ABSTRACT
Title
Autophagy as a new therapeutic target in Duchenne muscular dystrophy
Authors
S. Cheli1, C. De Palma1, S. Carnio2,3, M. Sandri2,3, E. Clementi1,4,5
1Unit of Clinical Pharmacology, Department Of Clinical Science, University Hospital L.Sacco, University of Milan, Milan, Italy. 2Department of Biology, University of Padova, Italy.3Venetian Institute of Molecular Medicine, Padova, Italy;4Consiglio Nazionale delle Ricerche Institute of Neuroscience, Milano, Italy ; 5E.Medea Institute, Bosisio Parini, Lecco, Italy.
1Unit of Clinical Pharmacology, Department Of Clinical Science, University Hospital L.Sacco, University of Milan, Milan, Italy. 2Department of Biology, University of Padova, Italy.3Venetian Institute of Molecular Medicine, Padova, Italy;4Consiglio Nazionale delle Ricerche Institute of Neuroscience, Milano, Italy ; 5E.Medea Institute, Bosisio Parini, Lecco, Italy.
Abstract
Muscular dystrophies are clinically, genetically, and molecularly an heterogeneous group of neuromuscular disorders characterized by progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissue [1-2]. Several lines of evidence indicates that authophagy is an important mechanism to prevent muscle damage [3-5].Furthermore, a recent paper reveals that the failure of this process has a major role in the pathogenesis of thedystrophic phenotype in Col6a1-/- mice, causing accumulation of abnormal organelles and apoptotic degeneration of muscle fibers [3]. Here we demonstrate that authophagy is impaired also in mdx mice. Skeletal muscle of mdx mice displayed a reduction in the delipidated form of LC3(LC3-II) which is generated during autophagosome formation. Moreover mdx muscle showed decreased-p62-levels, a well-known substrate of the autophagy-lysosome system, compared to wild-type mice. In addition the mammalian target of rapamycin pathway, which negatively regulates autophagy, was kept functional in mdx skeletal muscle, as indicated by the persistent phosphorylation of 4E-binding protein (4E-BP1) and ribosomal protein S6 (RP S6), the two major targets downstream mTOR. Fasting for 24h accounted for autophagosome formation in wild-type but not in mdx muscle, as revealed by electron microscopy of diaphragm and tibialis anterior. The decreased amount of autophagosomes and the reduced LC3 delipidation in mdx muscle could be due to defective autophagy induction. Our results support the new idea that points out autophagy as new therapeutic target to prevent the accumulation of toxic molecules and damaged organelles and to improve dystrophic phenotype.
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2. Sewry, C.A., Muscular dystrophies: an update on pathology and diagnosis. Acta Neuropathol, 2010. 120(3): p. 343-58.
3. Grumati, P., et al., Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat Med, 2010. 16(11): p. 1313-20.
4. Levine, B. and G. Kroemer, Autophagy in the pathogenesis of disease. Cell, 2008. 132(1): p. 27-42.
5. Masiero, E., et al., Autophagy is required to maintain muscle mass. Cell Metab, 2009. 10(6): p. 507-15.
1. Emery, A.E., The muscular dystrophies. Lancet, 2002. 359(9307): p. 687-95.
2. Sewry, C.A., Muscular dystrophies: an update on pathology and diagnosis. Acta Neuropathol, 2010. 120(3): p. 343-58.
3. Grumati, P., et al., Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat Med, 2010. 16(11): p. 1313-20.
4. Levine, B. and G. Kroemer, Autophagy in the pathogenesis of disease. Cell, 2008. 132(1): p. 27-42.
5. Masiero, E., et al., Autophagy is required to maintain muscle mass. Cell Metab, 2009. 10(6): p. 507-15.