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Stress and muscle wasting¹

Department of Surgery, University of Cincinnati, Cincinnati, OH 45267-0558

² Correspondence: 231 Albert Sabin Way (phone: 513-584-4841; fax: 513-584-2958; E-mail: hasselp{at}uc.edu).

Abstract

One of the metabolic hallmarks of sepsis and severe injury is the catabolic response in skeletal muscle, mainly reflecting increased protein breakdown, in particular myofibrillar protein breakdown. This review describes recent knowledge regarding the molecular mechanisms of sepsis-induced muscle wasting. Among different intracellular proteolytic pathways, the energy-ubiquitin-dependent pathway is particularly important for the regulation of muscle protein breakdown during sepsis, both in animals and humans. The gene expression of ubiquitin, ubiquitin-conjugating enzyme E2_14k, ubiquitin ligase E3, and several components of the 20S proteasome is up-regulated and the activity of the 20S proteasome is increased in muscle during sepsis. In addition, sepsis-induced muscle proteolysis can be blocked by specific proteasome inhibitors, both in vivo and in vitro. Sepsis is also associated with increased calcium levels and upregulated gene expression of calpains in skeletal muscle. Calcium-calpaindependent release of myofilaments from the sarcomere provides substrates for the ubiquitin-proteasome pathway and may be an early component of sepsis-induced muscle wasting.

¹ Supported in part by NIH grant DK 37908 and by grants from the Shriners of North America.