The mdx/mTR mouse model combines dystrophin-deficiency with telomere dysfunction/shortening. Because it is expected to recapitulate several of the human characteristics of DMD myopathology (progressive muscle weakness and damage, skeletal muscle fibrosis, diminished muscle stem cell regenerative capacity, dilated cardiomyopathy, heart failure and shortened life-span), these mice may be a superior Duchenne muscular dystrophy model.
IMR Colony, The Jackson Laboratory
Dr. Carol Greider, Johns Hopkins Univ School of Medicine
Paul T. Martin, The Research Institute at Nationwide Children's Hospital
Duchenne muscular dystrophy (DMD) is a progressive muscular disorder caused by an imbalance between muscle degeneration and regeneration resulting in muscle degeneration, necrosis, accumulation of fat and fibrosis, and insufficient regeneration/loss of myofibers. The genetic cause of DMD are mutations of the dystrophin muscular dystrophy gene (DMD) on the X chromosome. Both the Dmdmdx (termination codon in exon 23) and Dmdmdx-4Cv (nonsense point mutation in exon 53) mutations in mice are predicted to express a truncated protein. Females heterozygous for either mutation are viable and fertile with no gross phenotypic abnormalities. Homozygous females and hemizygous males are viable and fertile with myopathic features of DMD; although the myopathology is both less severe than the human disease course and variable by mouse strain genetic background.
Specifically, the muscle pathology observed for C57BL/10ScSn-Dmdmdx mice (C57BL/10.mdx ; Stock No. 001801) and B6Ros.Cg-Dmdmdx-4Cv mice (B6.mdx-4Cv ; Stock No. 002378) includes active fiber necrosis, cellular infiltration, a wide range of fiber sizes, and numerous centrally nucleated regenerating fibers. However, despite the absence of dystrophin in skeletal and cardiac muscles, adult C57BL/10.mdx and B6.mdx-4Cv mice fail to exhibit several of features of DMD, including severe muscle weakness, progressive cardiomyopathy and shortened lifespan. In addition, these animals do not show other skeletal muscle characteristics of DMD (such as smaller number of myofibers, accumulation of fat and fibrosis, insufficient myofiber regeneration, and loss of muscle weight).
Differences between the two mutations exist. The Dmdmdx-4Cv allele has very low frequency of reversion to the wildtype allele in skeletal muscle (~10-fold lower frequency than the Dmdmdx mutation). In addition, the Dmdmdx-4Cv mutation affects more of the transcripts arising from alternative promoter usage within the dystrophin gene compared to the Dmdmdx mutation.
While telomere shortening is normally observed over time in mitotically active tissues, muscle tissue exhibits a lower proliferation rate and less telomere shortening with age. However, increased telomere shortening is associated with dystrophic human muscle cells and DMD patients. C57BL/6J mice homozygous for the telomerase RNA component null allele (C57BL/6J.mTR-/- ; Stock No. 004132) lack telomerase activity. Early generation homozygous mice have intact telomeres and appear grossly unaffected and healthy. However, telomere length is progressively shortened with successive generations of breeding mTR-/- mice together; resulting in dysfunction of the reproductive and hematopoietic systems, but little or no skeletal muscle abnormalities.
To investigate how telomere dysfunction affects the severity of muscular dystrophy seen in Dmdmdx mice, The Jackson Laboratory Repository bred C57BL/6J-mTR-/- mice with C57BL/10-mdx mice to create the double mutant mdx/mTR colony (Stock No. 018915). These mice may be expected to have a similar phenotype as the C57BL/6J-congenic mdx/mTRKO mouse model (Stock No. 023535) that has the Dmdmdx-4Cv mutation rather than the Dmdmdx mutation. Those C57BL/6J-congenic mdx/mTRKO mice (Stock No. 023535) exhibit several features of severe human muscular dystrophy, including severe muscle weakness, progressive cardiomyopathy and shortened lifespan. The dystrophy phenotype of Stock No. 023535 becomes more severe with each successive generation of breeding mdx/mTRKO mice together (because such breeding results in progressively shorter telomere lengths with each generation).
In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for these mice. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.
These mdx/mTR mice harbor two mutations; the mTR null allele (Terctm1Rdp) and the spontaneous X-linked muscular dystrophy mutation (Dmdmdx).
