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Chronic stress targets mitochondrial respiratory efficiency in the skeletal muscle of C57BL/6 mice [Methylome Dataset]

ABSTRACT: 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 (ƞ-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.

ORGANISM(S): Mus musculus

PROVIDER: GSE210509 | GEO | 2023/04/03

REPOSITORIES: GEO

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Project description:Episodes of chronic stress can result in psychic disorders like post-traumatic stress disorder, but also promote the development of metabolic syndrome and type 2 diabetes. We hypothesize that muscle, as main regulator of whole-body energy expenditure, is a central target of acute and adaptive molecular effects of stress in this context. Here, we investigate the immediate effect of a stress period on energy metabolism in Musculus gastrocnemius in our established C57BL/6 chronic variable stress (Cvs) mouse model. Cvs decreased lean body mass despite increased energy intake, reduced circadian energy expenditure (EE), and substrate utilization. Cvs altered the proteome of metabolic components but not of the oxidative phosphorylation system (OXPHOS), or other mitochondrial structural components. Functionally, Cvs impaired the electron transport chain (ETC) capacity of complex I and complex II, and reduces respiratory capacity of the ETC from complex I to ATP synthase. Complex I-OXPHOS correlated to diurnal EE and complex II-maximal uncoupled respiration correlated to diurnal and reduced nocturnal EE. Bioenergetics assessment revealed higher optimal thermodynamic efficiencies (ƞ-opt) of mitochondria via complex II after Cvs. Interestingly, transcriptome and methylome were unaffected by Cvs, thus excluding major contributions to supposed metabolic adaptation processes. In summary, the preclinical Cvs model shows that metabolic pressure by Cvs is initially compensated by adaptation of mitochondria function associated with high thermodynamic efficiency and decreased EE to manage the energy balance. This counter-regulation of mitochondrial complex II may be the driving force to longitudinal metabolic changes of muscle physiological adaptation as the basis of stress memory.Chronic stress targets mitochondrial respiratory efficiency in the skeletal muscle of C57BL/6 mice.Nikolic A, Fahlbusch P, Wahlers N, Riffelmann NK, Jacob S, Hartwig S, Kettel U, Dille M, Al-Hasani H, Kotzka J, Knebel B. Cell Mol Life Sci. 2023 Mar 29;80(4):108. doi: 10.1007/s00018-023-04761-4.PMID: 36988756

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Chronic stress targets mitochondrial respiratory efficiency in the skeletal muscle of C57BL/6 mice [Methylome Dataset]

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