Research Article: Ishemia-Reperfusion enhances GAPDH nitration in aging skeletal muscle

Date Published: October 23, 2011

Publisher: Impact Journals LLC

Author(s): C. Eric Bailey, David W. Hammers, James H. DeFord, Vincent L. Dimayuga, James K. Amaning, Roger Farrar, John Papaconstantinou.

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Abstract

Aging and skeletal muscle ischemia/reperfusion (I/R) injury leads to decreased contractile force generation that increases severely with age. Our studies show that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protein expression is significantly decreased at 3 and 5 days reperfusion in the young mouse muscle and at 1, 3, 5, and 7 days in the aged muscle. Using PCR, we have shown that GAPDH mRNA levels in young and old muscle increase at 5 days reperfusion compared to control, suggesting that the protein deficit is not transcriptional. Furthermore, while total tyrosine nitration did not increase in the young muscle, GAPDH nitration increased significantly at 1 and 3 days reperfusion. In contrast, total tyrosine nitration in aged muscle increased significantly at 1, 3, and 5 days of reperfusion, with increases in GAPDH nitration at the same time points. We conclude that GAPDH protein levels decrease following I/R, that this is not transcriptionally mediated, that the aged muscle experiences greater oxidative stress, protein modification and GAPDH degradation, possibly contributing to decreased muscle function. We propose that tyrosine nitration enhances GAPDH degradation following I/R and that the persistent decrease of GAPDH in aged muscle is due to the prolonged increase in oxidative modification in this age group.

Partial Text

Skeletal muscle dysfunction associated with ischemia/reperfusion (I/R) injury is in part attributed to increased oxidative stress and oxidative protein modification [1-3] This oxidative stress is associated with mitochondrial ROS production, the inflammatory response resulting from the action of cytokines and the infiltration of inflammatory cells which increase in I/R during reoxygenation following reperfusion [1, 4].

We have presented evidence that following I/R, GAPDH protein levels decrease in both young and old mouse skeletal muscle while levels of nitrated GAPDH increase. Our observations are consistent with the reports that oxidative protein modifications increase protein degradation [29, 30] and suggest a model of protein homeostasis in which increased oxidative modification and subsequent degradation of proteins leads to decreases in protein pool levels.

 

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