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Received December 10, 2004
Revised February 1, 2005
Accepted after revision March 14, 2005
1 West Virginia University School of Medicine
2 University of West Virginia School of Medicine
* To whom correspondence should be addressed. E-mail: salway{at}hsc.wvu.edu.
Apoptosis has been implicated in the regulation of denervation-induced muscle atrophy. However, the activation of apoptotic signal transduction during muscle denervation has not been fully elucidated. The present study examined the apoptotic responses to denervation in rat gastrocnemius muscle. Following 14 days of denervation the extent of apoptotic DNA fragmentation as determined by a cytosolic nucleosome ELISA was increased by 100% in the gastrocnemius muscle. RT-PCR and immunoblot analyses indicated that Bax was dramatically up regulated while Bcl-2 was modestly increased; however, the Bax/Bcl-2 ratio was significantly increased in denervated muscles relative to control muscles. Analyses of ELISA and immunoblots from mitochondria-free cytosol extracts showed a significance increase mitochondria-associated apoptotic factors including cytochrome c, Smac/DIABLO, and AIF. In addition to the upregulation of caspase-3 and -9 mRNA, pro-/cleaved caspase protein, and proteolytic activity levels, the XIAP protein level was down regulated. The cleaved product of PARP was detected in muscle samples following denervation. Although we did not find a difference in Id2 and c-Myc protein contents between the denervated and control muscles, the protein content of tumour suppressor p53 was significantly increased in both the nuclear and the cytosolic fractions with denervation. Moreover, denervation increased the protein content of HSP70 whereas the MnSOD protein content was diminished which indicated that denervation might have induced cellular and/or oxidative stress. Our data show that mitochondria-associated apoptotic signalling is up regulated during muscle denervation. We interpret these findings to indicate that apoptosis has a physiologically important role in regulating denervation-induced muscle atrophy.
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