Deficiency of the Bax gene attenuates denervation-induced apoptosis |
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Authors: | P M Siu S E Alway |
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Institution: | (1) Laboratory of Muscle Biology and Sarcopenia, Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, West Virginia, 26506;(2) Division of Exercise Physiology, School of Medicine, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506-9227, USA |
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Abstract: | 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 H2O2, 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. |
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Keywords: | apoptosis BCL-2 muscle atrophy neuromuscular disease |
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