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J Muscle Res Cell Motil. 2016 Jun;37(3):83-93. doi: 10.1007/s10974-016-9448-2. Epub 2016 Jul 13.

Interplay between the effects of a Protein Kinase C phosphomimic (T204E) and a dilated cardiomyopathy mutation (K211Δ or R206W) in rat cardiac troponin T blunts the magnitude of muscle length-mediated crossbridge recruitment against the β-myosin heavy chain background.

Author information

1
Department of Integrative Physiology and Neuroscience, Washington State University, 205 Veterinary Biomedical Research Building, Pullman, WA, 99164-7620, USA.
2
Department of Integrative Physiology and Neuroscience, Washington State University, 205 Veterinary Biomedical Research Building, Pullman, WA, 99164-7620, USA. murali@vetmed.wsu.edu.

Abstract

Failing hearts of dilated cardiomyopathy (DCM)-patients reveal systolic dysfunction and upregulation of several Protein Kinase C (PKC) isoforms. Recently, we demonstrated that the functional effects of T204E, a PKC phosphomimic of cardiac troponin T (TnT), were differently modulated by α- and β-myosin heavy chain (MHC) isoforms. Therefore, we hypothesized that the interplay between the effects of T204E and a DCM-linked mutation (K211Δ or R206W) in TnT would modulate contractile parameters linked-to systolic function in an MHC-dependent manner. To test our hypothesis, five TnT variants (wildtype, K211Δ, K211Δ + T204E, R206W, and R206W + T204E) were generated and individually reconstituted into demembranated cardiac muscle fibers from normal (α-MHC) and propylthiouracil-treated (β-MHC) rats. Steady-state and mechano-dynamic measurements were performed on reconstituted fibers. Myofilament Ca(2+) sensitivity (pCa50) was decreased by both K211Δ and R206W to a greater extent in α-MHC fibers (~0.15 pCa units) than in β-MHC fibers (~0.06 pCa units). However, T204E exacerbated the attenuating influence of both mutants on pCa50 only in β-MHC fibers. Moreover, the magnitude of muscle length (ML)-mediated crossbridge (XB) recruitment was decreased by K211Δ + T204E (~47 %), R206W (~34 %), and R206W + T204E (~36 %) only in β-MHC fibers. In relevance to human hearts, which predominantly express β-MHC, our data suggest that the interplay between the effects of DCM mutations, PKC phosphomimic in TnT, and β-MHC lead to systolic dysfunction by attenuating pCa50 and the magnitude of ML-mediated XB recruitment.

KEYWORDS:

Dilated cardiomyopathy; Muscle length-mediated crossbridge recruitment dynamics; Myosin heavy chain; Protein Kinase C; Troponin T

PMID:
27411801
DOI:
10.1007/s10974-016-9448-2
[Indexed for MEDLINE]

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