Ca(2+)-dependent proteolysis in muscle wasting.
Skeletal muscle wasting is a prominent feature of cachexia, a complex systemic syndrome that frequently complicates chronic diseases such as inflammatory and autoimmune disorders, cancer and AIDS. Muscle wasting may also develop as a manifestation of primary or neurogenic muscular disorders. It is now generally accepted that muscle depletion mainly arises from increased protein catabolism. The ubiquitin-proteasome system is believed to be the major proteolytic machinery in charge of such protein breakdown, yet there is evidence suggesting that Ca(2+)-dependent system, lysosomes and, in some conditions at least, even caspases are involved as well. The role of Ca(2+)-dependent proteolysis in skeletal muscle wasting is reviewed in the present paper. This system relies on the activity of calpains, a family of Ca(2+)-dependent cysteine proteases, whose regulation is complex and not completely elucidated. Modulations of Ca(2+)-dependent proteolysis have been associated with muscle protein depletion in various pathological contexts and particularly with muscle dystrophies. Calpains can only perform a limited proteolysis of their substrates, however they may play a critical role in initiating the breakdown of myofibrillar protein, by releasing molecules that become suitable for further degradation by proteasomes. Some evidence would also support a role for lysosomes and caspases in muscle wasting. Thus it cannot be excluded that different intracellular proteolytic systems may coordinately concur in shifting muscle protein turnover towards excess catabolism. Many different signals have been proposed as potentially involved in triggering the enhanced protein breakdown that underlies muscle wasting. How they are transduced to initiate the hypercatabolic response and to activate the proteolytic pathways remains largely unknown, however.
Costelli
Paola
P
Dipartimento di Medicina e Oncologia Sperimentale, Università di Torino, Corso Raffaello 30, 10125 Torino, Italy. paola.costelli@unito.it
Reffo
Patrizia
P
Penna
Fabio
F
Autelli
Riccardo
R
Bonelli
Gabriella
G
Baccino
Francesco M
FM
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009133:Muscular Atrophy / Q000139:chemically induced / Q000378:metabolism*; D009210:Myofibrils / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism
D009124:Muscle Proteins; D014452:Ubiquitins; D002154:Calpain; D046988:Proteasome Endopeptidase Complex; D002118:Calcium