Mechanisms of skeletal muscle depletion in wasting syndromes: role of ATP-ubiquitin-dependent proteolysis.
OBJECTIVE
Muscle protein wasting frequently complicates patient outcome in several chronic pathologies. The underlying mechanisms remain largely obscure, although studies on experimental models have clarified that a complex interplay of different factors such as nutrient supply, classical hormones, cytokines and other less well defined factors likely concur in causing muscle depletion. The aim of the present review is to highlight some crucial points in the interpretation of the data available about the contribution of the different proteolytic systems, with particular reference to the ubiquitin-proteasome system, in the onset of muscle protein wasting in disease states.


RESULTS
Much effort has been directed to understanding the role of different signals, transduction pathways, and proteolytic mechanisms in the acceleration of muscle protein catabolism. Several reports propose that ATP-ubiquitin-dependent proteolysis plays a critical role in the enhancement of muscle protein catabolism observed in different pathological states. Other papers, however, suggest that the lysosomal or the calcium-dependent proteolytic pathways or both may be involved. Finally, the studies have been extended to evaluate the possibility of interfering pharmacologically with the onset of muscle protein hypercatabolism.


CONCLUSIONS
As the present overview points out, several questions still remain unanswered in the issue of muscle wasting. While many different signals that have the potential to enforce the acceleration of muscle protein breakdown have been identified, it is largely unknown how they are transduced and converge into the hypercatabolic response and how the proteolytic pathways involved are activated. The concept seems to emerge that there may be a coordinated action of different proteolytic pathways in setting up muscle protein turnover towards excess catabolism.
Costelli
Paola
P
Department of Experimental Medicine and Oncology, University of Torino, Italy. paola.costelli@unito.it
Baccino
Francesco M
FM
D000255:Adenosine Triphosphate / Q000494:pharmacology / Q000502:physiology*; D002100:Cachexia / Q000209:etiology / Q000378:metabolism; D006801:Humans; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009133:Muscular Atrophy / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism; D014452:Ubiquitins / Q000494:pharmacology / Q000502:physiology*; D019282:Wasting Syndrome / Q000378:metabolism*
D009124:Muscle Proteins; D014452:Ubiquitins; D000255:Adenosine Triphosphate