Journal of Cachexia, Sarcopenia and Muscle最新文献

{"title":"How can we design a proper trial for vitamin D treatment of diseases? Facts and numbers","authors":"Shuang Zheng,&nbsp;Zhaohua Zhu,&nbsp;Changhai Ding","doi":"10.1002/jcsm.13200","DOIUrl":"https://doi.org/10.1002/jcsm.13200","url":null,"abstract":"<p>Vitamin D deficiency is a globally common situation and closely related with many chronic diseases. It is a hot topic to examine if vitamin D supplementation is effective for the treatment of diseases, and there have been dozens of clinical trials published in recent years. However, most studies have not proved the extra-skeletal benefits of vitamin D supplementation on these diseases. Some inherent shortcomings of these trials, such as inclusion with vitamin D-sufficient and obese participants, low response rate from participants and the insensitive changes in chosen outcomes over a shorter period, may be main reasons why most studies have yet to demonstrate effects of vitamin D supplementation. In this editorial, we aim to discuss the perspectives on how can we design a proper trial for vitamin D treatment of diseases based on the evidence-based practice framework PICOS (participants, intervention, control, outcomes and study design) in the future. First, right participants should be chosen, which is crucial for the success of vitamin D clinical trials. Participants with vitamin D sufficiency (e.g., baseline 25(OH)D of &gt;50 nmol/L), obesity (e.g., body mass index &gt; 30 kg/m²) and/or high vitamin D response index could be excluded from the trials. Second, intervention with vitamin D in right forms or dosages should be used. Vitamin D₃ supplementation with appropriate dosages that keep 25(OH)D levels between 75 and 100 nmol/L is recommended. Third, ‘contamination’ in the control groups needs to pay attention. To diminish this, it is ideal to include participants less interfered by sun exposure (such as living in places at a high latitude) or with greater compliance (less interference by supplemental vitamin D-containing nutrients). Fourth, the outcome measures should be sensitive to change to avoid type II error. For outcomes such as bone density, radiographic osteoarthritis and cardiovascular diseases, follow-up period of 3–5 years may be required to observe the changes. Last, precision clinical trials may be the only way to prove the benefits of vitamin D supplementation.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1146-1149"},"PeriodicalIF":8.9,"publicationDate":"2023-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13200","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5708524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct electrical stimulation impacts on neuromuscular junction morphology on both stimulated and unstimulated contralateral soleus","authors":"Young il Lee,&nbsp;Nicola Cacciani,&nbsp;Ya Wen,&nbsp;Xiang Zhang,&nbsp;Yvette Hedstr?m,&nbsp;Wesley Thompson,&nbsp;Lars Larsson","doi":"10.1002/jcsm.13235","DOIUrl":"https://doi.org/10.1002/jcsm.13235","url":null,"abstract":"There is increasing evidence of crosstalk between organs. The neuromuscular junction (NMJ) is a peripheral chemical synapse whose function and morphology are sensitive to acetylcholine (ACh) release and muscle depolarization. In an attempt to improve our understanding of NMJ plasticity and muscle crosstalk, the effects of unilateral direct electrical stimulation of a hindlimb muscle on the NMJ were investigated in rats exposed long‐term post‐synaptic neuromuscular blockade.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1533-1545"},"PeriodicalIF":8.9,"publicationDate":"2023-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13235","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6142809","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":"Exercise for sarcopenia in older people: A systematic review and network meta-analysis","authors":"Yanjiao Shen,&nbsp;Qingyang Shi,&nbsp;Kailei Nong,&nbsp;Sheyu Li,&nbsp;Jirong Yue,&nbsp;Jin Huang,&nbsp;Birong Dong,&nbsp;Marla Beauchamp,&nbsp;Qiukui Hao","doi":"10.1002/jcsm.13225","DOIUrl":"https://doi.org/10.1002/jcsm.13225","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sarcopenia is a serious public health concern among older adults worldwide. Exercise is the most common intervention for sarcopenia. This study aimed to compare the effectiveness of different exercise types for older adults with sarcopenia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Randomized controlled trials (RCTs) that examined the effectiveness of exercise interventions on patient-important outcomes for older adults with sarcopenia were eligible. We systematically searched MEDLINE, Embase and Cochrane Central