Obese subcutaneous adipose tissue impairs human myogenesis, particularly in old skeletal muscle, via resistin-mediated activation of NF\u03baB

Mary F O’Leary,Simon W Jones,Graham R Wallace,Edward T Davis,Thomas Nicholson,Andrew J Bennett,David P Murphy,Kostas Tsintzas

doi:10.1038/s41598-018-33840-x

Abstract

Adiposity and adipokines are implicated in the loss of skeletal muscle mass with age and in several chronic disease states. The aim of this study was to determine the effects of human obese and lean subcutaneous adipose tissue secretome on myogenesis and metabolism in skeletal muscle cells derived from both young (18–30 yr) and elderly (>65 yr) individuals. Obese subcutaneous adipose tissue secretome impaired the myogenesis of old myoblasts but not young myoblasts. Resistin was prolifically secreted by obese subcutaneous adipose tissue and impaired myotube thickness and nuclear fusion by activation of the classical NFκB pathway. Depletion of resistin from obese adipose tissue secretome restored myogenesis. Inhibition of the classical NFκB pathway protected myoblasts from the detrimental effect of resistin on myogenesis. Resistin also promoted intramyocellular lipid accumulation in myotubes and altered myotube metabolism by enhancing fatty acid oxidation and increasing myotube respiration and ATP production. In conclusion, resistin derived from human obese subcutaneous adipose tissue impairs myogenesis of human skeletal muscle, particularly older muscle, and alters muscle metabolism in developing myotubes. These findings may have important implications for the maintenance of muscle mass in older people with chronic inflammatory conditions, or older people who are obese or overweight.

Highlights

The loss of skeletal muscle mass with ageing is accompanied by an increased systemic inflammatory burden[1] and accumulation of adipose tissue[2], which is known to be a prolific secretor of pro-inflammatory cytokines[3] termed adipokines
Since the adipokine resistin was significantly elevated in the adipose conditioned medium (ACM) of overweight/obese individuals, we examined the effect of stimulating myoblasts with recombinant resistin during their differentiation to myotubes
We describe for the first time the adverse myogenic effects of the obese human subcutaneous adipose tissue (SAT) secretome, generated using conditioned media

Summary

Introduction

The loss of skeletal muscle mass with ageing (sarcopenia) is accompanied by an increased systemic inflammatory burden[1] and accumulation of adipose tissue[2], which is known to be a prolific secretor of pro-inflammatory cytokines[3] termed adipokines. Circulatory levels of adiponectin and resistin are increased in old individuals, compared to the young, and are inversely associated with muscle strength[11] These studies indicate that sarcopenia in overweight and obese individuals is in part an adipokine-driven phenomenon. A single study has directly examined the effect of an inflammatory milieu secreted by human SAT adipocytes on primary human myotube morphology[24] This particular study showed that conditioned medium from SAT adipocytes derived from lean individuals does not alter the Myotube Thickness (MTT) or Nuclear Fusion Index (NFI) of myotubes in myogenic cultures isolated from a neonate[24]. Adipokine secretion by human adipose tissue – not just that by adipocytes – must be characterised and its effect on human myofibre size and function determined

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