Cell Biology of Sarcomeric Protein Engineering: Disease Modeling and Therapeutic Potential

Thompson, Brian R.; Metzger, Joseph M.

doi:10.1002/ar.22966

Cited by 17 publications

(14 citation statements)

References 65 publications

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“…This skewed ratio might explain the dysruption of the sarcomere organisation and the alteration of the kinematics and dynamics properties of the beating syncytia. In fact, the correct ratio of sarcomeric proteins is crucial to the proper formation of the sarcomere and thus to the contraction and relaxation activity of cardiac cells 50 .…”

Section: Discussionmentioning

confidence: 99%

Arsenic trioxide alters the differentiation of mouse embryonic stem cell into cardiomyocytes

Rebuzzini

Cebral

Fassina

et al. 2015

Sci Rep

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Chronic arsenic exposure is associated with increased morbidity and mortality for cardiovascular diseases. Arsenic increases myocardial infarction mortality in young adulthood, suggesting that exposure during foetal life correlates with cardiac alterations emerging later. Here, we investigated the mechanisms of arsenic trioxide (ATO) cardiomyocytes disruption during their differentiation from mouse embryonic stem cells. Throughout 15 days of differentiation in the presence of ATO (0.1, 0.5, 1.0 μM) we analysed: the expression of i) marker genes of mesoderm (day 4), myofibrillogenic commitment (day 7) and post-natal-like cardiomyocytes (day 15); ii) sarcomeric proteins and their organisation; iii) Connexin 43 and iv) the kinematics contractile properties of syncytia. The higher the dose used, the earlier the stage of differentiation affected (mesoderm commitment, 1.0 μM). At 0.5 or 1.0 μM the expression of cardiomyocyte marker genes is altered. Even at 0.1 μM, ATO leads to reduction and skewed ratio of sarcomeric proteins and to a rarefied distribution of Connexin 43 cardiac junctions. These alterations contribute to the dysruption of the sarcomere and syncytium organisation and to the impairment of kinematic parameters of cardiomyocyte function. This study contributes insights into the mechanistic comprehension of cardiac diseases caused by in utero arsenic exposure.

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Section: Discussionmentioning

confidence: 99%

Arsenic trioxide alters the differentiation of mouse embryonic stem cell into cardiomyocytes

Rebuzzini

Cebral

Fassina

et al. 2015

Sci Rep

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“…, 2011 ). Virus-mediated expression of sarcomeric proteins in ARVMs enables not only the study of the gross cellular phenotype of disease-associated mutations, but also detailed study of sarcomere dynamics ( Thompson and Metzger, 2014 ). The two approaches (surgical/transgenic and drug/virus) can also be combined to analyze signaling pathways downstream of pathogenic hypertrophic stimuli ( Métrich et al.…”

Section: Primary Cardiac Myocytesmentioning

confidence: 99%

Biology of the cardiac myocyte in heart disease

Peter

Bjerke

Leinwand

2016

MBoC

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Cardiac hypertrophy is a major risk factor for heart failure, and it has been shown that this increase in size occurs at the level of the cardiac myocyte. Cardiac myocyte model systems have been developed to study this process. Here we focus on cell culture tools, including primary cells, immortalized cell lines, human stem cells, and their morphological and molecular responses to pathological stimuli. For each cell type, we discuss commonly used methods for inducing hypertrophy, markers of pathological hypertrophy, advantages for each model, and disadvantages to using a particular cell type over other in vitro model systems. Where applicable, we discuss how each system is used to model human disease and how these models may be applicable to current drug therapeutic strategies. Finally, we discuss the increasing use of biomaterials to mimic healthy and diseased hearts and how these matrices can contribute to in vitro model systems of cardiac cell biology.

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“…The interaction is also present in the X-ray structure of the fast skeletal core troponin complex 46 , suggesting that it contributes to pH insensitivity in fast skeletal muscle as well. Some have advocated cardiac gene therapy to introduce the TnI A162H mutation in patients with severe cardiac ischemia 47 , since the Ca 2+ sensitivity of the ischemic heart is reduced by cytosolic acidosis 40 .…”

Section: Structure and Function Of Cardiac Troponin C Within The Tropmentioning

confidence: 99%

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Hwang

2015

Gene

106

105

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In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca2+ or Mg2+ under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure.

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Cell Biology of Sarcomeric Protein Engineering: Disease Modeling and Therapeutic Potential

Cited by 17 publications

References 65 publications

Arsenic trioxide alters the differentiation of mouse embryonic stem cell into cardiomyocytes

Arsenic trioxide alters the differentiation of mouse embryonic stem cell into cardiomyocytes

Biology of the cardiac myocyte in heart disease

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

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