Targeted knockdown of Smn in muscle stem cells induces non-cell autonomous loss of motor neurons
Abstract
Spinal muscular atrophy (SMA) is due to a deficit in SMN, a ubiquitously expressed protein encoded by the Survival of Motor Neuron 1 (SMN1) gene. Recently, SMN-targeted disease-modifying treatments have greatly improved the clinical outcomes of this neuromuscular disease. However, uncertainties remain regarding their long-term efficacy and non-neuronal tissue involvement in disease progression. Skeletal muscle tissue and the muscle stem cells (MuSC) that sustain its postnatal growth and regenerative capacity are affected by SMN deficit. While a direct contribution of muscle tissue in the disease progression has been demonstrated, the extent to which MuSC are involved in this process remains to be established. Using SMA type II patient muscle biopsies and several mutant mouse models, we performed an accurate study of SMN role in MuSC function during postnatal growth and adulthood. We found that SMA type II patient muscles display a reduced number of quiescent PAX7+ MuSC. In SMA mice, we showed that SMN is an important regulator of myogenic progenitor fate during early postnatal growth, and that SMN deficit compromises MuSC reservoir establishment. In Pax7 Cre-driven conditional knockout mouse models, we demonstrated that deletion of a single Smn allele is sufficient to induce quiescent MuSC apoptosis in adult muscle, showing that high levels of SMN are required for the maintenance of the quiescent MuSC reservoir. We further established that depletion of MuSC yielded neuromuscular junction remodelling followed by a non-cell autonomous loss of part of the alpha motor neurons (MN) in the long term. Overall, our findings demonstrate an interdependence between quiescent MuSC and the MN reservoirs, supporting that MuSC may be important therapeutic targets for the long-term treatment of SMA. Moreover, we provide important insights into the specific SMN requirements of MuSC, which could be valuable for to the development of next-generation combinatorial therapies.
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BibTeX
@article{mecca2026targeted,
title = {{Targeted knockdown of Smn in muscle stem cells induces non-cell autonomous loss of motor neurons}},
author = {Jordan Mecca and Julien Mignot and Marianne Gervais and Teoman Ozturk and Stéphanie Astord and Juliette Berthier and Stéphanie Bauché and Julien Messéant and Maria Biferi and Hélène Rouard and Martine Barkats and Frédéric Relaix and Nathalie Didier},
journal = {Brain - A Journal of Neurology},
year = {2026},
month = sep,
doi = {10.1093/brain/awag045},
url = {https://hal.science/hal-05751133v1},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Targeted knockdown of Smn in muscle stem cells induces non-cell autonomous loss of motor neurons
AU - Jordan Mecca
AU - Julien Mignot
AU - Marianne Gervais
AU - Teoman Ozturk
AU - Stéphanie Astord
AU - Juliette Berthier
AU - Stéphanie Bauché
AU - Julien Messéant
AU - Maria Biferi
AU - Hélène Rouard
AU - Martine Barkats
AU - Frédéric Relaix
AU - Nathalie Didier
PY - 2026
DA - 2026/09/07
JO - Brain - A Journal of Neurology
DO - 10.1093/brain/awag045
UR - https://hal.science/hal-05751133v1
AB - Spinal muscular atrophy (SMA) is due to a deficit in SMN, a ubiquitously expressed protein encoded by the Survival of Motor Neuron 1 (SMN1) gene. Recently, SMN-targeted disease-modifying treatments have greatly improved the clinical outcomes of this neuromuscular disease. However, uncertainties remain regarding their long-term efficacy and non-neuronal tissue involvement in disease progression. Skeletal muscle tissue and the muscle stem cells (MuSC) that sustain its postnatal growth and regenerative capacity are affected by SMN deficit. While a direct contribution of muscle tissue in the disease progression has been demonstrated, the extent to which MuSC are involved in this process remains to be established. Using SMA type II patient muscle biopsies and several mutant mouse models, we performed an accurate study of SMN role in MuSC function during postnatal growth and adulthood. We found that SMA type II patient muscles display a reduced number of quiescent PAX7+ MuSC. In SMA mice, we showed that SMN is an important regulator of myogenic progenitor fate during early postnatal growth, and that SMN deficit compromises MuSC reservoir establishment. In Pax7 Cre-driven conditional knockout mouse models, we demonstrated that deletion of a single Smn allele is sufficient to induce quiescent MuSC apoptosis in adult muscle, showing that high levels of SMN are required for the maintenance of the quiescent MuSC reservoir. We further established that depletion of MuSC yielded neuromuscular junction remodelling followed by a non-cell autonomous loss of part of the alpha motor neurons (MN) in the long term. Overall, our findings demonstrate an interdependence between quiescent MuSC and the MN reservoirs, supporting that MuSC may be important therapeutic targets for the long-term treatment of SMA. Moreover, we provide important insights into the specific SMN requirements of MuSC, which could be valuable for to the development of next-generation combinatorial therapies.
SN - 0006-8950
SN - 1460-2156
ER -