Examinando por Autor "Persson, Kaspar W."

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    mTOR Ser1261 is an AMPK-­ dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity
    (John Wiley & Sons Inc., 2025-01-31) Li, Jingwen; Madsen, Agnete B.; Knudsen, Jonas R.; Henríquez-Olguín, Carlos; Persson, Kaspar W.; Li, Zhencheng; Raun, Steffen H.; Li, Tianjiao; Kiens, Bente; Wojtaszewski, Jørgen F. P.; Richter, Erik A.; Nogara, Leonardo; Blaauw, Bert; Ogasawara, Riki; Jensen, Thomas E.
    The kinases AMPK, and mTOR as part of either mTORC1 or mTORC2, are major orchestrators of cellular growth and metabolism. Phosphorylation of mTOR Ser1261 is reportedly stimulated by both insulin and AMPK activation and a regulator of both mTORC1 and mTORC2 activity. Intrigued by the possibilities that Ser1261 might be a convergence point between insulin and AMPK signaling in skeletal muscle, we investigated the regulation and function of this site using a combination of human exercise, transgenic mouse, and cell culture models. Ser1261 phosphorylation on mTOR did not respond to insulin in any of our tested models, but instead responded acutely to contractile activity in human and mouse muscle in an AMPK activity-dependent manner. Contraction-stimulated mTOR Ser1261 phosphorylation in mice was decreased by Raptor muscle knockout (mKO) and increased by Raptor muscle overexpression, yet was not affected by Rictor mKO, suggesting most of Ser1261 phosphorylation occurs within mTORC1 in skeletal muscle. In accordance, HEK293 cells mTOR Ser1261Ala mutation strongly impaired phosphorylation of mTORC1 substrates but not mTORC2 substrates. However, neither mTORC1 nor mTORC2-dependent
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    Muscle-specific AXIN1 and AXIN2 double knockout does not alter AMPK/mTORC1 signalling or glucose metabolism
    (The Physiological Society, 2025-07-01) Persson, Kaspar W.; Meneses-Valdés, Roberto; Andersen, Nicoline R.; Pedersen, Frederik S.; Gallo, Samantha; Hesselager, Sofie A.; Henríquez-Olguín, Carlos; Jensen, Thomas E.
    AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) are crucial kinase signalling hubs that regulate the balance between catabolism and anabolism in skeletal muscle. The scaffold protein AXIN1 has been proposed to regulate the switch between these pathways and be required for GLUT4 translocation in skeletal muscle and adipocyte cell lines. Muscle-specific AXIN1 knockout (KO) mice exhibit no discernable phenotype, possibly due to compensation by AXIN2 upon AXIN1 loss. Thus we generated and characterized muscle-specific inducible AXIN1 and AXIN2 double knockout (dKO) mice. Surprisingly AXIN1/2 dKO mice displayed normal AMPK and mTORC1 signalling and glucose uptake in response to 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), insulin and in situ muscle contraction. These findings suggest that AXIN proteins are not essential for the regulation of AMPK and mTORC1 signalling or glucose uptake in skeletal muscle. This study challenges the previously indicated critical roles of AXIN1 in exercise-stimulated AMPK activation and GLUT4-mediated glucose uptake in skeletal muscle. KEY POINTS: Phenotyping of tamoxifen-inducible muscle-specific AXIN1/2 double knockout (dKO) mice. We find no evidence for AXIN-dependent AMPK or mTORC1 regulation in skeletal muscle by insulin, AMPK activation or contraction. Glucose uptake regulation by insulin and AMPK activation is normal in AXIN1/2 dKO mice.
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    Revisiting insulin-stimulated hydrogen peroxide dynamics reveals a cytosolic reductive shift in skeletal muscle
    (Elsevier, 2025-04-25) Henríquez-Olguín, Carlos; Gallero, Samantha; Reddy, Anita; Persson, Kaspar W.; Schlabs, Farina L.; Voldstedlund, Christian T.; Valentinaviciute, Gintare; Meneses-Valdés, Roberto; Sigvardsen, Casper M.; Kiens, Bente; Chouchani, Edward T.; Richter, Erik A.; Jensen, Thomas E.
    The intracellular redox state is crucial for insulin responses in peripheral tissues. Despite the longstanding belief that insulin signaling increases hydrogen peroxide (H2O2) production leading to reversible oxidation of cysteine thiols, evidence is inconsistent and rarely involves human tissues. In this study, we systematically investigated insulin-dependent changes in subcellular H2O2 levels and reversible cysteine modifications across mouse and human skeletal muscle models. Utilizing advanced redox tools including genetically encoded H2O2 sensors and non-reducing immunoblotting we consistently observed no increase in subcellular H2O2 levels following insulin stimulation. Instead, stoichiometric cysteine proteome analyses revealed a selective pro-reductive shift in cysteine modifications affecting insulin transduction related proteins, including Cys179 on GSK3β and Cys416 on Ras and Rab Interactor 2 (RIN2). Our findings challenge the prevailing notion that insulin promotes H2O2 generation in skeletal muscle and suggest that an insulin-stimulated pro-reductive shift modulates certain aspects of insulin signal transduction.