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, John M. Shelton, James A. Richardson, Francesco Falciani, Perrin C. White, Paul M. Stewart, Keith L. Parker, Daniel R. McMillan

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)8453-8461
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number13
DOIs
StatePublished - Mar 28 2008

Fingerprint

Unfolded Protein Response
Muscular Diseases
Muscle
Sarcoplasmic Reticulum
Endoplasmic Reticulum
Proteins
Glucocorticoids
Skeletal Muscle
Calsequestrin
Sarcoplasmic Reticulum Calcium-Transporting ATPases
11-beta-Hydroxysteroid Dehydrogenases
Insulin
Calreticulin
Pentoses
Protein folding
Pentose Phosphate Pathway
Muscles
Protein Unfolding
Endoplasmic Reticulum Stress
Gene encoding

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Lavery, G. G., Walker, E. A., Turan, N., Rogoff, D., Ryder, J. W., Shelton, J. M., ... McMillan, D. R. (2008). Deletion of hexose-6-phosphate dehydrogenase activates the unfolded protein response pathway and induces skeletal myopathy. Journal of Biological Chemistry, 283(13), 8453-8461. https://doi.org/10.1074/jbc.M710067200

Deletion of hexose-6-phosphate dehydrogenase activates the unfolded protein response pathway and induces skeletal myopathy. / Lavery, Gareth G.; Walker, Elizabeth A.; Turan, Nil; Rogoff, Daniela; Ryder, Jeffery W.; Shelton, John M.; Richardson, James A.; Falciani, Francesco; White, Perrin C.; Stewart, Paul M.; Parker, Keith L.; McMillan, Daniel R.

In: Journal of Biological Chemistry, Vol. 283, No. 13, 28.03.2008, p. 8453-8461.

Research output: Contribution to journalArticle

Lavery, GG, Walker, EA, Turan, N, Rogoff, D, Ryder, JW, Shelton, JM, Richardson, JA, Falciani, F, White, PC, Stewart, PM, Parker, KL & McMillan, DR 2008, 'Deletion of hexose-6-phosphate dehydrogenase activates the unfolded protein response pathway and induces skeletal myopathy', Journal of Biological Chemistry, vol. 283, no. 13, pp. 8453-8461. https://doi.org/10.1074/jbc.M710067200
Lavery, Gareth G. ; Walker, Elizabeth A. ; Turan, Nil ; Rogoff, Daniela ; Ryder, Jeffery W. ; Shelton, John M. ; Richardson, James A. ; Falciani, Francesco ; White, Perrin C. ; Stewart, Paul M. ; Parker, Keith L. ; McMillan, Daniel R. / Deletion of hexose-6-phosphate dehydrogenase activates the unfolded protein response pathway and induces skeletal myopathy. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 13. pp. 8453-8461.
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AU - Shelton, John M.

AU - Richardson, James A.

AU - Falciani, Francesco

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