Molecular regulation of regenerative myogenesis

The ability of skeletal muscle to regenerate has long been attributed to the activation of muscle satellite cells. To determine the potential contribution of other cell type in this process, we analyzed the regenerative ability of Pax7−/− mice which lack satellite cells. Adult Pax7−/− mice in a 129Sv/J genetic background were viable but from 6 month of age displayed an aggravated muscle wasting phenotype characterized by spinal kyphosis, loss of fast myofibers and calcification. Acute injury resulted in a profound regeneration deficit characterized by extensive calcification, deposition of adipose and fibrotic tissues. In addition, rare myofibers with central nuclei were readily detected i regenerated Pax7−/− muscles. Strikingly, MyoD‐expressing myoblasts were recovered from whole muscle homogenates at a frequency of 1/150 relative to wild type muscle. Pax7−/− myogenic cells co‐expressed Pax3 and MyoD but were unable to sustain proliferation in culture and yielded small colonies of terminally differentiated myocytes. Similar numbers of Pax3‐expressing cells were detected in wild type and Pax7‐deficient muscle by in situ hybridization. Unlike wild type muscle, CD45+ stem cells isolated from regenerating Pax7−/− muscle did not give rise to any MyoD‐expressing myogenic progenitors. Together these data indicate that adult muscle contains a novel lineage of Pax3‐expressing myogenic progenitors that appear distinct from the Pax7‐dependent satellite cell lineage. Nevertheless, Pax‐3‐expressing progenitors are not capable of normal muscle regeneration and their role remains to be identified.