Mechanisms of Sarcomere Protein Mutation-Induced Cardiomyopathies

Barefield, David; Alvarez-Arce, Alejandro; Araujo, Kelly

doi:10.1007/s11886-023-01876-9

Cited by 7 publications

(2 citation statements)

References 115 publications

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“…Hypertrophic (HCM) and Dilated Cardiomyopathy (DCM) are considered diseases of the sarcomere, as these myopathies involve mutations in β-cardiac myosin and other sarcomeric proteins critical to muscle function [33][34][35][36] . Although cardiac contractility in HCM and DCM patients differ dramatically, i.e., hyper-contractile 37 and hypo-contractile 38 , respectively, the underlying myofilament-based mechanisms that dictate these contractile differences may be common.…”

Section: Discussionmentioning

confidence: 99%

Tail Length and E525K Dilated Cardiomyopathy Mutant Alter Human β-Cardiac Myosin Super-Relaxed State

Duno-Miranda,

Nelson,

Rasicci

et al. 2023

Preprint

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Dilated cardiomyopathy (DCM) is characterized by impaired cardiac function due to myocardial hypo-contractility and is associated with point mutations in β-cardiac myosin, the molecular motor that powers cardiac contraction. Myocardial function can be modulated through sequestration of myosin motors into an auto-inhibited "super relaxed" state (SRX), which is further stabilized by a structural state known as the "Interacting Heads Motif" (IHM). Therefore, hypo-contractility of DCM myocardium may result from: 1) reduced function of individual myosin, and/or; 2) decreased myosin availability due to increased IHM/SRX stabilization. To define the molecular impact of an established DCM myosin mutation, E525K, we characterized the biochemical and mechanical activity of wild-type (WT) and E525K human β-cardiac myosin constructs that differed in the length of their coiled-coil tail, which dictates their ability to form the IHM/SRX state. Single-headed (S1) and a short-tailed, double-headed (2HEP) myosin constructs exhibited low (∼10%) IHM/SRX content, actin-activated ATPase activity of ∼5s-1and fast velocities in unloaded motility assays (∼2000nm/s). Double-headed, longer-tailed (15HEP, 25HEP) constructs exhibited higher IHM/SRX content (∼90%), and reduced actomyosin ATPase (<1s-1) and velocity (∼800nm/s). A simple analytical model suggests that reduced velocities may be attributed to IHM/SRX-dependent sequestration of myosin heads. Interestingly, the E525K 15HEP and 25HEP mutants showed no apparent impact on velocity or actomyosin ATPase at low ionic strength. However, at higher ionic strength, the E525K mutation stabilized the IHM/SRX state. Therefore, the E525K-associated DCM human cardiac hypo-contractility may be attributable to reduced myosin head availability caused by enhanced IHM/SRX stability.SummaryThis research investigates the E525K mutation in human β-cardiac myosin, crucial for heart contraction, and its role in causing Dilated Cardiomyopathy (DCM). It demonstrates that the length of the myosin tail influences its self-inhibition, and the E525K mutation strengthens this effect, potentially reducing heart contractility in DCM.

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Section: Discussionmentioning

confidence: 99%

Tail Length and E525K Dilated Cardiomyopathy Mutant Alter Human β-Cardiac Myosin Super-Relaxed State

Duno-Miranda,

Nelson,

Rasicci

et al. 2023

Preprint

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“…It is possible that, in some cases, cardiomyopathy is triggered by a combination of acquired and genetic factors [4,5]. The three original sub-types of primary cardiomyopathy are hypertrophic (HCM), which occurs in 1:200-500 individuals [6][7][8]; dilated (DCM), which occurs in 1:500 individuals [9,10]; and less common restrictive (RCM), which only represents up to 5% of all cardiomyopathy cases [1,11]. Another uncommon cardiac disorder, left ventricular non-compaction cardiomyopathy (LVNC), was classified by the American Heart Association as a primary form of cardiomyopathy in 2006 [12,13].…”

Section: Introductionmentioning

confidence: 99%

Mouse Models of Cardiomyopathies Caused by Mutations in Troponin C

Tikunova

Thuma

Davis

2023

IJMS

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Cardiac muscle contraction is regulated via Ca2+ exchange with the hetero-trimeric troponin complex located on the thin filament. Binding of Ca2+ to cardiac troponin C, a Ca2+ sensing subunit within the troponin complex, results in a series of conformational re-arrangements among the thin filament components, leading to an increase in the formation of actomyosin cross-bridges and muscle contraction. Ultimately, a decline in intracellular Ca2+ leads to the dissociation of Ca2+ from troponin C, inhibiting cross-bridge cycling and initiating muscle relaxation. Therefore, troponin C plays a crucial role in the regulation of cardiac muscle contraction and relaxation. Naturally occurring and engineered mutations in troponin C can lead to altered interactions among components of the thin filament and to aberrant Ca2+ binding and exchange with the thin filament. Mutations in troponin C have been associated with various forms of cardiac disease, including hypertrophic, restrictive, dilated, and left ventricular noncompaction cardiomyopathies. Despite progress made to date, more information from human studies, biophysical characterizations, and animal models is required for a clearer understanding of disease drivers that lead to cardiomyopathies. The unique use of engineered cardiac troponin C with the L48Q mutation that had been thoroughly characterized and genetically introduced into mouse myocardium clearly demonstrates that Ca2+ sensitization in and of itself should not necessarily be considered a disease driver. This opens the door for small molecule and protein engineering strategies to help boost impaired systolic function. On the other hand, the engineered troponin C mutants (I61Q and D73N), genetically introduced into mouse myocardium, demonstrate that Ca2+ desensitization under basal conditions may be a driving factor for dilated cardiomyopathy. In addition to enhancing our knowledge of molecular mechanisms that trigger hypertrophy, dilation, morbidity, and mortality, these cardiomyopathy mouse models could be used to test novel treatment strategies for cardiovascular diseases. In this review, we will discuss (1) the various ways mutations in cardiac troponin C might lead to disease; (2) relevant data on mutations in cardiac troponin C linked to human disease, and (3) all currently existing mouse models containing cardiac troponin C mutations (disease-associated and engineered).

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