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Proteomic analysis of physiological versus pathological cardiac remodeling in animal models expressing mutations in myosin essential light chains.

ABSTRACT: In this study we aimed to provide an in-depth proteomic analysis of differentially expressed proteins in the hearts of transgenic mouse models of pathological and physiological cardiac hypertrophy using tandem mass tag labeling and liquid chromatography tandem mass spectrometry. The ?43 mouse model, expressing the 43-amino-acid N-terminally truncated myosin essential light chain (ELC) served as a tool to study the mechanisms of physiological cardiac remodeling, while the pathological hypertrophy was investigated in A57G (Alanine 57 ? Glycine) ELC mice. The results showed that 30 proteins were differentially expressed in ?43 versus A57G hearts as determined by multiple pair comparisons of the mutant versus wild-type (WT) samples with P < 0.05. The A57G hearts showed differential expression of nine mitochondrial proteins involved in metabolic processes compared to four proteins for ?43 hearts when both mutants were compared to WT hearts. Comparisons between ?43 and A57G hearts showed an upregulation of three metabolically important mitochondrial proteins but downregulation of nine proteins in ?43 hearts. The physiological model of cardiac hypertrophy (?43) showed no changes in the levels of Ca(2+)-binding proteins relative to WT, while the pathologic model (A57G) showed the upregulation of three Ca(2+)-binding proteins, including sarcalumenin. Unique differences in chaperone and fatty acid metabolism proteins were also observed in ?43 versus A57G hearts. The proteomics data support the results from functional studies performed previously on both animal models of cardiac hypertrophy and suggest that the A57G- and not ?43- mediated alterations in fatty acid metabolism and Ca(2+) homeostasis may contribute to pathological cardiac remodeling in A57G hearts.

SUBMITTER: Gomes AV

PROVIDER: S-EPMC4847725 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Proteomic analysis of physiological versus pathological cardiac remodeling in animal models expressing mutations in myosin essential light chains.

Gomes Aldrin V AV Kazmierczak Katarzyna K Cheah Jenice X JX Gilda Jennifer E JE Yuan Chen-Ching CC Zhou Zhiqun Z Szczesna-Cordary Danuta D

Journal of muscle research and cell motility 20151214 6

In this study we aimed to provide an in-depth proteomic analysis of differentially expressed proteins in the hearts of transgenic mouse models of pathological and physiological cardiac hypertrophy using tandem mass tag labeling and liquid chromatography tandem mass spectrometry. The Δ43 mouse model, expressing the 43-amino-acid N-terminally truncated myosin essential light chain (ELC) served as a tool to study the mechanisms of physiological cardiac remodeling, while the pathological hypertrophy ...[more]

PMID: 26668058

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Project description:We examined the regulatory importance of interactions between regulatory light chain (RLC), essential light chain (ELC), and adjacent heavy chain (HC) in the regulatory domain of smooth muscle heavy meromyosin. After mutating the HC, RLC, and/or ELC to disrupt their predicted interactions (using scallop myosin coordinates), we measured basal ATPase, V(max), and K(ATPase) of actin-activated ATPase, actin-sliding velocities, rigor binding to actin, and kinetics of ATP binding and ADP release. If unphosphorylated, all mutants were similar to wild type showing turned-off behaviors. In contrast, if phosphorylated, mutation of RLC residues smM129Q and smG130C in the F-G helix linker, which interact with the ELC (Ca(2+) binding in scallop), was sufficient to abolish motility and diminish ATPase activity, without altering other parameters. ELC mutations within this interacting ELC loop (smR20M and smK25A) were normal, but smM129Q/G130C-R20M or -K25A showed a partially recovered phenotype suggesting that interaction between the RLC and ELC is important. A molecular dynamics study suggested that breaking the RLC/ELC interface leads to increased flexibility at the interface and ELC-binding site of the HC. We hypothesize that this leads to hampered activation by allowing a pre-existing equilibrium between activated and inhibited structural distributions (Vileno, B., Chamoun, J., Liang, H., Brewer, P., Haldeman, B. D., Facemyer, K. C., Salzameda, B., Song, L., Li, H. C., Cremo, C. R., and Fajer, P. G. (2011) Broad disorder and the allosteric mechanism of myosin II regulation by phosphorylation. Proc. Natl. Acad. Sci. U.S.A. 108, 8218-8223) to be biased strongly toward the inhibited distribution even when the RLC is phosphorylated. We propose that an important structural function of RLC phosphorylation is to promote or assist in the maintenance of an intact RLC/ELC interface. If the RLC/ELC interface is broken, the off-state structures are no longer destabilized by phosphorylation.

Dataset Information

Proteomic analysis of physiological versus pathological cardiac remodeling in animal models expressing mutations in myosin essential light chains.

Publications

Proteomic analysis of physiological versus pathological cardiac remodeling in animal models expressing mutations in myosin essential light chains.

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