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This Article Full Text Full Text (PDF) All Versions of this Article: 92/3/561    most recent expphysiol.2006.035790v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Smith, I. J. Articles by Dodd, S. L. Search for Related Content PubMed PubMed Citation Articles by Smith, I. J. Articles by Dodd, S. L. Related Collections Muscle

¹ Muscle Physiology Laboratory, Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USA

The role of the calpain proteases in skeletal muscle atrophy is poorly understood. One goal of these experiments was to clarify whether calpains act upstream of the ubiquitin–proteasome pathway (UPP). Calpain activation may also inhibit the anabolic signalling of Akt, since a molecular chaperone previously shown to mediate Akt activity, heat shock protein 90 (HSP 90), is a calpain substrate. Thus, an additional objective was to determine whether calpain activation affects the Akt signalling pathway. Ex vivo experiments were conducted using isolated rat diaphragm muscle. Calpain activation increased total protein degradation by 65%. Proteasome inhibition prevented this large rise in proteolysis, demonstrating that the proteasome was necessary for calpain-activated protein degradation. In addition, calpain activation increased proteasome-dependent proteolysis by 144%, further supporting the idea of sequential proteolytic pathways. Calpain reduced Akt and mammalian target of rapamycin (mTOR) phosphorylation by 35 and 50%, respectively, and activated glycogen synthase kinase-3 beta (GSK-3ß) by 40%. Additionally, calpain activation reduced HSP 90ß and mTOR protein content by 33 and 50%, respectively. These data suggest that calpains play a dual role in protein metabolism by concomitantly activating proteasome-dependent proteolysis and inhibiting the Akt pathway of protein synthesis.

(Received 18 September 2006; accepted after revision 1 February 2007; first published online 1 February 2007)
Corresponding author I. J. Smith: GSRB-1, Room 1043, 595 LaSalle Street, Duke University, Durham, NC 27710, USA. Email: ira4{at}duke.edu

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