Myoblast transplantation has potential benefits for both muscle replacement and in the enhancement of muscle regeneration. Genetically engineered myoblasts may serve to deliver growth and differentiation factors locally to skeletal muscle in patients with developmental defects, disease or trauma. Muscle regeneration follows an orderly progression of biologic events from activation of muscle precursor cells (satellite cells), to formation of multinucleated myofibers from the fusion of satellite cells and finally, to maturation of the myofibers. The regenerative response of muscle may be enhanced or retarded by factors that affect the activation, proliferation and/or fusion of satellite cells. The investigators have shown that masseter muscles of mice have an impaired regenerative ability in both disease and injury due in part to quantitative and qualitative deficiencies of the intrinsic myoblast populations within these muscles. The main objectives of this proposal are (1) to evaluate the ability of growth factors to increase the proliferative capability of masseter muscle stem cells in vitro and using this knowledge, to use genetically engineered muscle cells as a means of enhancing muscle repair; (2) to define the role of the transcription factor, NFAT (nuclear factor of activated T cells), in regulating gene expression during muscle repair and maintenance. NFAT is a transcription factor, originally identified in T cells that is also expressed by non-lymphoid cells including skeletal muscle. The role of NFAT isoforms in non-lymphoid cells is unknown. However, pharmacologic agents which block NFAT-mediated transcription in skeletal muscle cells affect muscle cell growth and differentiation, thereby suggesting a critical role for NFAT proteins in skeletal muscle. Manipulation of the signal transduction pathways involved in regulating NFAT-mediated transcription during muscle repair and maintenance could be a target for drug development. The specific hypotheses to be tested are (1) masseter myoblasts will grow normally with the proper supply of growth factors; (2) muscle regeneration can be enhanced using regulated expression of growth and differentiation factors via myoblast-mediated gene therapy; (3) changes in skeletal muscle physiology result in activation of NFAT-mediated transcription; (4) NFAT regulates the expression of proteins with known roles in muscle growth, repair and maintenance; and (5) alterations in muscle repair and maintenance occur when NFAT-mediated transcription in skeletal muscle is specifically blocked.
| Mitchell, Patrick O; Mills, Todd; O'Connor, Roddy S et al. (2005) Sca-1 negatively regulates proliferation and differentiation of muscle cells. Dev Biol 283:240-52 |
| Horsley, Valerie; Pavlath, Grace K (2004) Forming a multinucleated cell: molecules that regulate myoblast fusion. Cells Tissues Organs 176:67-78 |
| Mitchell, Patrick O; Pavlath, Grace K (2004) Skeletal muscle atrophy leads to loss and dysfunction of muscle precursor cells. Am J Physiol Cell Physiol 287:C1753-62 |
| Bondesen, Brenda A; Mills, Stephen T; Kegley, Kristy M et al. (2004) The COX-2 pathway is essential during early stages of skeletal muscle regeneration. Am J Physiol Cell Physiol 287:C475-83 |
| Pavlath, Grace K; Dominov, Janice A; Kegley, Kristy M et al. (2003) Regeneration of transgenic skeletal muscles with altered timing of expression of the basic helix-loop-helix muscle regulatory factor MRF4. Am J Pathol 162:1685-91 |
| Friday, Bret B; Mitchell, Patrick O; Kegley, Kristy M et al. (2003) Calcineurin initiates skeletal muscle differentiation by activating MEF2 and MyoD. Differentiation 71:217-27 |
| Horsley, Valerie; Jansen, Katie M; Mills, Stephen T et al. (2003) IL-4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell 113:483-94 |
| Horsley, Valerie; Pavlath, Grace K (2003) Prostaglandin F2(alpha) stimulates growth of skeletal muscle cells via an NFATC2-dependent pathway. J Cell Biol 161:111-8 |
| Mitchell, Patrick O; Pavlath, Grace K (2002) Multiple roles of calcineurin in skeletal muscle growth. Clin Orthop Relat Res :S197-202 |
| Horsley, Valerie; Pavlath, Grace K (2002) NFAT: ubiquitous regulator of cell differentiation and adaptation. J Cell Biol 156:771-4 |
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