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Phosphorylation-dependent alteration in myofilament ca2+ sensitivity but normal mitochondrial function in septic
B Tavernier1, A Mebazaa, P Mateo
1INSERM U-446, Laboratoire de Cardiologie Cellulaire et Moléculaire, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France. btavernier@chru-lille.fr
American Journal of Respiratory and Critical Care Medicine
|February 17, 2001
Summary
Sepsis impairs heart muscle contractility by reducing calcium sensitivity in muscle fibers, not by affecting energy production. Protein phosphorylation changes, not mitochondrial function, appear to be key in sepsis-induced cardiac depression.
Area of Science:
- Cardiology
- Cellular Biology
- Biochemistry
Background:
- Myocardial depression is a critical complication of sepsis, but its underlying subcellular mechanisms are not fully understood.
- Existing research suggests impaired cardiac energy metabolism may contribute to contractile dysfunction during sepsis.
Purpose of the Study:
- To investigate the energetic and mechanical properties of cardiac muscle fibers in a rabbit model of endotoxemia.
- To determine whether sepsis affects mitochondrial function, creatine kinase activity, or myofibrillar calcium sensitivity.
Main Methods:
- Skinned ventricular fibers were isolated from rabbits 36 hours after lipopolysaccharide (LPS) injection or saline control.
- Mitochondrial respiration, oxidative phosphorylation coupling, and creatine kinase function were assessed.
- Calcium-activated force and calcium sensitivity (pCa50) were measured, along with the effects of protein kinase A (PKA), alkaline phosphatase, and nitric oxide (NO) donors.
Main Results:
- Mitochondrial respiration, oxidative phosphorylation, and creatine kinase function were unchanged in endotoxemic versus control fibers.
- Maximal calcium-activated force was similar, but calcium sensitivity (pCa50) was significantly reduced in LPS-treated fibers.
- Treatment with PKA or alkaline phosphatase normalized the pCa50 difference between LPS and control fibers, suggesting a role for protein phosphorylation.
Conclusions:
- Cardiac mitochondrial and creatine kinase systems are not significantly altered during sepsis-induced hypotension.
- Decreased myofibrillar calcium sensitivity, likely due to altered protein phosphorylation, contributes to cardiac contractility depression in sepsis.