Muscle-specific Plin2 down-regulation affects accumulation of ectopic lipid metabolites including ceramides

Aging is characterized by dramatic changes in body composition, leading to a decline in muscle mass and quality, and thus to sarcopenia. The mechanism underlying sarcopenia and are not completely understood, however a role for high accumulation of ectopic lipid metabolites, causing lipotoxicity, has been proposed. Fat accumulates within lipid droplets (LDs), surrounded by perilipins (Plins). In skeletal muscle one of the most abundant is PLIN2, known for its role in lipid storage and considered as marker of lipid accumulation. Recently we found that Plin2 expression in humans increases with age, is inversely associated with muscle mass and strength. We analyzed muscle samples from mice undergone denervation-induced atrophy, and we found a higher expression of PLIN2 and atrogenes in denervated muscle with respect to the non denervate side. Moreover, muscle-specific in vivo silencing experiments showed a higher cross-sectional area of PLIN2 down-regulated fibres. It is not clear whether such manipulation of PLIN2 affects the intracellular accumulation of lipid metabolites. We therefore measured lipid species by TLC technique in Tibialis muscle from mice with either denervation, or PLIN2 down-regulation. Results indicate that denervation and PLIN2 down-regultion induce a dramatic change of intramuscular lipid metabolites and in particular of ceramides. As a whole, these data suggest that PLIN2 moduòation plays a role in intracellular lipid accumulation likely affecting sarcopania. Therefore a modification of PLIN2 could be a key factoer to reduce muscle atrophy and therapeutic approaches to sarcopenia associates with lipotoxicity.