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