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1.Discovery of Follistatin-derived Peptides as Efficient Myostatin Inhibitors and Metabolic Modifiers.Myostatin, a member of the transforming growth factor (TGF)-β superfamily, plays a potent inhibitory role in controlling skeletal muscle mass.Inhibition of myostatin dramatically increases skeletal muscle mass in various species including human.Various peptides including follistatin, better knows as an activin antagonist, can bind and neutralized myostatin.Our group has developed a number of myostatin inhibitors derived from follistatins, which do not affect activins (Faseb J.22, 477-478, 2008).FS I-I is one of the follistatin-derived myostatin inhibitors and we have developed FS I-I transgenic mice under skeletal muscle specific promoter.We found that myostatin inhibition by FS I-I increases skeletal muscle mass and decreases fat accumulation.FS I-I Tg mice showed decreased fat accumulation even on a control chow diet.Intriguingly, sizes of adipocytes in FS I-I Tg mice were smaller than those of wild-type mice.Furthermore,they were resistant to high-fat diet-induce obesity and hepatic steatosis and had lower hepatic fatty acid levels.Composition of fatty acid in liver was altered.FS I-I Tg mice have improved glucose tolerance and insulin resistance on a high-fat diet.Our data indicate that inhibiting myostatin with follistatin-derived peptides provide a novel therapeutic option to decrease adiposity, and prevent obesity and hepatic steatosis, and improve glucose metabolism.2.Discovery of Stem Cells Involved in Fatty Degeneration in Skeletal Muscle.Fatty degeneration is one of the characteristics of muscular disorders.However the origin of ectopic fat was largely unknown.We have prospectively isolated mononuclear cells from skeletal muscle by FACS and studied adipoeyte differentiation properties.We identify PDGF α+ mesenchymal stem cells as being distinct from satellite cells and located in the muscle interstitium.Of the muscle-derived cell populations, only PDGFRα+ cells show efficient adipogenic differentiation both in vitro and in vivo.PDGFRα+ stem cells are the major contributor to ectopic fat cell formation in skeletal muscle, and emphasize that interaction between muscle cells and PDGFRα+ mesenchymal stem cells has a considerable impact on muscle homeostasis.