Ying-Hsi Lin

Passive stiffness of the heart is determined largely by extracellular matrix and titin, which functions as a molecular spring within sarcomeres. Titin stiffening is associated with the development of diastolic dysfunction (DD), while augmented titin compliance appears to impair systolic performance in dilated cardiomyopathy. We found that myofibril stiffness was elevated in mice lacking histone deacetylase 6 (HDAC6). Cultured adult murine ventricular myocytes treated with a selective HDAC6 inhibitor also exhibited increased myofibril stiffness. Conversely, HDAC6 overexpression in cardiomyocytes led to decreased myofibril stiffness, as did ex vivo treatment of mouse, rat, and human myofibrils with recombinant HDAC6. Modulation of myofibril stiffness by HDAC6 was dependent on 282 amino acids encompassing a portion of the PEVK element of titin. HDAC6 colocalized with Z-disks, and proteomics analysis suggested that HDAC6 functions as a sarcomeric protein deacetylase. Finally, increased myofibril stiffness in HDAC6-deficient mice was associated with exacerbated DD in response to hypertension or aging. These findings define a role for a deacetylase in the control of myofibril function and myocardial passive stiffness, suggest that reversible acetylation alters titin compliance, and reveal the potential of targeting HDAC6 to manipulate the elastic properties of the heart to treat cardiac diseases.

Cardiomyopathies represent a heterogeneous group of cardiac disorders that perturb cardiac contraction and/or relaxation, and can result in arrhythmias, heart failure, and sudden cardiac death. Based on morphological and functional differences, cardiomyopathies have been classified into hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM). It has been well documented that mutations in genes encoding sarcomeric proteins are associated with the onset of inherited cardiomyopathies. However, correlating patient genotype to the clinical phenotype has been challenging because of the complex genetic backgrounds, environmental influences, and lifestyles of individuals. Thus, "scaling down" the focus to the basic contractile unit of heart muscle using isolated single myofibril function techniques is of great importance and may be used to understand the molecular basis of disease-causing sarcomeric mutations. Single myofibril bundles harvested from diseased human or experimental animal hearts, as well as cultured adult cardiomyocytes or human cardiomyocytes derived from induced pluripotent stem cells, can be used, thereby providing an ideal multi-level, cross-species platform to dissect sarcomeric function in cardiomyopathies. Here, we will review the myofibril function technique, and discuss alterations in myofibril mechanics, which are known to occur in sarcomeric genetic mutations linked to inherited HCM, DCM, and RCM, and describe the therapeutic potential for future target identification.