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This Article Full Text Full Text (PDF) All Versions of this Article: 107/1/224    most recent 90932.2008v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map 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 Google Scholar Articles by Plant, P. J. Articles by Batt, J. PubMed PubMed Citation Articles by Plant, P. J. Articles by Batt, J.

Absence of caspase-3 protects against denervation-induced skeletal muscle atrophy

¹Department of Medicine St. Michael's Hospital, ³Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Toronto; and ²Department of Surgery, McMaster University, Hamilton, Ontario, Canada

Submitted 16 July 2008 ; accepted in final form 16 April 2009

The ubiquitin-proteasome system is a key proteolytic pathway activated during skeletal muscle atrophy. The proteasome, however, cannot degrade intact myofibrils or actinomyosin complexes. In rodent models of diabetes mellitus and uremia, caspase-3 is involved in actinomyosin cleavage, generating fragments that subsequently undergo ubiquitin-proteasome-mediated degradation. Here, we demonstrate that caspase-3 also mediates denervation-induced muscle atrophy. At 2 wk after tibial nerve transection, the denervated gastrocnemius of caspase-3-knockout mice weighed more and demonstrated larger fiber-type-specific cross-sectional area than the denervated gastrocnemius of wild-type mice. However, there was no difference between caspase-3-knockout and wild-type denervated muscles in the magnitude or pattern of actinomyosin degradation, as determined by Western blotting for actin and the 14-kDa actin fragment. Similarly, there was no difference between caspase-3-knockout and wild-type denervated muscles in the magnitude of increase in proteasome activity, total protein ubiquitination, or atrogin-1 and muscle-specific ring finger protein 1 transcript levels. In contrast, there was an increase in TdT-mediated dUTP nick end label-positive nuclei in the denervated muscle of wild-type compared with caspase-3-knockout mice. Apoptotic signaling upstream of caspase-3 remained intact, with equivalent mitochondrial Bax translocation and cytochrome c release and caspase-9 activation in the denervated gastrocnemius muscle of wild-type and caspase-3-knockout mice. In contrast, diminished poly(ADP-ribose) polymerase cleavage in the denervated muscle of caspase-3-knockout compared with wild-type mice revealed that apoptotic signaling downstream of caspase-3 was impaired, suggesting that the absence of caspase-3 protects against denervation-induced muscle atrophy by suppressing apoptosis as opposed to ubiquitin-proteasome-mediated protein degradation.

14-kDa actin fragment; ubiquitin-proteasome; poly(ADP-ribose) polymerase; apoptosis