Posttranslational Arginylation Regulates Striated Muscle Function

Leite, Felipe de Souza; Kashina, Anna; Rassier, Dilson E.

doi:10.1249/jes.0000000000000079

Cited by 8 publications

(5 citation statements)

References 32 publications

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“…In the present study, we found reduced PKC activity and improved titin-PEVK site-specific phosphorylation after treatment with the sGC activator, both of which may have contributed to the reduced cardiomyocyte stiffness. Additional posttranslational modifications that alter the stiffness of titin include arginylation (Leite Fde et al, 2016) and various oxidative modifications, such as disulfide bonding (Grutzner et al, 2009;Giganti et al, 2018), S-glutathionylation (Alegre-Cebollada et al, 2014), and sulphenylation (Beedle et al, 2016). Therefore, since the sGC activator reduces oxidative stress, improved cardiomyocyte stiffness could be related, in part, to reduced titin oxidation.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Cardiomyocyte Function in Hypertensive Rats With Diastolic Dysfunction and Human Heart Failure Patients After Acute Treatment With Soluble Guanylyl Cyclase (sGC) Activator

et al. 2020

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Aims: Our aim was to investigate the effect of nitric oxide (NO)-independent activation of soluble guanylyl cyclase (sGC) on cardiomyocyte function in a hypertensive animal model with diastolic dysfunction and in biopsies from human heart failure with preserved ejection fraction (HFpEF). Methods: Dahl salt-sensitive (DSS) rats and control rats were fed a high-salt diet for 10 weeks and then acutely treated in vivo with the sGC activator BAY 58-2667 (cinaciguat) for 30 min. Single skinned cardiomyocyte passive stiffness (F passive) was determined in rats and human myocardium biopsies before and after acute treatment. Titin phosphorylation, activation of the NO/sGC/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) cascade, as well as hypertrophic pathways including NO/sGC/cGMP/PKG, PKA, calcium-calmodulin kinase II (CaMKII), extracellular signalregulated kinase 2 (ERK2), and PKC were assessed. In addition, we explored the contribution of pro-inflammatory cytokines and oxidative stress levels to the modulation of cardiomyocyte function. Immunohistochemistry and electron microscopy were used to assess the translocation of sGC and connexin 43 proteins in the rat model before and after treatment. Results: High cardiomyocyte F passive was found in rats and human myocardial biopsies compared to control groups, which was attributed to hypophosphorylation of total

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Section: Discussionmentioning

confidence: 99%

Enhanced Cardiomyocyte Function in Hypertensive Rats With Diastolic Dysfunction and Human Heart Failure Patients After Acute Treatment With Soluble Guanylyl Cyclase (sGC) Activator

et al. 2020

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“…Furthermore, the relevance of titin oxidation in heart disease is largely unknown. Other PTMs (such as arginylation ) may also alter titin‐based passive stiffness and warrant further investigation into the role they may play in both healthy and diseased hearts. Finally, PTMs of titin that alter titin‐based myocardial passive stiffness represent a promising potential target for therapeutic intervention in HF patients with overly stiff hearts (such as in HFpEF), despite recent setbacks in some preclinical studies regarding to the role of cGMP‐PKG activation for myocardial stiffness in vivo .…”

Section: Discussionmentioning

confidence: 99%

Posttranslational modifications of titin from cardiac muscle: how, where, and what for?

Koser¹,

Loescher²,

Linke³

2019

The FEBS Journal

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Titin is a giant elastic protein expressed in the contractile units of striated muscle cells, including the sarcomeres of cardiomyocytes. The last decade has seen enormous progress in our understanding of how titin molecular elasticity is modulated in a dynamic manner to help cardiac sarcomeres adjust to the varying hemodynamic demands on the heart. Crucial events mediating the rapid modulation of cardiac titin stiffness are post‐translational modifications (PTMs) of titin. In this review, we first recollect what is known from earlier and recent work on the molecular mechanisms of titin extensibility and force generation. The main goal then is to provide a comprehensive overview of current insight into the relationship between titin PTMs and cardiomyocyte stiffness, notably the effect of oxidation and phosphorylation of titin spring segments on titin stiffness. A synopsis is given of which type of oxidative titin modification can cause which effect on titin stiffness. A large part of the review then covers the mechanically relevant phosphorylation sites in titin, their location along the elastic segment, and the protein kinases and phosphatases known to target these sites. We also include a detailed coverage of the complex changes in phosphorylation at specific titin residues, which have been reported in both animal models of heart disease and in human heart failure, and their correlation with titin‐based stiffness alterations. Knowledge of the relationship between titin PTMs and titin elasticity can be exploited in the search for therapeutic approaches aimed at softening the pathologically stiffened myocardium in heart failure patients.

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“…The fifth site, Asp32535, is present in the Is3 region between Ig domains M4 and M5 in the M-band (321). Similarly, several arginylation sites on titin were discovered in mouse heart lysates residing to Ig domains within its A-band portion and the TK domain in the M-band (320). In particular, Leu7960 resides in the first Ig domain of the seven-domain super repeat, Val15013 in the second Ig domain of the 11-domain super repeat, and Cys24818 in the TK domain (residues correspond to the N2B-titin sequence NP_082280.2).…”

Section: Titin (Aka Connectin)mentioning

confidence: 99%

“…Similarly, isolated myofibrils from a skeletal muscle specific knockout of arginyl-transferase exhibit reduced passive force development (321). Given that titin is the primary regulator of passive force in the sarcomere, it is likely that titin arginylation contributes to the regulation of passive stiffness (320, 321). Since all of the arginylation sites localize to titin’s inextensible region, and not the extensible I-band region, it was further proposed that titin arginylation regulates passive force possibly through modifying its anchorage to the thick filament (320, 321).…”

Section: Titin (Aka Connectin)mentioning

confidence: 99%

Thick Filament Protein Network, Functions, and Disease Association

Wang

Geist

Grogan

et al. 2018

Comprehensive Physiology

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Sarcomeres consist of highly ordered arrays of thick myosin and thin actin filaments along with accessory proteins. Thick filaments occupy the center of sarcomeres where they partially overlap with thin filaments. The sliding of thick filaments past thin filaments is a highly regulated process that occurs in an ATP-dependent manner driving muscle contraction. In addition to myosin that makes up the backbone of the thick filament, four other proteins which are intimately bound to the thick filament, myosin binding protein-C, titin, myomesin, and obscurin play important structural and regulatory roles. Consistent with this, mutations in the respective genes have been associated with idiopathic and congenital forms of skeletal and cardiac myopathies. In this review, we aim to summarize our current knowledge on the molecular structure, subcellular localization, interacting partners, function, modulation via posttranslational modifications, and disease involvement of these five major proteins that comprise the thick filament of striated muscle cells. © 2018 American Physiological Society. Compr Physiol 8:631-709, 2018.

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Posttranslational Arginylation Regulates Striated Muscle Function

Cited by 8 publications

References 32 publications

Enhanced Cardiomyocyte Function in Hypertensive Rats With Diastolic Dysfunction and Human Heart Failure Patients After Acute Treatment With Soluble Guanylyl Cyclase (sGC) Activator

Enhanced Cardiomyocyte Function in Hypertensive Rats With Diastolic Dysfunction and Human Heart Failure Patients After Acute Treatment With Soluble Guanylyl Cyclase (sGC) Activator

Posttranslational modifications of titin from cardiac muscle: how, where, and what for?

Thick Filament Protein Network, Functions, and Disease Association

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