Diabetes with heart failure increases methylglyoxal modifications in the sarcomere, which inhibit function

Papadaki, Maria; Holewinski, Ronald J.; Previs, Samantha Beck; Martin, Thomas G.; Stachowski, Marisa J.; Li, Amy; Blair, Cheavar A.; Moravec, Christine S.; Eyk, Jennifer E. Van; Campbell, Kenneth S.; Warshaw, David M.; Kirk, Jonathan A.

doi:10.1172/jci.insight.121264

Cited by 53 publications

(61 citation statements)

References 64 publications

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“…4). Therefore, as found with the ACTA1 CFTD D292V mutation (Rynkiewicz et al 2017), K291 modification may likewise contribute to the observed decrease in Ca 2+ sensitivity of MG-treated thin filaments in vitro (Papadaki et al 2018).…”

Section: Figure 3 Mutations Adjacent To the Actin A-triad Can Trigger Congenital Myopathymentioning

confidence: 66%

“…In addition to acetylation, actin has recently been shown to be subject to methylglyoxal (MG) modifications (Papadaki et al 2018). MG is a reactive carbonyl species that induces PTM through an irreversible, non-enzymatic reaction with unprotonated arginine and lysine residues.…”

Section: Figure 3 Mutations Adjacent To the Actin A-triad Can Trigger Congenital Myopathymentioning

confidence: 99%

“…For example, the small molecule, anaesthetic compound propofol is a known myocardial depressant that decreases force and Ca 2+ sensitivity in intact and skinned cardiac trabeculae (Ding et al 2011;Fujinaka et al 2012;Meng et al 2016). Mass spectrometry and molecular docking (Papadaki et al 2018).…”

Section: Small Molecules That Influence Muscle Function Potentially Affect the Actin A-triadmentioning

confidence: 99%

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The actin ‘A‐triad's’ role in contractile regulation in health and disease

Schmidt

Cammarato

2019

The Journal of Physiology

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Striated muscle contraction is regulated by Ca 2+ -dependent modulation of myosin cross-bridge binding to F-actin by the thin filament troponin (Tn)-tropomyosin (Tm) complex. In the absence of Ca 2+ , Tn binds to actin and constrains Tm to an azimuthal location where it sterically occludes myosin binding sites along the thin filament surface. This limits force production and promotes muscle relaxation. In addition to Tn-actin interactions, inhibitory Tm positioning requires associations between other thin filament constituents. For example, the actin 'A-triad' , composed of residues K326, K328 and R147, forms numerous, highly favourable electrostatic contacts with Tm that are critical for establishing its inhibitory azimuthal binding position. Here, we review recent findings, including the identification and interrogation of modifications within and proximal to the A-triad that are associated with disease and/or altered muscle behaviour, which highlight the surface feature's role in F-actin-Tm interactions and contractile regulation.

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Section: Figure 3 Mutations Adjacent To the Actin A-triad Can Trigger Congenital Myopathymentioning

confidence: 66%

Section: Figure 3 Mutations Adjacent To the Actin A-triad Can Trigger Congenital Myopathymentioning

confidence: 99%

Section: Small Molecules That Influence Muscle Function Potentially Affect the Actin A-triadmentioning

confidence: 99%

See 1 more Smart Citation

The actin ‘A‐triad's’ role in contractile regulation in health and disease

Schmidt

Cammarato

2019

The Journal of Physiology

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“…Most importantly, protein kinase A, activated upon β-adrenergic stimulation in cardiac muscle, phosphorylates TnI, resulting in a decrease in Ca 2+ sensitivity via weakening of the TnI-TnC interaction (see Solaro and Rarick, 1998 for details). Likewise, other translational modifications such as glycation (Papadaki et al, 2018) and acetylation (Gupta et al, 2008) may affect Ca 2+ sensitivity.…”

Section: Modulation Of Myofibrillar Ca 2+ Sensitivitymentioning

confidence: 99%

Thermal Activation of Thin Filaments in Striated Muscle

et al. 2020

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In skeletal and cardiac muscles, contraction is triggered by an increase in the intracellular Ca 2+ concentration. During Ca 2+ transients, Ca 2+-binding to troponin C shifts the "on-off" equilibrium of the thin filament state toward the "on" sate, promoting actomyosin interaction. Likewise, recent studies have revealed that the thin filament state is under the influence of temperature; viz., an increase in temperature increases active force production. In this short review, we discuss the effects of temperature on the contractile performance of mammalian striated muscle at/around body temperature, focusing especially on the temperature-dependent shift of the "on-off" equilibrium of the thin filament state.

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“…As oxidative . Conjugates with malondialdehyde are depicted here as an exemplary LPP but many others including 4-hydroxynonenal and glycolysis side products such as glyoxal and methylglyoxal have been reported [53,71]. LPP can either react via Schiff base formation (7, 9) or by Michael-addition (10, 11).…”

Section: Protein Degradation Triggered By Oxidative Damagementioning

confidence: 99%

Irreversible oxidative post-translational modifications in heart disease

Tomin

Schittmayer

Honeder

et al. 2019

Expert Review of Proteomics

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Introduction: Development of specific biomarkers aiding early diagnosis of heart failure is an ongoing challenge. Biomarkers commonly used in clinical routine usually act as readouts of an already existing acute condition rather than disease initiation. Functional decline of cardiac muscle is greatly aggravated by increased oxidative stress and damage of proteins. Oxidative post-translational modifications occur already at early stages of tissue damage and are thus regarded as potential up-coming disease markers. Areas covered: Clinical practice regarding commonly used biomarkers for heart disease is briefly summarized. The types of oxidative post-translational modification in cardiac pathologies are discussed with a special focus on available quantitative techniques and characteristics of individual modifications with regard to their stability and analytical accessibility. As irreversible oxidative modifications trigger protein degradation pathways or cause protein aggregation, both influencing biomarker abundance, a chapter is dedicated to their regulation in the heart.

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Diabetes with heart failure increases methylglyoxal modifications in the sarcomere, which inhibit function

Cited by 53 publications

References 64 publications

The actin ‘A‐triad's’ role in contractile regulation in health and disease

The actin ‘A‐triad's’ role in contractile regulation in health and disease

Thermal Activation of Thin Filaments in Striated Muscle

Irreversible oxidative post-translational modifications in heart disease

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