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Molecular sport nutrition
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Mark Hearris, Nathan Hodson, Javier Gonzalez, James P. Morton
Various metabolic proteins are known to interact and localise within the glycogen granule (89). Of these proteins, the mammalian AMP-activated protein kinase (AMPK), which plays a central role in monitoring cellular energy status, contains a glycogen binding domain on its β-subunit. This binding domain permits glycogen to bind to this kinase and allows AMPK to act as a sensor of endogenous glycogen stores. In this way, under conditions of low glycogen availability, the exercise-induced activity and phosphorylation of AMPK are all enhanced (88, 90, 91). Despite its apparent regularly role, the signal created by low glycogen alone (i.e. without exercise) may be insufficient to activate AMPK (90, 91) given the comparatively large increase in AMPK activation that occurs when exercise is commenced with low muscle glycogen. As such, it appears that the combination of low glycogen and exercise provides the most powerful signal to activate AMPK. In fact, in some cases, the typical increase in AMPK that occurs in response to exercise can be completely supressed under conditions of normal glycogen stores (90, 91). As AMPK plays an important role in the activation of various transcription factors and co-activators within the signal transduction network, it is clear to see the regulatory role that glycogen exerts. For example, AMPK can phosphorylate and histone deacetylase 5 (HDAC5) resulting it its removal from the nucleus, subsequently allowing for the myocyte enhancer factor 2 (MEF2) to bind and activate PGC-1α. As discussed in chapter 9, the activation of PGC-1α is central to the transcription of many genes associated with endurance training adaptations.
GRK2 and GRK5 as therapeutic targets and their role in maladaptive and pathological cardiac hypertrophy
Published in Expert Opinion on Therapeutic Targets, 2019
GRK5, like GRK2, can phosphorylate GPCR and non-GPCR substrates. GRK5 has not been studied as much as GRK2 for these non-GPCR interactions and how they affect pathophysiology. Indeed, GRK2 and GRK5 share and interact with overlapping substrates. However, GRK5’s distinct structural features give it unique characteristics. GRK5 can enter the nucleus through its nuclear localization signal to influence gene transcription. One of the earliest evidence for GRK5 promoting pathological hypertrophy was its ability to phosphorylate class II histone deacetylase-5 (HDAC5) [38]. Class IIa HDACs are able to regulate cardiac gene expression through repression of important transcription factors including MEF2, NFAT, SRF, and Nkx2-5 [48]. Upon HDAC5 phosphorylation by GRK5, HDAC5 is exported out of the nucleus and no longer able to repress MEF2. MEF2 activation causes increased hypertrophic gene expression and is required for cardiac hypertrophy [49]. In fact, HDAC5 knockout mice develop cardiac hypertrophy with age and have an exaggerated hypertrophic response to constitutive calcineurin activation [50]. GRK5 overexpressing NRVMs were observed to have increased MEF2 activity, which was exaggerated with coinfection with AdCAM-Gq, as expected. GRK5 was revealed with directly phosphorylate HDAC5 at Ser-259 through immunoprecipitation and phosphorylation assays. Mutation of Ser-259 → Ala abolished HDAC5 phosphorylation by GRK5. HDAC kinase activity is dependent on GRK5’s nuclear localization. GRK2 does not display HDAC5 kinase activity [38]. Interestingly, GRK5 nuclear localization is not observed with physiological hypertrophy induced by high-intensity swim [51].
Fifty years of experience with loxapine for the rapid non-coercive tranquilization of acute behavioral disturbances in schizophrenia patients, and beyond
Published in Expert Review of Neurotherapeutics, 2022
Philippe Nuss, Emmanuelle Corruble, Emmanuelle Baloche, Ricardo P. Garay, Pierre-Michel Llorca
ADPKD is a common and serious genetic disease that leads to end-stage renal failure [123]. It is mainly caused by mutations in polycystin-1 or polycystin-2, which alters the maintenance of the renal epithelial architecture through the nuclear export of histone deacetylase 5 (HDAC5). To date, there are few therapeutic interventions against this disease.
Myokine-mediated exercise effects: the role of myokine meteorin-like hormone (Metrnl)
Published in Growth Factors, 2021
Myokine Metrnl has been shown to beneficially affect glucose metabolism. Exercise-induced Metrnl has been shown to improve glucose uptake in skeletal muscle (Lee et al. 2020). Lee et al. showed that exercise-induced Metrnl increases muscle glucose uptake through the phosphorylation of AMP-activated kinase (AMPK), a master muscle energy-sensing protein, which then modulates the phosphorylation of several other proteins which in turn increase GLUT4-mediated glucose uptake in skeletal muscle (Lee et al. 2020). Exercise-induced Metrnl, as the highest-upstream molecule in the glucose uptake-mediating signalling pathway, increases the calcium ions which then bind to the Calmudolin protein which in turn activates Ca2+/Calmodulin-Dependent Protein Kinase Kinase-2 (CaKKM2) (Lee et al. 2020). CaKKM2 subsequently activates AMPK which then activates p38 mitogen-activated protein kinase (MAPK) (Lee et al. 2020). P38 MAPK, as the downstream of AMPK, afterwards increases the muscle glucose uptake via improving GLUT-4 translocation (Lee et al. 2020). Another Metrnl-mediated signalling pathway for muscle glucose uptake is through the phosphorylation of Histone deacetylase 5 (HDAC5) (Lee et al. 2020). HDAC5, the main repressor of GLUT-4, is exported phosphorylated from nucleus into the cytosol. Metrnl increases the expression of GLUT-4 via increasing HDAC5 phosphorylation which decreases HDAC5 binding to GLUT-4 promoter (Lee et al. 2020). This Metrnl-mediated increased expression of GLUT-4 via reducing HDAC5 binding to GLUT-4 promoter is also mediated through AMPK (Lee et al. 2020). The last Metrnl-mediated signalling pathway for muscle glucose uptake is via TBC1D1, a Rab-GTPase-activating protein involved in GLUT4 trafficking and is known to be activated by AMPK (Lee et al. 2020). Metrnl-mediated muscle glucose uptake is depicted in Figure 2.