Exercise Mitigates Increased Diastolic Stiffness in the Titin IA KO Mouse

Abstract

The giant sarcomeric protein titin spans the length of the half sarcomere and consists of an I-band region that functions as a molecular spring and an A-band region. Here we use a mouse model in which a portion of titin near the IA junction has been removed (IA KO) resulting in diastolic dysfunction and increased total and titin-based passive tension. We test the hypothesis that exercise ameliorates increased titin-based stiffness. In this study, 3 month old male IA KO and WT mice were allowed free access to a running wheel for 28 days and distance, speed, and duration were recorded each night. After 28 days mice were sacrificed and the LV was used for skinned muscle mechanics, analysis gels, and western blots. WT and IA KO mice ran for the same duration but IA KO mice ran slower and therefore less distance than their WT counterparts (WT mice ran ∼6 km per night while IA KOs ran ∼4.5 km). Stiffness in both WT and IA KO mice was reduced after exercise; titin-based tension at a sarcomere length of 2.3 μm was reduced by ∼16% and ∼20% respectively. No changes in titin isoform ratios were observed but exercised mice showed hypo-phosphorylation of S26, a PKC site in titin's PEVK region. S26 phosphorylation is known to increase titin's stiffness so hypo-phosphorylation is consistent with the reduction in stiffness observed in exercised mice. We conclude that exercise improves diastolic dysfunction though modulation of titin phosphorylation.