Muscle cachexia: current concepts of intracellular mechanisms and molecular regulation.
OBJECTIVE
To review present knowledge of intracellular mechanisms and molecular regulation of muscle cachexia.


BACKGROUND
Muscle cachexia, mainly reflecting degradation of myofibrillar proteins, is an important clinical feature in patients with severe injury, sepsis, and cancer. The catabolic response in skeletal muscle may result in muscle wasting and weakness, delaying or preventing ambulation and rehabilitation in these patients and increasing the risk for pulmonary complications.


RESULTS
Muscle cachexia, induced by severe injury, sepsis, and cancer, is associated with increased gene expression and activity of the calcium/calpain- and ubiquitin/proteasome-proteolytic pathways. Calcium/calpain-regulated release of myofilaments from the sarcomere is an early, and perhaps rate-limiting, component of the catabolic response in muscle. Released myofilaments are ubiquitinated in the N-end rule pathway, regulated by the ubiquitin-conjugating enzyme E2(14k) and the ubiquitin ligase E3 alpha, and degraded by the 26S proteasome.


CONCLUSIONS
An understanding of the mechanisms regulating muscle protein breakdown is important for the development of therapeutic strategies aimed at treating or preventing muscle cachexia in patients with severe injury, sepsis, cancer, and perhaps other catabolic conditions as well.
Hasselgren
P O
PO
Department of Surgery, University of Cincinnati, Cincinnati, Ohio 45267-0558, USA. hasselp@uc.edu
Fischer
J E
JE
D002100:Cachexia / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism; D015398:Signal Transduction; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism; D014947:Wounds and Injuries / Q000378:metabolism
D009097:Multienzyme Complexes; D014452:Ubiquitins; D002154:Calpain; D002118:Calcium