Multi-modal and multiscale imaging approaches reveal novel cardiovascular pathophysiology in Drosophila melanogaster.

Constance G Weismann,Anthony Cammarato,Brendan K Huang,Joyce Li,Stephan M Jonas,Anna Blice-Baum,Tangji Tong,Michael A Choma

doi:10.1242/bio.044339

Abstract

ABSTRACTEstablishing connections between changes in linear DNA sequences and complex downstream mesoscopic pathology remains a major challenge in biology. Herein, we report a novel, multi-modal and multiscale imaging approach for comprehensive assessment of cardiovascular physiology in Drosophila melanogaster. We employed high-speed angiography, optical coherence tomography (OCT) and confocal microscopy to reveal functional and structural abnormalities in the hdp2 mutant, pre-pupal heart tube and aorta relative to controls. hdp2 harbor a mutation in wupA, which encodes an ortholog of human troponin I (TNNI3). TNNI3 variants frequently engender cardiomyopathy. We demonstrate that the hdp2 aortic and cardiac muscle walls are disrupted and that shorter sarcomeres are associated with smaller, stiffer aortas, which consequently result in increased flow and pulse wave velocities. The mutant hearts also displayed diastolic and latent systolic dysfunction. We conclude that hdp2 pre-pupal hearts are exposed to increased afterload due to aortic hypoplasia. This may in turn contribute to diastolic and subtle systolic dysfunction via vascular-heart tube interaction, which describes the effect of the arterial loading system on cardiac function. Ultimately, the cardiovascular pathophysiology caused by a point mutation in a sarcomeric protein demonstrates that complex and dynamic micro- and mesoscopic phenotypes can be mechanistically explained in a gene sequence- and molecular-specific manner.

Highlights

Establishing connections between changes in linear DNA sequences and downstream mesoscopic pathology remains a major challenge in biology, especially when the ensuing defects involve complex physiological motions and fluid flows
We studied the coupled heart tubeaorta physiology in held-up2 pre-pupae. hdp2 flies harbor a mutation in the wings up A gene that results in an A55V substitution in the troponin I (TNNI3, OMIM #191044) ortholog (Beall and Fyrberg, 1991)
We show for the first time that aortic pathology and heart tube dysfunction coexist and likely interact in hdp2 prepupae, which express a myopathy-inducing troponin I variant

Summary

Introduction

Establishing connections between changes in linear DNA sequences and downstream mesoscopic pathology remains a major challenge in biology, especially when the ensuing defects involve complex physiological motions and fluid flows. Received 26 April 2019; Accepted 7 August 2019 genes impact multiple levels of the cardiovascular system, from nanoscopic molecular function to myofiber organization and dynamic pump performance of the heart. Multiscale physiology seeks to integrate molecular genetic information with nanoscopic and constitutive properties at the tissue and organ level. The use of multimodal optical imaging to yield insight into multiscale physiology remains in its infancy. The downstream functional consequences of DNA defects in sarcomeric genes are difficult to predict because (1) baseline micro- and mesoscopic physiology is not completely known and (2) there are no adequate multiscale models to assess such predictions. Establishing direct multiscale imaging is indispensable in studying specific biomedically relevant questions of cardiovascular physiology

Methods

Results

Conclusion