Regulatory Light Chains in Cardiac Development and Disease

Markandran, Kasturi; Poh, Jane Wenjin; Ferenczi, Michael A.; Cheung, Christine

doi:10.3390/ijms22094351

Cited by 15 publications

(18 citation statements)

References 125 publications

(167 reference statements)

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“…These functional changes correlated with decreased RLC phosphorylation, increased cTnT phosphorylation, and increased cMyBP-C phosphorylation at Ser302 (Figures 3, 4). It was previously suggested that RLC phosphorylation is affected by aging (Markandran et al, 2021). Despite, there are no statistical differences in RLC phosphorylation between aged WT vs. aged KO mice (Figures 3A,B,H); there is a trend of decreased phosphorylation in the aged KO mice group (p = 0.07) suggesting that the deletion of β-arrestin-2 in aged mice, besides aging, contributes even more to decreased levels in RLC phosphorylation.…”

Section: Discussionmentioning

confidence: 71%

B-arrestin-2 Signaling Is Important to Preserve Cardiac Function During Aging

et al. 2021

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Experiments reported here tested the hypothesis that β-arrestin-2 is an important element in the preservation of cardiac function during aging. We tested this hypothesis by aging β-arrestin-2 knock-out (KO) mice, and wild-type equivalent (WT) to 12–16months. We developed the rationale for these experiments on the basis that angiotensin II (ang II) signaling at ang II receptor type 1 (AT1R), which is a G-protein coupled receptor (GPCR) promotes both G-protein signaling as well as β-arrestin-2 signaling. β-arrestin-2 participates in GPCR desensitization, internalization, but also acts as a scaffold for adaptive signal transduction that may occur independently or in parallel to G-protein signaling. We have previously reported that biased ligands acting at the AT1R promote β-arrestin-2 signaling increasing cardiac contractility and reducing maladaptations in a mouse model of dilated cardiomyopathy. Although there is evidence that ang II induces maladaptive senescence in the cardiovascular system, a role for β-arrestin-2 signaling has not been studied in aging. By echocardiography, we found that compared to controls aged KO mice exhibited enlarged left atria and left ventricular diameters as well as depressed contractility parameters with preserved ejection fraction. Aged KO also exhibited depressed relaxation parameters when compared to WT controls at the same age. Moreover, cardiac dysfunction in aged KO mice was correlated with alterations in the phosphorylation of myofilament proteins, such as cardiac myosin binding protein-C, and myosin regulatory light chain. Our evidence provides novel insights into a role for β-arrestin-2 as an important signaling mechanism that preserves cardiac function during aging.

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Section: Discussionmentioning

confidence: 71%

B-arrestin-2 Signaling Is Important to Preserve Cardiac Function During Aging

et al. 2021

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“…Some of the mutations disrupt phosphorylation sites of the myosin regulatory light chains that is proposed to be mediated by Ca 2+ /calmodulin-dependent protein kinase and essential for muscle contraction. 28 Mutations in myosin-binding protein C also leads to hypertrophy 29 and decreased desmin expression levels associated with the progression of heart failure. 30 Imaging studies demonstrate reduced contractility in the atria of people with severe obesity, with remodeling and improved contractility following weight loss interventions.…”

Section: Clinical Importancementioning

confidence: 99%

Gene and metabolite expression dependence on body mass index in human myocardium

Roman

Yusoff

et al. 2021

Preprint

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We hypothesized that body mass index (BMI) dependent changes in myocardial gene expression and energy-related metabolites underlie the biphasic association between BMI and mortality (the obesity paradox) in cardiac surgery. We performed transcriptome profiling and measured a panel of 144 metabolites in 53 and 55, respectively, myocardial biopsies from a cohort of sixty-seven adult patients undergoing coronary artery bypass grafting (registration: NCT02908009). The initial analysis identified 239 transcripts with biphasic BMI dependence. 120 displayed u-shape and 119 n-shape expression patterns. The identified local minima or maxima peaked at BMI 28-29. Based on these results and to best fit the WHO classification, we grouped the patients into three groups: BMI<25, 25≤BMI≤32, and BMI>32. The group analysis indicated that protein translation-related pathways were downregulated in 25≤BMI≥32 compared with BMI<25 patients. Muscle contraction transcripts were upregulated in 25≤BMI≥32 patients, and cholesterol synthesis and innate immunity transcripts were upregulated in the BMI>32 group. Transcripts involved in translation, muscle contraction and lipid metabolism also formed distinct correlation networks with biphasic dependence on BMI. Metabolite analysis identified acylcarnitines and ribose-5-phosphate increasing in the BMI>32 group and α-ketoglutarate increasing in the BMI<25 group. Molecular differences in the myocardium mirror the biphasic relationship between BMI and mortality.

