Pseudophosphorylation of Cardiac Troponin I Residues 23/24 Decreases Myofilament Ca2+ Sensitivity in Transgenic Mice Containing D230N Mutation in α-Tropomyosin

Michael, John J.; Tal, Lauren; Tardiff, Jil C.; Chandra, Murali

doi:10.1016/j.bpj.2012.11.2663

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“…Because α‐ and β‐MHC differentially influence the functional effects of TnT, as demonstrated by an ever‐increasing number of studies, it is imperative that studies are carried out against the relevant MHC background to meaningfully evaluate the functional implications of DCM‐linked mutations in human TnT. Second, complications arising from DCM‐linked pathology may not only be dependent on the primary dysfunction caused by the mutation, but also on changes in post‐translational modifications (PTMs) . In this regard, we chose to focus on one PTM and its link to DCM‐mediated contractile dysfunction and pathogenesis.…”

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confidence: 99%

“…Second, complications arising from DCM-linked pathology may not only be dependent on the primary dysfunction caused by the mutation, but also on changes in post-translational modifications (PTMs). 11,12 In this regard, we chose to focus on one PTM and its link to DCMmediated contractile dysfunction and pathogenesis. Specifically, we chose the protein kinase C (PKC)-mediated phosphorylation of TnT because PKC isoforms (a, bII, e, d, and f) that phosphorylate TnT (residues T195, S199, T204, S276, and T285 in rat TnT) [13][14][15] are upregulated in failing human hearts.…”

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confidence: 99%

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Interplay Between the Effects of Dilated Cardiomyopathy Mutation (R206L) and the Protein Kinase C Phosphomimic (T204E) of Rat Cardiac Troponin T Are Differently Modulated by α‐ and β‐Myosin Heavy Chain Isoforms

Michael

Chandra

2016

JAHA

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BackgroundWe hypothesized that the functional effects of R206L—a rat analog of the dilated cardiomyopathy (DCM) mutation R205L in human cardiac troponin T (TnT)—were differently modulated by myosin heavy chain (MHC) isoforms and T204E, a protein kinase C (PKC) phosphomimic of TnT. Our hypothesis was based on two observations: (1) α‐ and β‐MHC differentially influence the functional effects of TnT; and (2) PKC isoforms capable of phosphorylating TnT are upregulated in failing human hearts.Methods and ResultsWe generated 4 recombinant TnT variants: wild type; R206L; T204E; and R206L+T204E. Functional effects of the TnT variants were tested in cardiac muscle fibers (minimum 14 per group) from normal (α‐MHC) and propylthiouracil‐treated rats (β‐MHC) using steady‐state and dynamic contractile measurements. Notably, in α‐MHC fibers, Ca2+‐activated maximal tension was attenuated by R206L (≈32%), T204E (≈63%), and R206L+T204E (≈64%). In β‐MHC fibers, maximal tension was unaffected by R206L, but was attenuated by T204E (≈33%) and R206L+T204E (≈40%). Thus, β‐MHC differentially counteracted the attenuating effects of the TnT variants on tension. However, in β‐MHC fibers, R206L+T204E attenuated tension to a greater extent when compared to T204E alone. In β‐MHC fibers, R206L+T204E attenuated the magnitude of the length‐mediated recruitment of new cross‐bridges (≈28%), suggesting that the Frank‐Starling mechanism was impaired.ConclusionsOur findings are the first (to our knowledge) to demonstrate that the functional effects of a DCM‐linked TnT mutation are not only modulated by MHC isoforms, but also by the pathology‐associated post‐translational modifications of TnT.

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confidence: 99%

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confidence: 99%