Cardiac-specific deletion of protein phosphatase 1β promotes increased myofilament protein phosphorylation and contractile alterations

There are 3 protein phosphatase 1 (PP1) catalytic isoforms (alpha, beta and gamma) encoded within the mammalian genome. These 3 gene products share similar to 90% amino acid homology within their catalytic domains but each has unique Nand C-termini that likely underlie distinctive subcellular localization or functionality. In this study, we assessed the effect associated with the loss of each PP1 isoform in the heart using a conditional Cre-loxP targeting approach in mice. Ppp1ca-loxP, Ppp1cb-loxP and Ppp1cc-loxP alleles were crossed with either an Nkx2.5-Cre knock-in containing allele for early embryonic deletion or a tamoxifen inducible alpha-myosin heavy chain (alpha MHC)-MerCreMer transgene for adult and cardiac-specific deletion. We determined that while deletion of Ppp1ca (PP1 alpha) or Ppp1cc (PP1 gamma) had little effect on the whole heart, deletion of Ppp1cb (PP1 beta) resulted in concentric remodeling of the heart, interstitial fibrosis and contractile dysregulation, using either the embryonic or adult-specific Cre-expressing alleles. However, myocytes isolated from Ppplcb deleted hearts surprisingly showed enhanced contractility. Mechanistically we found that deletion of any of the 3 PP1 gene-encoding isoforms had no effect on phosphorylation of phospholamban, nor were Ca2+ handling dynamics altered in adult myocytes from Ppplcb deleted hearts. However, the loss of Ppplcb from the heart, but not Ppp1ca or Ppp1cc, resulted in elevated phosphorylation of myofilament proteins such as myosin light chain 2 and cardiac myosin binding protein C, consistent with an enriched localization profile of this isoform to the sarcomeres. These results suggest a unique functional role for the PP1 beta isoform in affecting cardiac contractile function. (C) 2015 Elsevier Ltd. All rights reserved.