JCSM rapid communications最新文献

{"title":"Recruitment strategies for sarcopenia trials: lessons from the LACE randomized controlled trial","authors":"Miles D. Witham, Marcus Achison, Terry J. Aspray, Alison Avenell, Margaret M. Band, Peter T. Donnan, Jacob George, Adrian Hapca, Cheryl Hume, Paul Kemp, Kristina Pilvinyte, Avan A. Sayer, Karen T. Smith, Allan D. Struthers, Deepa Sumukadas","doi":"10.1002/rco2.38","DOIUrl":"10.1002/rco2.38","url":null,"abstract":"Sarcopenia is rarely diagnosed and is not recorded electronically in routine clinical care, posing challenges to trial recruitment. We describe the performance of four components of a strategy to efficiently recruit participants with sarcopenia to a trial of perindopril and/or leucine for sarcopenia: primary care vs. hospital recruitment, a comparison of central vs. local telephone pre‐screening, performance of a questionnaire on physical function conducted as part of the pre‐screening telephone call, and performance of bioimpedance measurement to identify low muscle mass.","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"4 2","pages":"93-102"},"PeriodicalIF":0.0,"publicationDate":"2021-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.38","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43631226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mediators and clinical treatment for cancer cachexia: a systematic review","authors":"Zhipeng Cao,&nbsp;Andrew M. Scott,&nbsp;Nick J. Hoogenraad,&nbsp;Laura D. Osellame","doi":"10.1002/rco2.30","DOIUrl":"10.1002/rco2.30","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cachexia, a complex multi-organ syndrome, shortens survival time of patients, particularly those with cancer. Many studies and clinical trials have been carried out to identify cachexia-inducing factors and potential treatments for cancer cachexia over the last 20 years. Of these factors, some are promising targets for treatment in humans, owing to their expression profiles in patients. Several clinical interventions, which act on either cachexia-inducing factors or tissues affected by cachexia, have been developed. Some have had positive effects in the treatment of cancer cachexia; however, the question remains whether these interventions reverse cancer cachexia and could be used as standard interventions for disease treatment. The aim of this review is to understand the basic mechanisms and factors that induce cancer cachexia and their efficacies in clinical trials, providing a better outlook for future studies of cancer cachexia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A systematic search was performed using PubMed and ClinicalTrials.gov databases for cachexia mediators and clinical trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of all databases and peer-reviewed facts considered, 256 papers and 35 clinical trials were included in this systematic review. Twenty-one mediators were identified, and 17 clinical interventions were reported in these studies. Outcomes of these clinical trials were assessed on changes in overall survival, body weight, lean body mass, appetite, muscle strength, muscle function, quality of life, and cytokine levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>There is no current standard or successful intervention for treating cancer cachexia. Further research is needed to improve our understanding of initiators of cachexia to achieve successful outcomes in cachexia clinical trials.</p>\u0000 </section>\u0000 </div>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"4 2","pages":"166-186"},"PeriodicalIF":0.0,"publicationDate":"2021-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.30","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48201716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of new biomarkers for sarcopenia and characterization of cathepsin D biomarker","authors":"Corine L'hôte,&nbsp;Benoît Cordier,&nbsp;Alain Labasse,&nbsp;Christelle Boileau,&nbsp;Bérénice Costes,&nbsp;Yves Henrotin","doi":"10.1002/rco2.26","DOIUrl":"10.1002/rco2.26","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sarcopenia is the progressive generalized loss of skeletal muscle mass, strength, and function that occurs with aging. This study was undertaken to identify new biomarkers of sarcopenia by proteomics analysis of female sera.