Allosteric Modulation of GSK-3β as a New Therapeutic Approach in Limb Girdle Muscular Dystrophy R1 Calpain 3-Related

Rico, Anabel; Guembelzu, Garazi; Palomo, Valle; Martı́nez, Ana; Aiastui, Ana; Casas-Fraile, Leire; Valls, Andrea; Munáin, Adolfo López de; Sáenz, Amets

doi:10.3390/ijms22147367

Cited by 7 publications

(10 citation statements)

References 68 publications

(81 reference statements)

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“…Study has also revealed Tideglusib’s ability in activating PI3K/Akt signaling pathway in myotubes, hypoxic-ischemic brain injury, etc. [ 14 , 38 , 39 ]. In this study, we found that Tideglusib could promote the activation of PI3K/Akt signaling pathway in EpiSCs, thus accelerating wound healing not only in young rats but also in aged rats.…”

Section: Discussionmentioning

confidence: 99%

Tideglusib promotes wound healing in aged skin by activating PI3K/Akt pathway

et al. 2022

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Background Aging disturbs the skin morphology and function, manifested as thinned epithelium and impaired wound healing. As a major type of skin cells, epidermal stem cells (EpiSCs) are inevitably affected by aging. The effect of age on EpiSCs and wound healing needs to be further explored. Methods Skin RNA-seq data of young (5 months) and old (30 months) CB6F1 mice were obtained from GEO Series GSE35322 with 10 in each age group. Differentially expressed genes were analyzed, and EpiSCs-related pathways were enriched by KEGG. The age-related changes of the screened PI3K/Akt pathway were validated by Western Blot and immunofluorescence of epidermis of SD rats (2, 17, and 23 months, n = 6). The expression of upstream protein EGFR was assessed by immunofluorescence in skin of mice (4, 13, and 23 months, n = 6) and human (respectively, 23, 28, 30 years old in the young group and 69, 73, 78 years old in the old group) skin. Inhibitors of EGFR were used to verify its effects on EpiSCs and wound healing. The small molecule drug Tideglusib was tested for its effects on signaling pathways of EpiSCs and wound healing of aged rats. Western Blot was used for the detection of signaling pathways in in vitro experiments. Cell migration assays were used to assess cell migration ability. Flow cytometry was used to detect changes in cell cycle and apoptosis levels. Sulforhodamine B assay and CCK-8 assay were used to evaluate cell proliferation and viability, respectively. Student’s t test and one-way analysis of variance (ANOVA) followed by the multiple comparisons Bonferroni test were used for statistical analysis. The 0.05 level of confidence was accepted as a significant difference. Results EpiSCs-related PI3K/Akt pathway was enriched by KEGG and verified by decreased phosphorylation of Akt (32.1 ± 13.8%, P < 0.01) and mTOR (38.9 ± 11.8%, P < 0.01) in aged epidermis of rats. Furthermore, the expression of PI3K/Akt-upstream EGFR decreased with age in the epidermis of mouse (27.6 ± 5.5%, P < 0.01) and human (25.8 ± 9.3%, P < 0.01). With EGFR blocked by Erlotinib, EpiSCs showed reduced phosphorylation of Akt (30.4 ± 10.6%, P < 0.01) and mTOR (39.8 ± 12.8%, P < 0.01), impaired proliferation and migration after incubated for 24 h and 36 h (P < 0.05), and higher levels of apoptosis (11.9 ± 1.7%, P < 0.05), and rats showed slower wound healing from d7 to d14 after wounding (P < 0.01). In addition to slower wound healing rates, aged rats also showed a decrease in the efficacy of EGF, partly due to the downregulated EGFR expression. By activating PI3K/Akt pathway, Tideglusib promoted the proliferation and migration of EpiSCs with apoptosis inhibited (P < 0.01) and accelerated wound healing in aged rats from d7 to d14 after wounding (P < 0.05). Notably, the combined use of Tideglusib and EGF could further enhance wound healing in aged rats. Conclusions The decreased expression of EGFR in epidermis with age resulted in decreased activity of the PI3K/Akt pathway and limited EGF efficacy. Tideglusib could assist wound healing in aged rats via activating PI3K/Akt pathway, which may be considered as an ingredient for medical and cosmetics use.

