ABSTRACT
Title
Mitochondrial Dysfunction in the Pathogenesis of Muscular Dystrophy and Involvement in a Nitric Oxide-based Therapy
Authors
S. Pambianco1, R. Corradino2, C. De Palma1, C. Sciorati3 and E. Clementi1,4
1 Unit of Pharmacology, Department of clinical Sciences, “Luigi Sacco” University Hospiatal, University of Milan, Italy;
2 Department of Pharmaco-Biological Science, University of Catanzaro Magna Graecia, Catanzaro, Italy;
3 San Raffaele Scientific Institute, Stem Cell Research Institute, Milan, Italy;
4 E. Medea Scientific Institute, BosisioParini, Italy.
1 Unit of Pharmacology, Department of clinical Sciences, “Luigi Sacco” University Hospiatal, University of Milan, Italy;
2 Department of Pharmaco-Biological Science, University of Catanzaro Magna Graecia, Catanzaro, Italy;
3 San Raffaele Scientific Institute, Stem Cell Research Institute, Milan, Italy;
4 E. Medea Scientific Institute, BosisioParini, Italy.
Abstract
Muscular dystrophies are a group of human and animal disorders that show myofiber degeneration and regeneration, typically associated with progressive weakness. Clinically and genetically, they are a heterogeneous group of inherited diseases. The most common and extensively studied muscular dystrophies are those that involve mutations of the dystrophin-dystroglycan-laminin network.
It has been demonstrated that HCT 1026, a nitric oxide-releasing derivative of flurbiprofen, has beneficial effects in a mouse model of muscular dystrophy (α-sarcoglycan-null mouse), ameliorating the morphological, biochemical, and functional phenotype in the absence of secondary effects and slowing down disease progression (Brunelli et al., 2007). This study demonstratedthe capacity of HCT 1026 to combine the multiple beneficial effects of NO on muscle function with the potent antiinflammatory action of flurbiprofen, but until now very little is known about the precise mechanism of action of this drug.
Mitochondrial dysfunction is closely associated with many muscular diseases and might contribute to the progression of muscular dystrophy.
Here we characterized the mitochondrial profile of αSG-/- mice in order to investigate the direct or indirect link between genetic defect and mitochondrial function.
We also compared αSG-/- mice, with or without treatment, to control animals in order to establish the presence of a prospective molecular link between the HCT-1026 treatment and the mitochondrial function.
The αSG-/- muscles contained fewer and swollen mitochondria than muscles isolated from wild type animals or dystrophic animals after treatment. These mitochondria displayed a latent dysfunction and we are carrying out bioenergetic experiments to value the activity of respiratory chain complexes and to discriminate which one is impaired.
Muscles isolated from dystrophic mice displayed different expression levels of mitochondrial proteins, in particular we showed high expression levels of Drp1 fission protein in αSG-/- mice than in control animals or in dystrophic animals treated with HCT 1026; this effect was not compensated by mitofusin expression, so we might suppose that mitochondria were fragmented
Moreover in dystrophic muscles the mRNA level of PGC1α was lower than in control mice, despite an higher protein level. Accordingly with the low mitochondrial content of αSG-/- mice, we propose a model in which the PGC1α-dependend mitochondrial biogenesis could be impaired by two mechanisms: an inhibitory post-translational modification of PGC1α as well as a reduced transcription of PCG1α.
In conclusion we demonstrated the mitochondrial involvement in the pathogenesis of muscular dystrophy and that the beneficial effects of HCT 1026 ameliorating the dystrophic phenotype are, at least in part, due to an action on mitochondrial function.
It has been demonstrated that HCT 1026, a nitric oxide-releasing derivative of flurbiprofen, has beneficial effects in a mouse model of muscular dystrophy (α-sarcoglycan-null mouse), ameliorating the morphological, biochemical, and functional phenotype in the absence of secondary effects and slowing down disease progression (Brunelli et al., 2007). This study demonstratedthe capacity of HCT 1026 to combine the multiple beneficial effects of NO on muscle function with the potent antiinflammatory action of flurbiprofen, but until now very little is known about the precise mechanism of action of this drug.
Mitochondrial dysfunction is closely associated with many muscular diseases and might contribute to the progression of muscular dystrophy.
Here we characterized the mitochondrial profile of αSG-/- mice in order to investigate the direct or indirect link between genetic defect and mitochondrial function.
We also compared αSG-/- mice, with or without treatment, to control animals in order to establish the presence of a prospective molecular link between the HCT-1026 treatment and the mitochondrial function.
The αSG-/- muscles contained fewer and swollen mitochondria than muscles isolated from wild type animals or dystrophic animals after treatment. These mitochondria displayed a latent dysfunction and we are carrying out bioenergetic experiments to value the activity of respiratory chain complexes and to discriminate which one is impaired.
Muscles isolated from dystrophic mice displayed different expression levels of mitochondrial proteins, in particular we showed high expression levels of Drp1 fission protein in αSG-/- mice than in control animals or in dystrophic animals treated with HCT 1026; this effect was not compensated by mitofusin expression, so we might suppose that mitochondria were fragmented
Moreover in dystrophic muscles the mRNA level of PGC1α was lower than in control mice, despite an higher protein level. Accordingly with the low mitochondrial content of αSG-/- mice, we propose a model in which the PGC1α-dependend mitochondrial biogenesis could be impaired by two mechanisms: an inhibitory post-translational modification of PGC1α as well as a reduced transcription of PCG1α.
In conclusion we demonstrated the mitochondrial involvement in the pathogenesis of muscular dystrophy and that the beneficial effects of HCT 1026 ameliorating the dystrophic phenotype are, at least in part, due to an action on mitochondrial function.