Regulation of titin-based cardiac stiffness by unfolded domain oxidation (UnDOx)

Significance Titin oxidation alters titin stiffness, which greatly contributes to overall myocardial stiffness. This stiffness is frequently increased in heart disease, such as diastolic heart failure. We have quantified the degree of oxidative titin changes in several murine heart and skeletal muscle models exposed to oxidant stress and mechanical load. Importantly, strain enhances in vivo oxidation of titin in the elastic region, but not the inextensible segment. The functional consequences include oxidation type-dependent effects on cardiomyocyte stiffness, titin-domain folding, phosphorylation, and inter-titin interactions. Thus, oxidative modifications stabilize the titin spring in a dynamic and reversible manner and help propagate changes in titin-based myocardial stiffness. Our findings pave the way for interventions that target the pathological stiffness of titin in disease.