scholarly journals The Interplay between S-glutathionylation and Phosphorylation of Cardiac Troponin I and Myosin Binding Protein C in End-Stage Human Failing Hearts

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1134
Author(s):  
Heidi Budde ◽  
Roua Hassoun ◽  
Melina Tangos ◽  
Saltanat Zhazykbayeva ◽  
Melissa Herwig ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein C ◽  
Troponin I ◽  
Reduced Glutathione ◽  
Binding Protein ◽  
Enzyme Treatment ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
End Stage

Oxidative stress is defined as an imbalance between the antioxidant defense system and the production of reactive oxygen species (ROS). At low levels, ROS are involved in the regulation of redox signaling for cell protection. However, upon chronical increase in oxidative stress, cell damage occurs, due to protein, DNA and lipid oxidation. Here, we investigated the oxidative modifications of myofilament proteins, and their role in modulating cardiomyocyte function in end-stage human failing hearts. We found altered maximum Ca2+-activated tension and Ca2+ sensitivity of force production of skinned single cardiomyocytes in end-stage human failing hearts compared to non-failing hearts, which was corrected upon treatment with reduced glutathione enzyme. This was accompanied by the increased oxidation of troponin I and myosin binding protein C, and decreased levels of protein kinases A (PKA)- and C (PKC)-mediated phosphorylation of both proteins. The Ca2+ sensitivity and maximal tension correlated strongly with the myofilament oxidation levels, hypo-phosphorylation, and oxidative stress parameters that were measured in all the samples. Furthermore, we detected elevated titin-based myocardial stiffness in HF myocytes, which was reversed by PKA and reduced glutathione enzyme treatment. Finally, many oxidative stress and inflammation parameters were significantly elevated in failing hearts compared to non-failing hearts, and corrected upon treatment with the anti-oxidant GSH enzyme. Here, we provide evidence that the altered mechanical properties of failing human cardiomyocytes are partially due to phosphorylation, S-glutathionylation, and the interplay between the two post-translational modifications, which contribute to the development of heart failure.

scholarly journals Roles of phosphorylation of myosin binding protein-C and troponin I in mouse cardiac muscle twitch dynamics

2004 ◽  
Vol 558 (3) ◽  
pp. 927-941 ◽  
Author(s):  
Carl W. Tong ◽  
Robert D. Gaffin ◽  
David C. Zawieja ◽  
Mariappan Muthuchamy
Keyword(s):  
Cardiac Muscle ◽  
Protein C ◽  
Troponin I ◽  
Binding Protein ◽  
Muscle Twitch ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

scholarly journals Cardiac Myosin-binding Protein C and Troponin-I Phosphorylation Independently Modulate Myofilament Length-dependent Activation

2015 ◽  
Vol 290 (49) ◽  
pp. 29241-29249 ◽  
Author(s):  
Mohit Kumar ◽  
Suresh Govindan ◽  
Mengjie Zhang ◽  
Ramzi J. Khairallah ◽  
Jody L. Martin ◽  
...  
Keyword(s):  
Protein C ◽  
Troponin I ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
Length Dependent Activation

A novel mutation in the cardiac myosin-binding protein C gene is responsible for hypertrophic cardiomyopathy with severe ventricular hypertrophy and sudden death

2005 ◽  
Vol 110 (1) ◽  
pp. 125-131 ◽  
Author(s):  
Tetsuo Konno ◽  
Masami Shimizu ◽  
Hidekazu Ino ◽  
Noboru Fujino ◽  
Katsuharu Uchiyama ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Sudden Death ◽  
Protein C ◽  
Binding Protein ◽  
Gene Mutations ◽  
Clinical Phenotypes ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
End Stage

It has been demonstrated previously that clinical phenotypes of HCM (hypertrophic cardiomyopathy) caused by mutations in the cardiac MyBP-C (myosin-binding protein C) gene show late onset, low penetrance and favourable clinical course. However, we have encountered severe phenotypes in several carriers of the MyBP-C gene mutations. The aim of the present study was to screen novel MyBP-C gene mutations in patients with HCM and to investigate the genetic differences in affected subjects with severe phenotypes. The MyBP-C gene was screened in 292 Japanese probands with HCM, and a novel c.2067+1G→A mutation was present in 15 subjects in five families. Clinical phenotypes of carriers of the c.2067+1G→A mutation were compared with those of a previously identified Arg820Gln (Arg820→Gln) mutation in the MyBP-C gene. The disease penetrance in subjects aged ≥30 years was 90% in carriers of the c.2067+1G→A mutation and 61% in carriers of the Arg820Gln mutation. Sudden death occurred in four subjects from three families with the c.2067+1G→A mutation and in two subjects from one family with the Arg820Gln mutation. Two carriers of the c.2067+1G→A mutation had substantial hypertrophy (maximal wall thickness ≥30 mm). In contrast, two carriers of the Arg820Gln mutation had end-stage HCM. In conclusion, the c.2067+1G→A mutation is associated with HCM with substantial hypertrophy and moderate incidence of sudden death, whereas the Arg820Gln mutation is associated with end-stage HCM. These observations may provide important prognostic information regarding the clinical practice of HCM.

scholarly journals Evolution of the regulatory control of vertebrate striated muscle: the roles of troponin I and myosin binding protein-C

2010 ◽  
Vol 42 (3) ◽  
pp. 406-419 ◽  
Author(s):  
Justin F. Shaffer ◽  
Todd E. Gillis
Keyword(s):  
Protein Kinase ◽  
Protein C ◽  
Troponin I ◽  
Striated Muscle ◽  
Contractile Function ◽  
Binding Protein ◽  
Tissue Specific ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Troponin I (TnI) and myosin binding protein-C (MyBP-C) are key regulatory proteins of contractile function in vertebrate muscle. TnI modulates the Ca2+ activation signal, while MyBP-C regulates cross-bridge cycling kinetics. In vertebrates, each protein is distributed as tissue-specific paralogs in fast skeletal (fs), slow skeletal (ss), and cardiac (c) muscles. The purpose of this study is to characterize how TnI and MyBP-C have changed during the evolution of vertebrate striated muscle and how tissue-specific paralogs have adapted to different physiological conditions. To accomplish this we have completed phylogenetic analyses using the amino acid sequences of all known TnI and MyBP-C isoforms. This includes 99 TnI sequences (fs, ss, and c) from 51 different species and 62 MyBP-C sequences from 26 species, with representatives from each vertebrate group. Results indicate that the role of protein kinase A (PKA) and protein kinase C (PKC) in regulating contractile function has changed during the evolution of vertebrate striated muscle. This is reflected in an increased number of phosphorylatable sites in cTnI and cMyBP-C in endothermic vertebrates and the loss of two PKC sites in fsTnI in a common ancestor of mammals, birds, and reptiles. In addition, we find that His132, Val134, and Asn141 in human ssTnI, previously identified as enabling contractile function during cellular acidosis, are present in all vertebrate cTnI isoforms except those from monotremes, marsupials, and eutherian mammals. This suggests that the replacement of these residues with alternative residues coincides with the evolution of endothermy in the mammalian lineage.

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