Post-Translational Regulation of Cardiac Muscle Contraction by Myofilamental Acetylation

Sanjeev G. Shroff, Ph.D.
University of Houston
We report, for the first time, that reversible myofilament protein acetylation carried out by
histone acetyltransferases (HATs) and deacetylases (HDACs) can also regulate cardiac muscle
contractile activity. Immunohistochemical and electron microscopic analyses revealed that
both HDAC4 (a Class II HDAC) and PCAF (a HAT) associate with the Z-disc and I- and A-bands
of cardiac sacromeres. Increased acetylation of myofilament proteins by HDAC inhibition
under in vitro conditions enhanced myofilament calcium sensitivity. The Z-disc-associated
protein, MLP, a sensor of cardiac mechanical stretch was acetylated. Also HDAC inhibition
increased myofilament calcium sensitivity of wild-type, but not of MLP knock-out mice,
demonstrating a role of MLP in acetylation-dependent increased myofilament contractile
activity. Current studies are to develop novel therapeutic approaches for enhancing cardiac
muscle contractile activity using this new regulatory pathway under in vivo conditions.