You are here

| Muscle Stem Cells

Alterations to Silent Chromatin Underlie Loss of Function in Aging Stem Cells

Review of “Dissecting Murine Muscle Stem Cell Aging through Regeneration Using Integrative Genomic Analysis” from Cell Reports by Stuart P. Atkinson

The alterations to metabolism, accumulation of DNA damage, loss of proteostasis, and aberrant chromatin packaging [1] that occur during normal aging can prompt significant deficits in stem cell function. For example, a decrease in the number and function of muscle stem cells (MuSCs) during aging [2] can lead to the decline in the health and repair of skeletal muscle [3] and prompt the onset of physical frailty [4]. 

With the aim of better understanding the complex molecular mechanisms at play in aging MuSCs, researchers led by Carlos A. Aguilar (University of Michigan, Ann Arbor, MI, USA) compared gene expression profiles and the chromatin landscape of murine MuSCs isolated from mice of different ages. Their new study, published recently in Cell Reports [5], now reports that natural aging negatively affects muscle regeneration through interconnected alterations to metabolomic profiles, silent chromatin domains, transcription factor binding patterns, and gene expression profiles in MuSCs.

Shcherbina and Larouche et al. first evaluated muscle tissue regeneration following the injection of barium chloride, which destroys muscle fibers but not MuSCs, into the hindlimb muscles of mice of various ages. Initial gene expression analysis of MuSCs isolated at seven days post-injury suggested that young MuSCs maintained quiescence and supported the efficient regeneration of muscle tissue to a much greater extent than older MuSCs. 

Interestingly, a detailed analysis of aged MuSCs from uninjured mouse muscle revealed significant differences in their metabolomic profile compared to young MuSCs. Said differences included an increased flux through folate metabolism and the one-carbon cycle in older MuSCs, with the latter mechanism able to generate substrates required for histone methylation [6]. Interestingly, the authors detected altered levels of silent-chromatin associated histone methylation and the relevant histone-modifying enzymes – while young MuSCs displayed high levels of H3K9me3, aged MuSCs displayed high levels of H3K27me3. This change indicates a switch from H3K9me3-associated constitutive heterochromatin, which usually forms at condensed, permanently inactive chromosomal sites, to H3K27me3-associated facultative heterochromatin, which possesses the ability to switch between silent and active states. 

Consequently, aged MuSCs possessed a chromatin landscape with increased accessibility, with a significant number of said sites previously demarcated by facultative heterochromatin, which then significantly affect the DNA binding of a wide-range of muscle-associated transcription factors, such as MyoD, either alone or in combination.  The authors linked these-aging related adverse effects to the inability of aged MuSCs to raise a similar regenerative response observed by young MuSCs.

Overall, the authors hope that their new findings will facilitate a more complete understanding of how the function of MuSCs and other tissue-resident stem cells alters during aging and healing.

For more on how alterations to silent chromatin induce the loss of function in aging MuSCs, stay tuned to the Stem Cells Portal!

References

  1. Singh PP, Demmitt BA, Nath RD, et al., The Genetics of Aging: A Vertebrate Perspective. Cell 2019;177:200-220.
  2. Blau HM, Cosgrove BD, and Ho ATV, The central role of muscle stem cells in regenerative failure with aging. Nature Medicine 2015;21:854-862.
  3. Yin H, Price F, and Rudnicki MA, Satellite Cells and the Muscle Stem Cell Niche. Physiological Reviews 2013;93:23-67.
  4. Marcell TJ, Review Article: Sarcopenia: Causes, Consequences, and Preventions. The Journals of Gerontology: Series A 2003;58:M911-M916.
  5. Shcherbina A, Larouche J, Fraczek P, et al., Dissecting Murine Muscle Stem Cell Aging through Regeneration Using Integrative Genomic Analysis. Cell Reports 2020;32.
  6. Mentch Samantha J, Mehrmohamadi M, Huang L, et al., Histone Methylation Dynamics and Gene Regulation Occur through the Sensing of One-Carbon Metabolism. Cell Metabolism 2015;22:861-873.