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Am J Physiol Renal Physiol (May 25, 2004). doi:10.1152/ajprenal.00440.2003
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Submitted on December 12, 2003
Accepted on May 18, 2004

Acidosis Impairs Insulin Receptor Substrate-1-Associated Phosphoinositide 3-Kinase Signaling in Muscle Cells: Consequences on Proteolysis

Harold A. Franch1*, Sina Raissi2, Xiaonan Wang2, Bin Zheng2, James L. Bailey2, and S. Russ Price2

1 Research Service, Atlanta Veterans Affairs Medical Center, Decatur, GA, USA
2 Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA

* To whom correspondence should be addressed. E-mail: hfranch{at}emory.edu.

Chronic acidosis is a stimulus for proteolysis in muscle in vivo but the mechanism of this response is unknown. We tested the hypothesis that acidosis or TNF{alpha}, a cytokine whose production increases in acidosis, regulates proteolysis by inhibiting insulin signaling through phosphoinositide 3-kinase (PI3K). In cultured L6 myotubes, acidified (pH 7.1) media did not accelerate the basal protein degradation rate, but it inhibited insulin's ability to suppress proteolysis. IRS-1-associated PI3K activity was not altered in cells acidified for 10 minutes but was strongly inhibited in cells incubated at pH 7.1 for 24 h. Phosphorylation of Akt was also suppressed by acidification for 24 h. Acidification did not induce changes in IRS-1 abundance, insulin-stimulated IRS-1 tyrosine phosphorylation, or the amount of PI3K p85 regulatory subunit. In contrast to acidification, TNF{alpha} suppressed proteolysis in the presence or absence of insulin but had no effect on IRS-1 associated PI3K activity. To establish that the PI3K pathway can regulate protein degradation in muscle, we measured proteolysis in cells following inhibition of PI3K activity with LY294002 or infection with an adenovirus encoding a dominant negative PI3K p85{alpha} subunit. Both approaches inhibited insulin-induced suppression of proteolysis to a degree similar to that seen with acidification. We conclude that acidosis accelerates protein degradation by impairing insulin signaling through PI3K in muscle cells.




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