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A case–control study was set up, for which 19 sarcopenic subjects and 20 control subjects, according to the European Working Group on Sarcopenia Older People criteria published in 2010 (EWGSOP1), were enrolled. All the subjects were at least 65 years old and in majority female. Biomarker screening was performed by a comparative mass spectrometry analysis. Protein expression levels between the two groups were compared. One of the identified biomarkers, cathepsin D, was measured by immunoassay on the serum of the full sample set (<i>n</i> = 39). Its diagnostic performance was evaluated with a receiver operating characteristic curve (ROC curve).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Two biomarkers were identified: fructose-biphosphate aldolase A (<i>P</i> ≤ 0.05) and cathepsin D (<i>P</i> ≤ 0.05). The levels of all of them were higher in sarcopenic patients. It was confirmed by immunoassay that cathepsin D levels in serum were significantly higher in the sarcopenic group of patients (<i>P</i> = 0.038). An inverse correlation (−0.385) was observed between cathepsin D levels in serum and gait speed. The area under the ROC curve measurement (AUC = 0.696) demonstrated that cathepsin D levels could discriminate between sarcopenic and non-sarcopenic subjects. A predictive model including cathepsin D, age, and body mass index was established to improve the diagnostic performance (AUC = 0.908).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Cathepsin D has been identified as a diagnostic biomarker of sarcopenia.</p>\u0000 </section>\u0000 </div>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"4 2","pages":"122-132"},"PeriodicalIF":0.0,"publicationDate":"2021-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.26","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46036271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using a quick timed-up-and-go test to predict surgical risk","authors":"Catherine L. Boereboom,&nbsp;Rachel B. McGuinness,&nbsp;Philip J. J. Herrod,&nbsp;James E. M. Blackwell,&nbsp;Tanvir S. Sian,&nbsp;Hannah Boyd-Carson,&nbsp;John P. Williams,&nbsp;Jonathan N. Lund,&nbsp;Bethan E. Phillips","doi":"10.1002/rco2.36","DOIUrl":"10.1002/rco2.36","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cardiorespiratory fitness (CRF) has important implications for post-operative recovery. The timed-up-and-go (TUG) test is a cheap and simple method to assess a patient's functional performance; although how well TUG correlates with results of a cardiopulmonary exercise test (CPET), the gold standard measure of CRF is unknown. Therefore, the aim of this study was to assess the correlation between CPET-derived parameters of CRF and TUG times in a group of older adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Ninety-eight independent community dwelling older adults [mean age: 72 years (range: 61–86), mean body mass index: 26.3 ± 3.1 kg/m², 54 male] were recruited to this study; completing 180 CPET and TUG testing sessions over a 28 month period. The correlation between CPET-derived CRF parameters and TUG time was assessed, and receiver operating characteristic curve analysis was performed to determine clinically useful cut-off points in TUG time.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Median TUG time was 7.1 s [interquartile range (IQR): 4–8.5], median VO₂ peak was 24.4 mL/kg/min (IQR: 20.2–29.2), and the median anaerobic threshold (AT) was 13.4 mL/kg/min (IQR: 8.6–16.5). There was a statistically significant negative correlation between TUG time and AT (<i>r</i> = −0.317, <i>P</i> = &lt;0.0001) and TUG time and VO₂ peak (<i>r</i> = −0.4247, <i>P</i> &lt; 0.0001). Receiver operating characteristic curve analysis determined a TUG time of ≥6.5 s to have an 82% sensitivity and 60% specificity to detect an AT &lt;11.0 mL/kg/min, the point at below which perioperative mortality is known to increase.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Despite strong evidence for the utility of pre-operative CPET in stratifying surgical risk, CPET is not universally available. Our finding of a correlation between TUG time and CPET-derived parameters of CRF (AT/VO₂ peak) suggests that TUG may be a useful surrogate in the pre-operative setting.