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

Eugenia Migliavacca, Stacey K. H. Tay, Harnish P. Patel, Tanja Sonntag, Gabriele Civiletto, Craig McFarlane, Terence Forrester, Sheila J. Barton, Melvin K. Leow, Elie Antoun, Aline Charpagne, Yap Seng Chong, Patrick Descombes, Lei Feng, Patrice Francis-Emmanuel, Emma S. Garratt, Maria Pilar Giner, Curtis O. Green, Sonia Karaz, Narasimhan Kothandaraman, Julien Marquis, Sylviane Metairon, Sofia Moco, Gail Nelson, Sherry Ngo, Tony Pleasants, Frederic Raymond, Avan A. Sayer, Chu Ming Sim, Jo Slater-Jefferies, Holly E. Syddall, Pei Fang Tan, Philip Titcombe, Candida Vaz, Leo D. Westbury, Gerard Wong, Wu Yonghui, Cyrus Cooper, Allan Sheppard, Keith M. Godfrey (), Karen A. Lillycrop (), Neerja Karnani () and Jerome N. Feige ()
Additional contact information
Eugenia Migliavacca: Nestle Research, EPFL Innovation Park
Stacey K. H. Tay: KTP-National University Children’s Medical Institute, National University Hospital
Harnish P. Patel: University of Southampton
Tanja Sonntag: Nestle Research, EPFL Innovation Park
Gabriele Civiletto: Nestle Research, EPFL Innovation Park
Craig McFarlane: James Cook University
Terence Forrester: University of West Indies
Sheila J. Barton: University of Southampton
Melvin K. Leow: Singapore Institute for Clinical Sciences (A*STAR)
Elie Antoun: Institute of Developmental Sciences, University of Southampton
Aline Charpagne: Nestle Research, EPFL Innovation Park
Yap Seng Chong: Singapore Institute for Clinical Sciences (A*STAR)
Patrick Descombes: Nestle Research, EPFL Innovation Park
Lei Feng: National University of Singapore
Patrice Francis-Emmanuel: University of West Indies
Emma S. Garratt: National Institute for Health Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust
Maria Pilar Giner: Nestle Research, EPFL Innovation Park
Curtis O. Green: University of West Indies
Sonia Karaz: Nestle Research, EPFL Innovation Park
Narasimhan Kothandaraman: Singapore Institute for Clinical Sciences (A*STAR)
Julien Marquis: Nestle Research, EPFL Innovation Park
Sylviane Metairon: Nestle Research, EPFL Innovation Park
Sofia Moco: Nestle Research, EPFL Innovation Park
Gail Nelson: University of West Indies
Sherry Ngo: Liggins Institute, University of Auckland
Tony Pleasants: Liggins Institute, University of Auckland
Frederic Raymond: Nestle Research, EPFL Innovation Park
Avan A. Sayer: , University of Southampton
Chu Ming Sim: Singapore Institute for Clinical Sciences (A*STAR)
Jo Slater-Jefferies: Institute of Developmental Sciences, University of Southampton
Holly E. Syddall: University of Southampton
Pei Fang Tan: Singapore Institute for Clinical Sciences (A*STAR)
Philip Titcombe: University of Southampton
Candida Vaz: Singapore Institute for Clinical Sciences (A*STAR)
Leo D. Westbury: University of Southampton
Gerard Wong: Singapore Institute for Clinical Sciences (A*STAR)
Wu Yonghui: Singapore Institute for Clinical Sciences (A*STAR)
Cyrus Cooper: University of Southampton
Allan Sheppard: Liggins Institute, University of Auckland
Keith M. Godfrey: University of Southampton
Karen A. Lillycrop: National Institute for Health Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust
Neerja Karnani: Singapore Institute for Clinical Sciences (A*STAR)
Jerome N. Feige: Nestle Research, EPFL Innovation Park

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13694-1

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