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

Eugenia Migliavacca ,Terence Forrester ,Cyrus Cooper ,Sylviane Métairon ,Elie Antoun ,Stacey Kiat Hong Tay ,Neerja Karnani ,Yonghui Wu ,Karen A Lillycrop ,Curtis O Green ,Tony Pleasants ,Sofia Moco ,J.l Slater-Jefferies ,Allan Sheppard ,Lei Feng ,Gabriele Civiletto ,Yap Seng Chong ,Gerard Wong ,Sonia Karaz ,Gail A Nelson ,Harnish P Patel ,Maria Pilar Giner ,Kothandaraman Narasimhan ,Craig Mcfarlane ,Holly Syddall ,Patrice Francis-Emmanuel ,Sheila J Barton ,Philip Titcombe ,Leo Westbury ,Melvin Khee‐Shing Leow ,Chu Ming Sim ,Aline Charpagne ,Julien Marquis ,Sherry Ngo ,Candida Vaz ,Tanja Sonntag ,Frédéric Raymond ,Keith M Godfrey ,Pei Fang Tan ,Patrick Descombes ,Avan A Sayer ,Emma Garratt ,Jérôme N Feige

doi:10.1038/s41467-019-13694-1

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.

Highlights

The causes of impaired skeletal muscle mass and strength during aging are well-studied in healthy populations
For the first time we demonstrate that mitochondrial bioenergetic dysfunction is the strongest molecular signature of sarcopenia in three distinct ethnic populations, with major impairments of oxidative phosphorylation, mitochondrial dynamics, and mitochondrial quality control through the UPRmt
Sarcopenia was defined based on harmonized consensus clinical definitions of the AWGSOP (SSS) or EWGSOP (HSS/JSS)[26], using skeletal muscle mass evaluation by DXA measurement of appendicular lean body mass index (ALMi), grip strength, and gait speed (Supplementary Table 2)

Summary

Introduction

The causes of impaired skeletal muscle mass and strength during aging are well-studied in healthy populations. 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. This associates with the downregulation of an ERRα/PGC-1α/NRF1 regulatory module, lower NAD+ levels and alterations of mitochondrial respiratory complex protein expression and activity in human sarcopenia

Methods

Results

Conclusion