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

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. HarridgeNicholas Hart, Hugh E. Montgomery

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	926-935
Journal	Thorax
Volume	73
Issue number	10
Early online date	6 Jul 2018
DOIs	https://doi.org/10.1136/thoraxjnl-2017-211073
Publication status	Published - Oct 2018

Keywords

ARDS
respiratory muscles

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Puthucheary, Z. A., Astin, R., Mcphail, M. J. W., Saeed, S., Pasha, Y., Bear, D. E., Constantin, D., Velloso, C., Manning, S., Calvert, L., Singer, M., Batterham, R. L., Gomez-Romero, M., Holmes, E., Steiner, M. C., Atherton, P. J., Greenhaff, P., Edwards, L. M., Smith, K., ... Montgomery, H. E. (2018). Metabolic phenotype of skeletal muscle in early critical illness. Thorax, 73(10), 926-935. https://doi.org/10.1136/thoraxjnl-2017-211073

@article{ddd8e0f054a44886b0e4f8b970fe4f11,

title = "Metabolic phenotype of skeletal muscle in early critical illness",

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",

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

year = "2018",

month = oct,

doi = "10.1136/thoraxjnl-2017-211073",

language = "English",

volume = "73",

pages = "926--935",

journal = "Thorax",

issn = "0040-6376",

publisher = "BRITISH MED JOURNAL PUBL GROUP",

number = "10",

}

Puthucheary, ZA, Astin, R, Mcphail, MJW, Saeed, S, Pasha, Y, Bear, DE, Constantin, D, Velloso, C, Manning, S, Calvert, L, Singer, M, Batterham, RL, Gomez-Romero, M, Holmes, E, Steiner, MC, Atherton, PJ, Greenhaff, P, Edwards, LM , Smith, K , Harridge, SD , Hart, N & Montgomery, HE 2018, 'Metabolic phenotype of skeletal muscle in early critical illness', Thorax, vol. 73, no. 10, pp. 926-935. https://doi.org/10.1136/thoraxjnl-2017-211073

TY - JOUR

T1 - Metabolic phenotype of skeletal muscle in early critical illness

AU - Puthucheary, Zudin A.

AU - Astin, Ronan

AU - Mcphail, Mark J. W.

AU - Saeed, Saima

AU - Pasha, Yasmin

AU - Bear, Danielle E.

AU - Constantin, Despina

AU - Velloso, Cristiana

AU - Manning, Sean

AU - Calvert, Lori

AU - Singer, Mervyn

AU - Batterham, Rachel L.

AU - Gomez-Romero, Maria

AU - Holmes, Elaine

AU - Steiner, Michael C.

AU - Atherton, Philip J.

AU - Greenhaff, Paul

AU - Edwards, Lindsay M.

AU - Smith, Kenneth

AU - Harridge, Stephen D.

AU - Hart, Nicholas

AU - Montgomery, Hugh E.

PY - 2018/10

Y1 - 2018/10

N2 - 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.

AB - 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.

KW - ARDS

KW - respiratory muscles

UR - http://www.scopus.com/inward/record.url?scp=85049674625&partnerID=8YFLogxK

U2 - 10.1136/thoraxjnl-2017-211073

DO - 10.1136/thoraxjnl-2017-211073

M3 - Article

AN - SCOPUS:85049674625

SN - 0040-6376

VL - 73

SP - 926

EP - 935

JO - Thorax

JF - Thorax

IS - 10

ER -

Metabolic phenotype of skeletal muscle in early critical illness

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Keywords

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