</p>\u0000 </section>\u0000 </div>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"4 2","pages":"159-165"},"PeriodicalIF":0.0,"publicationDate":"2021-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.36","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42352599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiotensin receptor blockers use and changes in frailty, muscle mass, and function indexes: Singapore Longitudinal Ageing Study","authors":"Tze Pin Ng,&nbsp;Tu N. Nguyen,&nbsp;Qi Gao,&nbsp;Ma Shwe Zin Nyunt,&nbsp;Keng Bee Yap,&nbsp;Shiou-Liang Wee","doi":"10.1002/rco2.31","DOIUrl":"10.1002/rco2.31","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pre-clinical studies suggest that renin–angiotensin system blockade may improve muscle function. Clinical reports of the effect of angiotensin converting enzyme inhibitors (ACEIs) on physical functioning are inconsistent. There are no reports of the effect of angiotensin receptor blockers (ARBs) treatment in older adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analysed data of 1268 participants in the Singapore Longitudinal Ageing Study (SLAS-2) who provided information on the use of ACEI, ARB, and other antihypertensive drugs at baseline and follow-up (mean 4.5 years later). Baseline and follow-up outcome measures were cumulated deficits frailty index (CD-FI), physical phenotype frailty index (PP-FI), calf circumference (CC), knee extension strength, composite muscle mass and strength (MMS) <i>z</i>-score, and gait speed (GS). In primary analyses, we compared the use and non-use of an anti-hypertensive drug class among participants with hypertensive and cardiac disease, and secondarily with participants having other chronic diseases, and those who reported no chronic diseases. Multi-variable analyses adjusted for socioeconomic status, body mass index ≥30, ≥5 comorbidities, ≥5 drugs use, other non-ARB or non-ACEI drugs (calcium channel blockers, beta blockers, or hydrochlorothiazide), MMSE &lt;23, Geriatric Depression Scale score, Nutrition Screening Initiative nutritional risk, physical activities, baseline frailty, and physical performance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among study participants, 7.8% (<i>N</i> = 99) were ARB users (62% used losartan), 11.7% (<i>N</i> = 148) were ACEI users (53% used enalapril), and 34.2% (<i>N</i> = 434) were users of other anti-hypertensive drug classes. The cohort participants overall showed increases in the mean levels and changes in CD-FI and PP-FI and decreases in knee extension strength, GS, CC, and MMS. However, among groups, ARB users showed decreasing trends in CD-FI and increasing trends of CC and MMS. Among participants with hypertensive and cardiovascular disease, there were significant differences in CD-FI and PP-FI changes, adjusted for confounding variables: ARB users compared with non-users showed lesser declines in CD-FI (0.013 vs. 0.028, <i>P</i> = 0.018) and PP-FI (0.924 vs. 1.170, <i>P</i> = 0.017). ARB users also showed statistically significantly greater gains in MMS <i>z</i>-scores: 0.329 vs. 0.076, <i>P</i> = 0.022. There was no association of ACEI or other anti-hypertensive class use with changes in frailty, MMS, or GS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conc","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"4 2","pages":"111-121"},"PeriodicalIF":0.0,"publicationDate":"2021-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.31","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47146039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans","authors":"Alyssa Marie M. Castillo,&nbsp;Trang T. Vu,&nbsp;Sophia G. Liva,&nbsp;Min Chen,&nbsp;Zhiliang Xie,&nbsp;Justin Thomas,&nbsp;Bryan Remaily,&nbsp;Yizhen Guo,&nbsp;Uma L. Subrayan,&nbsp;Travis Costa,&nbsp;Timothy H. Helms,&nbsp;Donald J. Irby,&nbsp;Kyeongmin Kim,&nbsp;Dwight H. Owen,&nbsp;Samuel K. Kulp,&nbsp;Thomas A. Mace,&nbsp;Mitch A. Phelps,&nbsp;Christopher C. Coss","doi":"10.1002/rco2.32","DOIUrl":"10.1002/rco2.32","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Monoclonal antibody (mAb) immune checkpoint inhibitor (ICI) therapies have dramatically impacted oncology this past decade. However, only about one-third of patients respond to treatment, and biomarkers to predict responders are lacking. Recent ICI clinical pharmacology data demonstrate high baseline drug clearance (CL₀) significantly associates with shorter overall survival, independent of ICI exposure, in patients receiving ICI mAb therapies. This suggests CL₀ may predict outcomes from ICI therapy, and cachectic signalling may link elevated CL₀ and poor response. Our aim was to determine if mouse models of cancer cachexia will be useful for studying these phenomena and their underlying mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We evaluated pembrolizumab CL in the C26 and Lewis lung carcinoma mouse models of cancer cachexia. A single treatment of vehicle or pembrolizumab, at a dose of 2 or 10 mg/kg, was administered intravenously by tail vein injection. Pembrolizumab was quantified by an ELISA in serial plasma samples, and FcRn gene (<i>Fcgrt</i>) expression was assessed in liver using real-time quantitative reverse transcription PCR. Non-compartmental and mixed-effects pharmacokinetics analyses were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We observed higher pembrolizumab CL₀ and decreased <i>Fcgrt</i> expression in whole liver tissue from tumour-bearing vs. tumour-free mice. In multivariate analysis, presence of tumour, total murine IgG, muscle weight and <i>Fcgrt</i> expression were significant covariates on CL, and total murine IgG was a significant covariate on V1 and Q.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These data demonstrate increases in catabolic clearance of monoclonal antibodies observed in humans can be replicated in cachectic mice, in which <i>Fcgrt</i> expression is also reduced. Notably, FcRn activity is essential for proper antigen presentation and antitumour immunity, which may permit the study of cachexia's impact on FcRn-mediated clearance and efficacy of ICI therapies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"4 2","pages":"232-244"},"PeriodicalIF":0.0,"publicationDate":"2021-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.32","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39411380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skeletal muscle-specific over-expression of the nuclear sirtuin SIRT6 blocks cancer-associated cachexia by regulating multiple targets.","authors":"Sadhana A Samant, Vinodkumar B Pillai, Mahesh P Gupta","doi":"10.1002/rco2.27","DOIUrl":"10.1002/rco2.27","url":null,"abstract":"<p><strong>Background: </strong>During cancer cachexia, cytokines released from tumour cells can alter body's metabolism, which can lead to onset of this disease process. Biological basis of cachexia is multifactorial; hence, it is important to identify and modulate multiple targets to curtail the process of cachexia. Previously, we reported that the nuclear sirtuin, SIRT6, blocks expression of myostatin, a negative regulator of muscle growth, through modulation of the NF-κB signalling. This study was undertaken to test whether muscle-specific over-expression of SIRT6 can block the cancer-associated muscle wasting <i>in vivo</i> and to identify additional relevant targets of SIRT6, which can explain its ability to maintain muscle health.</p><p><strong>Methods: </strong>We generated a skeletal muscle-specific SIRT6 over-expressing transgenic mouse line (Sk.T6Tg) expressing SIRT6 at a moderate (two-fold to four-fold) level, compared with its control littermates. To generate a cancer-cachexia model, B16F10 mouse melanoma cells were injected subcutaneously in the flanks of mice. Gastrocnemius muscle tissues from non-tumour and tumour controls and Sk.T6Tg mice (<i>n</i> = 5-20) were analysed by histology, immunoblotting, and RT-qPCR. Plasma samples of mice were evaluated using cytokine arrays and ELISA in both non-tumour and tumour conditions.</p><p><strong>Results: </strong>Our results demonstrate dual benefits of muscle-specific moderate over-expression of SIRT6 in a mouse model of cancer-cachexia. In tumour-bearing mice, SIRT6 over-expression preserved muscle weight (<i>P</i> < 0.001) and fibre size (<i>P</i> < 0.005) as well as suppressed tumour growth (<i>P</i> < 0.05). SIRT6 over-expression significantly reduced myostatin expression and plasma free fatty acids levels but maintained plasma insulin levels in tumour-bearing mice. These positive effects of SIRT6 were associated with downregulation of the circulatory chemokine, CXCL10, and the myokine, WNT4. SIRT6 also upregulated expression of GLUT4, the major glucose transporter in the skeletal muscle. These results for the first time demonstrate that SIRT6 regulates multiple targets to limit tumour growth and cancer-associated muscle atrophy.</p><p><strong>Conclusion: </strong>Given the multifactorial nature of cachexia, SIRT6, which concurrently controls multiple pathways, can be a valuable therapeutic target to overcome this debilitating syndrome.