Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration

TLDR

Skeletal muscle repair involves multiple cell types, including satellite cells and other myogenic populations. The study aimed to determine the relative contribution of satellite cells versus other cell types to muscle repair and to identify adult muscle stem cells. A conditional satellite‑cell depletion model was created by expressing a human diphtheria toxin receptor under the Pax7 promoter. Selective ablation of Pax7+ satellite cells caused severe loss of muscle tissue, impaired regeneration, inflammation, and adipogenesis, and could not be compensated by other cells, but transplantation of Pax7+ cells restored regeneration, demonstrating that satellite cells are indispensable for muscle repair.

Abstract

Distinct cell populations with regenerative capacity have been reported to contribute to myofibres after skeletal muscle injury, including non-satellite cells as well as myogenic satellite cells. However, the relative contribution of these distinct cell types to skeletal muscle repair and homeostasis and the identity of adult muscle stem cells remain unknown. We generated a model for the conditional depletion of satellite cells by expressing a human diphtheria toxin receptor under control of the murine Pax7 locus. Intramuscular injection of diphtheria toxin during muscle homeostasis, or combined with muscle injury caused by myotoxins or exercise, led to a marked loss of muscle tissue and failure to regenerate skeletal muscle. Moreover, the muscle tissue became infiltrated by inflammatory cells and adipocytes. This localised loss of satellite cells was not compensated for endogenously by other cell types, but muscle regeneration was rescued after transplantation of adult Pax7(+) satellite cells alone. These findings indicate that other cell types with regenerative potential depend on the presence of the satellite cell population, and these observations have important implications for myopathic conditions and stem cell-based therapeutic approaches.