scholarly journals Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Thomas G. Martin ◽  
Valerie D. Myers ◽  
Praveen Dubey ◽  
Shubham Dubey ◽  
Edith Perez ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mass Spectrometry ◽  
Protein Turnover ◽  
Human Heart ◽  
Molecular Mechanisms ◽  
Selective Autophagy ◽  
Sarcomeric Protein ◽  
Proteotoxic Stress ◽  
Generating Capacity ◽  
Stress Dependent

AbstractThe association between reduced myofilament force-generating capacity (Fmax) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show impaired Fmax arises from reduced BAG3-mediated sarcomere turnover. Myofilament BAG3 expression decreases in human HF and positively correlates with Fmax. We confirm this relationship using BAG3 haploinsufficient mice, which display reduced Fmax and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via chaperone-assisted selective autophagy (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA complex localization is BAG3/proteotoxic stress-dependent. Using mass spectrometry, we characterize the myofilament CASA interactome in the human heart and identify eight clients of BAG3-mediated turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/Fmax, HF mice were treated with rAAV9-BAG3. Gene therapy fully rescued Fmax and CASA protein turnover after four weeks. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.

scholarly journals Cardiomyocyte Contractile Impairment in Heart Failure Results from Reduced BAG3-mediated Sarcomeric Protein Turnover

2020 ◽  
Author(s):  
Thomas G. Martin ◽  
Valerie D. Myers ◽  
Praveen Dubey ◽  
Shubham Dubey ◽  
Edith Perez ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mass Spectrometry ◽  
Protein Turnover ◽  
Molecular Mechanisms ◽  
Selective Autophagy ◽  
Sarcomeric Protein ◽  
Proteotoxic Stress ◽  
Generating Capacity ◽  
Sarcomere Proteins ◽  
Stress Dependent

ABSTRACTThe association between reduced myofilament force-generating capacity (Fmax) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show the Fmax decrease arises from impaired BAG3-mediated sarcomere turnover. Myofilament BAG3 decreased in human HF and predicted the extent of Fmax decrease. This relationship was confirmed using BAG3+/- mice, which had reduced Fmax and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via the chaperone-assisted selective autophagy complex (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA localization is BAG3/proteotoxic stress-dependent. To determine if increasing BAG3 expression in HF would restore sarcomere proteostasis/Fmax, HF mice were treated with AAV9/BAG3. Gene therapy fully restored Fmax after four weeks and decreased ubiquitination. Using mass spectrometry, we identified several sarcomere proteins with increased ubiquitination in HF and four that decreased with AAV9/BAG3. Our findings indicate BAG3-mediated sarcomere turnover is required for myofilament functional maintenance.

scholarly journals Circulating acylcarnitine profile in human heart failure: a surrogate of fatty acid metabolic dysregulation in mitochondria and beyond

2017 ◽  
Vol 313 (4) ◽  
pp. H768-H781 ◽  
Author(s):  
Matthieu Ruiz ◽  
François Labarthe ◽  
Annik Fortier ◽  
Bertrand Bouchard ◽  
Julie Thompson Legault ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mass Spectrometry ◽  
Fatty Acid ◽  
Ejection Fraction ◽  
Disease Severity ◽  
Human Heart ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Human Heart Failure ◽  
Control Subjects

