mTOR Signaling in Cellular Growth and Skeletal Muscle Maturation
A Serine/Threonine kinase, mTOR, is a cellular target of rapamycin and plays a role in cellular growth and proliferation by regulating translation through the phosphorylation of 4E-BP1 and S6K. Here, I investigated the function of mTOR for the activation of newly found S6K1 homologue, S6K2, and for the regulation of skeletal muscle myotube growth. My results showed that S6K2 requires mTOR and its kinase activity for its activation. Amino acid and nuclear-cytoplasmic shuttling of mTOR were shown to be required for S6K2 activation. Skeletal myogenesis is a well-coordinated process composed of the determination of myogenic lineage of somitic stem cell, cell cycle withdrawal, the expression of myogenic specific genes and the fusion of myoblasts to form multinucleated myotubes. Skeletal myofibers also undergo hypertrophy with work overload, characterized by size increase and biochemical changes. I showed that the IGF-I-mediated skeletal muscle hypertrophy requires mTOR and its kinase activity, as well as its major downstream effector S6K1. My results also showed that mTOR pathway separate the myogenic process into two stages at the molecular level. First stage is the formation of nascent myotube, which does not require mTOR kinase activity. The maturation of myotubes, which involves the second stage of fusion, requires mTOR kinase activity. The production of secreted factor(s) is responsible for the second stage of fusion and requires mTOR kinase activity. Genomic approach with microarray was used as an attempt to compare biological difference between the mature myotubes and nascent myotubes and to find the secreted factor(s) required for maturation. In conclusion, mTOR pathway regulates skeletal myotube growth by playing distinct roles depending on the stages of growth.
University of Illinois - Urbana-Champaign
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University of Illinois at Urbana-Champaign