title: Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition.
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.
authors.affiliation: Department of Pathology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Ana Caroline Silva
authors.initials: AC
authors.lastname: Freitas
authors.affiliation: Department of Pathology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Figueiredo
authors.affiliation: Department of Physiotherapy, Faculty of Physical Education, Federal University of Uberlandia, Minas Gerais, Brazil.
authors.forename: Erica Carolina
authors.initials: EC
authors.lastname: Campos
authors.affiliation: Department of Histology, Embryology and Cellular Biology, Federal University of Goias, Goias, Brazil.
authors.forename: Danilo Figueiredo
authors.initials: DF
authors.lastname: Soave
authors.affiliation: Department of Pathology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Simone Gusmao
authors.initials: SG
authors.lastname: Ramos
authors.affiliation: Departments of Pathology and medicine, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, United States of America.
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
authors.affiliation: Department of Pathology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.|Institute of Tropical Pathology and Public Health, Federal University of Goias, Goias, Brazil.
authors.forename: Mara Rúbia N
authors.identifier: http://orcid.org/0000-0002-4733-007X
authors.initials: MR
authors.lastname: Celes
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009202:Cardiomyopathies / Q000150:complications / Q000473:pathology; D004195:Disease Models, Animal; D016189:Dystrophin / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D007976:Leupeptins / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009218:Myosins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D018805:Sepsis / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D000199:Actins; D016189:Dystrophin; D007976:Leupeptins; D025801:Ubiquitin; C063261:acetylleucyl-leucyl-norleucinal; D058570:TOR Serine-Threonine Kinases; D002154:Calpain; D046988:Proteasome Endopeptidase Complex; D009218:Myosins