Metabolic phenotype of skeletal muscle in early critical illness

Zudin A Puthucheary; Ronan Astin; Mark J W Mcphail; Saima Saeed; Yasmin Pasha; Danielle E Bear; Despina Constantin; Cristiana Velloso; Sean Manning; Lori Calvert; Mervyn Singer; Rachel L Batterham; Maria Gomez-Romero; Elaine Holmes; Michael C Steiner; Philip J Atherton; Paul Greenhaff; Lindsay M Edwards; Kenneth Smith; Stephen D Harridge; Nicholas Hart; Hugh E Montgomery

doi:10.1136/thoraxjnl-2017-211073

Metabolic phenotype of skeletal muscle in early critical illness

Thorax. 2018 Oct;73(10):926-935. doi: 10.1136/thoraxjnl-2017-211073. Epub 2018 Jul 6.

Authors

Zudin A Puthucheary^{1

2

3

4}, Ronan Astin^{1

2}, Mark J W Mcphail^{5

6}, Saima Saeed⁷, Yasmin Pasha⁵, Danielle E Bear^{4

8

9

10}, Despina Constantin¹¹, Cristiana Velloso⁴, Sean Manning^{12

13

14}, Lori Calvert¹⁵, Mervyn Singer^{3

7}, Rachel L Batterham^{12

13}, Maria Gomez-Romero¹⁶, Elaine Holmes¹⁶, Michael C Steiner¹⁷, Philip J Atherton¹¹, Paul Greenhaff¹¹, Lindsay M Edwards¹⁸, Kenneth Smith¹¹, Stephen D Harridge⁴, Nicholas Hart^{10

19}, Hugh E Montgomery^{1

2}

Affiliations

¹ Institute for Sport, Exercise and Health, University College London, London, UK.
² Department of Medicine, Centre for Human Health and Performance, University College London, London, UK.
³ Intensive Care Unit, Royal Free London NHS Foundation Trust, London, UK.
⁴ Centre for Human and Applied Physiological Sciences, King's College London, London, UK.
⁵ Hepatology and Gastroenterology, St Mary's Hospital, Imperial College London, London, UK.
⁶ Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London, UK.
⁷ Wolfson Institute Centre for Intensive Care Medicine, University College London, London, UK.
⁸ Department of Nutrition and Dietetics, Guy's and St Thomas' NHS Foundation Trust, London.
⁹ Department of Critical Care, Guy's and St Thomas' NHS Foundation Trust, London.
¹⁰ Lane Fox Clinical Respiratory Physiology Research Centre, St Thomas' Hospital, Guy's and St Thomas' Foundation Trust, London, London, UK.
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 Centre for Obesity Research, University College London, London, UK.
¹³ National Institute of Health Research, UCLH Biomedical Research Centre, University College London Hospitals, London.
¹⁴ School of Medicine, University College Cork, Cork, Ireland.
¹⁵ Northwest Anglia foundation Trust, Peterborough City Hospital NHS Trust, Peterborough, UK.
¹⁶ Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, London, UK.
¹⁷ Institute for Lung Health, Leicester NIHR Biomedical Research Centre-Respiratory, University of Leicester, Leicester, UK.
¹⁸ Digital, Data & Analytics Unit, Respiratory Therapy Area, GlaxoSmithKline Medicines Research Centre, Stevenage, UK.
¹⁹ Lane Fox Respiratory Service, St Thomas' Hospital, Guy's and St Thomas' Foundation Trust, London, UK.

PMID: 29980655
DOI: 10.1136/thoraxjnl-2017-211073

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.

Keywords: ARDS; respiratory muscles.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Critical Illness*
Energy Metabolism / physiology
Female
Humans
Intensive Care Units
Male
Middle Aged
Mitochondria / metabolism
Muscle, Skeletal / metabolism*
Muscular Atrophy / metabolism*
Phenotype

Associated data

ClinicalTrials.gov/NCT01106300

Abstract

Publication types

MeSH terms

Associated data

Grants and funding