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Mitochondrial oxidative capacity and NAD biosynthesis are reduced in human sarcopenia across ethnicities

Mitochondrial oxidative capacity and NAD biosynthesis are reduced in human sarcopenia across ethnicities
Mitochondrial oxidative capacity and NAD biosynthesis are reduced in human sarcopenia across ethnicities
The causes of impaired skeletal muscle mass and strength during aging are well-studied in healthy populations. Less is known on pathological age-related muscle wasting and weakness termed sarcopenia, which directly impacts physical autonomy and survival. Here, we compare genome-wide transcriptional changes of sarcopenia versus age-matched controls in muscle biopsies from 119 older men from Singapore, Hertfordshire UK and Jamaica. Individuals with sarcopenia reproducibly demonstrate a prominent transcriptional signature of mitochondrial bioenergetic dysfunction in skeletal muscle, with low PGC-1α/ERRα signalling, and downregulation of oxidative phosphorylation and mitochondrial proteostasis genes. These changes translate functionally into fewer mitochondria, reduced mitochondrial respiratory complex expression and activity, and low NAD+ levels through perturbed NAD+ biosynthesis and salvage in sarcopenic muscle. We provide an integrated molecular profile of human sarcopenia across ethnicities, demonstrating a fundamental role of altered mitochondrial metabolism in the pathological loss of skeletal muscle mass and function in older people.
2041-1723
Migliavacca, Eugenia
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Barton, Sheila
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Chong, Yap-Seng
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Descombes, Patrick
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Feng, Lei
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Karaz, Sonia
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Sim, Chu Ming
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Titcombe, Philip
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Wong, Gerard
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Cooper, Cyrus
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Sheppard, Allan
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Godfrey, Keith
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Lillycrop, Karen
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Karnani, Neerja
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Feige, Jerome
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Migliavacca, Eugenia
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Tay, Stacey KH
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Patel, Harnish
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Sonntag, Tanja
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Civiletto, Gabriele
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McFarlane, Craig
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Forrester, Terrence
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Barton, Sheila
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Leow, Melvin Khee-Shing
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Antoun, Elie
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Charpagne, Aline
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Chong, Yap-Seng
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Descombes, Patrick
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Feng, Lei
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Green, Curtis O.
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Karaz, Sonia
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Kothandaraman, Narasimhan
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Marquis, Julien
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Metairon, S.
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Moco, Sofia
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Nelson, Gail
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Ngo, Sherry
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Aihie Sayer, Avan
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Sim, Chu Ming
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Slater-Jefferies, Joanne
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Syddall, Holly Emma
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Tang, Pei Fang
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Titcombe, Philip
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Vaz, Candida
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Westbury, Leo
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Wong, Gerard
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Wu, Yonghui
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Cooper, Cyrus
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Sheppard, Allan
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Godfrey, Keith
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Lillycrop, Karen
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Karnani, Neerja
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Feige, Jerome
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Migliavacca, Eugenia, Tay, Stacey KH, Patel, Harnish, Sonntag, Tanja, Civiletto, Gabriele, McFarlane, Craig, Forrester, Terrence, Barton, Sheila, Leow, Melvin Khee-Shing, Antoun, Elie, Charpagne, Aline, Chong, Yap-Seng, Descombes, Patrick, Feng, Lei, Francis-Emmanuel, Patrice, Garratt, Emma, Pilar Giner, Maria, Green, Curtis O., Karaz, Sonia, Kothandaraman, Narasimhan, Marquis, Julien, Metairon, S., Moco, Sofia, Nelson, Gail, Ngo, Sherry, Pleasants, Tony, Raymond, Frederic, Aihie Sayer, Avan, Sim, Chu Ming, Slater-Jefferies, Joanne, Syddall, Holly Emma, Tang, Pei Fang, Titcombe, Philip, Vaz, Candida, Westbury, Leo, Wong, Gerard, Wu, Yonghui, Cooper, Cyrus, Sheppard, Allan, Godfrey, Keith, Lillycrop, Karen, Karnani, Neerja and Feige, Jerome (2019) Mitochondrial oxidative capacity and NAD biosynthesis are reduced in human sarcopenia across ethnicities. Nature Communications, 10, [5808]. (doi:10.1038/s41467-019-13694-1).

