Transcriptional and posttranslational modifications of titin: implications for diastole.

Myocardial diastolic stiffness has been variably attributed to extracellular matrix composition, cytoskeletal properties of cardiomyocytes, or residual diastolic crossbridge cycling because of incomplete relaxation or cytosolic calcium removal.1 Extracellular matrix and cardiomyocyte cytoskeleton are presumed to mediate chronic rises in myocardial diastolic stiffness, as occur during aging, pressure overload or heart failure, whereas residual diastolic crossbridge cycling accounts for acute changes, as observed during ischemia, exercise, or pharmacological interventions. The elegant study by Krüger et al, published in this issue of Circulation Research, challenges this conceptual framework.2 The study demonstrates that protein kinase (PK)G is capable of phosphorylating the giant cytoskeletal protein titin, as previously reported for PKA3,4 and that phosphorylation by PKG or PKA of a serine residue within the N2B fragment of titin leads to an acute fall in cardiomyofibrillar stiffness. An acute effect produced by a cytoskeletal protein invalidates the concept of distinct mediators for chronic or acute changes in myocardial diastolic stiffness. From these and other recent observations it becomes evident that the cytoskeletal protein titin can alter myocardial diastolic stiffness, both acutely and chronically, through multiple mechanisms such as isoform shifts, phosphorylation by PKG or PKA, and titin–actin interaction at the Z-disc (Figure).