt;Joshua Barzilay&lt;/p&gt;&lt;p&gt;Yuri Battaglia&lt;/p&gt;&lt;p&gt;Philipp Baumert&lt;/p&gt;&lt;p&gt;Annette Bellar&lt;/p&gt;&lt;p&gt;Marc Beltrà&lt;/p&gt;&lt;p&gt;Maximilien Bencze&lt;/p&gt;&lt;p&gt;Cécile Bétry&lt;/p&gt;&lt;p&gt;Jose-Ramon Blanco&lt;/p&gt;&lt;p&gt;Marc Bonnefoy&lt;/p&gt;&lt;p&gt;Piers Boshier&lt;/p&gt;&lt;p&gt;Pedro Braga&lt;/p&gt;&lt;p&gt;Ellen Breen&lt;/p&gt;&lt;p&gt;David Brigstock&lt;/p&gt;&lt;p&gt;Marco Brotto&lt;/p&gt;&lt;p&gt;Jacob B","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 6","pages":"2901-2903"},"PeriodicalIF":9.4,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13686","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809264","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}

{"title":"Feature Engineering for the Prediction of Scoliosis in 5q-Spinal Muscular Atrophy","authors":"Tu-Lan Vu-Han,&nbsp;Vikram Sunkara,&nbsp;Rodrigo Bermudez-Schettino,&nbsp;Jakob Schwechten,&nbsp;Robin Runge,&nbsp;Carsten Perka,&nbsp;Tobias Winkler,&nbsp;Sebastian Pokutta,&nbsp;Claudia Weiß,&nbsp;Matthias Pumberger","doi":"10.1002/jcsm.13599","DOIUrl":"10.1002/jcsm.13599","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;5q-Spinal muscular atrophy (SMA) is now one of the 5% treatable rare diseases worldwide. As disease-modifying therapies alter disease progression and patient phenotypes, paediatricians and consulting disciplines face new unknowns in their treatment decisions. Conclusions made from historical patient data sets are now mostly limited, and new approaches are needed to ensure our continued best standard-of-care practices for this exceptional patient group. Here, we present a data-driven machine learning approach to a rare disease data set to predict spinal muscular atrophy (SMA)-associated scoliosis.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We collected data from 84 genetically confirmed 5q-SMA patients who have received novel SMA therapies. We performed expert domain knowledge-directed feature engineering, correlation and predictive power score (PPS) analyses for feature selection. To test the predictive performance of the selected features, we trained a Random Forest Classifier and evaluated model performance using standard metrics.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The SMA data set consisted of 1304 visits and over 360 variables. We performed feature engineering for variables related to ‘interventions’, ‘devices’, ‘orthosis’, ‘ventilation’, ‘muscle contractures’ and ‘motor milestones’. Through correlation and PPS analysis paired with expert domain knowledge feature selection, we identified relevant features for scoliosis prediction in SMA that included disease progression markers: Hammersmith Functional Motor Scale Expanded ‘HFMSE’ (PPS = 0.27) and 6-Minute Walk Test ‘6MWT’ scores (PPS = 0.44), ‘age’ (PPS = 0.41) and ‘weight’ (PPS = 0.49), ‘contractures’ (PPS = 0.17), the use of ‘assistive devices’ (PPS = 0.39, ‘ventilation’ (PPS = 0.16) and the presence of ‘gastric tubes’ (PPS = 0.35) in SMA patients. These features were validated using expert domain knowledge and used to train a Random Forest Classifier with an observed accuracy of 0.82 and an average receiver operating characteristic (ROC) area of 0.87.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The introduction of disease-modifying SMA therapies, followed by the implementation of SMA in newborn screenings, has presented physicians with never-seen patients. We used feature engineering tools to overcome one of the main challenges when using data-driven approaches in rare disease data sets. Through predictive modelling of this data, we defined disease progression markers, which are easily assessed during patient visits and can help anti","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13599","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782374","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}

{"title":"Comment on “Total Magnesium Intake and Risk of Frailty in Older Women” by Struijk et al.—The Authors' Reply","authors":"Ellen A. Struijk,&nbsp;Teresa T. Fung,&nbsp;Heike A. Bischoff-Ferrari,&nbsp;Walter C. Willett,&nbsp;Esther Lopez-Garcia","doi":"10.1002/jcsm.13653","DOIUrl":"10.1002/jcsm.13653","url":null,"abstract":"<p>We would like to thank you for the opportunity to respond to the issues raised in the letter by Drs Guo, Lan, Zhou and Liu [<span>1</span>]. The authors raise the concern that the long follow-up of our cohort study has affected the robustness of the study results. The data used from the Nurses' Health Study have the advantage of repeated dietary measurements over a long study period. Therefore, the cumulative average of dietary magnesium intake was assessed in association with frailty incidence since this best reflects long-term intake [<span>2</span>]. However, due to the strong increase in supplement intake over the years, we used a different approach for the supplemental magnesium intake and considered the most recent supplemental magnesium intake before frailty onset or the end of follow-up. Additionally, when no specific supplement brand was given, the supplemental magnesium intake was estimated as well as possible based on the most frequently used supplement on the market in the year the food frequency questionnaire was returned.</p><p>The authors of the letter are right that supplement users may be more likely to already have a deteriorated functional status. We have addressed this by repeating the analysis excluding women who were prefrail and by excluding women with cancer, diabetes, or heart disease at baseline; the association between supplemental magnesium and frailty remained non-significant.</p><p>We agree that social workers are important players in supporting the needs of older adults and more research is needed to understand how supplement use can improve health among older adults. Older adults for whom healthy eating can be a challenge due to dental problems, chewing difficulties, high costs of healthy foods or loss of appetite, a multivitamin supplement including magnesium may be of benefit to reach an adequate nutrient intake [<span>3</span>].</p><p>The main message of our study is that, for most older adults, an optimal palatable diet pattern that provides enough minerals, as well as an optimal macronutrient composition, is likely to help prevent the development of geriatric syndromes.</p>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13653","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763181","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}