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

Migliavacca, Eugenia, Tay, Stacey K.H., Patel, Harnish P., Sonntag, Tanja, Civiletto, Gabriele, McFarlane, Craig McFarlane, Forrester, Terence, Barton, Sheila J., Leow, Melvin K., Antoun, Elie, Charpagne, Aline, Seng Chong, Yap, Descombes, Patrick, Feng, Lei, Francis-Emmanuel, Patrice, Garratt, Emma S., Giner, Maria Pilar, Green, Curtis O., Karaz, Sonia, Kothandaraman, Narasimhan, Marquis, Julien, Metairon, Sylviane, Moco, Sofia, Nelson, Gail, Ngo, Sherry, Pleasants, Tony, Raymond, Frederic, Sayer, Avan A., Ming Sim, Chu, Slater-Jefferies, Jo, Syddall, Holly E., Fang Tan, Pei, Titcombe, Philip, Vaz, Candida, Westbury, Leo D., Wong, Gerard, Wu, Yonghui, Cooper, Cyrus, Sheppard, Allan, Godfrey, Keith M., Lillycrop, Karen, Karnani, Neerja, and Feige, Jerome N. (2019) Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities. Nature Communications, 10. 5808.

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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.

Item ID: 61478
Item Type: Article (Research - C1)
ISSN: 2041-1723
Copyright Information: Open Access. This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly fromthe copyright holder. To view a copy of this license, visithttp://creativecommons.org/licenses/by/4.0/.
Funders: Medical Research Council (MRC), Arthritis Research UK, National Osteoporosis Society, International Osteoporosis Foundation, Cohen Trust, NIHR Southampton Biomedical Research Centre, University of Southampton, University Hospital Southampton NHS Foundation Trust, NIHR Musculoskeletal Biomedical Research
Projects and Grants: MRC MC_U47585827, MRC MC_ST_U2055
Date Deposited: 13 Feb 2020 01:11
FoR Codes: 06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060104 Cell Metabolism @ 40%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060102 Bioinformatics @ 20%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060111 Signal Transduction @ 40%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920116 Skeletal System and Disorders (incl. Arthritis) @ 25%
97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 35%
97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 40%
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