Purpose: Trimetazidine (TMZ) is a modulator of cell metabolism. TMZ is used to treat angina pectoris since it enhances the efficiency of myocardium metabolism. Its ability to optimize energy production in cardiac muscle cells led us to investigate the effect of TMZ also on skeletal muscle cells, in particular during myogenic dif- ferentiation and during muscle regeneration. We have recently found that TMZ has a protective effect against atrophy in vitro this supporting a possible reappraisal of TMZ in the treatment of cachexia. Among several features, cachexia is also associ- ated with loss of regenerative potential, which we analysed upon TMZ treatment. Methods: We incubated immortalised C2C12, satellite myoblasts and mesan- gioblasts with TMZ during differentiation. We also administered TMZ to mice during regeneration following muscle injury by cardiotoxin. Results: Our data showed that TMZ significantly stimulates glucose and glycogen consumption in C2C12 myotubes. TMZ also transcriptionally down-regulates PDK. Notably, we also found that the administration of TMZ potentiates myogenic differen- tiation in both C2C12 and satellite cells. In fact, TMZ up-regulates MyoD, Myogenin, MyHC and Desmin and increases myoblast fusion in differentiating cells. Finally, we found that TMZ does not induce apoptosis in our cell lines as demonstrated by absence of Caspase-3 and PARP cleavage and that TMZ has no effect on cell proliferation, as assessed by BrdU staining and cell cycle analysis by propidium iodide. In order to study the effectiveness of TMZ on muscle regeneration in vivo, we administered TMZ to mice following focal injury on tibialis anterior (TA) skeletal muscle. TA analysis after the injury showed that TMZ increases the expression of MyoD, Myogenin, neonatal myosin heavy chain (neoMyHC) and Desmin used as markers of satellite cell activation and differentiation into nascent regenerating myofibers. Conclusions: Our finding strongly suggest that TMZ stimulates myoblast differentiation and muscle regeneration following injury; this makes this drug appealing for its possible use in the treatment of several skeletal muscle pathologies.
Possible reappraisal of the angina pectoris drug trimetazidine in the treatment of skeletal muscle atrophy
Ferraro E
2015-01-01
Abstract
Purpose: Trimetazidine (TMZ) is a modulator of cell metabolism. TMZ is used to treat angina pectoris since it enhances the efficiency of myocardium metabolism. Its ability to optimize energy production in cardiac muscle cells led us to investigate the effect of TMZ also on skeletal muscle cells, in particular during myogenic dif- ferentiation and during muscle regeneration. We have recently found that TMZ has a protective effect against atrophy in vitro this supporting a possible reappraisal of TMZ in the treatment of cachexia. Among several features, cachexia is also associ- ated with loss of regenerative potential, which we analysed upon TMZ treatment. Methods: We incubated immortalised C2C12, satellite myoblasts and mesan- gioblasts with TMZ during differentiation. We also administered TMZ to mice during regeneration following muscle injury by cardiotoxin. Results: Our data showed that TMZ significantly stimulates glucose and glycogen consumption in C2C12 myotubes. TMZ also transcriptionally down-regulates PDK. Notably, we also found that the administration of TMZ potentiates myogenic differen- tiation in both C2C12 and satellite cells. In fact, TMZ up-regulates MyoD, Myogenin, MyHC and Desmin and increases myoblast fusion in differentiating cells. Finally, we found that TMZ does not induce apoptosis in our cell lines as demonstrated by absence of Caspase-3 and PARP cleavage and that TMZ has no effect on cell proliferation, as assessed by BrdU staining and cell cycle analysis by propidium iodide. In order to study the effectiveness of TMZ on muscle regeneration in vivo, we administered TMZ to mice following focal injury on tibialis anterior (TA) skeletal muscle. TA analysis after the injury showed that TMZ increases the expression of MyoD, Myogenin, neonatal myosin heavy chain (neoMyHC) and Desmin used as markers of satellite cell activation and differentiation into nascent regenerating myofibers. Conclusions: Our finding strongly suggest that TMZ stimulates myoblast differentiation and muscle regeneration following injury; this makes this drug appealing for its possible use in the treatment of several skeletal muscle pathologies.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
