Discovery and application of myogenetic oligodeoxynucleotides (myoDNs)
Tomohide Takaya1,2.
- Department of Agriculture, Graduate School of Science and Technology, Shinshu University, Japan.
- Department of Biomolecular Innovation, Institute for Biomedical Sciences, Shinshu University, Japan.
International Joint Seminar 2019 Sejong University-Shinshu University-Kasetsart University (Seoul, Korea), 2019/09/24 (Talk).
Abstract
Muscle atrophy is a severe problem for the motor function of elderly people and for the prognosis of the patients with cancer or heart failure. Homeostasis of skeletal muscle tissue is maintained by myogenic precursor cells called myoblasts. After several rounds of cell divisions, myoblasts differentiate into contractile myocytes in order to regenerate muscle myofibers. However, the differentiation ability of myoblasts decline due to aging or diseases, which a part of the reason of muscle atrophy. To develop the drugs or supplement to overcome muscle atrophy, we have screened the various molecules or extracts that induce myoblast differentiation.
Recently, we successfully identified a series of oligodeoxynucleotides which intensely promote myotube formation of human myoblasts. These nucleotides named myoDNs (myogenetic oligodeoxynucleotides) are the 18-nt single-stranded phosphorothioate-DNAs having a tandem telomeric sequence. iSN04, the most effective myoDN, is spontaneously incorporated into cytoplasm and drive myogenic gene expression program. Computational simulation and experimental analyses revealed that myogenetic activities of iSN04 is molecular structure-dependent. We further found that the isoquinoline alkaloid that interacts with iSN04 and enhances its myogenetic activity. We are now trying to apply iSN04 to various muscle disorders including muscle atrophy.
In this talk, we introduce the effects of iSN04 on the myoblasts exposed to cancer secretion, the myoblasts from diabetic patients, and rhabdomyosarcoma cells from children. Intriguingly, iSN04 is able to regulate the fate of pluripotent stem cells, which will be useful for regenerative medicine. We also present our current challenge to shorten myoDNs. Development of shorter myoDNs will reduce synthetic cost, stabilize the molecular structure, and improve absorption into the cells, which finally contribute to progress clinical and dietary applications of myoDNs as drugs or supplements.
Keywords: myoblast, oligodeoxynucleotide, skeletal muscle.