Register of Controlled Trials via Ovid until 3 June 2022. We used frequentist random-effects network meta-analyses to summarize the evidence and applied the Grading of Recommendations, Assessment, Development, and Evaluations framework to rate the certainty of evidence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our search identified 5988 citations, of which 42 RCTs proved eligible with 3728 participants with sarcopenia (median age: 72.9 years, female: 73.3%) with a median follow-up of 12 weeks. We are interested in patient-important outcomes that include mortality, quality of life, muscle strength and physical function measures. High or moderate certainty evidence suggested that resistance exercise with or without nutrition and the combination of resistance exercise with aerobic and balance training were the most effective interventions for improving quality of life compared to usual care (standardized mean difference from 0.68 to 1.11). Moderate certainty evidence showed that resistance and balance exercise plus nutrition (mean difference [MD]: 4.19 kg) was the most effective for improving handgrip strength (minimally important difference [MID]: 5 kg). Resistance and balance exercise with or without nutrition (MD: 0.16 m/s, moderate) were the most effective for improving physical function measured by usual gait speed (MID: 0.1 m/s). Moderate certainty evidence showed that resistance and balance exercise (MD: 1.85 s) was intermediately effective for improving physical function measured by timed up and go test (MID: 2.1 s). High certainty evidence showed that resistance and aerobic, or resistance and balance, or resistance and aerobic exercise plus nutrition (MD from 1.72 to 2.28 s) were intermediately effective for improving physical function measured by the five-repetition chair stand test (MID: 2.3 s).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In older adults with sarcopenia, high or moderate certainty evidence showed that resistance exercise with or without nutrition and the combin","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1199-1211"},"PeriodicalIF":8.9,"publicationDate":"2023-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6126821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of exercise habits in adolescence and older age on sarcopenia risk in older adults: the Bunkyo Health Study","authors":"Hiroki Tabata,&nbsp;Hikaru Otsuka,&nbsp;Huicong Shi,&nbsp;Mari Sugimoto,&nbsp;Hideyoshi Kaga,&nbsp;Yuki Someya,&nbsp;Hitoshi Naito,&nbsp;Naoaki Ito,&nbsp;Abulaiti Abudurezake,&nbsp;Futaba Umemura,&nbsp;Mai Kiya,&nbsp;Tsubasa Tajima,&nbsp;Saori Kakehi,&nbsp;Yasuyo Yoshizawa,&nbsp;Ryuzo Kawamori,&nbsp;Hirotaka Watada,&nbsp;Yoshifumi Tamura","doi":"10.1002/jcsm.13218","DOIUrl":"https://doi.org/10.1002/jcsm.13218","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sarcopenia, defined as an age-associated loss of skeletal muscle mass and function, is a major risk factor for requiring long-term care. Because physical activity in adolescence and older age enhances peak muscle function in youth and prevents muscle function decline in older age, older adults with exercise habits during both periods may be at a lower risk for sarcopenia. We investigated the relationship between exercise habits in adolescence and older age and sarcopenia and its components in community-dwelling older Japanese adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study included 1607 community-dwelling individuals (aged 65–84, medians 73 years, 679 men and 928 women) with complete health examinations, including measurements of skeletal muscle index, handgrip strength and gait speed, who were enrolled in the Bunkyo Health Study. We divided the participants into four groups according to exercise habits in adolescence and older age: no exercise in either period (none-none; NN), exercise only in adolescence (active-none; AN), exercise only in older age (none-active; NA) and exercise in both periods (active-active; AA). Multivariate-adjusted logistic regression models were used to estimate the odds ratios (ORs) and associated 95% confidence intervals (CIs) in each group for the prevalence of sarcopenia, defined as low muscle mass and low muscle performance, as compared with the NN group. Low muscle performance was defined as low muscle strength and/or low gait speed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The total prevalence of sarcopenia was 6.6% (45/679) in men and 1.7% (16/928) in women, the total prevalence of low muscle mass was 14.3% (97/679) in men and 5.2% (48/928) in women, and the total prevalence of low muscle performance was 25.6% (174/679) in men and 19.6% (182/928) in women. In men, the ORs (95% CIs) for sarcopenia, low muscle mass and low muscle performance were significantly lower in the AA group (sarcopenia: 0.29 [0.09–0.95], <i>P</i> = 0.041; low muscle mass: 0.21 [0.09–0.52], <i>P</i> = 0.001; and low muscle performance: 0.52 [0.28–0.97], <i>P</i> = 0.038). In women, the OR (95% CI) for low muscle performance was significantly lower in the AA group than in the other groups (0.48 [0.27–0.84], <i>P</i> = 0.010), whereas none of the ORs for sarcopenia and low muscle mass were significant.