AAV9 gene transfer of cMyBPC N-terminal domains ameliorates cardiomyopathy in cMyBPC-deficient mice

Li, Jiayang; Mamidi, Ranganath; Doh, Chang Yoon; Holmes, Joshua B.; Bharambe, Nikhil; Ramachandran, Rajesh; Stelzer, Julian E.

doi:10.1172/jci.insight.130182

Cited by 20 publications

(35 citation statements)

References 72 publications

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“…In contrast, compensatory hyper-phosphorylation of the unablated phosphoregulatory sites was associated with stabilization of sarcomere structure and tissue myoarchitecture in agreement with previous reports that cMyBP-C phosphorylation can restore sarcomere dysregulation [17] and myoarchitecture [18]. However, we wanted to further test the sufficiency of the C0-C2 region of cMyBP-C in rescuing normal actomyosin interactions [19,20] and, hence, contractile function. To accomplish this, rC0-C2 was applied to permeabilized skinned cardiomyocytes from TG and cMyBP-C null mice, as well as biopsy of tissue from human HF, and force-pCa relationships were compared to those from NTG mice.…”

Section: Introductionsupporting

confidence: 84%

“…The C0-C2 region alone has been previously shown to rescue biochemical defects of cMyBP-C deficiency in neonates in vivo [20]. Thus, we next hypothesized that the C0-C2 region alone, instead of full-Fig.…”

Section: Restoration Of Previously Ablated C0-c2 Promotes Normal Thick and Thin Filament Interactionsmentioning

confidence: 99%

“…However, it is not known whether in vivo rC0-C2 expression in the heart at a level similar to that of full-length cMyBP-C results in therapeutic restoration of cardiac function. To address this issue, Li et al demonstrated that AAV9 gene transfer of C0-C2 can regulate in vivo cardiac function, thereby increasing ejection fraction and reducing cross-bridge kinetics and the histopathology of cardiomyopathy [20]. These data suggest the increased therapeutic potential of the C0-C2 region for normalizing myofilament function during disease.…”

Section: Introduction Of the C0-c2 Region Restores Thin And Thick Filament Interactionsmentioning

confidence: 99%

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Amino terminus of cardiac myosin binding protein-C regulates cardiac contractility

Lynch

Kumar

McNamara

et al. 2021

Journal of Molecular and Cellular Cardiology

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Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) regulates cardiac contraction through modulation of actomyosin interactions mediated by the protein's amino terminal (N ′ )-region (C0-C2 domains, 358 amino acids). On the other hand, dephosphorylation of cMyBP-C during myocardial injury results in cleavage of the 271 amino acid C0-C1f region and subsequent contractile dysfunction. Yet, our current understanding of amino terminus region of cMyBP-C in the context of regulating thin and thick filament interactions is limited. A novel cardiac-specific transgenic mouse model expressing cMyBP-C, but lacking its C0-C1f region (cMyBP-C ∆C0-C1f ), displayed dilated cardiomyopathy, underscoring the importance of the N ′ -region in cMyBP-C. Further exploring the molecular basis for this cardiomyopathy, in vitro studies revealed increased interfilament lattice spacing and rate of tension redevelopment, as well as faster actin-filament sliding velocity within the C-zone of the transgenic sarcomere. Moreover, phosphorylation of the unablated phosphoregulatory sites was increased, Abbreviations: cMyBP-C FL , full-length cardiac myosin binding protein C; cMyBP-C ∆C0-C1f , cMyBP-C lacking the C0-C1f region; TG, transgenic; WT, wild type; S2, subfragment 2; RLC, regulatory light chain; non-transgenic, NTG; C0-C1f, the first 271 residues of N ′ -region of cMyBP-C; I-R, ischemia-reperfusion; N ′ , amino terminal; t/t, cMyBP-C null homozygous mice; HF, heart failure; C0-C2, the first 448 residues of N ′ -region of cMyBP-C.

