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Depletion of SAM leading to loss of heterochromatin drives muscle stem cell ageing

ABSTRACT: The global loss of heterochromatin during aging has been observed in eukaryotes from yeast to humans, and this has been proposed to be one of the causes of aging. However, the cause of this age-associated loss of heterochromatin has remained enigmatic. Here we show that heterochromatin markers, including histone H3K9 di-/tri-methylation and HP1, decrease with age in murine muscle stem cells (MuSCs) as a consequence of the depletion of the methyl donor SAM. We find that restoration of intracellular SAM in aged MuSCs restores heterochromatin content to youthful levels and rejuvenates age-associated features including DNA damage accumulation, increased cell death, and defective muscle regeneration. SAM is not only a methyl group donor for transmethylation but it is also an aminopropyl donor for polyamine synthesis. Excessive consumption of SAM in polyamine synthesis may reduce its availability for transmethylation. Consistent with this premise, we observe that perturbation of increased polyamine synthesis by inhibiting spermidine synthase (Srm) restores the intracellular SAM content as well as heterochromatin formation, leading to improvements in aged MuSC function and regenerative capacity. Together, our studies demonstrate a direct causal link between polyamine metabolism and epigenetic dysregulation during MuSC aging.

ORGANISM(S): Mus musculus

PROVIDER: GSE229853 | GEO | 2023/11/17

REPOSITORIES: GEO

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Depletion of SAM leading to loss of heterochromatin drives muscle stem cell ageing

Project description:The global loss of heterochromatin during aging has been observed in eukaryotes from yeast to humans, and this has been proposed to be one of the causes of aging. However, the cause of this age-associated loss of heterochromatin has remained enigmatic. Here we show that heterochromatin markers, including histone H3K9 di-/tri-methylation and HP1, decrease with age in murine muscle stem cells (MuSCs) as a consequence of the depletion of the methyl donor SAM. We find that restoration of intracellular SAM in aged MuSCs restores heterochromatin content to youthful levels and rejuvenates age-associated features including DNA damage accumulation, increased cell death, and defective muscle regeneration. SAM is not only a methyl group donor for transmethylation but it is also an aminopropyl donor for polyamine synthesis. Excessive consumption of SAM in polyamine synthesis may reduce its availability for transmethylation. Consistent with this premise, we observe that perturbation of increased polyamine synthesis by inhibiting spermidine synthase (Srm) restores the intracellular SAM content as well as heterochromatin formation, leading to improvements in aged MuSC function and regenerative capacity. Together, our studies demonstrate a direct causal link between polyamine metabolism and epigenetic dysregulation during MuSC aging.

2023-11-17 | GSE229851 | GEO

Changes of the muscle stem cell niche during aging

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Changes of the muscle stem cell niche during aging

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RNA-Sequencing of young and aged satellite cells before and after transplantation into the young niche

Project description:The function of skeletal muscle stem cells (MuSC) declines during aging, contributing to the advent of age-related myopathies. However, whether this decline is the result of accumulating cellular damage, altered heterogeneity in stem cell populations or due to the effect of the changing niche environment remains largely unknown. By scRNA-Seq, we show that the age-related reduction in the MuSC pool is not stochastic, with different subpopulations being distinctly affected in aging. Using an in vivo allogeneic stem cell transplantation model, we show that exposure of MuSCs from old mice to a youthful niche environment significantly restores the gene expression of genes that are altered in aging. We show that age-related changes in the MuSC transcriptome are mainly driven by alterations in chromatin and transcription but are not due to posttranscriptional mechanisms affecting RNA stability. Furthermore, our data indicates that the portion of the genome that is activated in aging is significantly more responsive to restoration by niche factors compared to the repressed counterpart. Taken together, our data reveals that the niche environment plays a decisive role in controlling the transcriptional activity of MuSCs.

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Project description:During aging and neuromuscular diseases, there is a progressive loss of skeletal muscle volume and function, which is often associated with denervation and a loss of muscle stem cells (MuSCs). A relationship between MuSCs and innervation has not been established however. Herein, we administered neuromuscular trauma to a MuSC lineage tracing model and observed a subset of MuSCs specifically engraft in a position proximal to the neuromuscular junction (NMJ). In aging and in a model of neuromuscular degeneration (Sod1-/-), this localized engraftment behavior was reduced. Genetic rescue of motor neurons in Sod1-/- mice reestablished integrity of the NMJ and partially restored MuSC ability to engraft into NMJ proximal positions. Using single cell RNA-sequencing of MuSCs, we demonstrate that a subset of MuSCs are molecularly distinguishable from MuSCs responding to myofiber injury. These data reveal unique features of MuSCs that respond to synaptic perturbations caused by aging and other stressors.

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2023-06-26 | PXD041614 | Pride

Elevated CD47 is a hallmark of dysfunctional aged muscle stem cells that can be targeted to augment regeneration

Project description:In aging, skeletal muscle strength and regenerative capacity declines due, in part, to functional impairment of muscle stem cells MuSCs, yet the underlying mechanisms remain elusive. Here we capitalize on mass-cytometry to identify high CD47 expression as a hallmark of dysfunctional MuSCs CD47hi with impaired regenerative capacity that predominate with aging. The prevalent CD47 hi MuSC subset suppresses the residual functional CD47 lo MuSC subset through a paracrine signaling loop, leading to impaired proliferation. We uncover that elevated CD47 levels on aged MuSCs result from increased U1 snRNA expression, which disrupts alternative polyadenylation. The deficit in aged MuSC function in regeneration can be overcome either by morpholino-mediated blocking of CD47 alternative polyadenylation or antibody blockade of CD47 signaling, leading to improved regeneration in aged mice, with therapeutic implications. Our findings highlight a previously unrecognized age-dependent alteration in CD47 levels and function in MuSCs, which underlies reduced muscle repair in aging.

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