GSE210509
Chronic stress targets mitochondrial respiratory efficiency in the skeletal muscle of C57BL/6 mice [Methylome Dataset]
Chronic stress can result in dysregulation of the cellular metabolism leading to severe disorders including depression, posttraumatic stress disorder but also the metabolic syndrome and type 2 diabetes. We aimed to determine the acute and adaptive effect of stress on energy metabolism in muscle tissue as the main determinant of whole-body energy expenditure. C57Bl6 mice under 15 days of chronic variable stress (Cvs) showed decreased lean mass despite increased energy intake. This was accompanied by reduced energy expenditure (EE) with a concomitant shift in substrate utilization depending on the circadian rhythm. The combination of omics approaches excluded stress effects on transcription and methylation processes in gastrocnemius muscle. Nevertheless, Cvs interfered with altered proteome composition in mitochondria on metabolic components, whilst OXPHOS and structural relevant components were unaltered. Functionally, Cvs resulted in impaired complex independent mitochondrial electron flow and reduced coupling efficiency that correlate for oxidative phosphorylation (state 3) of complex I to diurnal energy expenditure (EE) and for maximal uncoupled respiration (state 3u) of complex II to reduced diurnal and nocturnal EE. Bioenergetics assessment of mitochondria revealed higher optimal thermodynamic efficiencies (?-opt) in Cvs muscle. Conclusion: These results show, that the Cvs reduced mitochondria respiration is associate with low rate of total EE, but does not primary affect transcription and genome methylation in muscle. However, the counter regulation by increased efficiency of complex II may be the driving force in to pave the way to longitudinal metabolic changes as basis of stress memory to muscle physiological adaptation. Overall design: C57/Bl6 male mice were stressed with our Cvs protocol as previously described (doi:https://doi.org/10.1016/j.molmet.2018.06.012), or left untreated (Ctrl). Transcriptome analyses (MTA array, Affymetrix) was performed in Ctrl and Cvs gastrocmnemius muscle biopsies of each condition. Mice were phenotyped for body composition, serum analyses, methylome,  mitochondrial proteome and mitochondrial function and thermodymamic efficency immediately after stress to determine CVS dependant molecular alterations im metabolic regulation.