Muscle-specific Perilipin2 down-regulation affects lipid metabolism and induces myofiber hypertrophy.

BACKGROUND: Perilipin2 (Plin2) belongs to a family of five highly conserved proteins, known for their role in lipid storage. Recent data indicate that Plin2 has an important function in cell metabolism and is involved in several human pathologies, including liver steatosis and Type II diabetes. An association between Plin2 and lower muscle mass and strength has been found in elderly and inactive people, but its function in skeletal muscle is still unclear. Here, we addressed the role of Plin2 in adult muscle by gain and loss of function experiments. METHODS: By mean of in vivo Plin2 down-regulation (shPlin2) and overexpression (overPlin2) in murine tibialis anterior muscle, we analysed the effects of Plin2 genetic manipulations on myofiber size and lipid composition. An analysis of skeletal muscle lipid composition was also performed in vastus lateralis samples from young and old patients undergoing hip surgery. RESULTS: We found that Plin2 down-regulation was sufficient to induce a 30% increase of myofiber cross-sectional area, independently of mTOR pathway. Alterations of lipid content and modulation of genes involved in lipid synthesis occurred in hypertrophic muscles. In particular, we showed a decrease of triglycerides, ceramides, and phosphatidylcoline:phosphatidylethanolamine ratio, a condition known to impact negatively on muscle function. Plin2 overexpression did not change fibre size; however, lipid composition was strongly affected in a way that is similar to that observed in human samples from old patients. CONCLUSIONS: Altogether these data indicate that Plin2 is a critical mediator for the control of muscle mass, likely, but maybe not exclusively, through its critical role in the regulation of intracellular lipid content and composition

Muscle-specific Perilipin2 down-regulation affects lipid metabolism and induces myofiber hypertrophy.

BACKGROUND: Perilipin2 (Plin2) belongs to a family of five highly conserved proteins, known for their role in lipid storage. Recent data indicate that Plin2 has an important function in cell metabolism and is involved in several human pathologies, including liver steatosis and Type II diabetes. An association between Plin2 and lower muscle mass and strength has been found in elderly and inactive people, but its function in skeletal muscle is still unclear. Here, we addressed the role of Plin2 in adult muscle by gain and loss of function experiments. METHODS: By mean of in vivo Plin2 down-regulation (shPlin2) and overexpression (overPlin2) in murine tibialis anterior muscle, we analysed the effects of Plin2 genetic manipulations on myofiber size and lipid composition. An analysis of skeletal muscle lipid composition was also performed in vastus lateralis samples from young and old patients undergoing hip surgery. RESULTS: We found that Plin2 down-regulation was sufficient to induce a 30% increase of myofiber cross-sectional area, independently of mTOR pathway. Alterations of lipid content and modulation of genes involved in lipid synthesis occurred in hypertrophic muscles. In particular, we showed a decrease of triglycerides, ceramides, and phosphatidylcoline:phosphatidylethanolamine ratio, a condition known to impact negatively on muscle function. Plin2 overexpression did not change fibre size; however, lipid composition was strongly affected in a way that is similar to that observed in human samples from old patients. CONCLUSIONS: Altogether these data indicate that Plin2 is a critical mediator for the control of muscle mass, likely, but maybe not exclusively, through its critical role in the regulation of intracellular lipid content and composition

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