Activation of both the calpain and ubiquitin-proteasome systems contributes to septic cardiomyopathy through dystrophin loss/disruption and mTOR inhibition

Ana Caroline Silva Freitas, Maria Jose Figueiredo, Erica Carolina Campos, Danilo Figueiredo Soave, Simone Gusmao Ramos, Herbert B. Tanowitz, Mara Rúbia N Celes

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Cardiac dysfunction caused by the impairment of myocardial contractility has been recognized as an important factor contributing to the high mortality in sepsis. Calpain activation in the heart takes place in response to increased intracellular calcium influx resulting in proteolysis of structural and contractile proteins with subsequent myocardial dysfunction. The purpose of the present study was to test the hypothesis that increased levels of calpain in the septic heart leads to disruption of structural and contractile proteins and that administration of calpain inhibitor-1 (N-acetyl-leucinyl-leucinyl-norleucinal (ALLN)) after sepsis induced by cecal ligation and puncture prevents cardiac protein degradation. We also tested the hypothesis that calpain plays a role in the modulation of protein synthesis/degradation through the activation of proteasome-dependent proteolysis and inhibition of the mTOR pathway. Severe sepsis significantly increased heart calpain-1 levels and promoted ubiquitin and Pa28β over-expression with a reduction in the mTOR levels. In addition, sepsis reduced the expression of structural proteins dystrophin and β-dystroglycan as well as the contractile proteins actin and myosin. ALLN administration prevented sepsis-induced increases in calpain and ubiquitin levels in the heart, which resulted in decreased of structural and contractile proteins degradation and basal mTOR expression levels were re-established. Our results support the concept that increased calpain concentrations may be part of an important mechanism of sepsis-induced cardiac muscle proteolysis.

Original languageEnglish (US)
Article numbere0166839
JournalPLoS One
Volume11
Issue number11
DOIs
StatePublished - Nov 1 2016

Fingerprint

dystrophin
Dystrophin
calpain
Calpain
cardiomyopathy
proteasome endopeptidase complex
Proteasome Endopeptidase Complex
ubiquitin
Ubiquitin
Cardiomyopathies
Proteolysis
Contractile Proteins
Sepsis
contractile proteins
Chemical activation
structural proteins
heart
proteolysis
Degradation
protein degradation

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Freitas, A. C. S., Figueiredo, M. J., Campos, E. C., Soave, D. F., Ramos, S. G., Tanowitz, H. B., & Celes, M. R. N. (2016). Activation of both the calpain and ubiquitin-proteasome systems contributes to septic cardiomyopathy through dystrophin loss/disruption and mTOR inhibition. PLoS One, 11(11), [e0166839]. https://doi.org/10.1371/journal.pone.0166839

Activation of both the calpain and ubiquitin-proteasome systems contributes to septic cardiomyopathy through dystrophin loss/disruption and mTOR inhibition. / Freitas, Ana Caroline Silva; Figueiredo, Maria Jose; Campos, Erica Carolina; Soave, Danilo Figueiredo; Ramos, Simone Gusmao; Tanowitz, Herbert B.; Celes, Mara Rúbia N.

In: PLoS One, Vol. 11, No. 11, e0166839, 01.11.2016.

Research output: Contribution to journalArticle

Freitas, Ana Caroline Silva ; Figueiredo, Maria Jose ; Campos, Erica Carolina ; Soave, Danilo Figueiredo ; Ramos, Simone Gusmao ; Tanowitz, Herbert B. ; Celes, Mara Rúbia N. / Activation of both the calpain and ubiquitin-proteasome systems contributes to septic cardiomyopathy through dystrophin loss/disruption and mTOR inhibition. In: PLoS One. 2016 ; Vol. 11, No. 11.
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