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

Nature Communications

10.1038/s41467-019-13694-1

https://doi.org/10.1038/s41467-019-13694-1

Eugenia Migliavacca, Stacey K. H. Tay, Harnish P. Patel, Tanja Sonntag, Gabriele Civiletto, Craig McFarlane, Terrence Forrester, Shelia J. Barton, Melvin K. Leow, Elie Antoun, Aline Charpagne, Yap Seng 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, Gerald Wong, Yonghui Wu, Cyrus Cooper, Allan Sheppard, Keith M. Godfrey, Karen .A. Lillycrop, Neerja Karnani, Jerome N. Feige

Ageing, energy metabolism, skeletal muscle

20 December 2019

Migliavacca E, Tay SKH, Patel HP, Sonntag T, Civiletto G, McFarlane C, Forrester T, Barton SJ, Leow MK, Antoun E, Charpagne A, Seng Chong Y, Descombes P, Feng L, Francis-Emmanuel P, Garratt ES, Giner MP, Green CO, Karaz S, Kothandaraman N, Marquis J, Metairon S, Moco S, Nelson G, Ngo S, Pleasants T, Raymond F, Sayer AA, Ming Sim C, Slater-Jefferies J, Syddall HE, Fang Tan P, Titcombe P, Vaz C, Westbury LD, Wong G, Yonghui W, Cooper C, Sheppard A, Godfrey KM, Lillycrop KA, Karnani N, Feige JN. “Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities”. Nat Commun. 2019 Dec 20;10(1):5808. doi: 10.1038/s41467-019-13694-1.

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.

http://creativecommons.org/licenses/by/4.0/

This work was supported by grants from the Medical Research Council (MC_U47585827, MC_ST_U2055), Arthritis Research UK, National Osteoporosis Society, International Osteoporosis Foundation, Cohen Trust, NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, and NIHR Musculoskeletal Biomedical Research Unit, University of Oxford. K.M.G. is supported by the UK Medical Research Council (MC_UU_20/4), the US National Institute On Aging of the National Institutes of Health (award number U24AG047867), the UK Economic and Social Research Council and the Biotechnology and Biological Sciences Research Council (award number ES/M0099X/), the National Institute for Health Research (as an NIHR Senior Investigator (NF-SI-055–0042) and through the NIHR Southampton Biomedical Research Centre) and the European Union’s Erasmus + Capacity-Building ENeA SEA Project and Seventh Framework Program (FP7/2007-203) project EarlyNutrition (grant agreement number 289346). Data analysis done in Singapore was supported by the Strategic Positioning Fund (SPF) available to NK through Agency for Science, Technology and Research (A*STAR), Singapore. H.P.P. is supported by the National Institute for Health Research through the NIHR Southampton Biomedical Research Centre.

https://oar.a-star.edu.sg/communities-collections/articles/15069

2041-1723

Singapore Institute for Clinical Sciences