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Older men with exercise habits in both adolescence and older age were at a lower risk of sarcopenia, low muscle mass and low muscle per","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1299-1311"},"PeriodicalIF":8.9,"publicationDate":"2023-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5828740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle","authors":"Wanni Zhao,&nbsp;Yansong Zhang,&nbsp;Siyuan Lin,&nbsp;Yajuan Li,&nbsp;Alan Jian Zhu,&nbsp;Hanping Shi,&nbsp;Min Liu","doi":"10.1002/jcsm.13233","DOIUrl":"https://doi.org/10.1002/jcsm.13233","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Malnutrition is implicated in human metabolic disorders, including hepatic steatosis and myosteatosis. The corresponding nutrient signals and sensors as well as signalling pathways have not yet been well studied. This study aimed to unravel the nutrient-sensing mechanisms in the pathogenesis of steatosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Plin2, a lipid droplet (LD) protein-inhibiting lipolysis, is associated with steatosis in liver and muscle. Taking advantage of the Gal4-UAS system, we used the <i>Drosophila melanogaster</i> wing imaginal disc as an in vivo model to study the regulation of Plin2 proteostasis and LD homeostasis. <i>Drosophila</i> Schneider 2 (S2) cells were used for western blotting, immunoprecipitation assays, amino acid-binding assays and ubiquitination assays to further investigate the regulatory mechanisms of Plin2 in response to nutrient signals. Mouse AML12 hepatocytes, human JHH-7 and SNU-475 hepatoma cells were used for immunofluorescence, western blotting and immunoprecipitation to demonstrate that the mode of Plin2 regulation is evolutionarily conserved. In addition, we purified proteins from HEK293 cells and reconstituted in vitro cell-free systems in amino acid-binding assays, pulldown assays and ubiquitination assays to directly demonstrate the molecular mechanism by which Ubr1 senses amino acids to regulate Plin2 proteostasis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>As a lipolysis inhibitor, Plin2 was significantly elevated in liver (<i>P</i> &lt; 0.05) and muscle (<i>P</i> &lt; 0.05) in patients with steatosis. Consistently, we found that the ubiquitin moiety can be conjugated to any Lys residue in Plin2, ensuring robust clearance of Plin2 by protein degradation. We further demonstrated that the E3 ubiquitin ligase Ubr1 targets Plin2 for degradation in an amino acid-dependent manner. Ubr1 uses two canonical substrate-binding pockets, independent of each other, to bind basic and bulky hydrophobic amino acids, respectively. Mechanistically, amino acid binding allosterically activates Ubr1 by alleviating Ubr1's auto-inhibition. In the absence of amino acids, or when the amino acid-binding capacity of Ubr1 is diminished, Ubr1-mediated Plin2 degradation is inactivated, leading to steatosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We identified Ubr1 as an amino acid sensor regulating Plin2 proteostasis, bridging the knowledge gap between steatosis and nutrient sensing. Our work may provide new strategies for the prevention and treatment of steatosis.</p>\u0000","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1454-1467"},"PeriodicalIF":8.9,"publicationDate":"2023-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13233","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5665869","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":"A Phase 1 study for safety and pharmacokinetics of BIO101 (20-hydroxyecdysone) in healthy young and older adults","authors":"Waly Dioh,&nbsp;Cendrine Tourette,&nbsp;Susanna Del Signore,&nbsp;Louiza Daudigny,&nbsp;Philippe Dupont,&nbsp;Christine Balducci,&nbsp;Pierre J. Dilda,&nbsp;René Lafont,&nbsp;Stanislas Veillet","doi":"10.1002/jcsm.13195","DOIUrl":"https://doi.org/10.1002/jcsm.13195","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sarcopenia is an age-related skeletal muscle disorder characterized by loss of muscle mass and strength leading to mobility disability. 