The link between exercise and titin passive stiffness

NEW FINDINGS: What is the topic of this review? This review focuses on how in vivo and molecular measurements of cardiac passive stiffness can predict exercise tolerance and how exercise training can reduce cardiac passive stiffness. What advances does it highlight? This review highlights advances in understanding the relationship between molecular (titin-based) and in vivo (left ventricular) passive stiffness, how passive stiffness modifies exercise tolerance, and how exercise training may be therapeutic for cardiac diseases with increased passive stiffness. Exercise can help alleviate the negative effects of cardiovascular disease and cardiovascular co-morbidities associated with sedentary behaviour; this may be especially true in diseases that are associated with increased left ventricular passive stiffness. In this review, we discuss the inverse relationship between exercise tolerance and cardiac passive stiffness. Passive stiffness is the physical property of cardiac muscle to produce a resistive force when stretched, which, in vivo, is measured using the left ventricular end diastolic pressure-volume relationship or is estimated using echocardiography. The giant elastic protein titin is the major contributor to passive stiffness at physiological muscle (sarcomere) lengths. Passive stiffness can be modified by altering titin isoform size or by post-translational modifications. In both human and animal models, increased left ventricular passive stiffness is associated with reduced exercise tolerance due to impaired diastolic filling, suggesting that increased passive stiffness predicts reduced exercise tolerance. At the same time, exercise training itself may induce both short- and long-term changes in titin-based passive stiffness, suggesting that exercise may be a treatment for diseases associated with increased passive stiffness. Direct modification of passive stiffness to improve exercise tolerance is a potential therapeutic approach. Titin passive stiffness itself may be a treatment target based on the recent discovery of RNA binding motif 20, which modifies titin isoform size and passive stiffness. Translating these discoveries that link exercise and left ventricular passive stiffness may provide new methods to enhance exercise tolerance and treat patients with cardiovascular disease.