Muscle atrophy, accompanied by the loss of regenerative capacity, is a debilitating consequence of aging, which remains only marginally understood and is recalcitrant to a therapeutic intervention. This work will characterize muscle precursor/progenitor cells derived from mice of different age in an approach to understand why old muscle tissue regenerates worse than young. Primary myoblasts will be compared in their ability to proliferate, differentiate, and respond to IGF-1. Our preliminary data show age-related differences in the intrinsic properties of these cells. Muscle lineage will be characterized in an adult organism, and potential age-related changes in the relative abundance of muscle precursor cells and in their regenerative capacity will be determined. Role of Notch in the cell fate determination in an adult muscle, and potential age- related changes in Notch presence/activity will be studied. This work will also address the diminished responsiveness of old muscle to IGF-1, by testing whether physiologic signaling by IGF- 1 in primary murine myoblasts requires Cn activity, and whether this pathway changes with age.
These aims are designed to reveal key mechanistic differences in regenerative capacity between young/adult and old muscle, and to provide an understanding of muscle atrophy with age. Obtained data may provide a therapeutic opportunity to restore regenerative capacity and growth factor responsiveness in old muscle; and to generate an antibody panel defining adult myogenic lineage proactively.
| Brack, Andrew S; Conboy, Irina M; Conboy, Michael J et al. (2008) A temporal switch from notch to Wnt signaling in muscle stem cells is necessary for normal adult myogenesis. Cell Stem Cell 2:50-9 |
