Diaphragm weakness and proteomics (global and redox) modifications in heart failure with reduced ejection fraction in rats

We considered statistically significant changes in protein abundance when ANOVA p-value < 0.05, fold change ≥ 1.5, each protein with at least three unique peptides, and a false discovery rate of 1%

Rachel C. Kelley; Brian McDonagh; Babette Brumback; Glenn A. Walter; Ravneet Vohra; Leonardo F. Ferreira

2020

Scholarcy highlights

  • As the main inspiratory muscle, the diaphragm is essential in ventilatory and non-ventilatory behaviors
  • Serum BNP, a biomarker of heart failure, was significantly elevated when all heart failure with reduced ejection fraction animals were compared to sham
  • The main findings of our study were: 1) moderate and severe HFrEF caused diaphragm fiber atrophy; 2) maximal diaphragm specific force was diminished in severe HFrEF, but not moderate HFrEF; 3) severe HFrEF decreased abundance of proteins involved in ribosomal function and glucose and glycolytic metabolism; 4) redox proteomics in severe HFrEF showed heightened reversible cysteine oxidation of thin-filament proteins, filamin C, and SERCA1, and increased methionine oxidation in sarcomeric actin
  • Our study shows that diaphragm fiber atrophy occurs in moderate and severe HFrEF, and loss of diaphragm fiber force occurs in severe HFrEF
  • Our global proteomic analysis revealed downregulation of ribosomal and glucose metabolism/glycolysis proteins that will contribute to fiber atrophy or anabolic resistance and further accelerate fatigue in severe HFrEF
  • The redox proteomics investigation showed, among sarcomeric proteins, heightened abundance of reversibly oxidized cysteine and methionine residues in thinfilament proteins. These redox modifications are known to decrease skeletal muscle calcium sensitivity, shortening velocity, and force – contractile abnormalities previously reported in severe HFrEF
  • Our data outline intrinsic abnormalities in diaphragm morphology, contractile function, metabolism, and redox balance as therapeutic targets to prevent or mitigate the progressive inspiratory impairment in heart failure with reduced ejection fraction

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