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

Abstract

Limb-girdle muscular dystrophy R1 calpain 3-related (LGMDR1) is an autosomal recessive muscular dystrophy produced by mutations in the CAPN3 gene. It is a rare disease and there is no cure or treatment for the disease while the pathophysiological mechanism by which the absence of calpain 3 provokes the dystrophy in muscles is not clear. However, key proteins implicated in Wnt and mTOR signaling pathways, which regulate muscle homeostasis, showed a considerable reduction in their expression and in their phosphorylation in LGMDR1 patients' muscles. Finally, the administration of tideglusib and VP0.7, ATP non-competitive inhibitors of glycogen synthase kinase 3β (GSK-3β), restore the expression and phosphorylation of these proteins in LGMDR1 cells, opening the possibility of their use as therapeutic options.

• Authors: Anabel Rico, Garazi Guembelzu, Valle Palomo, Ana Martínez, Ana Aiastui, Leire Casas-Fraile, Andrea Valls, Adolfo López de Munain, Amets Sáenz
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 14 (Jul 08 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34298987 (Publication Type: Journal Article)

Chemical References

• CD56 Antigen
• Hydrazines
• Intracellular Signaling Peptides and Proteins
• Muscle Proteins
• NCAM1 protein, human
• Nerve Tissue Proteins
• Quinolones
• Thiadiazoles
• small molecule VP 0.7
• Adenosine Triphosphate
• MTOR protein, human
• AKT1 protein, human
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• CAPN3 protein, human
• Calpain
• tideglusib

Topics

• Adenosine Triphosphate (metabolism)
• Allosteric Site (drug effects)
• CD56 Antigen (analysis)
• Calpain (deficiency, genetics)
• Fibroblasts (drug effects, metabolism)
• Gene Expression Regulation (drug effects)
• Glycogen Synthase Kinase 3 beta (antagonists & inhibitors, chemistry)
• Humans
• Hydrazines (pharmacology, therapeutic use)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Muscle Fibers, Skeletal (drug effects, metabolism)
• Muscle Proteins (deficiency, genetics)
• Muscular Dystrophies, Limb-Girdle (drug therapy, enzymology)
• Nerve Tissue Proteins (antagonists & inhibitors, chemistry)
• Phosphorylation
• Protein Processing, Post-Translational (drug effects)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, physiology)
• Quinolones (pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, physiology)
• Thiadiazoles (pharmacology, therapeutic use)
• Wnt Signaling Pathway (drug effects)