Depletion of SAM leading to loss of heterochromatin drives muscle stem cell ageing
The global loss of heterochromatin during ageing has been observed in eukaryotes from yeast to humans, and this has been proposed as one of the causes of ageing. However, the cause of this age-associated loss of heterochromatin has remained enigmatic. Here we show that heterochromatin markers, inclu...
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| Published in: | Nature metabolism Vol. 6; no. 1; pp. 153 - 168 |
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| Main Authors: | , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
London
Nature Publishing Group UK
01-01-2024
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | The global loss of heterochromatin during ageing has been observed in eukaryotes from yeast to humans, and this has been proposed as one of the causes of ageing. 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 muscle stem cells (MuSCs) as a consequence of the depletion of the methyl donor S-adenosylmethionine (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 restores intracellular SAM content and heterochromatin formation, leading to improvements in aged MuSC function and regenerative capacity in male and female mice. Together, our studies demonstrate a direct causal link between polyamine metabolism and epigenetic dysregulation during murine MuSC ageing.
During ageing, S-adenosylmethionine (SAM) is depleted from muscle stem cells (MuSCs) because of increased synthesis of the polyamine spermidine, leading to loss of heterochromatin and dysfunction of MuSCs. SAM restoration rescues the mouse MuSC defects. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS J.K. designed the studies and carried out experiments with assistance from D.I.B., S.K., J.S.S., G.D., R.L., A.G., and J.O.B. with guidance from T.A.R. throughout. J.K. interpreted the results with guidance and input from T.A.R. and L.L. J.K., and T.A.R. wrote the manuscript and assembled the data with assistance from D.I.B. |
| ISSN: | 2522-5812 2522-5812 |
| DOI: | 10.1038/s42255-023-00955-z |