Stress and muscle wasting

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 E3α, 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-calpain-dependent release of myofilaments from the sarcomere provides substrates for the ubiquitin-proteasome pathway and may be an early component of sepsis-induced muscle wasting.

Implications

Sepsis-induced muscle wasting is a significant clinical problem resulting in muscle weakness and fatigue and whole-body protein loss. Although ubiquitin-proteasome-dependent breakdown of myofibrillar proteins plays a central role in muscle atrophy during sepsis and after severe injury, multiple other regulatory mechanisms are involved as well. An increased understanding of the molecular regulation of muscle wasting in stress may help in the future to develop novel treatment strategies in patients with muscle wasting.

Key Words: Calpain, Muscles, Proteolysis, Sepsis, Ubiquitin

Ö2002 American Society of Animal Science. All rights reserved.
J. Anim. Sci. 80(E. Suppl. 2):E50-E55