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Caspase activation contributes to endotoxin-induced diaphragm weakness
Gerald S Supinski1, Leigh A Callahan
1Department of Medicine, 1120 15th St., Rm. BBR-5513, Medical College of Georgia, Augusta, GA 30912-3135, USA. gsupinski@mail.mcg.edu
Journal of Applied Physiology (Bethesda, Md. : 1985)
|February 18, 2006
Summary
Infections cause respiratory muscle weakness by activating caspase 3, which degrades proteins in the diaphragm. Inhibiting caspase 3 prevents this endotoxin-induced muscle weakness.
Area of Science:
- Physiology
- Biochemistry
- Immunology
Background:
- Infections can lead to significant respiratory muscle weakness.
- The precise mechanisms by which inflammation causes muscle force reduction are not fully understood.
- Previous research suggests caspase 3 activation may release contractile proteins.
Purpose of the Study:
- To investigate if infections activate caspase 3 in the diaphragm.
- To determine the effect of caspase inhibitors on endotoxin-induced diaphragm weakness.
Main Methods:
- Mice were treated with endotoxin, caspase inhibitors (zVAD-fmk, DEVD-CHO), or saline.
- Caspase 3 activation was measured via protein levels and substrate cleavage.
- Diaphragm force was assessed using electrical stimulation.
- Caspase-mediated spectrin degradation was analyzed by Western blotting.
Main Results:
- Endotoxin significantly increased active caspase 3 protein and activity in the diaphragm.
- Endotoxin exposure led to increased spectrin degradation and reduced diaphragm force.
- Caspase inhibitors zVAD-fmk and DEVD-CHO prevented endotoxin-induced diaphragm weakness and spectrin degradation.
Conclusions:
- Endotoxin administration activates caspase 3 in the diaphragm.
- Caspase 3 activation is a key mechanism underlying endotoxin-induced diaphragmatic weakness.
- Targeting caspase 3 may be a therapeutic strategy for respiratory muscle dysfunction during infections.