title: Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H.
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.
authors.affiliation: Department of Neurology, Center for Duchenne Muscular Dystrophy at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1606, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Kudryashova
authors.forename: Irina
authors.initials: I
authors.lastname: Kramerova
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Spencer
mesh_terms: D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D002453:Cell Cycle; D002454:Cell Differentiation; D002478:Cells, Cultured; D016922:Cellular Senescence; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D061251:Primary Cell Culture; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012038:Regeneration; D055948:Sarcopenia / Q000235:genetics / Q000473:pathology; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D058207:Sumoylation; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics
chemical_list: D050828:Protein Inhibitors of Activated STAT; C514011:TRIM32 protein, mouse; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt