Matrisome gene expression is altered during non-allometric heart growth in genetically enlargedDrosophila

Abstract

AbstractThe cardiac extracellular matrix (ECM) is critical to defining the biophysical properties of the heart that adapt to changing stresses with growth or disease. The ECM is commonly dysregulated in chronic disease such as hypertension, diabetes, and cardiomyopathies, often leading to the development of fibrosis. There are no treatment options to address most ECM cardiomyopathies, but developing therapeutic targets necessitates an understanding of the regulation of ECM remodelling. Here, we employ a larvalDrosophilaovergrowth model (“giant larvae”) to overload the heart and alter ECM remodellingin vivo. These larvae grow to immense sizes without exhibiting hallmarks of obesity. Remarkably, cardiac ECM organization scales allometrically despite overload. The main effect observed is a change in Collagen fibril thickness, possibly reflecting changes to tension in the system. Overgrowth-induced changes in gene expression similarly suggest changes in Collagen assembly, such as a dramatic increase in LOXL2, the main Collagen crosslinking enzyme. This could indicate that larvae may compensate for the stress of overgrowth by stabilizing the Collagen network. The enlarged hearts of giant larvae cannot contract fully at systole. Taken together, this reveals non-allometric changes to cardiac form and output with increasing body size. Overall, our overgrowth model presents an intriguing opportunity to examine the ability of a system to tolerate overgrowth without the metabolic inputs of obesity.