Hofmaenner, Daniel A

Kleyman, Anna

Singer, Mervyn

Critical Care

English

Daniel A. Hofmaenner

Anna Kleyman

Mervyn Singer

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Cholesterol and its association with muscle weakness in critical illness

UCL Discovery

Hofmaenner et al. Crit Care          (2021) 25:296  https://doi.org/10.1186/s13054-021-03722-2LETTERCholesterol and its association with muscle weakness in critical illnessDaniel A. Hofmaenner1* , Anna Kleyman1 and Mervyn Singer1 © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Dear Editor,With great interest we read and appreciated the recently published article by Goossens and colleagues [1]. They offer some important insights into the phenomenon of muscle weakness in critical illness and suggest a contrib-utory role of low cholesterol and potential utility from exogenous administration of 3-hydroxybutyrate. It has long been recognized that low serum cholesterol is com-monplace in sepsis and an important prognosticator of poor outcomes [2, 3]. They reported that 3-hydroxybu-tyrate (3-HB) increased plasma cholesterol levels in sep-tic mice with normalization of plasma mevalonate and increased expression of genes encoding cholesterol syn-thesis in muscle.We would like to raise some points of interest that merit discussion. First, the authors measured serum cho-lesterol levels in patients on ICU admission and day 3, whereas muscle strength was assessed at day 8. What was the rationale for the choice of these timepoints? Ideally, comparison of muscle strength should be made against contemporaneous cholesterol levels to reduce risks of confounding and to support causality arguments.Second, did the authors consider measuring endog-enous production of 3-HB and plasma levels in their septic animals? Endogenous hydroxybutyrate levels are altered in sepsis due to a shift towards fat metabolism and increased ketone body production [4]. Understand-ing of the pharmacokinetics/pharmacodynamics of exog-enous 3-HB administration would aid interpretation of its impact.Third, the authors present the fate of supplemented 3-HB as cholesterogenic or tricarboxylic acid cycle (TCA cycle) substrate (Figure  3). A complementary pathway worth considering is fatty acid synthesis which also relies upon acetyl-CoA as a basic substrate. Again, temporal measurement across the catabolic and recovery phases of sepsis would be informative.Fourth, to our knowledge, the liver produces ketone bodies but cannot directly metabolize them due to a lack of ketoacyl-CoA transferase. The observed elevation in mevalonate within the liver after exogenous 3-HB admin-istration may relate to indirect metabolic pathways, e.g. via fatty acids transported back to the liver.Authors’ responseReply to letter by Hofmaenner D.Lies Langouche2 and Greet Van den Berghe22 Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.We thank Hofmaenner D. et al. for the interest in our work on the role of cholesterol in ICU acquired weakness and the impact thereof on exogenous 3-hydroxybutyrate (3HB) and for raising several interesting points [1].The first point addressed the difference in timing between measurement of serum cholesterol and of mus-cle strength in the human study (EPaNIC RCT). In this study, the impact of omitting parenteral nutrition for one Open AccessThis comment refers to the article available online at https:// doi. org/ 10. 1186/ s13054- 021- 03688-1.*Correspondence:  d.hofmanner@ucl.ac.uk1 Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London WC1E 6BT, UKPage 2 of 2Hofmaenner et al. Crit Care          (2021) 25:296 week in ICU on ICU acquired weakness was assessed in a matched subgroup of 600 patients on post-randomi-zation day 8 [5]. Muscle strength assessment was per-formed in ICU for long-stay patients, and on the regular ward for short-stayers. Blood was only sampled during ICU stay, and thus no later samples were available for short-stayers. For the current analysis of a potential asso-ciation between plasma cholesterol and ICU acquired weakness, we therefore quantified plasma cholesterol in all patients on one timepoint, day 3 in ICU, which pre-ceded the muscle strength assessment, as selection bias would otherwise occur at a later time point.Second, the authors asked whether data on endog-enous production of 3HB and plasma concentrations were available for the septic mice. Indeed, as mentioned by Hofmaenner D. et al., endogenous production of 3HB is increased in the acute phase of critical illness, but this is abolished as soon as parenteral nutrition is initi-ated, as we have previously shown both in the septic mouse model [6], and in human patients [7, 8]. We agree that further insight in the pharmacokinetics/pharmaco-dynamics of exogenous 3HB administration would be informative when considering its further investigation in human ICU patients.The third and fourth points addressed the metabolic fate of the exogenous 3HB and whether use as substrate for fatty acid synthesis could be involved. Indeed, 3HB can in theory be converted into fatty acids. In the mouse model, 3HB supplementation has previously shown not to alter plasma fatty acid concentrations or triglycer-ide content in muscle or liver [6], whereas it was found to increase plasma triglyceride concentrations [6]. Indi-rectly, it is also possible that conversion of 3HB to fatty acids or mevalonate in non-hepatic tissues may have occurred which could then be further metabolized in the liver.We totally agree with Hofmaenner D. et al. that more research is needed to better understand the role of cho-lesterol in ICU acquired weakness and to assess the clini-cal potential of 3HB supplementation in human ICU patients.AcknowledgementsNone.Authors’ contributionsDAH drafted the first version of the manuscript. DAH, AK and MS have edited and proofread the final manuscript version.FundingNone.Availability of data and materialNot applicable.DeclarationsEthics approval and consent to participateNot applicable.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Received: 28 July 2021   Accepted: 29 July 2021References 1. Goossens C, Weckx R, Derde S, Vander Perre S, Derese I, van Veldhoven PP, et al. Altered cholesterol homeostasis in critical illness-induced muscle weakness: effect of exogenous 3-hydroxybutyrate. Crit Care. 2021;25(1):252. 2. Chien JY, Jerng JS, Yu CJ, Yang PC. Low serum level of high-density lipo-protein cholesterol is a poor prognostic factor for severe sepsis. Crit Care Med. 2005;33:1688–93. 3. van Leeuwen HJ, Heezius EC, Dallinga GM, van Strijp JA, Verhoef J, van Kessel KP. Lipoprotein metabolism in patients with severe sepsis. Crit Care Med. 2003;31:1359–66. 4. Wasyluk W, Zwolak A. Metabolic Alterations in Sepsis. J Clin Med. 2021;10(11):2412. 5. Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011;365(6):506. 6. Goossens C, Weckx R, Derde S, Dufour T, Vander Perre S, Pauwels L, et al. Adipose tissue protects against sepsis-induced muscle weakness in mice: from lipolysis to ketones. Crit Care. 2019;23(1):236. 7. De Bruyn A, Gunst J, Goossens C, Vander Perre S, Guerra GG, Verbruggen S, et al. Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit. Crit Care. 2020;24(1):536. 8. De Bruyn A, Langouche L, Vander Perre S, Gunst J, Van den Berghe G. Impact of withholding early parenteral nutrition in adult critically ill patients on ketogenesis in relation to outcome. Crit Care. 2021;25(1):102.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in pub-lished maps and institutional affiliations.

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Cholesterol and its association with muscle weakness in critical illness

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