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Section: Introductionsupporting

confidence: 84%

Section: Restoration Of Previously Ablated C0-c2 Promotes Normal Thick and Thin Filament Interactionsmentioning

confidence: 99%

Section: Introduction Of the C0-c2 Region Restores Thin And Thick Filament Interactionsmentioning

confidence: 99%

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Amino terminus of cardiac myosin binding protein-C regulates cardiac contractility

Lynch

Kumar

McNamara

et al. 2021

Journal of Molecular and Cellular Cardiology

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“…The C0C2 peptide contains the regulatory region of cMyBPC that includes phosphorylation sites that are important for the sarcomere's response adrenergic stimulation [43,53,54], so the peptide would be susceptible to modulation by phosphorylation in vivo. However, a recent study expressed the C0C2 peptide using AAV, and showed it was capable of rescuing function in a cMyBPC knockout mouse [55], suggesting the peptide is stable and functional in vivo.…”

Section: Discussionmentioning

confidence: 99%

Myofilament Glycation in Diabetes Reduces Contractility by Inhibiting Tropomyosin Movement, is Rescued by cMyBPC Domains

Papadaki

Kampaengsri

Barrick

et al. 2021

Preprint

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Diabetes doubles the risk of developing heart failure (HF). As the prevalence of diabetes grows, so will HF unless the mechanisms connecting these diseases can be identified. Methylglyoxal (MG) is a glycolysis by-product that forms irreversible modifications on lysine and arginine, called glycation. We previously found that myofilament MG glycation causes sarcomere contractile dysfunction and is increased in patients with diabetes and HF. The aim of this study was to discover the molecular mechanisms by which MG glycation of myofilament proteins cause sarcomere dysfunction and to identify therapeutic avenues to compensate. In humans with type 2 diabetes without HF, we found increased glycation of sarcomeric actin compared to non-diabetics and it correlated with decreased calcium sensitivity. Depressed calcium sensitivity is pathogenic for HF, therefore myofilament glycation represents a promising therapeutic target to inhibit the development of HF in diabetics. To identify possible therapeutic targets, we further defined the molecular actions of myofilament glycation. Skinned myocytes exposed to 100 μM MG exhibited decreased calcium sensitivity, maximal calcium-activated force, and crossbridge kinetics. Replicating MG’s functional affects using a computer simulation of sarcomere function predicted simultaneous decreases in tropomyosin’s blocked-to-closed rate transition and crossbridge duty cycle were consistent with all experimental findings. Stopped-flow experiments and ATPase activity confirmed MG decreased the blocked-to-closed transition rate. Currently, no therapeutics target tropomyosin, so as proof-of-principal, we used a n-terminal peptide of myosin-binding protein C, previously shown to alter tropomyosin’s position on actin. C0C2 completely rescued MG-induced calcium desensitization, suggesting a possible treatment for diabetic HF.

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“…Now that significant advancements have been made in understanding cMyBP-C regulation in both healthy and diseased cardiac tissue, the question of its suitability as a target for treatment of cardiac diseases, such as heart failure, is at the forefront. By far the most progress has been in the study of HCM and viral replacement of cMyBP-C as a therapeutic strategy, with success in ameliorating the HCM phenotype and improving cardiac function in small animal models showing promising results 75,76 . In terms of non-heritable disease, there is now clear evidence of cMyBP-C dysregulation, particularly that of phosphorylation, in hearts of patients with heart failure 36,37 , hypertension 77 and atrial fibrillation 78 , and it is clear that preservation of phosphorylation in particular may represent a therapeutic strategy.…”

Section: Future Perspectivesmentioning

confidence: 99%

Post-translational regulation of cardiac myosin binding protein-C: A graphical review

Main

Fuller

Baillie

2020

Cellular Signalling

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Cardiac myosin binding protein-C (cMyBP-C) is a fundamental component of the cardiac sarcomere involved in regulating systolic and diastolic activity, processes which must be tightly maintained to preserve cardiac function. Importantly, as a non-enzymatic protein, cMyBP-C relies solely on post-translational modifications and protein-protein interactions in order to modulate its function, and does so through phosphorylation, glutathionylation and acetylation amongst others. Although some are better understood than others, these modifications may represent novel therapeutic routes to modulate cMyBP-C function in the treatment of cardiac disease.

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AAV9 gene transfer of cMyBPC N-terminal domains ameliorates cardiomyopathy in cMyBPC-deficient mice

Cited by 20 publications

References 72 publications

Amino terminus of cardiac myosin binding protein-C regulates cardiac contractility

Amino terminus of cardiac myosin binding protein-C regulates cardiac contractility

Myofilament Glycation in Diabetes Reduces Contractility by Inhibiting Tropomyosin Movement, is Rescued by cMyBPC Domains

Post-translational regulation of cardiac myosin binding protein-C: A graphical review

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