[Regenerative medicine of skeletal muscle].
In the dystrophin-deficient mdx mice, an animal model of Duchenne muscular dystrophy (DMD), damaged skeletal muscles are efficiently regenerated and thus the animals thrive. The phenotypic differences between DMD patients and mdx mice suggest the existence of factors that modulate the muscle wasting in the mdx mice. To identify these factors, we searched for mRNAs affected by the mdx mutation using cDNA microarrays with newly established skeletal muscle cell lines derived from mdx and normal mice. We found that genes encoding thymosin beta4, frizzled related protein 2 (FRP2), and regeneration-associated muscle protease (RAMP) are up-regulated in skeletal muscle of mdx mice. Thymosin beta4 was induced in both regenerating muscle fibers and inflammatory cells after muscle injury. It stimulated migration and chemotaxis of myoblasts. FRP2 was dramatically induced upon muscle injury. RNA interference-mediated knockdown of FRP2 mRNA in myoblasts resulted in a massive cell death. Thus FRP2 may enhance the survival rate of myoblasts in the regenerative regions. RAMP mRNA was specifically induced in the regenerating areas of injured skeletal muscle. Expression of RAMP and FRP2 was much lower in individual muscle cell lines derived from biopsy specimens from several DMD patients compared to in a normal muscle cell line. Above results suggest that thymosin beta4, FRP2, and RAMP may play roles in the regeneration of skeletal muscle and that down-regulation of these molecules could be involved in the progression of DMD in humans.
Hara
Takahiko
T
Tokyo Metropolitan Organization for Medical Research, The Tokyo Metropolitan Institute of Medical Science, Department of Tumor Biochemistry.
Nakayama
Yuki
Y
Nara
Noriko
N
D000818:Animals; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics*; D032446:Myoblasts / Q000166:cytology; D012333:RNA, Messenger; D044968:Regenerative Medicine; D012697:Serine Endopeptidases / Q000009:adverse effects; D057057:Serine Proteases; D013947:Thymosin / Q000378:metabolism; D000099201:Thymosin beta(4); D000094742:Secreted Frizzled-Related Proteins
D008565:Membrane Proteins; D008666:Metalloendopeptidases; D012333:RNA, Messenger; D012697:Serine Endopeptidases; D057057:Serine Proteases; D013947:Thymosin; D000099201:Thymosin beta(4); C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C000602676:Pamr1 protein, mouse; C486046:PAMR1 protein, human