A Drosophila overgrowth model reveals extracellular matrix crosslinking limits cardiovascular scaling

Appropriate organ scaling is critical for many basic biological processes. However, very little is known about how invertebrates achieve appropriate scaling. A larval Drosophila model for overgrowth was employed here to examine the effects of increased body size on whole body physiology. Overgrown larvae reach over twice the size of controls and exhibit altered fat storage, decreased movement and speed, as well as decreased oxygen consumption. This points to an inability of the larvae to maintain appropriate physiology in this overgrowth model. Scaling of the heart was examined, and it was found to increase disproportionately with body size, and live imaging revealed decreased cardiac contractility and output. A potential cause for this defect was dramatically increased expression levels of the lysyl oxidase LOXL-2, a major Collagen crosslinking enzyme that increases matrix stiffness. Inhibiting the function of LOXL-2 significantly improved both physiological and cardiac defects observed in the overgrown larvae. Overall, we present an overgrowth model with intriguing possibilities for examining the ability of a system to tolerate overgrowth and show that inhibition of extracellular matrix crosslinking can be used to compensate for cardiac defects in this model.