Alterations in cardiac contractility and heart rate mediated by bone loading

Abstract

The skeleton is a dynamic organ in complex interplay with the other systems of the body and is highly responsive to input from the external environment. Increasingly, evidence is mounting that the skeleton is the source of endocrine factors which affect both long term cardiac outcomes and acute cardiac performance. Some factors, like FGF23, have been shown to augment calcium handling in cardiomyocytes while at the same time being used clinically as a predictor of cardiomorbidity in, for example, chronic kidney disease patients. Other factors, such as osteocalcin, have been shown to be sufficient to elicit a type of cardiac stress response, even in adrenalectomized mice. The circulating levels of these and other bone-derived factors are known to respond to activity level and exercise. A major environmental input for the skeleton, especially during exercise, is movement-induced strain. Media conditioned by MLO-Y4 osteocyte cell line culture under fluid flow sheer stress was used to model the acute effects of bone strain on the contraction magnitude and contraction rate of ex vivo Langendorf-perfused hearts. EKG was then used to measure cardiac parameters during tibial straining of anesthetized mice. A serum sample was collected after tibia strain and analyzed by LC/QToF MS. We found that MLO-Y4 conditioned media increased both the total force and the peak force of Langendorf-perfused hearts by approximately 25%. Somewhat paradoxically, in anesthetized mice we found that a 2-minute tibia strain induced a decrease in heart rate and an increase in heart rate variability which began within seconds, peaked after approximately one minute, then returned to baseline by the time tibia loading ended. LC/QToF was able to identify a variety of serum factors in the strained mice, which produced clusters when principle component analysis was used. One factor, which was the only factor statistically elevated in all groups, was increased in all individuals and had a molecular weight corresponding to acetate. The results obtained in this study strongly suggests that the skeleton, responding to exercise-like mechanical strain, has the potential to rapidly augment cardiac performance. This may have implications in exercise training as well as reduced-function settings, such as bedrest, and may shed additional light on the interplay between bone and heart health.