S-Space Graduate School of Convergence Science and Technology (융합과학기술대학원) Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과) Theses (Ph.D. / Sc.D._분자의학 및 바이오제약학과)
The role of c-Myc dependent pathway in insulin resistance uncovered by integrative analysis of skeletal muscle transcriptome
골격근 전사체 통합분석을 통해 발견한 c-Myc의 인슐린 저항성 조절 인자로서의 기능에 대한 연구
- 융합과학기술대학원 분자의학 및 바이오제약학과
- Issue Date
- 서울대학교 융합과학기술대학원
- c-Myc; insulin resistance; integrative microarray analysis; mitochondria; oxidative phosphorylation
- 학위논문 (박사)-- 서울대학교 융합과학기술대학원 : 분자의학 및 바이오제약학과, 2015. 8. 박경수.
- I aim to identify a novel pathway to regulate insulin resistance from transcriptional profiles of skeletal muscles from patients with diabetes and to demonstrate its role in experimental models of insulin resistance. I performed transcriptional profiling of skeletal muscles from subjects with or without diabetes. Through an integrative analysis of the dataset with four previous datasets, I identified the core gene sets associated with insulin resistance. Among the 46 core gene sets for transcriptional regulators, I focused on c-Myc with the highest regulatory power in the network of the core gene sets. c-Myc expression decreased in skeletal muscle from diet-induced obesity rodent model. In C2C12 myotubes, c-Myc transcriptional activity was decreased by palmitate or TNFα treatment inducing insulin resistance. Knockdown of c-Myc decreased expression of oxidative phosphorylation (OXPHOS) genes and PGC-1-related coactivator, but showed no change in PGC1α. ERK regulated c-Myc induction by insulin, and palmitate abrogated insulin-induced c-Myc expression by modulating ERK activation. These data demonstrate that ERK-c-Myc pathway regulates OXPHOS gene expression in skeletal muscle insulin resistance, independent of PGC1α. The unbiased integrative approach of transcriptional profiles revealed ERK-c-Myc pathway as a novel pathway for skeletal muscle insulin resistance.