Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-13694-1
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Funding
- 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
- University Hospital Southampton NHS Foundation Trust
- NIHR Musculoskeletal Biomedical Research Unit, University of Oxford
- UK Medical Research Council [MC_UU_20/4]
- US National Institute On Aging of the National Institutes of Health [U24AG047867]
- UK Economic and Social Research Council [ES/M0099X/]
- Biotechnology and Biological Sciences Research Council [ES/M0099X/]
- National Institute for Health Research [NF-SI-055-0042]
- National Institute for Health Research (NIHR Southampton Biomedical Research Centre)
- European Union [289346]
- Strategic Positioning Fund (SPF)
- National Institute for Health Research through the NIHR Southampton Biomedical Research Centre
- MRC [MC_U147585827, MC_UU_12011/4, G0400491, MC_U147585819] Funding Source: UKRI
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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-1 alpha/ERR alpha 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.
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