Eph/ephrin involvement in skeletal muscle development and regeneration

Abstract

Skeletal muscle development and regeneration is one of the best-described areas of vertebrate biology, due in large part to muscle cells' characteristic sequence of specification, determination, and differentiation. However, many questions still remain open, including the relative extent to which intrinsic lineage factors, local interactions with other myogenic cells, and systemic physiological factors affect muscle cell identity and activity. Eph/ephrin signaling can promote proliferation or differentiation, survival or death, adhesion or deadhesion, and repulsion or attraction, depending on the molecular and cellular context. In skeletal muscle tissue, the activity of Eph/ephrins in development and regeneration is not yet fully explored. This dissertation describes experiments into the roles two different Eph proteins may play in mediating muscle development, homeostasis, and regeneration. The first, EphA7, appears to act during both muscle development and muscle regeneration in the adult to promote myogenic specification and hypertrophy. The second, EphA3, is differentially expressed by activated satellite cells residing on fast vs. slow muscle fibers, potentially in response to expression of an ephrin ligand (ephrin-A3) solely on slow myofibers. The final data chapter focuses on a mouse model in which overexpression of PGC-1a, a transcriptional coactivator that promotes mitochondrial biogenesis, induces a shift from glycolytic (typical of fast myofibers) to oxidative (typical of slow myofibers) metabolism in the skeletal muscle. We note that surprisingly, in spite of this physiological adaptation, the expression of fast vs. slow myosin heavy chain isoforms is not significantly altered. The focus of this work is on molecular and cellular factors affecting skeletal muscle morphogenesis and fiber type patterning during development, homeostasis and regeneration, and highlights the potential for juxtacrine interactions to direct these processes.