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

E. Migliavacca, S.K.H. Tay, H.P. Patel, T. Sonntag, G. Civiletto, C. McFarlane, T. Forrester, S.J. Barton, M.K. Leow, E. Antoun, A. Charpagne, Y. Seng Chong, P. Descombes, L. Feng, P. Francis-Emmanuel, E.S. Garratt, M.P. Giner, C.O. Green, S. Karaz, N. KothandaramanJ. Marquis, S. Metairon, S. Moco, G. Nelson, S. Ngo, T. Pleasants, F. Raymond, A.A. Sayer, C. Ming Sim, J. Slater-Jefferies, H.E. Syddall, P. Fang Tan, P. Titcombe, C. Vaz, L.D. Westbury, G. Wong, W. Yonghui, C. Cooper, A. Sheppard, K.M. Godfrey, K.A. Lillycrop, N. Karnani, J.N. Feige

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

© 2019, The Author(s).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.
Original languageEnglish
Article number5808
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019
Externally publishedYes

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