20-Hydroxyecdysone (20E) is a polyhydroxylated plant steroid that demonstrates pharmacological effects in many disease animal models including ageing/sarcopenia. BIO101 is a 20E purified investigational drug (≥97%) that previously demonstrated good toxicology profiles in rat and dog. BIO101 is evaluated in healthy young and older adults in a Phase 1 study.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study is a Single Ascending Dose (SAD) followed by a 14-day Multiple Ascending Dose (MAD). In SAD, BIO101 was administered orally to 16 young adults at doses from 100 to 1400 mg and to 8 older adults (age ≥65 years) at 1400 mg. In MAD, doses of 350 mg once daily (qd), 350 mg twice daily (bid) and 450 mg bid were administered to 10 older adults. The primary objective was to evaluate safety and pharmacokinetics (PK), including dosing of circulating metabolites. Pharmacodynamic effects were investigated with regard to myostatin, procollagen-III-amino-terminal propeptide (PIIINP), myoglobin, creatine-kinase Muscle Brain (CKMB), renin and aldosterone plasma/serum levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>BIO101 showed a good safety profile with only mild to moderate adverse events and a satisfactory pharmacokinetic profile. In SAD, at 100 mg to 1400 mg, mean Cmax and areas under the curve increased less than dose-proportionally. Mean half-life was short (2.4–4.9 h), and mean renal clearance was comparable in all doses (4.05–5.05 L/h). Mean plasma exposure was slightly lower in older adults (22% lower for Cmax and 13%–15% lower for AUCs) compared with young subjects. In MAD, 350 and 450 mg bid led to a slight accumulation over 14 days (mean ratio of accumulation [Rac] of 1.31 in both cohorts). Reduction of biomarkers (myoglobin, CK-MB) mean serum levels (vs. baseline) was observed at 450 mg bid. Two major metabolites of 20E (14-deoxy-20-hydroxyecdysone and 14-deoxypoststerone) were identified and quantified.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>BIO101 shows a good safety and pharmacokinetic profile that led to the selection of doses for the subsequent interventional clinical trials of Phase 2 in age-related sarcopenia (SARA-INT) and Phase 3 in Covid-19 (COVA).</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1259-1273"},"PeriodicalIF":8.9,"publicationDate":"2023-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13195","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6234105","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":"Corrigendum to I.S. Sinam et al. J of Cachexia, Sarcopenia and Muscle, 13, 3122–3136. DOI: 10.1002/jcsm.13100","authors":"","doi":"10.1002/jcsm.13231","DOIUrl":"https://doi.org/10.1002/jcsm.13231","url":null,"abstract":"This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (Grant Number: 2022R1A2B5B03001929) and Korea Health Technology R&D Project, through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HR22C1832); (I-K. L); NRF grant funded by the Ministry of Science and ICT (NRF-2021R1A5A2021614 and NRF-2020R1C1C1012729) and Korea Health Technology R&D Project, through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HR22C1832); (J.-H.J.); NRF-2021R1F1A1061393 (D. C.); NRF-2022R1A2C1007857 (T. T.). CORR IGENDUM","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1585"},"PeriodicalIF":8.9,"publicationDate":"2023-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13231","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6183862","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":"Corrigendum to Yang et al. J of Cachexia, Sarcopenia and Muscle, 13, 728–742. https://doi.org/10.1002/jcsm.12882","authors":"","doi":"10.1002/jcsm.13232","DOIUrl":"https://doi.org/10.1002/jcsm.13232","url":null,"abstract":"<p>The correspondence address for author Ping Hu were previously incomplete. The complete correspondence address for Ping Hu is shown below:</p><p>Department of Pediatric Orthopedics, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Guangzhou Laboratory, Guangzhou, China; Max Planck Center for Tissue Stem Cells and Regenerative Medicine, Bioland Laboratory, Guangzhou, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1586"},"PeriodicalIF":8.9,"publicationDate":"2023-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13232","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6183863","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":"A novel orthotopic mouse model replicates human lung cancer cachexia","authors":"Wouter R.P.H. van de Worp,&nbsp;Jan Theys,&nbsp;Alba Sanz González,&nbsp;Brent van der Heyden,&nbsp;Frank Verhaegen,&nbsp;Duncan Hauser,&nbsp;Florian Caiment,&nbsp;Hubertus J.M. Smeets,&nbsp;Annemie M.W.J. Schols,&nbsp;Ardy van Helvoort,&nbsp;Ramon C.J. Langen","doi":"10.1002/jcsm.13222","DOIUrl":"https://doi.org/10.1002/jcsm.13222","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour-bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle-specific