Deficiency of the Bax gene attenuates denervation-induced apoptosis.
Apoptosis has been implicated in mediating denervation-induced muscle wasting. In this study we determined the effect of interference of apoptosis on muscle wasting during denervation by using mice genetically deficient in pro-apoptotic Bax. After denervation, muscle wasting was evident in both wild-type and Bax(-/-) muscles but reduction of muscle weight was attenuated in Bax(-/-) mice. Apoptotic DNA fragmentation increased in wild-type denervated muscles whereas there was no statistical increase in DNA fragmentation in denervated muscles from Bax(-/-) mice. Mitochondrial AIF and Smac/DIABLO releases and Bcl-2, p53 and HSP27 increased whereas XIAP and MnSOD decreased to a similar extent in muscles from wild-type and Bax(-/-) mice following denervation. Mitochondrial cytochrome c release was elevated in denervated muscles from wild-type mice but the increase was suppressed in muscles from Bax(-/-) mice. Increases in caspase-3 and -9 activities and oxidative stress markers H(2)O(2), MDA/4-HAE and nitrotyrosine were all evident in denervated muscles from wild-type mice but these changes were absent in muscles from Bax(-/-) mice. Moreover, ARC increased exclusively in denervated Bax(-/-) muscle. Our data indicate that under conditions of denervation, pro-apoptotic signalling is suppressed and muscle wasting is attenuated when the Bax gene is lacking. These findings suggest that interventions targeting apoptosis may be valuable in ameliorating denervation-associated pathologic muscle wasting in certain neuromuscular disorders that involve partial or full denervation.
Siu
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PM
Laboratory of Muscle Biology and Sarcopenia, Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, West Virginia 26506, USA.
Alway
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SE
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D003714:Denervation; D051379:Mice; D008810:Mice, Inbred C57BL; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics*
C494827:Bax protein, mouse; D051028:bcl-2-Associated X Protein