Abstract
Reversible lysine acetylation is a widespread post-translational modification controlling the activity of proteins in different subcellular compartments. We previously demonstrated that a class II histone deacetylase (HDAC), HDAC4, and a histone acetyltransferase, PCAF, associate with cardiac sarcomeres, and a class I and II HDAC inhibitor, trichostatin A, enhances contractile activity of myofilaments. In this study, we show that a class I HDAC, HDAC3, is also present at cardiac sarcomeres. By immunohistochemical and electron microscopic analyses, we found that HDAC3 was localized to the A band of sarcomeres and was capable of deacetylating myosin heavy chain (MHC) isoforms. The motor domains of both cardiac α- and β-MHC isoforms were found to be reversibly acetylated. Biomechanical studies revealed that lysine acetylation significantly decreased the K(m) for the actin-activated ATPase activity of both α- and β-MHC isoforms. By an in vitro motility assay, we found that lysine acetylation increased the actin sliding velocity of α-myosin by 20% and β-myosin by 36%, compared to their respective non-acetylated isoforms. Moreover, myosin acetylation was found to be sensitive to cardiac stress. During induction of hypertrophy, myosin isoform acetylation increased progressively with duration of stress stimuli, independent of isoform shift, suggesting that lysine acetylation of myosin could be an early response of myofilaments to increase contractile performance of the heart. These studies provide the first evidence for localization of HDAC3 at myofilaments and uncover a novel mechanism modulating the motor activity of cardiac MHC isoforms.
Highlights
Health Grants RO1 HL-77788 and HL-83423. □S The on-line version of this article contains supplemental Fig. 1. 1 To whom correspondence should be addressed: Dept. of Surgery, MC transfer the acetyl moiety from acetyl coenzyme A to the ⑀amino group of lysine within a protein [1]
myosin heavy chain (MHC) Are Reversibly Acetylated by histone acetyltransferases (HATs) and histone deacetylase (HDAC)— Previously, we have shown that p300/CBP-associated factor (PCAF) and HDAC4 are localized to the A band of sarcomeres [15]
We found that myosin heavy chains were acetylated when myofibrillar proteins extracted from adult mouse heart were incubated with acetylCoA, with or without HDAC inhibitors (Fig. 1A)
Summary
Health Grants RO1 HL-77788 and HL-83423. □S The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1. 1 To whom correspondence should be addressed: Dept. of Surgery, MC transfer the acetyl moiety from acetyl coenzyme A to the ⑀amino group of lysine within a protein [1]. Seven different SIRT isoforms (SIRT1 to -7) have been identified They are ubiquitously expressed and are implicated in the regulation of various biological functions, including cell growth, metabolism, and genetic control of aging [9]. During exercise-induced physiologic hypertrophy, there is no significant change in MHC isoform distribution, whereas during pathologic hypertrophy, -MHC levels are elevated at the expense of the ␣-MHC isoform This MHC isoform shift plays a major role in regulating the contractile function of rodents’ hearts [11]. Many studies conducted with skeletal muscle MHC isoforms have indicated that endurance exercise induces myosin ATPase activity of slow muscle fibers without a change of MHC isoform distributions [13, 14]. We demonstrate that this post-translational modification decreases the Km for the actin-activated ATPase of MHC isoforms and increases the motility of cardiac myosin motors
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