Expression of mdr1 is required for efficient long term regeneration of dystrophic muscle

The mouse mdr1a and mdr1b genes are expressed in skeletal muscle, though their precise role in muscle is unknown. Dystrophic muscle is characterized by repeated cycles of degeneration and regeneration. To explore the role of the mdr1 genes during muscle regeneration, we have created a triple knockou...

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Bibliographic Details
Published in:Experimental cell research 2007-07, Vol.313 (11), p.2438-2450
Main Authors: Israeli, David, Ziaei, Simindokht, Gjata, Bernard, Benchaouir, Rachid, Rameau, Philippe, Marais, Thibaut, Fukada, So-ichiro, Segawa, Masashi, Yamamoto, Hiroshi, Gonin, Patrick, Danos, Olivier, Garcia, Luis
Format: Article
Language:English
Subjects:
Animals
ATP Binding Cassette Transporter, Subfamily B - genetics
ATP Binding Cassette Transporter, Subfamily B - physiology
ATP-Binding Cassette Sub-Family B Member 4
ATP-Binding Cassette Transporters - genetics
ATP-Binding Cassette Transporters - physiology
Cellular biology
Dystrophin - genetics
Dystrophin - physiology
Gene expression
MDR1
mdx
Mice
Mice, Knockout
Molecular biology
Muscle
Muscle Development - genetics
Muscle Fibers, Skeletal - pathology
Muscle, Skeletal - blood supply
Muscle, Skeletal - pathology
Muscle, Skeletal - physiology
Muscular Dystrophy, Animal - genetics
Muscular Dystrophy, Animal - pathology
Muscular system
Myoblasts, Skeletal - metabolism
Myoblasts, Skeletal - physiology
Neovascularization, Physiologic - genetics
Regeneration
Rodents
Stem cells
Stem Cells - metabolism
Stem Cells - physiology
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Summary:The mouse mdr1a and mdr1b genes are expressed in skeletal muscle, though their precise role in muscle is unknown. Dystrophic muscle is characterized by repeated cycles of degeneration and regeneration. To explore the role of the mdr1 genes during muscle regeneration, we have created a triple knockout mouse lacking the mdr1a, mdr1b, and the dystrophin genes. The resulting ReX mice developed normally and were fertile. However, as adults, ReX had a higher proportion of degenerating muscle fibers and greater long-term loss of muscle mass than mdx. ReX muscles were also characterized by a reduced proportion of muscle side population (mSP) cells, of myogenic cells, and a reduced capacity for muscle regeneration. We found too that mSP cells derived from dystrophic muscle are more myogenic than those from normal muscle. Thus, in dystrophic muscle, the mdr1 gene plays an important role in the preservation of the mSP and of the myogenic regenerative potential. Moreover, our results suggest a hitherto unappreciated role of mdr1 in precursor cells of regenerating tissue; they therefore provide an important clue to the physiological significance of mdr1 expression in stem cells.
ISSN:0014-4827
1090-2422
DOI:10.1016/j.yexcr.2007.02.036