alterations associated with human lung cancer cachexia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour-bearing group. Syngeneic lung epithelium-derived adenocarcinoma cells (<i>K-ras</i>^<i>G12D</i>; <i>p53</i>^{<i>R172HΔG</i>}) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Two-third of the tumour-bearing mice developed cachexia based on predefined criteria. Final body weight (−13.7 ± 5.7%; <i>P</i> &lt; 0.01), muscle mass (−13.8 ± 8.1%; <i>P</i> &lt; 0.01) and muscle strength (−25.5 ± 10.5%; <i>P</i> &lt; 0.001) were reduced in cachectic mice compared with sham controls and median survival time post-surgery was 33.5 days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (<i>Fbxo32</i> and <i>Trim63</i>) and autophagy-lysosomal pathway (<i>Gabarapl1</i> and <i>Bnip3</i>), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E-BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin-2 (<i>P</i> &lt; 0.001) and CXCL1/KC (<i>P</i> &lt; 0.01) expression levels in blood plasma and increased mRNA expression of IκBα (<i>P</i> &lt; 0.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1410-1423"},"PeriodicalIF":8.9,"publicationDate":"2023-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13222","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6097676","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":"Specific miRNAs are associated with human cancer cachexia in an organ-specific manner","authors":"Tanja Krauss,&nbsp;Simone Heisz,&nbsp;Julius Honecker,&nbsp;Olga Prokopchuk,&nbsp;Marc Martignoni,&nbsp;Klaus-Peter Janssen,&nbsp;Melina Claussnitzer,&nbsp;Hans Hauner,&nbsp;Claudine Seeliger","doi":"10.1002/jcsm.13224","DOIUrl":"https://doi.org/10.1002/jcsm.13224","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cancer cachexia (CCx) is a complex and multi-organ wasting syndrome characterized by substantial weight loss and poor prognosis. An improved understanding of the mechanisms involved in the onset and progression of cancer cachexia is essential. How microRNAs contribute to the clinical manifestation and progression of CCx remains elusive. The aim of this study was to identify specific miRNAs related to organ-specific CCx and explore their functional role in humans.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>miRNA patterns in serum and in cachexia target organs (liver, muscle and adipose tissue) from weight stable (<i>N</i> ≤ 12) and cachectic patients (<i>N</i> ≤ 23) with gastrointestinal cancer were analysed. As a first step, a miRNA array (158 miRNAs) was performed in pooled serum samples. Identified miRNAs were validated in serum and corresponding tissue samples. Using <i>in silico</i> prediction, related genes were identified and evaluated. The findings were confirmed <i>in vitro</i> by siRNA knock-down experiments in human visceral preadipocytes and C2C12 myoblast cells and consecutive gene expression analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Validating the results of the array, a 2-fold down-regulation of miR-122-5p (<i>P</i> = 0.0396) and a 4.5-fold down-regulation of miR-194-5p (<i>P</i> &lt; 0.0001) in serum of CCx patients in comparison with healthy controls were detected. Only miR-122-5p correlated with weight loss and CCx status (<i>P</i> = 0.0367). Analysing corresponding tissues six muscle and eight visceral adipose tissue (VAT) cachexia-associated miRNAs were identified. miR-27b-3p, miR-375 and miR-424-5p were the most consistently affected miRNAs in tissues of CCx patients correlating negatively with the severity of body weight loss (<i>P</i> = 0.0386, <i>P</i> = 0.0112 and <i>P</i> = 0.0075, respectively). We identified numerous putative target genes of the miRNAs in association with muscle atrophy and lipolysis pathways. Knock-down experiments in C2C12 myoblast cells revealed an association of miR-27b-3p and the <i>in silico</i> predicted atrophy-related target genes <i>IL-15</i> and <i>TRIM63</i>. Both were up-regulated in miR-27b-3p knock-down cells (<i>P</i> &lt; 0.05). Concordantly, in muscle tissue of CCx individuals, significant higher expression levels of <i>IL-15</i> (<i>P</i> = 0.0237) and <i>TRIM63</i> (<i>P</i> = 0.0442) were detected. miR-424-5p was identified to regulate the expression of lipase genes. Knock-down experiments in human visceral preadipocytes revealed an inverse association of miR-424-5p with its predicted target genes <i>LIPE, PNPLA2, MGLL</i> and <","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1381-1394"},"PeriodicalIF":8.9,"publicationDate":"2023-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13224","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5994003","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}