</p>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"4 1","pages":"40-56"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39141426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-induced Cardiac Atrophy Adversely Affects Myocardial Redox State and Mitochondrial Oxidative Characteristics.","authors":"David E Lee,&nbsp;Jacob L Brown,&nbsp;Megan E Rosa-Caldwell,&nbsp;Richard A Perry,&nbsp;Lemuel A Brown,&nbsp;Wesley S Haynie,&nbsp;Tyrone A Washington,&nbsp;Michael P Wiggs,&nbsp;Narasimhan Rajaram,&nbsp;Nicholas P Greene","doi":"10.1002/rco2.18","DOIUrl":"https://doi.org/10.1002/rco2.18","url":null,"abstract":"<p><p>Cachexia presents in 80% of advanced cancer patients; however, cardiac atrophy in cachectic patients receives little attention. This cardiomyopathy contributes to increased occurrence of adverse cardiac events compared to age-matched population norms. Research on cardiac atrophy has focused on remodeling; however, alterations in metabolic properties may be a primary contributor.</p><p><strong>Purpose: </strong>Determine how cancer-induced cardiac atrophy alters mitochondrial turnover, mitochondrial mRNA translation machinery and <i>in-vitro</i> oxidative characteristics.</p><p><strong>Methods: </strong>Lewis lung carcinoma (LLC) tumors were implanted in C57BL6/J mice and grown for 28days to induce cardiac atrophy. Endogenous metabolic species, and markers of mitochondrial function were assessed. H9c2 cardiomyocytes were cultured in LLC-conditioned media with(out) the antioxidant MitoTempo. Cells were analyzed for ROS, oxidative capacity, and hypoxic resistance.</p><p><strong>Results: </strong>LLC heart weights were ~10% lower than controls. LLC hearts demonstrated ~15% lower optical redox ratio (FAD/FAD+NADH) compared to PBS controls. When compared to PBS, LLC hearts showed ~50% greater COX-IV and VDAC, attributed to ~50% lower mitophagy markers. mt-mRNA translation machinery was elevated similarly to markers of mitochondrial content. mitochondrial DNA-encoded Cytb was ~30% lower in LLC hearts. ROS scavengers GPx-3 and GPx-7 were ~50% lower in LLC hearts. Treatment of cardiomyocytes with LLC-conditioned media resulted in higher ROS (25%), lower oxygen consumption rates (10% at basal, 75% at maximal), and greater susceptibility to hypoxia (~25%) -- which was reversed by MitoTempo.</p><p><strong>Conclusion: </strong>These results substantiate metabolic cardiotoxic effects attributable to tumor-associated factors and provide insight into interactions between mitochondrial mRNA translation, ROS mitigation, oxidative capacity and hypoxia resistance.</p>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"4 1","pages":"3-15"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.18","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25471375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging-associated skeletal muscle defects in HER2/Neu transgenic mammary tumor model.","authors":"Ruizhong Wang,&nbsp;Brijesh Kumar,&nbsp;Poornima Bhat-Nakshatri,&nbsp;Mayuri S Prasad,&nbsp;Max H Jacobsen,&nbsp;Gabriela Ovalle,&nbsp;Calli Maguire,&nbsp;George Sandusky,&nbsp;Trupti Trivedi,&nbsp;Khalid S Mohammad,&nbsp;Theresa Guise,&nbsp;Narsimha R Penthala,&nbsp;Peter A Crooks,&nbsp;Jianguo Liu,&nbsp;Teresa Zimmers,&nbsp;Harikrishna Nakshatri","doi":"10.1002/rco2.23","DOIUrl":"https://doi.org/10.1002/rco2.23","url":null,"abstract":"<p><strong>Background: </strong>Loss of skeletal muscle volume and resulting in functional limitations are poor prognostic markers in breast cancer patients. Several molecular defects in skeletal muscle including reduced MyoD levels and increased protein turn over due to enhanced proteosomal activity have been suggested as causes of skeletal muscle loss in cancer patients. However, it is unknown whether molecular defects in skeletal muscle are dependent on tumor etiology.</p><p><strong>Methods: </strong>We characterized functional and molecular defects of skeletal muscle in MMTV-Neu (Neu+) mice (n= 6-12), an animal model that represents HER2+ human breast cancer, and compared the results with well-characterized luminal B breast cancer model MMTV-PyMT (PyMT+). Functional studies such as grip strength, rotarod performance, and ex vivo muscle contraction were performed to measure the effects of cancer on skeletal muscle. Expression of muscle-enriched genes and microRNAs as well as circulating cytokines/chemokines were measured. Since NF-κB pathway plays a significant role in skeletal muscle defects, the ability of NF-κB inhibitor dimethylaminoparthenolide (DMAPT) to reverse skeletal muscle defects was examined.