GDF15 Produced by the Failing Heart is Associated with Cardiac Cachexia 公开
Gupta, Ria (Spring 2022)
Abstract
Heart failure (HF) is a disease that affects 6.2 million adults in the United States with a 5-year mortality rate of 52.6%. One complication of HF is cachexia. Cachexia is the involuntary non-edematous weight loss that cannot be reversed solely by nutritional intake. Marked by continuous fat and muscle breakdown via metabolic imbalances, cachexia presents with anorexia and hypophagia. This chronic metabolic alteration is correlated with a specific increase of growth differentiation factor 15 (GDF15), suggesting this molecule as a driver of cachexia. GDF15 is a stress induced cytokine that increases in chronic diseases and continued nutritional and metabolic bodily stress. Although cachexia and elevated GDF15 levels are present in HF, no biological effect has been established between GDF15 in cardiac pathophysiology. Our hypothesis is that GDF15 is a myocardial derived hormone that causes anorexia and cardiac cachexia. My results suggest that GDF15 is a driver of cachexia through decreased fat and muscle mass, food intake, and altered body parameters. Our lab used a GDF15 KO mouse model that incurs HF through a mutation in the phospholamban (PLN) gene. This mutation alters calcium signaling in cardiomyocytes, a hallmark feature of HF in humans. I have used mouse models and lab techniques including Q-PCR, ELISA and RNA sequencing (RNA-seq), to study the role of GDF15 in HF. We establish that GDF15 is increased in a mouse model of HF, is secreted specifically by the failing heart, and alters peripheral metabolic changes in the body. While further experimentation is needed to test a direct role of GDF15 in cachexia, these and future findings may lead to novel drug therapeutics to treat HF and cachexia.
Table of Contents
Introduction ……………………………………………………………………………………….5
Heart Function and Failure……………………………………………………………………….5
Cardiac Cachexia…………………………………………………………………………………9
Cachexia and Growth Differentiation Factor 15 ………………………………………………..11
PLNR9C Mice Models …………………………………………………………………………….15
Methods ………………………………………………………………………………………… 18
Results ………………………………………………………………………………………….. 23
Specific Aims…………………………………………………………………………………… 28
Discussion………………………………………………………………………………………. 32
References………………………………………………………………………………………. 37
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