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Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H
Elena Kudryashova, … , Irina Kramerova, Melissa J. Spencer
Elena Kudryashova, … , Irina Kramerova, Melissa J. Spencer
Published April 16, 2012
Citation Information: J Clin Invest. 2012;122(5):1764-1776. https://doi.org/10.1172/JCI59581.
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Research Article Muscle biology Article has an altmetric score of 7

Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H

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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

Elena Kudryashova, Irina Kramerova, Melissa J. Spencer

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Figure 2

Trim32–/– muscles fail to regrow during reloading after hind limb suspension.

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Trim32–/– muscles fail to regrow during reloading after hind limb suspe...
Measurements of cross-sectional areas of (A) fast and (B) slow fibers in Trim32–/– and Trim32+/+ soleus muscles were performed on frozen sections immunostained with anti-fast and anti-slow myosin antibodies. Four groups of mice for each genotype (n = 6) were analyzed as follows: ambulatory control mice (control); mice subjected to 5 days of suspension (susp); mice subjected to 5 days of suspension followed by 3 days (3d rel) or 7 days (7d rel) of reloading. Values represent the mean of measurements in several independent fields of view for each of 6 slides (>100 fibers were measured per each slide). Error bars represent SEM (*P < 0.05). (C) qPCR analysis using RNA harvested from Trim32+/+ control, suspended, and reloaded muscles (n = 3) shows elevated Trim32 expression during suspension and reloading phases. Results from 3 samples in each group were run in triplicate, normalized to Gapdh, and expressed as percentage relative to ambulatory control (*P < 0.05). Data are shown as mean ± SEM. (D) Anti-TRIM32 Western blot demonstrates absence of TRIM32 in Trim32–/– muscles and increase of TRIM32 protein level in Trim32+/+ muscles during suspension and reloading phases. An anti-vinculin blot is shown as a loading control. Numbers in each lane under the TRIM32 blot represent fold change in TRIM32 normalized to vinculin relative to ambulatory control. Representative blots are shown.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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