posted on 2019-08-15, 10:50authored byZA Puthucheary, R Astin, MJW Mcphail, S Saeed, Y Pasha, DE Bear, D Constantin, C Velloso, S Manning, L Calvert, M Singer, RL Batterham, M Gomez-Romero, E Holmes, MC Steiner, PJ Atherton, P Greenhaff, LM Edwards, K Smith, SD Harridge, N Hart, HE Montgomery
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.
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.
History
Citation
Thorax, 2018, 73 (10), pp. 926-935
Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Infection, Immunity and Inflammation
Version
AM (Accepted Manuscript)
Published in
Thorax
Publisher
BMJ Publishing Group, British Thoracic Society (BTS)