期刊
JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY
卷 37, 期 3, 页码 83-93出版社
SPRINGER
DOI: 10.1007/s10974-016-9448-2
关键词
Protein Kinase C; Troponin T; Dilated cardiomyopathy; Myosin heavy chain; Muscle length-mediated crossbridge recruitment dynamics
类别
资金
- National Heart, Lung, and Blood Institute [R01-HL-075643]
- Poncin Fellowship
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 alpha- and beta-myosin heavy chain (MHC) isoforms. Therefore, we hypothesized that the interplay between the effects of T204E and a DCM-linked mutation (K211 Delta 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, K211 Delta, K211 Delta + T204E, R206W, and R206W + T204E) were generated and individually reconstituted into demembranated cardiac muscle fibers from normal (alpha-MHC) and propylthiouracil-treated (beta-MHC) rats. Steady-state and mechano-dynamic measurements were performed on reconstituted fibers. Myofilament Ca2+ sensitivity (pCa(50)) was decreased by both K211 Delta and R206W to a greater extent in alpha-MHC fibers (similar to 0.15 pCa units) than in beta-MHC fibers (similar to 0.06 pCa units). However, T204E exacerbated the attenuating influence of both mutants on pCa(50) only in beta-MHC fibers. Moreover, the magnitude of muscle length (ML)-mediated crossbridge (XB) recruitment was decreased by K211 Delta + T204E (similar to 47 %), R206W (similar to 34 %), and R206W + T204E (similar to 36 %) only in beta-MHC fibers. In relevance to human hearts, which predominantly express beta-MHC, our data suggest that the interplay between the effects of DCM mutations, PKC phosphomimic in TnT, and beta-MHC lead to systolic dysfunction by attenuating pCa(50) and the magnitude of ML-mediated XB recruitment.
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