Role of the ubiquitin-proteasome pathway in muscle atrophy in cachexia.
OBJECTIVE
Increased ubiquitin-proteasome-dependent proteolysis is a major determinant of muscle wasting in numerous catabolic states, including cachexia. We discuss the implication of both mechanistic and clinical recent observations for preventing or attenuating the loss of muscle proteins.


RESULTS
The ubiquitin-proteasome system (UPS) is the major proteolytic machinery systematically activated in cachexia and only proteasome inhibitors prevent increased proteolysis. The UPS has been recently demonstrated to degrade myosin heavy chain (i.e. a major contractile protein) and telethonin that plays a role in sarcomere integrity. The UPS is activated at the ubiquitination/deubiquitination and proteasome activity levels. The precise complex and interdependent signalling pathways and transcription factors (i.e. the FoxO family) responsible for the activation of the UPS are in part identified. Recent studies have also shown that FoxO3 activates not only the UPS, but also the transcription of autophagy-related genes.


CONCLUSIONS
The exact role of the different muscle proteolytic systems and their respective substrates are still largely unknown. However, current studies in animal models of cachexia already identified new pharmacological approaches that could be useful to block or partially prevent muscle wasting in cachectic patients.
Attaix
Didier
D
INRA, Centre Clermont-Ferrand-Theix, UMR1019, Unité Nutrition Humaine, St Genès Champanelle, France. attaix@clermont.inra.fr
Combaret
Lydie
L
Béchet
Daniel
D
Taillandier
Daniel
D
D002100:Cachexia / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D009133:Muscular Atrophy / Q000378:metabolism*; D009369:Neoplasms / Q000150:complications / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D015398:Signal Transduction; D025801:Ubiquitin / Q000502:physiology*
D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex