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Am J Physiol Regul Integr Comp Physiol (November 24, 2004). doi:10.1152/ajpregu.00341.2004
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Submitted on May 26, 2004
Accepted on November 15, 2004

SEPSIS STIMULATES CALPAIN ACTIVITY IN SKELETAL MUSCLE BY DECREASING CALPASTATIN ACTIVITY BUT DOES NOT ACTIVATE CASEPASE-3

Wei Wei1, Moin U Fareed1, Amy Evenson1, Michael J Menconi1, Hongmei Yang1, Victoria Petkova2, and Per-Olof Hasselgren1*

1 Departments of Surgery and Hematology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
2 Department of Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: phasselg{at}bidmc.harvard.edu.

We examined the influence of sepsis on the expression and activity of the calpain and caspase systems in skeletal muscle. Sepsis was induced in rats by cecal ligation and puncture (CLP). Control rats were sham-operated. Calpain activity was determined by measuring the calcium-dependent hydrolysis of casein and by casein zymography. The activity of the endogenous calpain inhibitor calpastatin was measured by determining the inhibitory effect on calpain activity in muscle extracts. Protein levels of µ- and m-calpain and calpastatin were determined by Western blotting and calpastatin mRNA was measured by real-time PCR. Caspase-3 activity was determined by measuring the hydrolysis of the fluorogenic caspase-3 substrate Ac-DEVD-AMC and by determining protein and mRNA expression for caspase-3 by Western blotting and real-time PCR, respectively. In addition, the role of calpains and caspase-3 in sepsis-induced muscle protein breakdown was determined by measuring protein breakdown rates in the presence of specific inhibitors. Sepsis resulted in increased muscle calpain activity caused by reduced calpastatin activity. In contrast, caspase-3 activity, mRNA levels, and activated caspase-3 29kDa fragment were not altered in muscle from septic rats. Sepsis-induced muscle proteolysis was blocked by the calpain inhibitor calpeptin but was not influenced by the caspase-3 inhibitor Ac-DEVD-CHO. The results suggest that sepsis-induced muscle wasting is associated with increased calpain activity, secondary to reduced calpastatin activity, and that caspase-3 activity is not involved in the catabolic response to sepsis.




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