The mTR null allele was designed by Dr. Ronald DePinho (Albert Einstein College of Medicine) with a neomycin cassette replacing the entire telomerase RNA component gene on chromosome 3. C57BL/6J-congenic mice harboring the mTR null allele are described and available from The Jackson Laboratory Repository as Stock No. 004132.
The spontaneous mutation "X chromosome-linked muscular dystrophy" (mdx) has as a C-to-T transition resulting in a termination codon at position 2983 (ENSMUST00000114000 chrX:g.83803333 C>T; p.Q995*) within exon 23 of the dystrophin muscular dystrophy gene (Dmd) on the X chromosome [note that Sicinski et al., 1989 originally reported termination codon at position 3185]. C57BL/10ScSn-Dmdmdx mice are described and available from The Jackson Laboratory Repository as Stock No. 001801.
To generate this mdx/mTR mutant line (Stock No. 018915), C57BL/6J-congenic mTR+/- males (Stock No. 004132) were bred with C57Bl/10ScSn-Dmdmdx/mdx females (Stock No. 001801). Because telomere length is progressively shortened with successive generations of breeding mTR-/- mice together, The Jackson Laboratory Repository will maintain the mdx/mTR colony by breeding:
i) mTR+/-;mdx-/- females with mTR+/+;mdx-/Y males (that is, females heterozygous for the Terctm1Rdp null allele and homozygous for the Dmdmdx allele with males wildtype at the Terc locus and hemizygous for the Dmdmdx allele)
ii) mTR+/+;mdx-/- females with mTR+/-;mdx-/Y males (that is, females wildtype at the Terc locus and homozygous for the Dmdmdx allele with males heterozygous for the Terctm1Rdp null allele and hemizygous for the Dmdmdx allele.
By this method, The Jackson Laboratory can distribute mTR+/-;mdx-/- females and mTR+/-;mdx-/Y males. This allows the receiving investigator to generate their own mTR/mdx homozygous colonies.
|Allele Name||targeted mutation 1, Ronald DePinho|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||mTerc-; mTR-; Terc-; TR-|
|Gene Symbol and Name||Terc, telomerase RNA component|
|Strain of Origin||STOCK 129/Sv and C57BL/6J and SJL|
|Molecular Note||Replacement of the entire gene with a neomycin cassette.|
|Mutations Made By|| |
Dr. Carol Greider, Johns Hopkins Univ School of Medicine
|Allele Name||X linked muscular dystrophy|
|Allele Synonym(s)||mdx; pke; pyruvate kinase expression|
|Gene Symbol and Name||Dmd, dystrophin, muscular dystrophy|
|Strain of Origin||C57BL/10ScSn|
|Molecular Note||This mutation arose in 1981 in a C57BL/10ScSn colony at University of Leicester. A C-to-T substitution in the CAA codon in exon 23 (ENSMUST00000114000 chrX:g.83803333C>T; c.2983C>T; p.Q995*) results in a termination codon (TAA) in place of a glutamine codon. This allele is predicted to produce a truncated protein.|
The Dmdmdx mutation is X-linked.
Because telomere length is progressively shortened with successive generations of breeding mTR-/- mice together, The Jackson Laboratory Repository will maintain the mdx/mTR colony by breeding:
i) mTR+/-;mdx-/- females with mTR+/+;mdx-/Y males (i.e., females heterozygous for the Terctm1Rdp null allele and homozygous for the Dmdmdx allele with males wildtype at the Terc locus and hemizygous for the Dmdmdx allele)
ii) mTR+/+;mdx-/- females with mTR+/-;mdx-/Y males (i.e., females wildtype at the Terc locus and homozygous for the Dmdmdx allele with males heterozygous for the Terctm1Rdp null allele and hemizygous for the Dmdmdx allele.
By this method, The Jackson Laboratory Repository can distribute dystrophin-deficient mice that are heterozygous for the mTR null allele (i.e., mTR+/-;mdx-/- females and mTR+/-;mdx-/Y males). This allows the receiving investigator to generate their own mTR/mdx homozygous colonies.
When using the mdx/mTR mouse strain in a publication, please cite the originating article(s) and include JAX stock #018915 in your Materials and Methods section.