Pro-regenerative mechanical-loading responses in the satellite-cell niche of a dystrophic mouse model revealed with single-nucleus RNA sequencing
June 24
Moderate mechanical stimulation is known to mitigate progressive fibrosis in dystrophic muscle, yet lineage-specific contributions to this benefit remain elusive. Here we applied single-nucleus RNA sequencing (snRNA-seq) to dissect the response to voluntary wheel-loading in the stem-cell niche surrounding skeletal-muscle fibres of male mdx mice. Transcriptomic adaptations to loading diverged between wild-type and dystrophic cohorts and were most pronounced in nascent myogenic progenitors. Mechanical input reinstated the expression of a subset of dystrophy-perturbed genes in a cell-type-restricted manner. We uncovered a vasculature-associated fibro-adipogenic progenitor subgroup whose abundance was diminished in dystrophy, whereas its signature programme was re-engaged by loading. Mechanical stimulation also amplified the transcriptional profile characteristic of regeneration-associated macrophages. Pericyte-derived progenitor cells exhibited the highest fraction of dysregulated genes rescued by loading. Finally, the principal observations were validated in a human Duchenne single-nucleus dataset. Collectively, these findings constitute a comprehensive resource for elucidating the molecular effectors of mechanical enhancement of tissue repair in degenerative myopathy.