Abstract
Increased proteasome activity has been implicated in the atrophy and deterioration associated with dystrophic muscles of Duchenne muscular dystrophy (DMD). While proteasome inhibitors show promise in the attenuation of muscle degeneration, proteasome inhibition-induced toxicity was a major drawback of this therapeutic strategy. Inhibitors that selectively target the proteasome subtype that is responsible for the loss in muscle mass and quality would reduce side effects and be less toxic. This study examined proteasome activity and subtype populations, along with muscle function, morphology and damage in wild-type (WT) mice and two murine models of DMD, dystrophin-deficient (MDX) and dystrophin- and utrophin-double-knockout (DKO) mice. We found that immunoproteasome content was increased in dystrophic muscles while the total proteasome content was unchanged among the three genotypes of mice. Proteasome proteolytic activity was elevated in dystrophic muscles, especially in DKO mice. These mice also exhibited more severe muscle atrophy than either WT or MDX mice. Muscle damage and regeneration, characterized by the activity of muscle creatine kinase in the blood and the percentage of central nuclei were equally increased in dystrophic mice. Accordingly, the overall muscle function was similarly reduced in both dystrophic mice compared with WT. These data demonstrated that there was transformation of standard proteasomes to immunoproteasomes in dystrophic muscles. In addition, DKO that showed greatest increase in proteasome activities also demonstrated more severe atrophy compared with MDX and WT. These results suggest a putative role for the immunoproteasome in muscle deterioration associated with DMD and provide a potential target for therapeutic intervention.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 191-201 |
| Number of pages | 11 |
| Journal | Journal of Muscle Research and Cell Motility |
| Volume | 35 |
| Issue number | 2 |
| DOIs | |
| State | Published - 2014 |
| Externally published | Yes |
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Keywords
- Duchenne muscular dystrophy
- Immunoproteasome
- LC3
- LMP2
- LMP7
- Proteasome
ASJC Scopus subject areas
- Physiology
- Cell Biology
- Biochemistry
- Medicine(all)
Cite this
Immunoproteasome in animal models of Duchenne muscular dystrophy. / Chen, Chiao Nan Joyce; Graber, Theodore; Bratten, Wendy M.; Ferrington, Deborah A.; Thompson, Ladora V.
In: Journal of Muscle Research and Cell Motility, Vol. 35, No. 2, 2014, p. 191-201.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Immunoproteasome in animal models of Duchenne muscular dystrophy
AU - Chen, Chiao Nan Joyce
AU - Graber, Theodore
AU - Bratten, Wendy M.
AU - Ferrington, Deborah A.
AU - Thompson, Ladora V.
PY - 2014
Y1 - 2014
N2 - Increased proteasome activity has been implicated in the atrophy and deterioration associated with dystrophic muscles of Duchenne muscular dystrophy (DMD). While proteasome inhibitors show promise in the attenuation of muscle degeneration, proteasome inhibition-induced toxicity was a major drawback of this therapeutic strategy. Inhibitors that selectively target the proteasome subtype that is responsible for the loss in muscle mass and quality would reduce side effects and be less toxic. This study examined proteasome activity and subtype populations, along with muscle function, morphology and damage in wild-type (WT) mice and two murine models of DMD, dystrophin-deficient (MDX) and dystrophin- and utrophin-double-knockout (DKO) mice. We found that immunoproteasome content was increased in dystrophic muscles while the total proteasome content was unchanged among the three genotypes of mice. Proteasome proteolytic activity was elevated in dystrophic muscles, especially in DKO mice. These mice also exhibited more severe muscle atrophy than either WT or MDX mice. Muscle damage and regeneration, characterized by the activity of muscle creatine kinase in the blood and the percentage of central nuclei were equally increased in dystrophic mice. Accordingly, the overall muscle function was similarly reduced in both dystrophic mice compared with WT. These data demonstrated that there was transformation of standard proteasomes to immunoproteasomes in dystrophic muscles. In addition, DKO that showed greatest increase in proteasome activities also demonstrated more severe atrophy compared with MDX and WT. These results suggest a putative role for the immunoproteasome in muscle deterioration associated with DMD and provide a potential target for therapeutic intervention.
AB - Increased proteasome activity has been implicated in the atrophy and deterioration associated with dystrophic muscles of Duchenne muscular dystrophy (DMD). While proteasome inhibitors show promise in the attenuation of muscle degeneration, proteasome inhibition-induced toxicity was a major drawback of this therapeutic strategy. Inhibitors that selectively target the proteasome subtype that is responsible for the loss in muscle mass and quality would reduce side effects and be less toxic. This study examined proteasome activity and subtype populations, along with muscle function, morphology and damage in wild-type (WT) mice and two murine models of DMD, dystrophin-deficient (MDX) and dystrophin- and utrophin-double-knockout (DKO) mice. We found that immunoproteasome content was increased in dystrophic muscles while the total proteasome content was unchanged among the three genotypes of mice. Proteasome proteolytic activity was elevated in dystrophic muscles, especially in DKO mice. These mice also exhibited more severe muscle atrophy than either WT or MDX mice. Muscle damage and regeneration, characterized by the activity of muscle creatine kinase in the blood and the percentage of central nuclei were equally increased in dystrophic mice. Accordingly, the overall muscle function was similarly reduced in both dystrophic mice compared with WT. These data demonstrated that there was transformation of standard proteasomes to immunoproteasomes in dystrophic muscles. In addition, DKO that showed greatest increase in proteasome activities also demonstrated more severe atrophy compared with MDX and WT. These results suggest a putative role for the immunoproteasome in muscle deterioration associated with DMD and provide a potential target for therapeutic intervention.
KW - Duchenne muscular dystrophy
KW - Immunoproteasome
KW - LC3
KW - LMP2
KW - LMP7
KW - Proteasome
UR - http://www.scopus.com/inward/record.url?scp=84904270015&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904270015&partnerID=8YFLogxK
U2 - 10.1007/s10974-014-9385-x
DO - 10.1007/s10974-014-9385-x
M3 - Article
C2 - 24934129
AN - SCOPUS:84904270015
VL - 35
SP - 191
EP - 201
JO - Journal of Muscle Research and Cell Motility
JF - Journal of Muscle Research and Cell Motility
SN - 0142-4319
IS - 2
ER -