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1.
Sci Transl Med ; 15(685): eadd5275, 2023 03.
Article in English | MEDLINE | ID: mdl-36857434

ABSTRACT

Duchenne muscular dystrophy (DMD) is a severe and progressive myopathy leading to motor and cardiorespiratory impairment. We analyzed samples from patients with DMD and a preclinical rat model of severe DMD and determined that compromised repair capacity of muscle stem cells in DMD is associated with early and progressive muscle stem cell senescence. We also found that extraocular muscles (EOMs), which are spared by the disease in patients, contain muscle stem cells with long-lasting regenerative potential. Using single-cell transcriptomics analysis of muscles from a rat model of DMD, we identified the gene encoding thyroid-stimulating hormone receptor (Tshr) as highly expressed in EOM stem cells. Further, TSHR activity was involved in preventing senescence. Forskolin, which activates signaling downstream of TSHR, was found to reduce senescence of skeletal muscle stem cells, increase stem cell regenerative potential, and promote myogenesis, thereby improving muscle function in DMD rats. These findings indicate that stimulation of adenylyl cyclase leads to muscle repair in DMD, potentially providing a therapeutic approach for patients with the disease.


Subject(s)
Muscular Dystrophy, Duchenne , Receptors, Thyrotropin , Animals , Rats , Receptors, G-Protein-Coupled , Muscle Fibers, Skeletal , Stem Cells , Regeneration , Thyrotropin
2.
Nat Commun ; 12(1): 3450, 2021 06 08.
Article in English | MEDLINE | ID: mdl-34103504

ABSTRACT

The epigenetic mechanisms coordinating the maintenance of adult cellular lineages and the inhibition of alternative cell fates remain poorly understood. Here we show that targeted ablation of the histone chaperone HIRA in myogenic cells leads to extensive transcriptional modifications, consistent with a role in maintaining skeletal muscle cellular identity. We demonstrate that conditional ablation of HIRA in muscle stem cells of adult mice compromises their capacity to regenerate and self-renew, leading to tissue repair failure. Chromatin analysis of Hira-deficient cells show a significant reduction of histone variant H3.3 deposition and H3K27ac modification at regulatory regions of muscle genes. Additionally, we find that genes from alternative lineages are ectopically expressed in Hira-mutant cells via MLL1/MLL2-mediated increase of H3K4me3 mark at silent promoter regions. Therefore, we conclude that HIRA sustains the chromatin landscape governing muscle cell lineage identity via incorporation of H3.3 at muscle gene regulatory regions, while preventing the expression of alternative lineage genes.


Subject(s)
Cell Cycle Proteins/metabolism , Cell Lineage , Histone Chaperones/metabolism , Muscle, Skeletal/pathology , Transcription Factors/metabolism , Acetylation , Animals , Cell Cycle Proteins/deficiency , Cell Line , Cell Lineage/genetics , Genetic Loci , Histone Chaperones/deficiency , Histones/metabolism , Lysine/metabolism , Mice , Muscle Development/genetics , Muscle, Skeletal/injuries , Muscle, Skeletal/physiopathology , Regeneration , Regulatory Sequences, Nucleic Acid/genetics , Satellite Cells, Skeletal Muscle/metabolism , Transcription Factors/deficiency
3.
Cell Stem Cell ; 24(6): 958-973.e9, 2019 06 06.
Article in English | MEDLINE | ID: mdl-31006622

ABSTRACT

Muscle satellite cells (MuSCs) are the quiescent muscle stem cells required for adult skeletal muscle repair. The impact of environmental stress such as pollution on MuSC behavior remains unexplored. We evaluated the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, a ubiquitous and highly toxic pollutant, on MuSCs by combining in vivo mouse molecular genetic models with ex vivo studies. While all MuSCs express the transcription factor PAX7, we show that a subset also express PAX3 and exhibit resistance to environmental stress. Upon systemic TCDD treatment, PAX3-negative MuSCs display impaired survival, atypical activation, and sporadic differentiation through xenobiotic aryl hydrocarbon receptor signaling. We further show that PAX3-positive MuSCs become sensitized to environmental stress when PAX3 function is impaired and that PAX3-mediated induction of mTORC1 is required for protection. Our study, therefore, identifies a functional heterogeneity of MuSCs in response to environmental stress controlled by PAX3.


Subject(s)
Adult Stem Cells/physiology , Environmental Pollution/adverse effects , PAX3 Transcription Factor/metabolism , PAX7 Transcription Factor/metabolism , Polychlorinated Dibenzodioxins/adverse effects , Satellite Cells, Skeletal Muscle/physiology , Animals , Cell Differentiation , Cell Survival , Cells, Cultured , Mechanistic Target of Rapamycin Complex 1/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , PAX3 Transcription Factor/genetics , PAX7 Transcription Factor/genetics , Receptors, Aryl Hydrocarbon/metabolism , Signal Transduction
4.
Genesis ; 55(4)2017 04.
Article in English | MEDLINE | ID: mdl-28196404

ABSTRACT

p57Kip2 (p57) is a maternally expressed imprinted gene regulating growth arrest which belongs to the CIP/KIP family of cyclin-dependent kinase inhibitors. While initially identified as a cell cycle arrest protein through inhibition of cyclin and cyclin-dependent kinase complexes, p57 activity has also been linked to differentiation, apoptosis, and senescence. In addition, p57 has recently been shown to be involved in tumorigenesis and cell fate decisions in stem cells. Yet, p57 function in adult tissues remains poorly characterized due to the perinatal lethality of p57 knock-out mice. To analyze p57 tissue-specific activity, we generated a conditional mouse line (p57FL-ILZ/+ ) by flanking the coding exons 2-3 by LoxP sites. To track p57-expressing or mutant cells, the p57FL-ILZ allele also contains an IRES-linked ß-galactosidase reporter inserted in the 3' UTR of the gene. Here, we show that the ß-galactosidase reporter expression pattern recapitulates p57 tissue specificity during development and in postnatal mice. Furthermore, we crossed the p57FL-ILZ/+ mice with PGK-Cre mice to generate p57cKO-ILZ/+ animals with ubiquitous loss of p57. p57cKO-ILZ/+ mice display developmental phenotypes analogous to previously described p57 knock-outs. Thus, p57FL-ILZ/+ is a new genetic tool allowing expression and functional conditional analyses of p57.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p57/genetics , Gene Targeting/methods , Mutation , Alleles , Animals , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p57/metabolism , Embryo, Mammalian/metabolism , Female , Genes, Reporter , Male , Mice , Mice, Inbred C57BL , Organ Specificity , Phenotype , beta-Galactosidase/genetics , beta-Galactosidase/metabolism
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