Truncation Of Titin'S Elastic PEVK Region Leads To Cardiomyopathy With Diastolic Dysfunction

The giant protein titin is important for proper myofilament assembly and structure, as well as the passive mechanical properties of the sarcomere. Within the sarcomeric I-band region of titin reside two elastic elements - the cardiac specific N2B element and the PEVK element. Unlike the N2B element that has been linked to metabolism and signal transduction, the PEVK region has so far solely been regarded as a mechanical spring. Here we have used a loss of function approach to delete exons 219-225 from the mouse titin gene, which encode all residues of the PEVK element present in N2B titin, the main titin isoform expressed in the heart. Homozygous PEVK knockout (KO) mice survived to adulthood and were fertile. Titin-based passive tension was highly increased, accompanied by diastolic dysfunction, as determined by echocardiography, isolated heart experiments, and muscle mechanics. Surprisingly, PEVK-KO mice had dilated and hypertrophied hearts and had increased FHL2 expression, contrasting the cardiac atrophy and decreased FHL2 levels that result from the deletion of the N2B element. This work indicates a concerted action of titin's elastic elements in providing proper diastolic function, but a distinct effect on the trophic properties of the heart.