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Muscle stem cell renewal suppressed by GAS1 can be reversed by GDNF in mice

Abstract

Muscle undergoes progressive weakening and regenerative dysfunction with age due in part to the functional decline of skeletal muscle stem cells (MuSCs). MuSCs are heterogeneous, but whether their gene expression changes with age and the implication of such changes are unclear. Here we show that in mice, growth arrest-specific gene 1 (Gas1) is expressed in a small subset of young MuSCs, with its expression progressively increasing in larger fractions of MuSCs later in life. Overexpression of Gas1 in young MuSCs and inactivation of Gas1 in aged MuSCs support that Gas1 reduces the quiescence and self-renewal capacity of MuSCs. GAS1 reduces RET signalling, which is required for MuSC quiescence and self-renewal. Indeed, we show that the RET ligand, glial-cell-line-derived neurotrophic factor can counteract GAS1 by stimulating RET signalling and enhancing MuSC self-renewal and regeneration, thus improving muscle function. We propose that strategies aimed at targeting this pathway can be exploited to improve the regenerative decline of MuSCs.

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Fig. 1: Gas1 is associated with the ageing-like properties of MuSCs.
Fig. 2: Gas1 mouse models display age-associated molecular signatures of MuSCs.
Fig. 3: Ret is downstream of Gas1 and is required for MuSC self-renewal.
Fig. 4: GAS1 and RET signalling affects compensatory hypertrophic growth of the plantaris muscle after synergistic ablation.
Fig. 5: GAS1 interaction with RET is required for function in MuSCs.
Fig. 6: GDNF enhances MuSC self-renewal and muscle regeneration in aged mice.

Data availability

All data that support the findings of this study are available from the corresponding author upon reasonable request. All sequencing data has been deposited with the NCBI Sequence Read Archive database under accession no. PRJNA494728.

Code availability

The custom code used during this study is available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Fan laboratory members and Y. Zheng for comments; E. Dikovsky for the mouse facility team; and S. Satchell for technical assistance. We especially thank T. Cheung for sharing the FACS protocol. L.L. is supported by the Carnegie Institution of Washington. M.R. was supported by a predoctoral fellowship from the NIH (no. HD075345). C.-M.F. is supported by the NIH (grant nos. R01AR060042, R01AR071976 and R01AR072644) and the Carnegie Institution of Washington.

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L.L., M.R. and C.-M.F. conceptualized the projects, designed the experiments and wrote the manuscript. L.L. and C.-M.F. performed the experiments, analysed the data and drew up the conclusions. S.Y. and C.L. assisted with the FACS and ChIP–seq. C.L. provided the mouse strains. X.Z. and F.J.T. performed the bioinformatic analyses.

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Correspondence to Chen-Ming Fan.

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Li, L., Rozo, M., Yue, S. et al. Muscle stem cell renewal suppressed by GAS1 can be reversed by GDNF in mice. Nat Metab 1, 985–995 (2019). https://doi.org/10.1038/s42255-019-0110-3

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