Author: Naghmeh Nikpoor

Publisher:

Published: 2019

Total Pages:

ISBN-13:

"Skeletal muscle plays a central role in whole body metabolism and serves as the major site for insulin-stimulated glucose disposal. Insulin resistance in skeletal muscle is considered an initiating factor in the development of Type 2 diabetes (T2D). Skeletal muscle is also known for its ability to regenerate after injury in the process called myogenesis. Aberrant myogenesis will lead to many muscle disorders including various types of muscular dystrophies. The comprehensive delineation of genes involved in muscle regeneration and metabolism is an essential step towards understanding muscle biology and pathophysiology. While many studies have identified and dissected the role of protein-coding genes in muscle differentiation and function, recent discoveries demonstrate that the human genome also contains thousands of non-protein-coding genes termed long non-coding RNAs (lncRNAs). However, the identity and functions of many of these new genes are still unknown. Here, we describe the systematic discovery and characterization of lncRNAs in skeletal muscle. We focused on two main aspects of muscle biology which are muscle regeneration and metabolism.We used total RNA transcriptome sequencing in a panel of primary human myoblasts and myotubes to identify 191 known and novel lncRNAs with differential expression during muscle differentiation in vitro. We focused on one lncRNA, RMD1, whose expression is increased during myoblast differentiation in both mouse and humans. RMD1 expression also increases in the acute and chronic in vivo models of myogenesis; and RMD1 knockdown in vitro leads to decreased expression of myogenesis markers, which highlights its potential role in regulating skeletal muscle regeneration.We also present for the first time a comprehensive profile of known and novel lncRNAs whose expression changes in skeletal muscle obtained from diabetic subjects. These include a lncRNA we named TDNC1 (T2D down-regulated non-coding RNA 1) that is located near a previously identified T2D-associated variant (rs2943641). TDNC1 expression is correlated with rs2943641 genotype and is reduced in T2D as well as in young normoglycemic individuals with a family history of T2D. Compounds known to alter insulin sensitivity regulate TDNC1 expression. Moreover, ectopic expression of this lncRNA results in specific up-regulation of genes involved in insulin signaling as well as increased activity of this pathway.Taken together, this thesis presents a comprehensive assessment of lncRNAs as novel regulators in muscle differentiation and metabolism. Broadly, this work suggests that uncharacterized lncRNAs may play important roles not just in muscle biology and disease, but also in other biological processes and pathogenesis of various diseases." --