Proteolytic degradation of atrial sarcomere proteins underlies contractile defects in atrial fibrillation

Abstract

(ii) ABSTRACTAimsAtrial fibrillation (AFib) is the most common cardiac rhythm disturbance. Treatment of AFib involves restoration of the atrial electrical rhythm. Following rhythm restoration, a period of depressed mechanical function known as atrial stunning occurs that involves decreased blood flow velocity and reduced atrial contractility. This suggests that defects in contractility occur in AFib and are revealed upon restoration of rhythm. The aim of this project is to define the contractile remodeling that occurs in AFibMethods and ResultsTo assess contractile function, we used a canine atrial tachypacing model of induced AFib. Mass spectrometry analysis showed dysregulation of contractile proteins in samples from AFib compared to sinus rhythm atria. Atrial cardiomyocytes showed reduced force of contraction in skinned single cardiomyocyte calcium-force studies. There were no significant differences in myosin heavy chain isoform expression. Resting tension is decreased in the AFib samples correlating with reduced full-length titin in the sarcomere. We measured degradation of other myofilament proteins including cMyBP-C, actinin, and cTnI, showing significant degradation in the AFib samples compared to sinus rhythm atria. Many of the protein degradation products appeared as discrete cleavage products that are generated by calpain proteolysis. We assessed calpain activity and found it to be significantly increased. Skinned cardiomyocytes from AFib atria showed decreased troponin I phosphorylation, consistent with the increased calcium sensitivity that was found within these cardiomyocytes.ConclusionsWith these results it can be concluded that AFib causes alterations in contraction that can be explained by both molecular changes occurring in myofilament proteins and overall myofilament protein degradation. These results provide an understanding of the contractile remodeling that occurs in AFib and provides insight into the molecular explanation for atrial stunning and the increased risk of atrial thrombus and stroke in AFib.

Myocardial SERCA2 Protects Against Cardiac Damage and Dysfunction Caused by Inhaled Bromine

“…Under adverse pathological conditions however, reduction or loss of SERCA2 activity can be detrimental resulting in deaths and long-term morbidity (Ahmad et al 2019;Goodman et al 2020;Guerrero-Beltran et al 2017;Heitner and Hollenberg 2009;Masjoan Juncos et al 2021). Calpains degrade proteins essential for cardiac contractility, such as titin (Cizauskas et al 2023;Lim et al 2004). This proteolytic activity expands to even SERCA2 itself, leading to further impaired Ca 2+ transport (Ahmad et al 2019;French et al 2006).…”