TRIM32 regulates skeletal muscle stem cell differentiation and is necessary for normal adult muscle regeneration.
Limb girdle muscular dystrophy type 2H (LGMD2H) is an inherited autosomal recessive disease of skeletal muscle caused by a mutation in the TRIM32 gene. Currently its pathogenesis is entirely unclear. Typically the regeneration process of adult skeletal muscle during growth or following injury is controlled by a tissue specific stem cell population termed satellite cells. Given that TRIM32 regulates the fate of mammalian neural progenitor cells through controlling their differentiation, we asked whether TRIM32 could also be essential for the regulation of myogenic stem cells. Here we demonstrate for the first time that TRIM32 is expressed in the skeletal muscle stem cell lineage of adult mice, and that in the absence of TRIM32, myogenic differentiation is disrupted. Moreover, we show that the ubiquitin ligase TRIM32 controls this process through the regulation of c-Myc, a similar mechanism to that previously observed in neural progenitors. Importantly we show that loss of TRIM32 function induces a LGMD2H-like phenotype and strongly affects muscle regeneration in vivo. Our studies implicate that the loss of TRIM32 results in dysfunctional muscle stem cells which could contribute to the development of LGMD2H.
Westfälische Wilhelms-Universität Münster, Zentrum für Molekularbiologie der Entzündung, Institute of Cell Biology, Stem Cell Biology and Regeneration Group, Münster, Germany.
Sarah
S
Nicklas
Anthony
A
Otto
Xiaoli
X
Wu
Pamela
P
Miller
Sandra
S
Stelzer
Yefei
Y
Wen
Shihuan
S
Kuang
Klaus
K
Wrogemann
Ketan
K
Patel
Hao
H
Ding
Jens C
JC
Schwamborn
D053687:Adult Stem Cells / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000235:genetics / Q000502:physiology; D009132:Muscles / Q000378:metabolism / Q000502:physiology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000473:pathology; D012038:Regeneration / Q000235:genetics* / Q000502:physiology; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C514011:TRIM32 protein, mouse; D044767:Ubiquitin-Protein Ligases