Taurine administration ablates sepsis induced diaphragm weakness

Abstract

Infection induced diaphragm weakness is a major contributor to death and prolonged mechanical ventilation in critically ill patients. Infection induced muscle dysfunction is associated with activation of muscle proteolytic enzymes, and taurine is known to suppress proteolysis. We therefore postulated that taurine administration may prevent infection induced diaphragm dysfunction. The purpose of this study was to test this hypothesis using a clinically relevant animal model of infection, i.e. cecal ligation puncture induced sepsis (CLP). Studies were performed on (n=5-7 mice/group): (a) sham operated controls, (b) animals with sepsis induced by CLP, (c) sham operated animals given taurine (75 mg/kg/d, intraperitoneally), and (d) CLP animals given taurine. At intervals after surgery animals were euthanized, diaphragm force generation measured in vitro, and diaphragm calpain, caspase and proteasomal activity determined. CLP elicited a large reduction in diaphragm specific force generation at 24 hours (1-150 Hz, p<0.001) and taurine significantly attenuated CLP induced diaphragm weakness at all stimulation frequencies (p<0.001). CLP induced significant increases in diaphragm calpain, caspase and proteasomal activity; taurine administration prevented increases in the activity of all three pathways. In additional time course experiments, diaphragm force generation remained at control levels over 72 hours in CLP animals treated with daily taurine administration, while CLP animals demonstrated severe, sustained reductions in diaphragm strength (p<0.01 for all time points). Our results indicate that taurine administration prevents infection induced diaphragm weakness and reduces activation of three major proteolytic pathways. Because this agent is has been shown to be safe, non-toxic when administered to humans, taurine may have a role in treating infection induced diaphragm weakness. Future clinical studies will be needed to assess this possibility.

MitoTEMPOL, a mitochondrial targeted antioxidant, prevents sepsis-induced diaphragm dysfunction

“…Caspase activity assay. Diaphragm caspase-3 activity was assessed as previously described (n ϭ 4/group) using the caspase-3-specific fluorogenic substrate (30 M N-acetyl-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin, Ac-DEVD-AMC) (42,48,49). For this assay, diaphragm samples were homogenized using a buffer consisting of 50 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 100 mM sodium chloride, 1% 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate, 10 mM dithiothreitol, 1 mM ethylene diamine tetraacetic acid, and 10% glycerol.…”

Calpain Activation and Organ Failure in Sepsis: Molecular Insights and Therapeutic Perspectives

“…As shown in Table 1, among all types of muscle dysfunction caused by sepsis, the role of calpain in the pathogenesis of sepsis-induced diaphragmatic dysfunction has attracted significant attention. Increased calpain activity or protein level (calpain-1 and calpain-2) as well as reduced diaphragm force during sepsis have been reported in a series of studies (70)(71)(72), and inhibiting calpain activation by overexpression of calpastatin significantly improved diaphragm function in sepsis (73). So far, there are at least three calpain isoforms in muscle, i.e.…”