This project is designed to obtain research training in the area of skeletal muscle biology using various genetic and molecular biology approaches. Loss of skeletal muscle mass is a devastating consequence of a number of chronic disease states and conditions. However, the cellular and molecular mechanisms which regulate skeletal muscle mass and function in various physiological and pathophysiological conditions remain less understood. Recent studies have suggested that Endoplasmic Reticulum (ER) stress-induced Unfolded Protein Response (UPR) pathways play an important role in skeletal muscle homeostasis and metabolic function. However, the role of the individual arms of the UPR in the regulation of skeletal muscle mass and function has not yet been investigated using genetic mouse models or molecular approaches. Our preliminary studies have suggested that the IRE1/XBP1 arm of the UPR is required for the maintenance of skeletal muscle mass and may have a critical role in post-natal skeletal muscle growth and overload-induced muscle hypertrophy. However, the specific role and the mechanisms of action of the IRE1/XBP1 pathway in the regulation of skeletal muscle mass remains completely unknown. To understand the role the IRE1/XBP1 arm of the UPR in the regulation of skeletal muscle mass, we will address following two specific aims.
AIM 1 : Establish the role and investigate the cellular mechanisms by which the IRE1/XBP1 arm of the UPR promotes skeletal muscle growth. In this aim, we will test the hypothesis that the IRE1/XBP1 pathway mediates skeletal muscle growth through a cell- autonomous and/or a non-cell autonomous manner.
AIM 2 : Investigate the molecular mechanisms by which the IRE1/XBP1 axis promotes muscle growth. In this aim, we will test the hypothesis that the activation of the IRE1/XBP1 arm of the UPR promotes skeletal muscle growth through augmenting protein synthesis, mitochondrial biogenesis, and inducing the expression of certain myokines. The proposed studies will identify a novel molecular pathway, which will significantly improve our understanding of the mechanisms involved in growth and maintenance of skeletal muscle mass. Moreover, this project will provide me outstanding training in the field of skeletal muscle biology.
Skeletal muscle loss or wasting is a devastating problem in a wide range of chronic diseased states, including cancer. We have identified the IRE1/XBP1 arm of the Unfolded Protein Response as a novel regulator of skeletal muscle growth. We will investigate the cellular and molecular mechanisms by which the IRE1/XBP1 pathway promotes skeletal muscle growth and prevents atrophy. Our proposed studies will provide strong basis to determining whether IRE1/XBP1 can be used as a novel molecular target for treatment of skeletal muscle wasting in diverse conditions.
