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J. Biol. Chem., Vol. 283, Issue 13, 8453-8461, March 28, 2008

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Deletion of Hexose-6-phosphate Dehydrogenase Activates the Unfolded Protein Response Pathway and Induces Skeletal Myopathy^*

Gareth G. Lavery, Elizabeth A. Walker, Nil Turan^¶, Daniela Rogoff^||, Jeffery W. Ryder^**1, John M. Shelton, James A. Richardson, Francesco Falciani^¶, Perrin C. White^||, Paul M. Stewart, Keith L. Parker, and Daniel R. McMillan^||2

From the Division of Medical Sciences and the ^¶School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TH, United Kingdom and the Departments of Internal Medicine, ^||Pediatrics, ^**Physiology, and Pathology and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Hexose-6-phosphate dehydrogenase (H6PD) is the initial component of a pentose phosphate pathway inside the endoplasmic reticulum (ER) that generates NADPH for ER enzymes. In liver H6PD is required for the 11-oxoreductase activity of 11β-hydroxysteroid dehydrogenase type 1, which converts inactive 11-oxo-glucocorticoids to their active 11-hydroxyl counterparts; consequently, H6PD null mice are relatively insensitive to glucocorticoids, exhibiting fasting hypoglycemia, increased insulin sensitivity despite elevated circulating levels of corticosterone, and increased basal and insulin-stimulated glucose uptake in muscles normally enriched in type II (fast) fibers, which have increased glycogen content. Here, we show that H6PD null mice develop a severe skeletal myopathy characterized by switching of type II to type I (slow) fibers. Running wheel activity and electrically stimulated force generation in isolated skeletal muscle are both markedly reduced. Affected muscles have normal sarcomeric structure at the electron microscopy level but contain large intrafibrillar membranous vacuoles and abnormal triads indicative of defects in structure and function of the sarcoplasmic reticulum (SR). SR proteins involved in calcium metabolism, including the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), calreticulin, and calsequestrin, show dysregulated expression. Microarray analysis and real-time PCR demonstrate overexpression of genes encoding proteins in the unfolded protein response pathway. We propose that the absence of H6PD induces a progressive myopathy by altering the SR redox state, thereby impairing protein folding and activating the unfolded protein response pathway. These studies thus define a novel metabolic pathway that links ER stress to skeletal muscle integrity and function.

Received for publication, December 10, 2007 , and in revised form, January 23, 2008.

^* This study was supported in part by Wellcome Trust Grants 066357 (to P. M. S.) and 074088/Z/04/Z (to E. A. W. and P. M. S.), National Institutes of Health Grant DK54480 and the Wilson Center for Biomedical Research (to K. L. P.), and National Institutes of Health Grant DK068101 and the Audre Newman Rapoport Chair in Pediatric Endocrinology (to P. C. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure and Tables S1 and S2.

¹ Supported as a postdoctoral fellow by National Institutes of Health Training Grant T32HL007360.

² To whom correspondence should be addressed: 5323 Harry Hines Blvd., Dallas, TX 75390-9063. Fax: 214-648-9772; E-mail: daniel.mcmillan{at}UTSouthwestern.edu.

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