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Metabolic phenotype of skeletal muscle in early critical illness
  1. Zudin A Puthucheary1,2,3,4,
  2. Ronan Astin1,2,
  3. Mark J W Mcphail5,6,
  4. Saima Saeed7,
  5. Yasmin Pasha5,
  6. Danielle E Bear4,8,9,10,
  7. Despina Constantin11,
  8. Cristiana Velloso4,
  9. Sean Manning12,13,14,
  10. Lori Calvert15,
  11. Mervyn Singer3,7,
  12. Rachel L Batterham12,13,
  13. Maria Gomez-Romero16,
  14. Elaine Holmes16,
  15. Michael C Steiner17,
  16. Philip J Atherton11,
  17. Paul Greenhaff11,
  18. Lindsay M Edwards18,
  19. Kenneth Smith11,
  20. Stephen D Harridge4,
  21. Nicholas Hart10,19,
  22. Hugh E Montgomery1,2
  1. 1 Institute for Sport, Exercise and Health, University College London, London, UK
  2. 2 Department of Medicine, Centre for Human Health and Performance, University College London, London, UK
  3. 3 Intensive Care Unit, Royal Free London NHS Foundation Trust, London, UK
  4. 4 Centre for Human and Applied Physiological Sciences, King’s College London, London, UK
  5. 5 Hepatology and Gastroenterology, St Mary’s Hospital, Imperial College London, London, UK
  6. 6 Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London, UK
  7. 7 Wolfson Institute Centre for Intensive Care Medicine, University College London, London, UK
  8. 8 Department of Nutrition and Dietetics, Guy’s and St Thomas' NHS Foundation Trust, London
  9. 9 Department of Critical Care, Guy’s and St Thomas' NHS Foundation Trust, London
  10. 10 Lane Fox Clinical Respiratory Physiology Research Centre, St Thomas’ Hospital, Guy’s and St Thomas’ Foundation Trust, London, London, UK
  11. 11 Medical Research Council/Arthritis Research UK Centre for Musculoskeletal Aging Research, National Institute for Health Research Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
  12. 12 Centre for Obesity Research, University College London, London, UK
  13. 13 National Institute of Health Research, UCLH Biomedical Research Centre, University College London Hospitals, London
  14. 14 School of Medicine, University College Cork, Cork, Ireland
  15. 15 Northwest Anglia foundation Trust, Peterborough City Hospital NHS Trust, Peterborough, UK
  16. 16 Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, London, UK
  17. 17 Institute for Lung Health, Leicester NIHR Biomedical Research Centre-Respiratory, University of Leicester, Leicester, UK
  18. 18 Digital, Data & Analytics Unit, Respiratory Therapy Area, GlaxoSmithKline Medicines Research Centre, Stevenage, UK
  19. 19 Lane Fox Respiratory Service, St Thomas’ Hospital, Guy’s and St Thomas’ Foundation Trust, London, UK
  1. Correspondence to Dr Zudin A Puthucheary, Institute for Sport, Exercise and Health, University College London, London W1T 7HA, UK; zudin.puthucheary.09{at}ucl.ac.uk

Abstract

Objectives To characterise the sketetal muscle metabolic phenotype during early critical illness.

Methods Vastus lateralis muscle biopsies and serum samples (days 1 and 7) were obtained from 63 intensive care patients (59% male, 54.7±18.0 years, Acute Physiology and Chronic Health Evaluation II score 23.5±6.5).

Measurements and main results From day 1 to 7, there was a reduction in mitochondrial beta-oxidation enzyme concentrations, mitochondrial biogenesis markers (PGC1α messenger mRNA expression (−27.4CN (95% CI −123.9 to 14.3); n=23; p=0.025) and mitochondrial DNA copy number (−1859CN (IQR −5557–1325); n=35; p=0.032). Intramuscular ATP content was reduced compared tocompared with controls on day 1 (17.7mmol/kg /dry weight (dw) (95% CI 15.3 to 20.0) vs. 21.7 mmol/kg /dw (95% CI 20.4 to 22.9); p<0.001) and decreased over 7 days (−4.8 mmol/kg dw (IQR −8.0–1.2); n=33; p=0.001). In addition, the ratio of phosphorylated:total AMP-K (the bioenergetic sensor) increased (0.52 (IQR −0.09–2.6); n=31; p<0.001). There was an increase in intramuscular phosphocholine (847.2AU (IQR 232.5–1672); n=15; p=0.022), intramuscular tumour necrosis factor receptor 1 (0.66 µg (IQR −0.44–3.33); n=29; p=0.041) and IL-10 (13.6 ng (IQR 3.4–39.0); n=29; p=0.004). Serum adiponectin (10.3 µg (95% CI 6.8 to 13.7); p<0.001) and ghrelin (16.0 ng/mL (IQR −7–100); p=0.028) increased. Network analysis revealed a close and direct relationship between bioenergetic impairment and reduction in muscle mass and between intramuscular inflammation and impaired anabolic signaling. ATP content and muscle mass were unrelated to lipids delivered.

Conclusions Decreased mitochondrial biogenesis and dysregulated lipid oxidation contribute to compromised skeletal muscle bioenergetic status. In addition, intramuscular inflammation was associated with impaired anabolic recovery with lipid delivery observed as bioenergetically inert. Future clinical work will focus on these key areas to ameliorate acute skeletal muscle wasting.

Trial registration number NCT01106300.

  • respiratory muscles
  • ARDS
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Footnotes

  • SDH, NH and HEM are joint senior authors.

  • Contributors Concept and design: ZAP, RA, MMM, CV, PJA, KS, LME, SDH, NH, HEM. Data collection: ZAP, MMM, SS, YP, CV, SM, LC, MS, RLB, MS. Analysis: ZAP, RA, MMM,SS, YP, DB, DC, CV, SM, LC, MS, RLB, MG-R, EH, MS, PG, LME, SDH, NH, HEM. Manuscript preparation: ZAP, RA, MMM, SS, YP, DB, DC, CV, SM, LC, MS, RLB, MG-R, EH, MS, PJA, KS, PG, LME, SDH, NH, HEM.

  • Funding ZAP was funded by the National Institute of Health Research (UK). Additional funding has been received from the European Society of Intensive Care Medicine, Guy’s & St Thomas' and King’s College London NIHR Comprehensive Biomedical Research Centre (BRC) and the Whittington Hospital NHS Trust. SDH received support from the Research Councils UK. NH received funding from the NIHR Clinical Research Facility and BRC at Guy’s and St Thomas’ NHS Foundation Trust (GSTT) and King’s College London. HEM was funded by University College London and UCLH BRC. The Clinical Phenotyping Centre is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. MJWM is grateful to the Wellcome Trust for support in the form of a Postdoctoral Training Fellowship for part of this work. YP is grateful to Merz Pharmaceuticals for support in the form of a training fellowship award.

  • Competing interests ZAP has received consultancy fees from Lyric Pharmaceuticals, and attended Specialist Advisory Boards for GlaxoSmithKline and Fresenius Kabi. Other authors have no competing interest to declare.

  • Ethics approval Ethical approval was obtained from University College London Ethics Committee A.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it was published. The footnote indicating joint senior authorship for SDH, NH and HEM was omitted.

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