Increased Plin2 Expression in Human Skeletal Muscle Is Associated with Sarcopenia and Muscle Weakness

Maria Conte,Claudio Franceschi,Laura Barberi,Elena Bellavista,Antonia D’Errico-Grigioni,Alessio Degiovanni,Francesco Vasuri,Stefano Salvioli,Ermanno Martucci,Giovanni Trisolino,Aurelia Santoro,Andrea B Maier,Olivier Seynnes,Marco V Narici,Daniela Caporossi,Miriam Capri,Antonio Musarò

doi:10.1371/journal.pone.0073709

Abstract

Human aging is associated with a progressive loss of muscle mass and strength and a concomitant fat accumulation in form of inter-muscular adipose tissue, causing skeletal muscle function decline and immobilization. Fat accumulation can also occur as intra-muscular triglycerides (IMTG) deposition in lipid droplets, which are associated with perilipin proteins, such as Perilipin2 (Plin2). It is not known whether Plin2 expression changes with age and if this has consequences on muscle mass and strength. We studied the expression of Plin2 in the vastus lateralis (VL) muscle of both healthy subjects and patients affected by lower limb mobility limitation of different age. We found that Plin2 expression increases with age, this phenomenon being particularly evident in patients. Moreover, Plin2 expression is inversely correlated with quadriceps strength and VL thickness. To investigate the molecular mechanisms underpinning this phenomenon, we focused on IGF-1/p53 network/signalling pathway, involved in muscle physiology. We found that Plin2 expression strongly correlates with increased p53 activation and reduced IGF-1 expression. To confirm these observations made on humans, we studied mice overexpressing muscle-specific IGF-1, which are protected from sarcopenia. These mice resulted almost negative for the expression of Plin2 and p53 at two years of age. We conclude that fat deposition within skeletal muscle in form of Plin2-coated lipid droplets increases with age and is associated with decreased muscle strength and thickness, likely through an IGF-1- and p53-dependent mechanism. The data also suggest that excessive intramuscular fat accumulation could be the initial trigger for p53 activation and consequent loss of muscle mass and strength.

Highlights

Human aging is characterized by increased levels of physical disability due at least in part to loss of muscle strength
Many studies have focused on the role of inter-muscular adipose tissue (IMAT), as it is known to be a source of inflammatory mediators [5], while much less is known about the possible role of intracellular lipid deposition, which occurs in form of lipid droplets (LDs)
We first checked the presence of lipid droplets by using classic Oil Red O staining in 16 samples of muscle biopsy from patients, and we found an age-related increase in the positivity of the fibres to this staining (Figure 1A–C)

Summary

Introduction

Human aging is characterized by increased levels of physical disability due at least in part to loss of muscle strength. This loss depends on both decrease in muscle mass and accumulation of inter-muscular adipose tissue (IMAT) [1,2]. LDs are vesicles formed by a phospholipid monolayer whose dynamics appears to be determined by a family of proteins named Perilipins (Plins), previously referred to as PAT proteins, which play a critical role in regulating intracellular lipid storage and mobilization [6,7]. Plin is mostly expressed in the type I fibres of skeletal muscle, which contain more fat than the type II fibres and where Plin promotes the uptake of fatty acids and their storage as triacylglycerols [13,14]

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