Record type: Article

Abstract

The causes of impaired skeletal muscle mass and strength during aging are well-studied in healthy populations. Less is known on pathological age-related muscle wasting and weakness termed sarcopenia, which directly impacts physical autonomy and survival. Here, we compare genome-wide transcriptional changes of sarcopenia versus age-matched controls in muscle biopsies from 119 older men from Singapore, Hertfordshire UK and Jamaica. Individuals with sarcopenia reproducibly demonstrate a prominent transcriptional signature of mitochondrial bioenergetic dysfunction in skeletal muscle, with low PGC-1α/ERRα signalling, and downregulation of oxidative phosphorylation and mitochondrial proteostasis genes. These changes translate functionally into fewer mitochondria, reduced mitochondrial respiratory complex expression and activity, and low NAD+ levels through perturbed NAD+ biosynthesis and salvage in sarcopenic muscle. We provide an integrated molecular profile of human sarcopenia across ethnicities, demonstrating a fundamental role of altered mitochondrial metabolism in the pathological loss of skeletal muscle mass and function in older people.

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Accepted/In Press date: 15 November 2019
e-pub ahead of print date: 20 December 2019
Published date: 20 December 2019

Identifiers

Local EPrints ID: 436768
URI: http://eprints.soton.ac.uk/id/eprint/436768
ISSN: 2041-1723
PURE UUID: b27105ec-f51a-41e5-a6a9-63309dd93db5
ORCID for Harnish Patel: ORCID iD orcid.org/0000-0002-0081-1802
ORCID for Sheila Barton: ORCID iD orcid.org/0000-0003-4963-4242
ORCID for Emma Garratt: ORCID iD orcid.org/0000-0001-5268-4203
ORCID for Joanne Slater-Jefferies: ORCID iD orcid.org/0000-0001-8325-1320
ORCID for Holly Emma Syddall: ORCID iD orcid.org/0000-0003-0171-0306
ORCID for Philip Titcombe: ORCID iD orcid.org/0000-0002-7797-8571
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709
ORCID for Keith Godfrey: ORCID iD orcid.org/0000-0002-4643-0618
ORCID for Karen Lillycrop: ORCID iD orcid.org/0000-0001-7350-5489

Catalogue record

Date deposited: 06 Jan 2020 17:30
Last modified: 26 Nov 2021 03:02

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Contributors

Author: Eugenia Migliavacca
Author: Stacey KH Tay
Author: Harnish Patel ORCID iD
Author: Tanja Sonntag
Author: Gabriele Civiletto
Author: Craig McFarlane
Author: Terrence Forrester
Author: Sheila Barton ORCID iD
Author: Melvin Khee-Shing Leow
Author: Elie Antoun
Author: Aline Charpagne
Author: Yap-Seng Chong
Author: Patrick Descombes
Author: Lei Feng
Author: Patrice Francis-Emmanuel
Author: Emma Garratt ORCID iD
Author: Maria Pilar Giner
Author: Curtis O. Green
Author: Sonia Karaz
Author: Narasimhan Kothandaraman
Author: Julien Marquis
Author: S. Metairon
Author: Sofia Moco
Author: Gail Nelson
Author: Sherry Ngo
Author: Tony Pleasants
Author: Frederic Raymond
Author: Avan Aihie Sayer
Author: Chu Ming Sim
Author: Pei Fang Tang
Author: Philip Titcombe ORCID iD
Author: Candida Vaz
Author: Leo Westbury
Author: Gerard Wong
Author: Yonghui Wu
Author: Cyrus Cooper ORCID iD
Author: Allan Sheppard
Author: Keith Godfrey ORCID iD
Author: Karen Lillycrop ORCID iD
Author: Neerja Karnani
Author: Jerome Feige

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