Thursday, November 21, 2024
11/21/2024
Project Abstract Skeletal muscle (SkM) function and strength, and intrinsic muscle quality are closely linked to the pathogenesis and pathophysiology of metabolic disease. However, the regulatory molecular mechanisms in SkM performance remain elusive. The current proposal will focus on identifying novel molecular pathways regulating muscle function and insulin signaling via the muscle-specific role of Fat Specific Protein 27 (FSP27). While the adipocyte actions of FSP27 have been well-recognized in the metabolic field, we unexpectedly discovered high FSP27 protein expression in SkM. Our preliminary data in humans identified a positive correlation of SkM FSP27 expression with indices of muscle performance such as aerobic capacity, muscle strength, and responsivity to exercise training. Also, our study in whole-body Fsp27-/- mice displayed severely impaired muscle endurance, muscle strength, and loss of fat in the SkM. Intramyocellular fat is a crucial source to meet the energy demand in the SkM for its function. Therefore, we hypothesized that FSP27 plays a major role in muscle performance and insulin sensitivity primarily via its role in regulating fat handling in the SkM. As a first step in understanding the clinical relevance of FSP27 in SkM insulin signaling and muscle function, we have generated an innovative gain-of-function transgenic mouse model expressing the human-FSP27 transgene, (M-FSP27tg), specifically in SkM without altering the expression of endogenous mouse Fsp27. Also, we have generated a loss-of-function muscle model through muscle-specific ablation of FSP27 (M-Fsp27-/-). Our preliminary studies in these mouse models are in-line with our hypothesis and suggest a critical role of SkM-specific FSP27 in muscle performance. We will utilize a three-pronged approach to identify the physiological and molecular mechanism of FSP27-mediated SkM function. In Aim 1, we will study the physiological action of FSP27 in SkM performance, and its role in protection against obesity-induced whole-body insulin resistance. In Aim 2, we will test our hypothesis that FSP27 handles intramyocellular fat fuel via its action on the motor activity of the cytoskeletal proteins along the FSP27-Rab18-p150-Dyenin axis in the SkM. In aim 3, we will test our hypothesis that in addition to its effect on cytoskeleton motor activity, FSP27 regulates exercise endurance and insulin sensitivity via the glucagon-like peptide 1 receptor (GLP1R)-AMPK pathway. A strength of this proposal is an interdisciplinary collaboration formed between Dr. Puri (expert in basic and translational research in lipid metabolism and signaling), Dr. Consitt (expert in SkM metabolism), Dr. Baumann (expert in SkM physiology), and Dr. Lee (expert in tissue insulin signaling), which will utilize their complementary expertise and build upon their collaborative work in this project. Successful completion of the proposed studies will identify a novel regulatory player in SkM performance and muscle biology.
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