Title

Adult murine skeletal muscle satellite cell developmental potential

Date of Completion

January 2008

Keywords

Biology, Genetics|Biology, Cell

Degree

Ph.D.

Abstract

Satellite cells are the resident stem cells found in adult skeletal muscle. These tissue-specific stem cells play a critical role in postnatal growth and the remarkable regenerative capacity of skeletal muscle. The developmental potential of satellite cells was investigated utilizing Cre/loxP lineage tracing technology. Mice with Cre recombinase knocked into the MyoD locus (MyoDiCre) and a Cre-dependent reporter allele were generated to permanently label satellite cells. We found that MyoDiCre-labeled satellite cells did not spontaneously adopt an adipogenic fate in culture, even when exposed to potent adipogenesis-inducing reagents. The function of the myogenic regulatory factors, MyoD and Myf-5 in satellite cell commitment to myogenesis was examined using the permanent lineage tracing system. MyoD and Myf-5-mutant mice were generated that also carried the MyoDiCre and Cre-dependent reporter alleles. Tibialis anterior muscles from MyoD and Myf-5-mutant mice were freeze injured and allowed 4 weeks to regenerate at which time the contribution of MyoDiCre-labeled satellite cells to non-myogenic tissues was analyzed. Contribution of labeled satellite cells to non-myogenic tissues in mice lacking MyoD and Myf-5 was not observed and indicates that neither MyoD nor Myf-5 alone control adult satellite cell specification and commitment to myogenesis. We also explored the ability of MyoDiCre-labeled satellite cells to contribute to non-myogenic lineages in a novel mouse muscular dystrophy model (rmd). Homozygous rmd mice exhibit a severe and rapidly progressive rostrocaudal muscular dystrophy phenotype where extensive fibrosis is observed. We found that MyoDiCre -labeled satellite cells were not the source of the fibrosis in rmd/rmd mice. Overall, this work demonstrates that adult skeletal muscle satellite cells are committed to the myogenic pathway and do not readily adopt non-myogenic lineages. ^