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      Metabolic profiling shows pre‐existing mitochondrial dysfunction contributes to muscle loss in a model of ICU‐acquired weakness

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          Abstract

          Background

          Surgery can lead to significant muscle loss, which increases recovery time and associates with increased mortality. Muscle loss is not uniform, with some patients losing significant muscle mass and others losing relatively little, and is likely to be accompanied by marked changes in circulating metabolites and proteins. Determining these changes may help understand the variability and identify novel therapeutic approaches or markers of muscle wasting.

          Methods

          To determine the association between muscle loss and circulating metabolites, we studied 20 male patients (median age, 70.5, interquartile range, 62.5–75) undergoing aortic surgery. Muscle mass was determined before and 7 days after surgery and blood samples were taken before surgery, and 1, 3, and 7 days after surgery. The circulating metabolome and proteome were determined using commercial services (Metabolon and SomaLogic).

          Results

          Ten patients lost more than 10% of the cross‐sectional area of the rectus femoris (RF CSA) and were defined as wasting. Metabolomic analysis showed that 557 circulating metabolites were altered following surgery ( q < 0.05) in the whole cohort and 104 differed between wasting and non‐wasting patients ( q < 0.05). Weighted genome co‐expression network analysis, identified clusters of metabolites, both before and after surgery, that associated with muscle mass and function ( r = −0.72, p = 6 × 10 −4 with RF CSA on Day 0, P = 3 × 10 −4 with RF CSA on Day 7 and r = −0.73, P = 5 × 10 −4 with hand‐grip strength on Day 7). These clusters were mainly composed of acyl carnitines and dicarboxylates indicating that pre‐existing mitochondrial dysfunction contributes to muscle loss following surgery. Surgery elevated cortisol to the same extent in wasting and non‐wasting patients, but the cortisol:cortisone ratio was higher in the wasting patients (Day 3 P = 0.043 and Day 7 P = 0.016). Wasting patients also showed a greater increase in circulating nucleotides 3 days after surgery. Comparison of the metabolome with inflammatory markers identified by SOMAscan® showed that pre‐surgical mitochondrial dysfunction was associated with growth differentiation factor 15 (GDF‐15) ( r = 0.79, P = 2 × 10 −4) and that GDF‐15, interleukin (IL)‐8), C‐C motif chemokine 23 (CCL‐23), and IL‐15 receptor subunit alpha (IL‐15RA) contributed to metabolic changes in response to surgery.

          Conclusions

          We show that pre‐existing mitochondrial dysfunction and reduced cortisol inactivation contribute to muscle loss following surgery. The data also implicate GDF‐15 and IL‐15RA in mitochondrial dysfunction.

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          Most cited references57

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          WGCNA: an R package for weighted correlation network analysis

          Background Correlation networks are increasingly being used in bioinformatics applications. For example, weighted gene co-expression network analysis is a systems biology method for describing the correlation patterns among genes across microarray samples. Weighted correlation network analysis (WGCNA) can be used for finding clusters (modules) of highly correlated genes, for summarizing such clusters using the module eigengene or an intramodular hub gene, for relating modules to one another and to external sample traits (using eigengene network methodology), and for calculating module membership measures. Correlation networks facilitate network based gene screening methods that can be used to identify candidate biomarkers or therapeutic targets. These methods have been successfully applied in various biological contexts, e.g. cancer, mouse genetics, yeast genetics, and analysis of brain imaging data. While parts of the correlation network methodology have been described in separate publications, there is a need to provide a user-friendly, comprehensive, and consistent software implementation and an accompanying tutorial. Results The WGCNA R software package is a comprehensive collection of R functions for performing various aspects of weighted correlation network analysis. The package includes functions for network construction, module detection, gene selection, calculations of topological properties, data simulation, visualization, and interfacing with external software. Along with the R package we also present R software tutorials. While the methods development was motivated by gene expression data, the underlying data mining approach can be applied to a variety of different settings. Conclusion The WGCNA package provides R functions for weighted correlation network analysis, e.g. co-expression network analysis of gene expression data. The R package along with its source code and additional material are freely available at .
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            Ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle : update 2019

