Ciliation of muscle stem cells is critical to maintain regenerative capacity and is lost during aging
Posted on: 4 May 2020
Preprint posted on 21 March 2020
Article now published in Nature Communications at http://dx.doi.org/10.1038/s41467-022-29150-6
Smoothening muscle ageing: activation of ciliary signalling rescues the regenerative capacity of aged muscle stem cells.
Selected by Mafalda Pimentel
Categories: cell biology, developmental biology
Background
With ageing, our muscle mass and strength gradually decrease. This is in part due to a decline in the number and function of adult Muscle Stem Cells (MuSCs), and thus due to reduced regenerative capacity.
As their microenvironment is altered through time, aged MuSCs adopt abnormal signal transduction profiles1. This loss of homeostasis leads to premature exit of quiescence and impaired proliferative potential.
The primary cilium has been recently implicated in MuSC self-renewal capacity2. Being an important signalling organelle, the cilium has the potential to integrate extrinsic clues and modulate MuSC function accordingly.
The authors of this preprint describe for the first time the importance of MuSC primary cilia in the context of muscle regeneration and ageing.
Key findings
The authors screened for drugs targeting membrane receptors that could enhance the proliferation of MuSCs isolated from aged mice (≈25 months old). They found that an agonist of a primary cilium receptor – Smoothened – robustly induced proliferation, among several other compounds with ciliary targets.
In order to investigate the role of primary cilia in muscle regeneration, the authors engineered a mouse model to specifically induce cilium abrogation in MuSCs at the age of interest (Pax7CreERT2;IFT88fl/fl). In these mice, the regeneration of injured muscle was hampered already at a young age (≈11 weeks old notoxin-injured Gastrocnemius).
By engrafting mutant MuSCs expressing luciferase, the authors confirmed that these cilium deficient cells have reduced expansion capacity in vivo. Remarkably, a single intramuscular injection of Smoothened agonist (SAG) significantly increased MuSC expansion post-injury in control mice.
In line with these results, the authors observed that the frequency of ciliated MuSCs becomes significantly lower with ageing. At the transcriptomic level, they detected a dysregulation of cilium related genes in aged mice, not only at a basal state but also post-injury.
The authors therefore questioned if stimulation with SAG could compensate for this ciliary ageing associated dysfunction. Treatment of MuSCs isolated from aged mice with SAG also increased their proliferation capacity and the expression of genes associated with ciliary pathways. Moreover, the recovery from muscle injury in aged mice treated with SAG was significantly improved resulting in increased strength and muscle mass.
What I like about this work
I like this preprint because the authors elegantly addressed an apparently simple, yet relevant question – Is the primary cilium important for muscle regeneration? With the right experimental setup, the authors clearly answered the question (yes) and opened the door to potential therapeutic strategies to ameliorate muscle ageing.
Standing questions for the future
1) Although the direct effect on MuSC and the benefits of SAG are clear, it could potentially have an effect in the remaining cell types at the muscle tissue. Could SAG treatment have a long-term effect, positive or negative?
2) Would it be possible for the abnormal signalling signature observed in aged MuSCs to resemble some of the gene expression alterations in IFT88-/- ?
3) Could cilia ablation in young Pax7CreERT2;IFT88fl/fl lead to premature muscle ageing phenotypes (not resulting from induced injury)?
References
- Blau, H. M., Cosgrove, B. D. & Ho, A. T. V. The central role of muscle stem cells in regenerative failure with aging. Nature Medicine 21, 854–862 (2015).
- Marican, N. H. J., Cruz-Migoni, S. B. & Borycki, A.-G. Asymmetric Distribution of Primary Cilia Allocates Satellite Cells for Self-Renewal. Stem Cell Reports 6, 798–805 (2016).
doi: https://doi.org/10.1242/prelights.19429
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