Increased skeletal muscle 11βHSD1 mRNA is associated with lower muscle strength in ageing

Alixe H M Kilgour; Iain J Gallagher; Alasdair M J MacLullich; Ruth Andrew; Calum D Gray; Philippa Hyde; Henning Wackerhage; Holger Husi; James A Ross; John M Starr; Karen E Chapman; Kenneth C H Fearon; Brian R Walker; Carolyn A Greig

doi:10.1371/journal.pone.0084057

Increased skeletal muscle 11βHSD1 mRNA is associated with lower muscle strength in ageing

Alixe H M Kilgour, Iain J Gallagher, Alasdair M J MacLullich, Ruth Andrew, Calum D Gray, Philippa Hyde, Henning Wackerhage, Holger Husi, James A Ross, John M Starr, Karen E Chapman, Kenneth C H Fearon, Brian R Walker, Carolyn A Greig

Medical Sciences

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Abstract

Background: Sarcopenia, the loss of muscle mass and function with age, is associated with increased morbidity and mortality. Current understanding of the underlying mechanisms is limited. Glucocorticoids (GC) in excess cause muscle weakness and atrophy. We hypothesized that GC may contribute to sarcopenia through elevated circulating levels or increased glucocorticoid receptor (GR) signaling by increased expression of either GR or the GC-amplifying enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) in muscle.

Methods: There were 82 participants; group 1 comprised 33 older men (mean age 70.2years, SD 4.4) and 19 younger men (22.2years, 1.7) and group 2 comprised 16 older men (79.1years, 3.4) and 14 older women (80.1years, 3.7). We measured muscle strength, mid-thigh cross-sectional area, fasting morning plasma cortisol, quadriceps muscle GR and 11 beta HSD1 mRNA, and urinary glucocorticoid metabolites. Data were analysed using multiple linear regression adjusting for age, gender and body size.

Results: Muscle strength and size were not associated with plasma cortisol, total urinary glucocorticoids or the ratio of urinary 5 beta-tetrahydrocortisol + 5 alpha-tetrahydrocortisol to tetrahydrocortisone (an index of systemic 11 beta HSD activity). Muscle strength was associated with 11 beta HSD1 mRNA levels (beta -0.35, p = 0.04), but GR mRNA levels were not significantly associated with muscle strength or size.

Conclusion: Although circulating levels of GC are not associated with muscle strength or size in either gender, increased cortisol generation within muscle by 11 beta HSD1 may contribute to loss of muscle strength with age, a key component of sarcopenia. Inhibition of 11 beta HSD1 may have therapeutic potential in sarcopenia.

Original language	English
Article number	e84057
Number of pages	6
Journal	PloS ONE
Volume	8
Issue number	12
DOIs	https://doi.org/10.1371/journal.pone.0084057
Publication status	Published - 31 Dec 2013

Bibliographical note

Copyright: © 2013 Kilgour et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors thank the British Heart Foundation and Chief Scientist Office of the Scottish Government for financial support. AHJK, AMJM and JMS are members of The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative. Funding from the BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords

11-beta-hydroxysteroid dehydrogenase type-1
glucocorticoid-receptors
body-composition
elderly-men
in-vivo
sarcopenia
cortisol
diagnosis
mass
pathogenesis

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10.1371/journal.pone.0084057

Increased skeletal muscle
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/
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Kilgour, A. H. M., Gallagher, I. J., MacLullich, A. M. J., Andrew, R., Gray, C. D., Hyde, P., Wackerhage, H., Husi, H., Ross, J. A., Starr, J. M., Chapman, K. E., Fearon, K. C. H., Walker, B. R., & Greig, C. A. (2013). Increased skeletal muscle 11βHSD1 mRNA is associated with lower muscle strength in ageing. PloS ONE, 8(12), Article e84057. https://doi.org/10.1371/journal.pone.0084057

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title = "Increased skeletal muscle 11βHSD1 mRNA is associated with lower muscle strength in ageing",

abstract = "Background: Sarcopenia, the loss of muscle mass and function with age, is associated with increased morbidity and mortality. Current understanding of the underlying mechanisms is limited. Glucocorticoids (GC) in excess cause muscle weakness and atrophy. We hypothesized that GC may contribute to sarcopenia through elevated circulating levels or increased glucocorticoid receptor (GR) signaling by increased expression of either GR or the GC-amplifying enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) in muscle.Methods: There were 82 participants; group 1 comprised 33 older men (mean age 70.2years, SD 4.4) and 19 younger men (22.2years, 1.7) and group 2 comprised 16 older men (79.1years, 3.4) and 14 older women (80.1years, 3.7). We measured muscle strength, mid-thigh cross-sectional area, fasting morning plasma cortisol, quadriceps muscle GR and 11 beta HSD1 mRNA, and urinary glucocorticoid metabolites. Data were analysed using multiple linear regression adjusting for age, gender and body size.Results: Muscle strength and size were not associated with plasma cortisol, total urinary glucocorticoids or the ratio of urinary 5 beta-tetrahydrocortisol + 5 alpha-tetrahydrocortisol to tetrahydrocortisone (an index of systemic 11 beta HSD activity). Muscle strength was associated with 11 beta HSD1 mRNA levels (beta -0.35, p = 0.04), but GR mRNA levels were not significantly associated with muscle strength or size.Conclusion: Although circulating levels of GC are not associated with muscle strength or size in either gender, increased cortisol generation within muscle by 11 beta HSD1 may contribute to loss of muscle strength with age, a key component of sarcopenia. Inhibition of 11 beta HSD1 may have therapeutic potential in sarcopenia.",

keywords = "11-beta-hydroxysteroid dehydrogenase type-1, glucocorticoid-receptors, body-composition, elderly-men, in-vivo, sarcopenia, cortisol, diagnosis, mass, pathogenesis",

author = "Kilgour, {Alixe H M} and Gallagher, {Iain J} and MacLullich, {Alasdair M J} and Ruth Andrew and Gray, {Calum D} and Philippa Hyde and Henning Wackerhage and Holger Husi and Ross, {James A} and Starr, {John M} and Chapman, {Karen E} and Fearon, {Kenneth C H} and Walker, {Brian R} and Greig, {Carolyn A}",

note = "Copyright: {\textcopyright} 2013 Kilgour et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors thank the British Heart Foundation and Chief Scientist Office of the Scottish Government for financial support. AHJK, AMJM and JMS are members of The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative. Funding from the BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",

