Acetylation of Sarcomeric Proteins Plays a Role in Regulating Cardiac Muscle Contractile Activity

02/10/2011 - 9:00am
Dr. Sanjeev Shroff
M-304 MSB (D.H. Barron Conference Room)

A role of protein phosphorylation in regulating cardiac contraction is well established. Our studies indicate, for the first time, that reversible protein acetylation carried out by histone acetyltransferases (HATs ) and deacetylases (HDACs) also plays a role in regulating cardiac muscle (myofilament) contractile activity. We found that a Class II HDAC, HDAC4, and an HAT, PCAF, associate with cardiac myofilaments. Primary cultures of cardiomyocytes as well as mouse heart sections examined by immunohistochemical and electron microscopic analyses revealed that both HDAC4 and PCAF associate with the Z-disc and I- and A-bands of cardiac sacromeres. Increased acetylation of sarcomeric proteins by HDAC inhibition (using class I and II HDAC inhibitors or anti-HDAC4 antibody) under in vitro conditions enhanced the myofilament calcium sensitivity. We found that a number of sarcomeric proteins were acetylated, including the Z-disc-associated protein, MLP, a sensor of cardiac mechanical stretch. We also show that trichostatin-A, a class I and II HDAC inhibitor, increases myofilament calcium sensitivity of wild-type, but not of MLP knock-out mice, thus demonstrating a role of MLP in acetylation-dependent increased contractile activity of myofilaments. Ongoing studies are aimed at examining whether there is any interaction between acetylation-mediated and phosphorylation-mediated regulations of cardiac contraction and whether the acetylation-mediated regulation can be demonstrated under in vivo conditions.

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