Sepsis stimulates release of myofilaments in skeletal muscle by a calcium-dependent mechanism

Sepsis is associated with a pronounced catabolic response in skeletal muscl e, mainly reflecting degradation of the myofibrillar proteins actin and myo sin. Recent studies suggest that sepsis-induced muscle proteolysis may refl ect ubiquitin-proteasome-dependent protein breakdown. An apparently conflic ting observation is that the ubiquitin-proteasome pathway does not degrade intact myofibrils. Thus, it is possible that actin and myosin need to be re leased from the myofibrils before they can be ubiquitinated and degraded by the proteasome. We tested the hypothesis that sepsis results in disruption of Z-bands, increased expression of calpains, and calcium-dependent releas e of myofilaments in skeletal muscle. Sepsis induced in rats by cecal ligat ion and puncture resulted in increased gene expression of mu-calpain, m-cal pain, and p94 and in Z-band disintegration in the extensor digitorum longus muscle. The release of myofilaments from myofibrillar proteins was increas ed in septic muscle. This response to sepsis was blocked by treating the ra ts with dantrolene, a substance that inhibits the release of calcium from i ntracellular stores to the cytoplasm. The present results provide evidence that sepsis is associated with Z-band disintegration and a calcium-dependen t release of myofilaments in skeletal muscle. Release of myofilaments may b e an initial and perhaps rate-limiting component of sepsis-induced muscle b reakdown.