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WWOX somatic ablation in skeletal muscles alters glucose metabolism.

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?SKM) results in weight gain, glucose intolerance, and insulin resistance. Furthermore, Wwox?SKM 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 (HIF1?) 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.

SUBMITTER: Abu-Remaileh M

PROVIDER: S-EPMC6437662 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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WWOX somatic ablation in skeletal muscles alters glucose metabolism.

Abu-Remaileh Muhannad M Abu-Remaileh Monther M Akkawi Rania R Knani Ibrahim I Udi Shiran S Pacold Micheal E ME Tam Joseph J Aqeilan Rami I RI

Molecular metabolism 20190131

<h4>Objective</h4>WWOX, a well-established tumor suppressor, is frequently lost in cancer and plays important roles in DNA damage response and cellular metabolism.<h4>Methods</h4>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.<h4>Results</h4>Several WWOX variants wer ...[more]

PMID: 30755385

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Project description:BackgroundMice lacking vitamin D receptor (VDR) exhibit a glycogen storage disorder, disrupting carbohydrate utilization in muscle. Here, we asked if the defective carbohydrate metabolism alters the fat utilization by the skeletal muscles of vdr-/- mice.MethodsTo check the effect of high-fat-containing diets on muscle mass and metabolism of vdr-/- mice, we subjected them to two different milk fat-based diets (milk fat diet with 60% of energy from milk fat and milk-based diet [MBD] with 37% of energy from milk fat) and lard-based high-fat diet (HFD) containing 60% of energy from lard fat. Skeletal muscles and pancreas from these mice were analysed using RNA sequencing, quantitative reverse transcription polymerase chain reaction and western blot to understand the changes in signalling and metabolic pathways. Microscopic analyses of cryosections stained with haematoxylin and eosin, BODIPY, succinate dehydrogenase and periodic acid-Schiff reagent were performed to understand changes in morphology and metabolism of muscle fibres and pancreatic islets.ResultsTranscriptomic analyses showed that the skeletal muscles of vdr-/- mice exhibit upregulation of the fatty acid oxidation pathways, suggesting a shift towards increased lipid utilization even in a carbohydrate-enriched regular chow diet (chow). Two different milk fat-enriched diets restored body weight (12.01 ± 0.33 g in chow vs. 17.99 ± 0.62 g in MBD) and muscle weights (38.58 ± 3.84 mg in chow vs. 110.72 ± 1.96 mg in MBD for gastrocnemius [GAS]) of vdr-/- mice. Muscle ATP levels (0.56 ± 0.18 μmol in chow vs. 1.48 ± 0.08 μmol in MBD) and protein synthesis (0.25 ± 0.04 A.U. in chow vs. 2.02 ± 0.06 A.U. in MBD) were upregulated by MBD. However, despite increasing muscle energy levels, HFD failed to restore the muscle mass and cross-sectional area to that of wild-type (WT) mice (104.95 ± 2.6 mg for WT mice on chow vs. 77.26 ± 1.7 mg for vdr-/- mice on HFD for GAS). Moreover, HFD disrupted glucose homeostasis in vdr-/- mice, while MBD restored it. We further analysed insulin response and pancreatic insulin levels of these mice to show that HFD led to reduced insulin levels in pancreatic beta cells of vdr-/- mice (mean intensity of 1.5 × 10-8 for WT mice on chow vs. 4.3 × 10-9 for vdr-/- mice on HFD). At the same time, MBD restored glucose-stimulated pancreatic insulin response (mean intensity of 9.2 × 10-9 ).ConclusionsSkeletal muscles of vdr-/- mice are predisposed to utilize fatty acids as their primary energy source to circumvent their defective carbohydrate utilization. Thus, HFDs could restore energy levels in the skeletal muscles of vdr-/- mice. This study reveals that when mice are subjected to a lard-based HFD, VDR signalling is essential for maintaining insulin levels in pancreatic islets. Our data show a critical role of VDR in muscle metabolic flexibility and pancreatic insulin response.

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WWOX somatic ablation in skeletal muscles alters glucose metabolism.

Publications

WWOX somatic ablation in skeletal muscles alters glucose metabolism.

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