Molecular Mechanism of Sarcomeric Cardiomyopathies

Thompson, Brian R.; Michelle, L.; Metzger, Joseph M.

doi:10.1007/978-3-319-44577-9_10

Cited by 2 publications

(2 citation statements)

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“…At the center of this chemo-mechanical regulation is the troponin complex, which ultimately directs the molecular motor of the sarcomere, myosin, to produce force and motion (2,3). Genetic and environmental perturbations can markedly alter these intermolecular interactions, resulting in depressed cardiac myocyte function and declining heart pump function (4). Consequently, gaining a deeper understanding of the structure-function relationship in sarcomeric proteins is critical to developing strategies to effectively redress the ischemic and failing heart.…”

Section: Introductionmentioning

confidence: 99%

TnI Structural Interface with the N-Terminal Lobe of TnC as a Determinant of Cardiac Contractility

Vetter

Houang

Sell

et al. 2018

Biophysical Journal

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The heterotrimeric cardiac troponin complex is a key regulator of contraction and plays an essential role in conferring Ca sensitivity to the sarcomere. During ischemic injury, rapidly accumulating protons acidify the myoplasm, resulting in markedly reduced Ca sensitivity of the sarcomere. Unlike the adult heart, sarcomeric Ca sensitivity in fetal cardiac tissue is comparatively pH insensitive. Replacement of the adult cardiac troponin I (cTnI) isoform with the fetal troponin I (ssTnI) isoform renders adult cardiac contractile machinery relatively insensitive to acidification. Alignment and functional studies have determined histidine 132 of ssTnI to be the predominant source of this pH insensitivity. Substitution of histidine at the cognate position 164 in cTnI confers the same pH insensitivity to adult cardiac myocytes. An alanine at position 164 of cTnI is conserved in all mammals, with the exception of the platypus, which expresses a proline. Prolines are biophysically unique because of their innate conformational rigidity and helix-disrupting function. To provide deeper structure-function insight into the role of the TnC-TnI interface in determining contractility, we employed a live-cell approach alongside molecular dynamics simulations to ascertain the chemo-mechanical implications of the disrupted helix 4 of cTnI where position 164 exists. This important motif belongs to the critical switch region of cTnI. Substitution of a proline at position 164 of cTnI in adult rat cardiac myocytes causes increased contractility independent of alterations in the Ca transient. Free-energy perturbation calculations of cTnC-Ca binding indicate no difference in cTnC-Ca affinity. Rather, we propose the enhanced contractility is derived from new salt bridge interactions between cTnI helix 4 and cTnC helix A, which are critical in determining pH sensitivity and contractility. Molecular dynamics simulations demonstrate that cTnI A164P structurally phenocopies ssTnI under baseline but not acidotic conditions. These findings highlight the evolutionarily directed role of the TnI-cTnC interface in determining cardiac contractility.

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Section: Introductionmentioning

confidence: 99%

TnI Structural Interface with the N-Terminal Lobe of TnC as a Determinant of Cardiac Contractility

Vetter

Houang

Sell

et al. 2018

Biophysical Journal

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“…There are three major components in a sarcomere, i.e., thick filament (A-band), thin filament (I-band) and Z-discs (Z-band). MYH7 and MYBPC3 are involved in the formation of myosin (thick filament) while TPM1 and TNNT2 are instrumental in the formation of actin (thin filament) [26]. The MYH7 gene has been extensively reported as one of the CMP-causing genes, especially in HCM, accounting for 14% of all cases [27].…”

Section: Discussionmentioning

confidence: 99%

Genetic investigation of point mutations in sarcomeric genes in Malaysian patients with cardiomyopathy

Tan¹,

Chua²,

Jones³

et al. 2023

ScienceAsia

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Cardiomyopathy comprises a diverse group of diseases affecting the myocardium. The genetic composition is one of the major disease-defining factors of cardiomyopathies, with globally more than 100 genes implicated in this pathogenesis. Most genetic studies were performed in the Western populations, with only limited data available for the Asian populations. In this study, 152 cardiomyopathy patients (104 dilated cardiomyopathy and 48 hypertrophic cardiomyopathy) were recruited. A total of 20 genetic mutations previously reported in Caucasian populations in MYBPC3, MYH7, TNNT2 and TPM1 genes were examined via Tetra Primer Amplification-Refractory Mutation System Polymerase Chain Reaction approach. Of all subjects, only one patient with hypertrophic cardiomyopathy was found as heterozygous carrier of a point mutation (c.1208G>A) in the MYH7 gene. The remaining 19 mutations were not observed among the cardiomyopathy patients in this study. Our finding suggests a different genetic architecture of the Malaysian cardiomyopathy patients compared to the Caucasian populations. Therefore, a more comprehensive mutation study on the Malaysian cardiomyopathy patients is essential for better illustration of the genetic causes of cardiomyopathy in Malaysia.

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Molecular Mechanism of Sarcomeric Cardiomyopathies

Cited by 2 publications

References 86 publications

TnI Structural Interface with the N-Terminal Lobe of TnC as a Determinant of Cardiac Contractility

TnI Structural Interface with the N-Terminal Lobe of TnC as a Determinant of Cardiac Contractility

Genetic investigation of point mutations in sarcomeric genes in Malaysian patients with cardiomyopathy

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