            Abstract This article details an updated version of the principles of ethical authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle (JCSM) and its two daughter journals JCSM Rapid Communication and JCSM Clinical Reports. We request of all author sending to the journal a paper for consideration that at the time of submission to JCSM, the corresponding author, on behalf of all co‐authors, needs to certify adherence to these principles. The principles are as follows: all authors listed on a manuscript considered for publication have approved its submission and (if accepted) approve publication in JCSM as provided; each named author has made a material and independent contribution to the work submitted for publication; no person who has a right to be recognized as author has been omitted from the list of authors on the submitted manuscript; the submitted work is original and is neither under consideration elsewhere nor that it has been published previously in whole or in part other than in abstract form; all authors certify that the submitted work is original and does not contain excessive overlap with prior or contemporaneous publication elsewhere, and where the publication reports on cohorts, trials, or data that have been reported on before the facts need to be acknowledged and these other publications must be referenced; all original research work has been approved by the relevant bodies such as institutional review boards or ethics committees; all relevant conflicts of interest, financial or otherwise, that may affect the authors' ability to present data objectively, and relevant sources of funding of the research in question have been duly declared in the manuscript; the manuscript in its published form will be maintained on the servers of JCSM as a valid publication only as long as all statements in the guidelines on ethical publishing remain true. If any of the aforementioned statements ceases to be true, the authors have a duty to notify as soon as possible the Editors of JCSM, JCSM Rapid Communication, and JCSM Clinical Reports, respectively, so that the available information regarding the published article can be updated and/or the manuscript can be withdrawn.
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              GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates

              GDF15 has potent anti-obesity effects, but its receptor was unknown. GFRAL has now been identified as the receptor and mediates GDF15's effects through central actions in the hindbrain.
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                Author and article information

                Contributors
                p.kemp@imperial.ac.uk
                Journal
                J Cachexia Sarcopenia Muscle
                J Cachexia Sarcopenia Muscle
                10.1007/13539.2190-6009
                JCSM
                Journal of Cachexia, Sarcopenia and Muscle
                John Wiley and Sons Inc. (Hoboken )
                2190-5991
                2190-6009
                16 July 2020
                October 2020
                : 11
                : 5 ( doiID: 10.1002/jcsm.v11.5 )
                : 1321-1335
                Affiliations
                [ 1 ] Cardiovascular and Respiratory Interface Section, National Heart and Lung Institute Imperial College London, South Kensington Campus London UK
                [ 2 ] Department of Intensive Care Guy's and St. Thomas' NHS Foundation Trust London UK
                [ 3 ] Muscle Metabolism Discovery Performance Unit GlaxoSmithKline, Inc Collegeville PA USA
                [ 4 ] Edgewise Therapeutics Boulder CO USA
                Author notes
                [*] [* ] Correspondence to: Dr Paul Kemp, National Heart and Lung Institute, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.

                Email: p.kemp@ 123456imperial.ac.uk

                Author information
                https://orcid.org/0000-0001-8975-7293
                Article
                JCSM12597 JCSM-D-19-00416
                10.1002/jcsm.12597
                7567140
                32677363
                1dfb5e63-7fd1-4134-9aec-177d1d339609
                © 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 18 September 2019
                : 01 May 2020
                : 27 May 2020
                Page count
                Figures: 4, Tables: 6, Pages: 15, Words: 6733
                Funding
                Funded by: National Institute for Health Research , open-funder-registry 10.13039/501100000272;
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                October 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.2 mode:remove_FC converted:16.10.2020

                Orthopedics
                metabolomics,muscle wasting,aortic surgery,mitochondrial dysfunction,cortisol
                Orthopedics
                metabolomics, muscle wasting, aortic surgery, mitochondrial dysfunction, cortisol

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