Induction of the nicotinamide riboside kinase NAD + salvage pathway in a model of sarcoplasmic reticulum dysfunction.

Autor: Doig CL; Institute of Metabolism and Systems Research, University of Birmingham, 2nd Floor IBR Tower, Edgbaston, Birmingham, B15 2TT, UK.; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK., Zielinska AE; Institute of Metabolism and Systems Research, University of Birmingham, 2nd Floor IBR Tower, Edgbaston, Birmingham, B15 2TT, UK., Fletcher RS; Institute of Metabolism and Systems Research, University of Birmingham, 2nd Floor IBR Tower, Edgbaston, Birmingham, B15 2TT, UK.; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK., Oakey LA; Institute of Metabolism and Systems Research, University of Birmingham, 2nd Floor IBR Tower, Edgbaston, Birmingham, B15 2TT, UK.; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK., Elhassan YS; Institute of Metabolism and Systems Research, University of Birmingham, 2nd Floor IBR Tower, Edgbaston, Birmingham, B15 2TT, UK.; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK., Garten A; Institute of Metabolism and Systems Research, University of Birmingham, 2nd Floor IBR Tower, Edgbaston, Birmingham, B15 2TT, UK., Cartwright D; Institute of Metabolism and Systems Research, University of Birmingham, 2nd Floor IBR Tower, Edgbaston, Birmingham, B15 2TT, UK.; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK., Heising S; Institute of Metabolism and Systems Research, University of Birmingham, 2nd Floor IBR Tower, Edgbaston, Birmingham, B15 2TT, UK.; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK., Alsheri A; Strathclyde Institute of Pharmacy and Medical Sciences, Hamnett Wing John Arbuthnott Building, Glasgow, G4 0RE, UK., Watson DG; Strathclyde Institute of Pharmacy and Medical Sciences, Hamnett Wing John Arbuthnott Building, Glasgow, G4 0RE, UK., Prehn C; Research Unit of Molecular Endocrinology and Metabolism, Helmholtz Zentrum Munchen GmbH, Ingolstadter Landstrasse 1, D-85764, Neuherberg, Germany.; Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising, Germany.; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117593, Singapore., Adamski J; Research Unit of Molecular Endocrinology and Metabolism, Helmholtz Zentrum Munchen GmbH, Ingolstadter Landstrasse 1, D-85764, Neuherberg, Germany.; Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising, Germany.; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117593, Singapore., Tennant DA; Institute of Metabolism and Systems Research, University of Birmingham, 2nd Floor IBR Tower, Edgbaston, Birmingham, B15 2TT, UK.; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK., Lavery GG; Institute of Metabolism and Systems Research, University of Birmingham, 2nd Floor IBR Tower, Edgbaston, Birmingham, B15 2TT, UK. g.g.lavery@bham.ac.uk.; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK. g.g.lavery@bham.ac.uk.; MRC-ARUK Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, UK. g.g.lavery@bham.ac.uk.
Jazyk: angličtina
Zdroj: Skeletal muscle [Skelet Muscle] 2020 Feb 19; Vol. 10 (1), pp. 5. Date of Electronic Publication: 2020 Feb 19.
DOI: 10.1186/s13395-019-0216-z
Abstrakt: Background: Hexose-6-Phosphate Dehydrogenase (H6PD) is a generator of NADPH in the Endoplasmic/Sarcoplasmic Reticulum (ER/SR). Interaction of H6PD with 11β-hydroxysteroid dehydrogenase type 1 provides NADPH to support oxo-reduction of inactive to active glucocorticoids, but the wider understanding of H6PD in ER/SR NAD(P)(H) homeostasis is incomplete. Lack of H6PD results in a deteriorating skeletal myopathy, altered glucose homeostasis, ER stress and activation of the unfolded protein response. Here we further assess muscle responses to H6PD deficiency to delineate pathways that may underpin myopathy and link SR redox status to muscle wide metabolic adaptation.
Methods: We analysed skeletal muscle from H6PD knockout (H6PDKO), H6PD and NRK2 double knockout (DKO) and wild-type (WT) mice. H6PDKO mice were supplemented with the NAD + precursor nicotinamide riboside. Skeletal muscle samples were subjected to biochemical analysis including NAD(H) measurement, LC-MS based metabolomics, Western blotting, and high resolution mitochondrial respirometry. Genetic and supplement models were assessed for degree of myopathy compared to H6PDKO.
Results: H6PDKO skeletal muscle showed adaptations in the routes regulating nicotinamide and NAD + biosynthesis, with significant activation of the Nicotinamide Riboside Kinase 2 (NRK2) pathway. Associated with changes in NAD + biosynthesis, H6PDKO muscle had impaired mitochondrial respiratory capacity with altered mitochondrial acylcarnitine and acetyl-CoA metabolism. Boosting NAD + levels through the NRK2 pathway using the precursor nicotinamide riboside elevated NAD + /NADH but had no effect to mitigate ER stress and dysfunctional mitochondrial respiratory capacity or acetyl-CoA metabolism. Similarly, H6PDKO/NRK2 double KO mice did not display an exaggerated timing or severity of myopathy or overt change in mitochondrial metabolism despite depression of NAD + availability.
Conclusions: These findings suggest a complex metabolic response to changes in muscle SR NADP(H) redox status that result in impaired mitochondrial energy metabolism and activation of cellular NAD + salvage pathways. It is possible that SR can sense and signal perturbation in NAD(P)(H) that cannot be rectified in the absence of H6PD. Whether NRK2 pathway activation is a direct response to changes in SR NAD(P)(H) availability or adaptation to deficits in metabolic energy availability remains to be resolved.
Databáze: MEDLINE
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