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Section: Discussionmentioning

confidence: 99%

Tideglusib promotes wound healing in aged skin by activating PI3K/Akt pathway

et al. 2022

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“…Notably, in mouse models of limb girdle muscular dystrophy R1 calpain 3-related (LGMDR1), in vivo administration of VP0.7 and Tideglusib restored the expression and phosphorylation of key proteins that are implicated in Wnt and mTOR signaling pathways and that are reduced in LGMDR1 patients. This suggests GSK-3β allosteric modulation could be a possible therapeutic strategy for this disease [ 98 ]. In addition, administration of VP0.7 and TDZD-8 in experimental mouse models of AE reduced pathology severity [ 99 ], hinting at GSK-3β as a feasible target for new therapeutic interventions for AE.…”

Section: Gsk-3β Inhibitionmentioning

confidence: 99%

GSK-3β Allosteric Inhibition: A Dead End or a New Pharmacological Frontier?

Balboni

Masi

Rocchia

et al. 2023

IJMS

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Most kinase inhibitors are designed to bind to highly homologous ATP-binding sites, which leads to promiscuity and possible off-target effects. Allostery is an alternative approach to pursuing selectivity. However, allostery is difficult to exploit due to the wide variety of underlying mechanisms and the potential involvement of long-range conformational effects that are difficult to pinpoint. GSK-3β is involved in several pathologies. This critical target has an ATP-binding site that is highly homologous with the orthosteric sites of other kinases. Unsurprisingly, there is also great similarity between the ATP-binding sites of GSK-3β and its isomer, which is not redundant and thus would benefit from selective inhibition. Allostery would also allow for a moderate and tunable inhibition, which is ideal for GSK-3β, because this target is involved in multiple pathways, some of which must be preserved. However, despite considerable research efforts, only one allosteric GSK-3β inhibitor has reached the clinic. Moreover, unlike other kinases, there are no X-ray structures of GSK-3β in complex with allosteric inhibitors in the PDB data bank. This review aims to summarize the state of the art in allosteric GSK-3β inhibitor investigations, highlighting the aspects that make this target challenging for an allosteric approach.

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“…Schlüsselproteine, die die Muskelhomöostase regulieren, zeigten eine beträchtliche Verringerung ihrer Expression und ihrer Phosphorylierung in Muskeln von LGMD2A/R1-Patienten. Die Verabreichung von Tideglusib und VP0.7, beides ATP-nicht-kompetitive Inhibitoren der Glykogensynthase Kinase 3β, führten in LGMD2A/R1 Zellen zur Wiederherstellung der Expression und Phosphorylierung von Proteinen, die an den Wnt-und mTOR-Signalwegen beteiligt sind, so dass sich hier neue therapeutische Optionen ergeben [14]. [15,16].…”

Section: Inhibitoren Der Glykogensynthase Kinase 3βunclassified

Molekulare Therapien erblicher Myopathien im Erwachsenenalter – eine kursive Rundschau

Schoser

2022

Fortschr Neurol Psychiatr

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ZusammenfassungUnterschiedliche Formen der molekularen Therapie sind zu einer neuen Möglichkeit in der Präzisionsbehandlung erblicher neuromuskulärer Erkrankungen geworden. Dieser kursive Überblick über die molekularen Therapien bei hereditären Myopathien wird sich auf ausgewählte aktuelle Phase 1 bis 3 Studien zu häufigen hereditären Myopathien im Erwachsenenalter wie die Dystrophinopathie Becker-Kiener, die Fazioskapulohumerale Muskeldystrophie, Calpainopathie, und die Dysferlinopathie fokussieren. Die Therapieoptionen zum Morbus Pompe dienen als Beispiel für die hereditären metabolischen Myopathien.

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Allosteric Modulation of GSK-3β as a New Therapeutic Approach in Limb Girdle Muscular Dystrophy R1 Calpain 3-Related

Cited by 7 publications

References 68 publications

Tideglusib promotes wound healing in aged skin by activating PI3K/Akt pathway

Tideglusib promotes wound healing in aged skin by activating PI3K/Akt pathway

GSK-3β Allosteric Inhibition: A Dead End or a New Pharmacological Frontier?

Molekulare Therapien erblicher Myopathien im Erwachsenenalter – eine kursive Rundschau

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