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“…RLC phosphorylation facilitates force production by increasing the maximal isometric tension, calcium sensitivity of force and rate of force redevelopment at intermediate and maximal calcium activation levels [ 16 , 17 ], and also enhances the motility of human beta-myosin under load as seen by in vitro motility assays [ 18 ]. The levels of RLC phosphorylation decreased in end-stage HF of both human and animals [ 19 ]. However, it is not known whether the changes in RLC phosphorylation drive the functional changes during HF progression, or vice versa.…”

Section: Introductionmentioning

confidence: 99%

Functional and Molecular Characterisation of Heart Failure Progression in Mice and the Role of Myosin Regulatory Light Chains in the Recovery of Cardiac Muscle Function

Markandran

Song

et al. 2021

IJMS

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Heart failure (HF) as a result of myocardial infarction (MI) is a major cause of fatality worldwide. However, the cause of cardiac dysfunction succeeding MI has not been elucidated at a sarcomeric level. Thus, studying the alterations within the sarcomere is necessary to gain insights on the fundamental mechansims leading to HF and potentially uncover appropriate therapeutic targets. Since existing research portrays regulatory light chains (RLC) to be mediators of cardiac muscle contraction in both human and animal models, its role was further explored In this study, a detailed characterisation of the physiological changes (i.e., isometric force, calcium sensitivity and sarcomeric protein phosphorylation) was assessed in an MI mouse model, between 2D (2 days) and 28D post-MI, and the changes were related to the phosphorylation status of RLCs. MI mouse models were created via complete ligation of left anterior descending (LAD) coronary artery. Left ventricular (LV) papillary muscles were isolated and permeabilised for isometric force and Ca2+ sensitivity measurement, while the LV myocardium was used to assay sarcomeric proteins’ (RLC, troponin I (TnI) and myosin binding protein-C (MyBP-C)) phosphorylation levels and enzyme (myosin light chain kinase (MLCK), zipper interacting protein kinase (ZIPK) and myosin phosphatase target subunit 2 (MYPT2)) expression levels. Finally, the potential for improving the contractility of diseased cardiac papillary fibres via the enhancement of RLC phosphorylation levels was investigated by employing RLC exchange methods, in vitro. RLC phosphorylation and isometric force potentiation were enhanced in the compensatory phase and decreased in the decompensatory phase of HF failure progression, respectively. There was no significant time-lag between the changes in RLC phosphorylation and isometric force during HF progression, suggesting that changes in RLC phosphorylation immediately affect force generation. Additionally, the in vitro increase in RLC phosphorylation levels in 14D post-MI muscle segments (decompensatory stage) enhanced its force of isometric contraction, substantiating its potential in HF treatment. Longitudinal observation unveils potential mechanisms involving MyBP-C and key enzymes regulating RLC phosphorylation, such as MLCK and MYPT2 (subunit of MLCP), during HF progression. This study primarily demonstrates that RLC phosphorylation is a key sarcomeric protein modification modulating cardiac function. This substantiates the possibility of using RLCs and their associated enzymes to treat HF.

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Regulatory Light Chains in Cardiac Development and Disease

Cited by 15 publications

References 125 publications

B-arrestin-2 Signaling Is Important to Preserve Cardiac Function During Aging

B-arrestin-2 Signaling Is Important to Preserve Cardiac Function During Aging

Gene and metabolite expression dependence on body mass index in human myocardium

Functional and Molecular Characterisation of Heart Failure Progression in Mice and the Role of Myosin Regulatory Light Chains in the Recovery of Cardiac Muscle Function

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