Adaptation of striated muscles to Wolframin deficiency in mice: Alterations in cellular bioenergetics

Abstract

Background: Wolfram syndrome (WS), caused by mutations in WFS1 gene, is a multi-targeting disease affecting multiple organ systems. Wolframin is localized in the membrane of the endoplasmic reticulum (ER), influencing Ca 2+ metabolism and ER interaction with mitochondria, but the exact role of the protein remains unclear. In this study we aimed to characterize alterations in energy metabolism in the cardiac and in the oxidative and glycolytic skeletal muscles in Wfs1-deficiency. Methods: Alterations in the bioenergetic profiles in the cardiac and skeletal muscles of Wfs1-knock-out (KO) male mice and their wild type male littermates were determined using high resolution respirometry, quantitative RT-PCR, NMR spectroscopy, and immunofluorescence confocal microscopy. Results: Oxygen consumption without ATP synthase activation (leak) was significantly higher in the glycolytic muscles of Wfs1 KO mice compared to wild types. ADP-stimulated respiration with glutamate and malate was reduced in the Wfs1-deficient cardiac as well as oxidative and glycolytic skeletal muscles. Conclusions: Wfs1-deficiency in both cardiac and skeletal muscles results in functional alterations of energy transport from mitochondria to ATP-ases. There was a substrate-dependent decrease in the maximal Complex I -linked respiratory capacity of the electron transport system in muscles of Wfs1 KO mice. Moreover, in cardiac and gastrocnemius white muscles a decrease in the function of one pathway were balanced by the increase in the activity of the parallel pathway. General significance: This work provides new insights to the muscle involvement at early stages of metabolic syndrome like WS as well as developing glucose intolerance.

Morphological, behavioral and cellular analyses revealed different phenotypes in Wolfram syndrome wfs1a and wfs1b zebrafish mutant lines

“…Expression of Wfs1 in the mouse is also seen in a multitude of different tissues, including skeletal and cardiac muscle ( 29 , 30 ) (see also http://www.informatics.jax.org/gxd/marker/MGI:1328355 ). Wfs1 -deficient mice show alterations in protein expression ( 31 ) and energy metabolism ( 32 ) in both muscle tissue types. In vitro assays have also demonstrated that the mammalian Wfs1 protein functions in the nuclear envelope to reposition muscle-specific genes during myogenesis ( 33 ).…”

Wolframin deficiency is accompanied with metabolic inflexibility in rat striated muscles

“…In our previous study we investigated alterations in mitochondrial metabolism of Wfs1KO mice muscles and found decreased and less coupled NADH-linked ADP-stimulated respiration in comparison with wild type (WT) littermates [ 43 ]. These alterations were largely substrate-dependent.…”

“…In Wfs1KO mice muscles the maximal mitochondrial respiration in the presence of Glutamate (Glut) and Malate (Mal) as respiratory system complex I (CI)-linked substrates was decreased in all studied muscle types, accompanied with significantly increased Leak respiration in glycolytic muscles. With Mal and Pyruvate (Pyr) as substrates the increased Leak was detected only in glycolytic muscles (rectus femoris (RF)) and white gastrocnemius (GW)) and decrease in CI linked oxygen consumption was significant only in GW [ 43 , 44 ]. Decrease in adenylate and creatine kinase enzymatic activities of skeletal muscles of wolframin-deficient glucose-intolerant animals and changes in coupling of these enzymes to oxidative phosphorylation (OxPhos) suggest the reconfiguration of energy transport networks and thus could affect muscle performance at higher workloads [ 43 ].…”

“…With Mal and Pyruvate (Pyr) as substrates the increased Leak was detected only in glycolytic muscles (rectus femoris (RF)) and white gastrocnemius (GW)) and decrease in CI linked oxygen consumption was significant only in GW [ 43 , 44 ]. Decrease in adenylate and creatine kinase enzymatic activities of skeletal muscles of wolframin-deficient glucose-intolerant animals and changes in coupling of these enzymes to oxidative phosphorylation (OxPhos) suggest the reconfiguration of energy transport networks and thus could affect muscle performance at higher workloads [ 43 ].…”