WWOX somatic ablation in skeletal muscles alters glucose metabolism

Muhannad Abu-Remaileh, Monther Abu-Remaileh, Rania Akkawi, Ibrahim Knani, Shiran Udi, Micheal E. Pacold, Joseph Tam, Rami I. Aqeilan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Objective: WWOX, a well-established tumor suppressor, is frequently lost in cancer and plays important roles in DNA damage response and cellular metabolism. Methods: We re-analyzed several genome-wide association studies (GWAS) using the Type 2 Diabetes Knowledge Portal website to uncover WWOX's association with metabolic syndrome (MetS). Using several engineered mouse models, we studied the effect of somatic WWOX loss on glucose homeostasis. Results: Several WWOX variants were found to be strongly associated with MetS disorders. In mouse models, somatic ablation of Wwox in skeletal muscle (Wwox ΔSKM ) results in weight gain, glucose intolerance, and insulin resistance. Furthermore, Wwox ΔSKM mice display reduced amounts of slow-twitch fibers, decreased mitochondrial quantity and activity, and lower glucose oxidation levels. Mechanistically, we found that WWOX physically interacts with the cellular energy sensor AMP-activated protein kinase (AMPK) and that its loss is associated with impaired activation of AMPK, and with significant accumulation of the hypoxia inducible factor 1 alpha (HIF1α) in SKM. Conclusions: Our studies uncover an unforeseen role of the tumor suppressor WWOX in whole-body glucose homeostasis and highlight the intimate relationship between cancer progression and metabolic disorders, particularly obesity and type-2 diabetes. Subject areas: Genetics, Metabolic Syndrome, Diabetes.

Original languageAmerican English
Pages (from-to)132-140
Number of pages9
JournalMolecular Metabolism
Volume22
DOIs
StatePublished - Apr 2019

Bibliographical note

Funding Information:
We are grateful to Ben Cohen, Daniel Steinberg, and Tirza Bidani for their technical help. The Aqeilan lab is supported by a Worldwide Cancer Research grant (grant agreement No. 14-1095 ) and an European Research Council (ERC)-Consolidator Grant under the European Union's Horizon 2020 research and innovation program (grant agreement No. 682118 ). This work was also supported in part by the Israel Science Foundation (ISF) grant ( #1471/14 to J.T.).

Funding Information:
We are grateful to Ben Cohen, Daniel Steinberg, and Tirza Bidani for their technical help. The Aqeilan lab is supported by a Worldwide Cancer Research grant (grant agreement No. 14-1095) and an European Research Council (ERC)-Consolidator Grant under the European Union's Horizon 2020 research and innovation program (grant agreement No. 682118). This work was also supported in part by the Israel Science Foundation (ISF) grant (#1471/14 to J.T.).

Publisher Copyright:
© 2019 The Authors

Keywords

  • AMPK
  • Metabolic syndrome
  • T2D
  • Tumor suppressor
  • WWOX

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