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

Funding

1Nestle Research, EPFL Innovation Park, Lausanne, Switzerland. 2KTP-National University Children’s Medical Institute, National University Hospital, Singapore, Singapore. 3Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 4Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK. 5National Institute for Health Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. 6Academic Geriatric Medicine, , University of Southampton, Southampton, UK. 7EPFL school of Life Sciences, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland. 8Department of Molecular & Cell Biology, College of Public Health, Medical & Veterinary Sciences, James Cook University, Townsville, Queensland, Australia. 9UWI Solutions for Developing Countries, UWI SODECO, University of West Indies, Kingston, Jamaica. 10Singapore Institute for Clinical Sciences (A*STAR), Singapore, Singapore. 11Department of Endocrinology, Tan Tock Seng Hospital, Singapore, Singapore. 12Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. 13Institute of Developmental Sciences, University of Southampton, Southampton, UK. 14Centre for Biological Sciences, University of Southampton, Southampton, UK. 15Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 16Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 17Liggins Institute, University of Auckland, Auckland, New Zealand. 18AGE Research Group, Institute of Neuroscience, Faculty of Medical Sciences, Newcastle University, Newcastle, UK. 19NIHR Newcastle Biomedical Research Centre, Newcastle upon-Tyne NHS Foundation Trust and Newcastle University, Newcastle, UK. 20National Institute for Health Research Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK. 21Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 22These authors contributed equally: Eugenia Migliavacca, Stacey K.H. Tay. 23These authors jointly supervised this work: Keith M. Godfrey, Karen A. Lillycrop, Neerja Karnani, Jerome N. Feige. *email: kmg@mrc.soton.ac.uk; K.A.Lillycrop@soton.ac.uk; neerja_karnani@sics.a-star.edu.sg; Jerome.feige@rd.nestle.com MEMOSA is a collaborative project involving the Nestlé Institute of Health Sciences (NIHS) and the EpiGen Consortium, an international alliance of researchers at the Universities of Auckland, New Zealand, and Southampton (Centre for Biological Sciences, Medical Research Council Lifecourse Epidemiology Unit), UK, the Singapore Institute for Clinical Sciences of the Agency for Science, Technology and Research (A*STAR), National University of Singapore and UWI Solutions for Developing Countries, University of the West Indies. We wish to thank the study participants for making this work possible and staff at our institutions for assistance in participant recruitment, performing the measurements and project management. We also thank Philipp Gut for critical reading of the paper. 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. This report is independent research and the views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funding bodies had no role in the design, collection, analysis, and interpretation of data, writing of the paper, or decision to submit for publication.

FundersFunder number
Cohen Trust
EpiGen Consortium
Medical Research Council Lifecourse Epidemiology Unit
Nestlé Institute of Health Sciences
Universities of Auckland
Foundation for the National Institutes of HealthU24AG047867
Society for Economic Anthropology
University of the West Indies
University Hospital Southampton NHS Foundation Trust
Seventh Framework Programme289346
NIHR Bristol Biomedical Research Centre
Medical Research CouncilMC_ST_U2055, MC_U47585827
Biotechnology and Biological Sciences Research CouncilES/M0099X/
National Institute for Health ResearchNF-SI-055–0042
National Osteoporosis Society
Arthritis Research UK
Research Councils UKMC_UU_20/4
University of Southampton
University of Oxford
European Commission
Agency for Science, Technology and ResearchSTAR
National University of Singapore
Singapore Institute for Clinical Sciences
Singapore Police Force
Seventh Framework ProgrammeFP7/2007-203
International Osteoporosis Foundation
National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology

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