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T1 - Increased skeletal muscle 11βHSD1 mRNA is associated with lower muscle strength in ageing

AU - Kilgour, Alixe H M

AU - Gallagher, Iain J

AU - MacLullich, Alasdair M J

AU - Andrew, Ruth

AU - Gray, Calum D

AU - Hyde, Philippa

AU - Wackerhage, Henning

AU - Husi, Holger

AU - Ross, James A

AU - Starr, John M

AU - Chapman, Karen E

AU - Fearon, Kenneth C H

AU - Walker, Brian R

AU - Greig, Carolyn A

N1 - Copyright: © 2013 Kilgour et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors thank the British Heart Foundation and Chief Scientist Office of the Scottish Government for financial support. AHJK, AMJM and JMS are members of The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative. Funding from the BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2013/12/31

Y1 - 2013/12/31

N2 - Background: Sarcopenia, the loss of muscle mass and function with age, is associated with increased morbidity and mortality. Current understanding of the underlying mechanisms is limited. Glucocorticoids (GC) in excess cause muscle weakness and atrophy. We hypothesized that GC may contribute to sarcopenia through elevated circulating levels or increased glucocorticoid receptor (GR) signaling by increased expression of either GR or the GC-amplifying enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) in muscle.Methods: There were 82 participants; group 1 comprised 33 older men (mean age 70.2years, SD 4.4) and 19 younger men (22.2years, 1.7) and group 2 comprised 16 older men (79.1years, 3.4) and 14 older women (80.1years, 3.7). We measured muscle strength, mid-thigh cross-sectional area, fasting morning plasma cortisol, quadriceps muscle GR and 11 beta HSD1 mRNA, and urinary glucocorticoid metabolites. Data were analysed using multiple linear regression adjusting for age, gender and body size.Results: Muscle strength and size were not associated with plasma cortisol, total urinary glucocorticoids or the ratio of urinary 5 beta-tetrahydrocortisol + 5 alpha-tetrahydrocortisol to tetrahydrocortisone (an index of systemic 11 beta HSD activity). Muscle strength was associated with 11 beta HSD1 mRNA levels (beta -0.35, p = 0.04), but GR mRNA levels were not significantly associated with muscle strength or size.Conclusion: Although circulating levels of GC are not associated with muscle strength or size in either gender, increased cortisol generation within muscle by 11 beta HSD1 may contribute to loss of muscle strength with age, a key component of sarcopenia. Inhibition of 11 beta HSD1 may have therapeutic potential in sarcopenia.

AB - Background: Sarcopenia, the loss of muscle mass and function with age, is associated with increased morbidity and mortality. Current understanding of the underlying mechanisms is limited. Glucocorticoids (GC) in excess cause muscle weakness and atrophy. We hypothesized that GC may contribute to sarcopenia through elevated circulating levels or increased glucocorticoid receptor (GR) signaling by increased expression of either GR or the GC-amplifying enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) in muscle.Methods: There were 82 participants; group 1 comprised 33 older men (mean age 70.2years, SD 4.4) and 19 younger men (22.2years, 1.7) and group 2 comprised 16 older men (79.1years, 3.4) and 14 older women (80.1years, 3.7). We measured muscle strength, mid-thigh cross-sectional area, fasting morning plasma cortisol, quadriceps muscle GR and 11 beta HSD1 mRNA, and urinary glucocorticoid metabolites. Data were analysed using multiple linear regression adjusting for age, gender and body size.Results: Muscle strength and size were not associated with plasma cortisol, total urinary glucocorticoids or the ratio of urinary 5 beta-tetrahydrocortisol + 5 alpha-tetrahydrocortisol to tetrahydrocortisone (an index of systemic 11 beta HSD activity). Muscle strength was associated with 11 beta HSD1 mRNA levels (beta -0.35, p = 0.04), but GR mRNA levels were not significantly associated with muscle strength or size.Conclusion: Although circulating levels of GC are not associated with muscle strength or size in either gender, increased cortisol generation within muscle by 11 beta HSD1 may contribute to loss of muscle strength with age, a key component of sarcopenia. Inhibition of 11 beta HSD1 may have therapeutic potential in sarcopenia.

KW - 11-beta-hydroxysteroid dehydrogenase type-1

KW - glucocorticoid-receptors

KW - body-composition

KW - elderly-men

KW - in-vivo

KW - sarcopenia

KW - cortisol

KW - diagnosis

KW - mass

KW - pathogenesis

U2 - 10.1371/journal.pone.0084057

DO - 10.1371/journal.pone.0084057

M3 - Article

SN - 1932-6203

VL - 8

JO - PloS ONE

JF - PloS ONE

IS - 12

M1 - e84057

ER -

Increased skeletal muscle 11βHSD1 mRNA is associated with lower muscle strength in ageing

Abstract

Bibliographical note

Keywords

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