</p><p><strong>Results: </strong>Neu+ mice showed skeletal muscle defects similar to accelerated aging. Compared to age and sex-matched wild type mice, Neu+ tumor-bearing mice had lower grip strength (202±6.9 vs. 179±6.8 g grip force, p=0.0069) and impaired rotarod performance (108±12.1 vs. 30±3.9 seconds, P<0.0001), which was consistent with reduced muscle contractibility (p<0.0001). Skeletal muscle of Neu+ mice (n=6) contained lower levels of CD82+ (16.2±2.9 vs 9.0±1.6) and CD54+ (3.8±0.5 vs 2.4±0.4) muscle stem and progenitor cells (p<0.05), suggesting impaired capacity of muscle regeneration, which was accompanied by decreased MyoD, p53 and miR-486 expression in muscles (p<0.05). Unlike PyMT+ mice, which showed skeletal muscle mitochondrial defects including reduced mitochondria levels and Pgc1β, Neu+ mice displayed accelerated aging-associated changes including muscle fiber shrinkage and increased extracellular matrix deposition. Circulating \"aging factor\" and cachexia and fibromyalgia-associated chemokine Ccl11 was elevated in Neu+ mice (1439.56±514 vs. 1950±345 pg/ml, p<0.05). Treatment of Neu+ mice with DMAPT significantly restored grip strength (205±6 g force), rotarod performance (74±8.5 seconds), reversed molecular alterations associated with skeletal muscle aging, reduced circulating Ccl11 (1083.26 ±478 pg/ml), and improved animal survival.</p><p><strong>Conclusions: </strong>These results suggest that breast cancer subtype has a specific impact on the type of molecular and structure changes in skeletal muscle, which needs to be taken into consideration while designing therapies to reduce breast cancer-induced skeletal muscle loss and functional limitations.</p>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"4 1","pages":"24-39"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.23","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25598818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced adenosine diphosphate sensitivity in skeletal muscle mitochondria increases reactive oxygen species production in mouse models of aging and oxidative stress but not denervation.","authors":"Gavin Pharaoh, Jacob Brown, Rojina Ranjit, Zoltan Ungvari, Holly Van Remmen","doi":"10.1002/rco2.29","DOIUrl":"10.1002/rco2.29","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial bioenergetics are sensitive to adenosine diphosphate (ADP) concentration. Reactive oxygen species (ROS) production and respiration [oxygen consumption rate (OCR)] are altered at physiological ADP concentrations (i.e. ADP insensitivity) in aged human muscle. Here, we investigate ADP sensitivity in mouse muscle mitochondria.</p><p><strong>Methods: </strong>We measured OCR and ROS production in permeabilized gastrocnemius fibres using an ADP titration protocol and the Oroboros O2k respirometer and fluorometer. We measured changes in ADP sensitivity in muscle from mice at different ages, after sciatic nerve transection (denervation), and in response to increased oxidative stress (<i>Sod1</i> ^-/- mice). Further, we asked whether the mitochondrial-targeted peptide SS-31 can modulate ADP insensitivity and contractile function in the <i>Sod1</i> ^-/- mouse model.</p><p><strong>Results: </strong>Reduced ADP sensitivity is associated with increases in mitochondrial ROS production in aged (62%) and <i>Sod1</i> ^-/- (33%) mice. The maximal capacity to produce ROS does not increase with age, and there is no effect of age on ADP sensitivity for OCR in mouse gastrocnemii. Denervation does not induce ADP insensitivity for either ROS generation or OCR. Treatment of <i>Sod1</i> ^-/- mice with SS-31 increases ADP sensitivity for both OCR and ROS, decreases maximal ROS production (^~40%), and improves resistance to muscle fatigue.</p><p><strong>Conclusions: </strong>Adenosine diphosphate sensitivity for ROS production decreases in aged mouse gastrocnemius muscle fibres, although aged mice do not exhibit a difference in OCR. Denervation does not induce ADP insensitivity; however, insensitivity to ADP is induced in a model of oxidative stress. ADP insensitivity could contribute to muscle fatigue, and SS-31 may be the first drug capable of targeting this aging phenotype.</p>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"4 1","pages":"75-89"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9503137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33483970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}