Heart failure (HF) is associated with metabolic perturbations, particularly of fatty acids (FAs), which remain to be better understood in humans. This study aimed at testing the hypothesis that HF patients with reduced ejection fraction display systemic perturbations in levels of energy-related metabolites, especially those reflecting dysregulation of FA metabolism, namely, acylcarnitines (ACs). Circulating metabolites were assessed using mass spectrometry (MS)-based methods in two cohorts. The main cohort consisted of 72 control subjects and 68 HF patients exhibiting depressed left ventricular ejection fraction (25.9 ± 6.9%) and mostly of ischemic etiology with ≥2 comorbidities. HF patients displayed marginal changes in plasma levels of tricarboxylic acid cycle-related metabolites or indexes of mitochondrial or cytosolic redox status. They had, however, 22–79% higher circulating ACs, irrespective of chain length ( P < 0.0001, adjusted for sex, age, renal function, and insulin resistance, determined by shotgun MS/MS), which reflects defective mitochondrial β-oxidation, and were significantly associated with levels of NH2-terminal pro-B-type natriuretic peptide levels, a disease severity marker. Subsequent extended liquid chromatography-tandem MS analysis of 53 plasma ACs in a subset group from the primary cohort confirmed and further substantiated with a comprehensive lipidomic analysis in a validation cohort revealed in HF patients a more complex circulating AC profile. The latter included dicarboxylic-ACs and dihydroxy-ACs as well as very long chain (VLC) ACs or sphingolipids with VLCFAs (>20 carbons), which are proxies of dysregulated FA metabolism in peroxisomes. Our study identified alterations in circulating ACs in HF patients that are independent of biological traits and associated with disease severity markers. These alterations reflect dysfunctional FA metabolism in mitochondria but also beyond, namely, in peroxisomes, suggesting a novel mechanism contributing to global lipid perturbations in human HF. NEW & NOTEWORTHY Mass spectrometry-based profiling of circulating energy metabolites, including acylcarnitines, in two cohorts of heart failure versus control subjects revealed multiple alterations in fatty acid metabolism in peroxisomes in addition to mitochondria, thereby highlighting a novel mechanism contributing to global lipid perturbations in heart failure. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/acylcarnitines-in-human-heart-failure/ .

scholarly journals CaMKII Phosphorylation of NaV1.5: Novel in Vitro Sites Identified by Mass Spectrometry and Reduced S516 Phosphorylation in Human Heart Failure

2015 ◽  
Vol 14 (5) ◽  
pp. 2298-2311 ◽  
Author(s):  
Anthony W. Herren ◽  
Darren M. Weber ◽  
Robert R. Rigor ◽  
Kenneth B. Margulies ◽  
Brett S. Phinney ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mass Spectrometry ◽  
Human Heart ◽  
Human Heart Failure

40 MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure

2007 ◽  
Vol 6 (1) ◽  
pp. 3-3
Author(s):  
T THUM ◽  
P GALUPPO ◽  
S KNEITZ ◽  
C WOLF ◽  
L VANLAAKE ◽  
...  
Keyword(s):  
Heart Failure ◽  
Human Heart

678 Molecular mechanisms of increased plasma endothelin-1 levels in congestive heart failure

2003 ◽  
Vol 2 (1) ◽  
pp. 139
Author(s):  
T VONLUEDER ◽  
H KJEKSHUS ◽  
T EDVARDSEN ◽  
E OIE ◽  
S URHEIM ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Molecular Mechanisms ◽  
Endothelin 1

A Mucin-Specific Protease Enables Molecular and Functional Analysis of Human Cancer-Associated Mucins

2018 ◽  
Author(s):  
Stacy A. Malaker ◽  
Kayvon Pedram ◽  
Michael J. Ferracane ◽  
Elliot C. Woods ◽  
Jessica Kramer ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
High Resolution Mass Spectrometry ◽  
Human Cancer ◽  
Glycosylation Sites ◽  
Bacterial Protease ◽  
Specific Protease ◽  
To Come ◽  
And Function

<div> <div> <div> <p>Mucins are a class of highly O-glycosylated proteins that are ubiquitously expressed on cellular surfaces and are important for human health, especially in the context of carcinomas. However, the molecular mechanisms by which aberrant mucin structures lead to tumor progression and immune evasion have been slow to come to light, in part because methods for selective mucin degradation are lacking. Here we employ high resolution mass spectrometry, polymer synthesis, and computational peptide docking to demonstrate that a bacterial protease, called StcE, cleaves mucin domains by recognizing a discrete peptide-, glycan-, and secondary structure- based motif. We exploited StcE’s unique properties to map glycosylation sites and structures of purified and recombinant human mucins by mass spectrometry. As well, we found that StcE will digest cancer-associated mucins from cultured cells and from ovarian cancer patient-derived ascites fluid. Finally, using StcE we discovered that Siglec-7, a glyco-immune checkpoint receptor, specifically binds sialomucins as biological ligands, whereas the related Siglec-9 receptor does not. Mucin-specific proteolysis, as exemplified by StcE, is therefore a powerful tool for the study of glycoprotein structure and function and for deorphanizing mucin-binding receptors. </p> </div> </div> </div>

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