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1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Medical College of Georgia, Augusta, GA, USA
* To whom correspondence should be addressed. E-mail: gsupinski{at}mail.mcg.edu.
Rationale: Infections produce significant respiratory muscle weakness but the mechanisms by which inflammation reduces muscle force remain incompletely understood. Recent work suggests that caspase 3 releases actin and myosin from the contractile protein lattice, so we postulated that infections may reduce skeletal muscle force by activating caspase 3. The current experiments were designed to test this hypothesis by determining: (a) diaphragm caspase 3 activation in the diaphragm following endotoxin, and (b) the effect of a broad spectrum caspase inhibitor, Z-Val-Ala-Asp(OCH3)-Fluoromethylketone (zVAD-fmk), and a selective caspase 3 inhibitor, N-Acetyl-Asp-Glu-Val-Asp-al (DEVD-CHO), on endotoxin induced diaphragm weakness. Methods: Caspase 3 activation was assessed by measuring caspase protein levels and by measuring cleavage of a fluorogenic substrate. Diaphragm force was measured in response to electrical stimulation (1-150 Hz). Caspase mediated spectrin degradation was assessed by Western blotting. Parameters were compared in mice given saline, endotoxin (12 mg/kg intraperitoneally), endotoxin plus zVAD-fmk (3 mg/kg intravenously), zVAD-fmk alone, or endotoxin plus DEVD-CHO (3 mg/kg intravenously). Results: Endotoxin increased diaphragm active caspase 3 protein (p<0.003), increased caspase 3 activity (p<0.002), increased diaphragm spectrin degradation (p<0.001), and reduced diaphragm force (p<0.001). Administration of zVAD-fmk or DEVD-CHO prevented endotoxin induced weakness (e.g. force in response to 150 Hz stimulation was 23.8 ±1.4, 12.1 ±1.3, and 23.5 ±0.8, 22.7 ±1.3 and 24.4 ±0.8 N/cm2, respectively, for control, endotoxin, endotoxin plus zVAD-fmk, endotoxin plus DEVD-CHO and zVAD-fmk alone treated groups, p<0.001). Caspase inhibitors also prevented spectrin degradation. Conclusions: Endotoxin administration elicits significant diaphragm caspase 3 activation and caspase mediated diaphragmatic weakness.
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