Aid-Vanakova 2019 MiP2019

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Adaptation of muscle OXPHOS in developing glucose intolerance - Wfs1 mice model.

Link: MiP2019

Aid-Vanakova J, Puurand M, Timohhina N, Eimre M, Peet N, Paju K, Kaambre T, Tepp K (2019)

Event: MiP2019

COST Action MitoEAGLE

Mutations in Wfs1 gene, which are responsible for synthesis of transmembrane endoplasmatic reticulum (ER) protein wolframin, cause a multi-targeting disease Wolfram syndrome (WS). The first symptom of the WS is diabetes mellitus, followed in most cases by optic atrophy, diabetes insipidus and deafness. Also, link between Wfs1 deficiency and mitochondrial dysfunction have shown, causing neurological degeneration, ataxia and alteration in heart and skeletal muscle performance [1]. WS is accompanied with progressive loss of pancreatic β-cells cell caused by alterations in cellular Ca2+ signaling related to ER stress and unfolded protein responses [2]. The precise role of wolframin and pathophysiology at organism level is still poorly understood. We used Wfs1KO mice characterized with impaired glucose tolerance and an activated pathway characteristic for metabolic diseases [3].

Aim of the study is to follow alterations in OXPHOS capacity and phosphotransfer networks caused by Wfs1 deficiency in different muscle types: oxidative heart and soleus muscle and glycolytic m. rectus femoris and m. gastrocnemius white.

Our results showed that all the studied muscles Wfs1KO mouse has a maximal of ADP-dependent respiration rate with glutamate and malate lower than that of wild-type (WT) animals. However, when pyruvate and malate is used as substrate, no significant difference was detected. At the same time the leak state without adenylates is higher in Wfs1KO in most muscles with both complex I substrate combinations used. At the same time respiration rates with succinate were unaffected by Wfs1 deficiency. It indicates to metabolic alterations in supporting of OXPHOS at the level of complex I.

Facilitated energy transfer by creatine kinase (CK), adenylate kinase (AK) and other energy transport pathways is governed by the metabolic status of the cell [4]. In Wfs1KO mice heart muscle AK pathway was more active than WT, while the creatine activated respiration is lower than WT. On the contrary, in the glycolytic m. rectus femoris the activity of AK pathway shows a slight decrease in comparison to the control. Results in energy transfer pathways in the heart and skeletal muscles of Wfs1KO mice indicate shift a in the energy pathway preferences. In addition, Wfs1KO mice showed changes in the coupling between OXPHOS and glycolysis in oxidative cardiac and in glycolytic gastrocnemius white muscle. These changes indicate to compensatory mechanism in response to metabolic alterations.


Bioblast editor: Plangger M, Tindle-Solomon L O2k-Network Lab: EE Tallinn Kaambre T, EE Tartu Paju K


Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Diabetes, Other 

Organism: Mouse  Tissue;cell: Heart, Skeletal muscle 


Coupling state: LEAK, OXPHOS  Pathway: N, S  HRR: Oxygraph-2k 


Affiliations

Aid-Vanakova J(1), Puurand M(1), Timohhina N(1), Eimre M(2), Peet N(2), Paju K(2), Käämbre T(1), Tepp K(1)
  1. Lab Chemical Biology, National Inst Chemical Physics Biophysics, Tallinn, Estonia
  2. Chair Pathological Physiology, Inst Bio- Translational Medicine, Univ Tartu, Tartu, Estonia. - kersti.tepp@kbfi.ee

References

  1. Delprat B, Maurice T, Delettre C (2018) Wolfram syndrome: MAMs' connection? Cell Death Dis 9:364.
  2. Ishihara H, Takeda S, Tamura A, Takahashi R, Yamaguchi S, Takei D, Yamada T, Inoue H, Soga H, Katagiri H, Tanizawa Y, Oka Y (2004) Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion. Hum Mol Genet 13:1159-70.
  3. Koks S, Soomets U, Paya-Cano JL, Fernandes C, Luuk H, Plaas M, Terasmaa A, Tillmann V, Noormets K, Vasar E, Schalkwyk LC (2009) Wfs1 gene deletion causes growth retardation in mice and interferes with the growth hormone pathway. Physiol Genomics 37:249-59.
  4. Saks V, Schlattner U, Tokarska-Schlattner M, Wallimann T, Bagur R, Zorman S, Pelosse M, Santos PD, Boucher F, Kaambre T and Guzun R (2014) Systems Level Regulation of Cardiac Energy Fluxes Via Metabolic Cycles: Role of Creatine, Phosphotransfer Pathways, and AMPK Signaling. Systems Biology of Metabolic and Signaling Networks: Energy, Mass and Information Transfer 16:261-320.