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Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H
- Source :
- Journal of Clinical Investigation. 122:1764-1776
- Publication Year :
- 2012
- Publisher :
- American Society for Clinical Investigation, 2012.
-
Abstract
- Mutations in the E3 ubiquitin ligase tripartite motif-containing 32 (TRIM32) are responsible for the disease limb-girdle muscular dystrophy 2H (LGMD2H). Previously, we generated Trim32 knockout mice (Trim32–/– mice) and showed that they display a myopathic phenotype accompanied by neurogenic features. Here, we used these mice to investigate the muscle-specific defects arising from the absence of TRIM32, which underlie the myopathic phenotype. Using 2 models of induced atrophy, we showed that TRIM32 is dispensable for muscle atrophy. Conversely, TRIM32 was necessary for muscle regrowth after atrophy. Furthermore, TRIM32-deficient primary myoblasts underwent premature senescence and impaired myogenesis due to accumulation of PIAS4, an E3 SUMO ligase and TRIM32 substrate that was previously shown to be associated with senescence. Premature senescence of myoblasts was also observed in vivo in an atrophy/regrowth model. Trim32–/– muscles had substantially fewer activated satellite cells, increased PIAS4 levels, and growth failure compared with wild-type muscles. Moreover, Trim32–/– muscles exhibited features of premature sarcopenia, such as selective type II fast fiber atrophy. These results imply that premature senescence of muscle satellite cells is an underlying pathogenic feature of LGMD2H and reveal what we believe to be a new mechanism of muscular dystrophy associated with reductions in available satellite cells and premature sarcopenia.
- Subjects :
- Male
Senescence
Sarcopenia
Satellite Cells, Skeletal Muscle
Ubiquitin-Protein Ligases
Primary Cell Culture
Apoptosis
Cell Count
Biology
Mice
Phosphatidylinositol 3-Kinases
Atrophy
medicine
Animals
Regeneration
Myocyte
Muscular dystrophy
Muscle, Skeletal
Myopathy
Cells, Cultured
Cellular Senescence
Mice, Knockout
Genetics
Mice, Inbred BALB C
Myogenesis
Cell Cycle
Sumoylation
Cell Differentiation
General Medicine
medicine.disease
Protein Inhibitors of Activated STAT
Muscle atrophy
Cell biology
Disease Models, Animal
Muscular Dystrophies, Limb-Girdle
medicine.symptom
Proto-Oncogene Proteins c-akt
Signal Transduction
Research Article
Limb-girdle muscular dystrophy
Subjects
Details
- ISSN :
- 00219738
- Volume :
- 122
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....f73d0d5e5d90bb251150b302bc77460b