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Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations

LGMDR1 is caused by mutations in the CAPN3 gene that encodes calpain 3 (CAPN3), a non-lysosomal cysteine protease necessary for proper muscle function. Our previous findings show that CAPN3 deficiency leads to reduced SERCA levels through increased protein degradation. This work investigates the pot...

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Autores principales: Lasa-Elgarresta, Jaione, Mosqueira-Martín, Laura, González-Imaz, Klaudia, Marco-Moreno, Pablo, Gerenu, Gorka, Mamchaoui, Kamel, Mouly, Vincent, López de Munain, Adolfo, Vallejo-Illarramendi, Ainara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8924035/
https://www.ncbi.nlm.nih.gov/pubmed/35309930
http://dx.doi.org/10.3389/fcell.2022.822563
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author Lasa-Elgarresta, Jaione
Mosqueira-Martín, Laura
González-Imaz, Klaudia
Marco-Moreno, Pablo
Gerenu, Gorka
Mamchaoui, Kamel
Mouly, Vincent
López de Munain, Adolfo
Vallejo-Illarramendi, Ainara
author_facet Lasa-Elgarresta, Jaione
Mosqueira-Martín, Laura
González-Imaz, Klaudia
Marco-Moreno, Pablo
Gerenu, Gorka
Mamchaoui, Kamel
Mouly, Vincent
López de Munain, Adolfo
Vallejo-Illarramendi, Ainara
author_sort Lasa-Elgarresta, Jaione
collection PubMed
description LGMDR1 is caused by mutations in the CAPN3 gene that encodes calpain 3 (CAPN3), a non-lysosomal cysteine protease necessary for proper muscle function. Our previous findings show that CAPN3 deficiency leads to reduced SERCA levels through increased protein degradation. This work investigates the potential contribution of the ubiquitin-proteasome pathway to increased SERCA degradation in LGMDR1. Consistent with our previous results, we observed that CAPN3-deficient human myotubes exhibit reduced SERCA protein levels and high cytosolic calcium concentration. Treatment with the proteasome inhibitor bortezomib (Velcade) increased SERCA2 protein levels and normalized intracellular calcium levels in CAPN3-deficient myotubes. Moreover, bortezomib was able to recover mutated CAPN3 protein in a patient carrying R289W and R546L missense mutations. We found that CAPN3 knockout mice (C3KO) presented SERCA deficits in skeletal muscle in the early stages of the disease, prior to the manifestation of muscle deficits. However, treatment with bortezomib (0.8 mg/kg every 72 h) for 3 weeks did not rescue SERCA levels. No change in muscle proteasome activity was observed in bortezomib-treated animals, suggesting that higher bortezomib doses are needed to rescue SERCA levels in this model. Overall, our results lay the foundation for exploring inhibition of the ubiquitin-proteasome as a new therapeutic target to treat LGMDR1 patients. Moreover, patients carrying missense mutations in CAPN3 and presumably other genes may benefit from proteasome inhibition by rescuing mutant protein levels. Further studies in suitable models will be necessary to demonstrate the therapeutic efficacy of proteasome inhibition for different missense mutations.
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spelling pubmed-89240352022-03-17 Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations Lasa-Elgarresta, Jaione Mosqueira-Martín, Laura González-Imaz, Klaudia Marco-Moreno, Pablo Gerenu, Gorka Mamchaoui, Kamel Mouly, Vincent López de Munain, Adolfo Vallejo-Illarramendi, Ainara Front Cell Dev Biol Cell and Developmental Biology LGMDR1 is caused by mutations in the CAPN3 gene that encodes calpain 3 (CAPN3), a non-lysosomal cysteine protease necessary for proper muscle function. Our previous findings show that CAPN3 deficiency leads to reduced SERCA levels through increased protein degradation. This work investigates the potential contribution of the ubiquitin-proteasome pathway to increased SERCA degradation in LGMDR1. Consistent with our previous results, we observed that CAPN3-deficient human myotubes exhibit reduced SERCA protein levels and high cytosolic calcium concentration. Treatment with the proteasome inhibitor bortezomib (Velcade) increased SERCA2 protein levels and normalized intracellular calcium levels in CAPN3-deficient myotubes. Moreover, bortezomib was able to recover mutated CAPN3 protein in a patient carrying R289W and R546L missense mutations. We found that CAPN3 knockout mice (C3KO) presented SERCA deficits in skeletal muscle in the early stages of the disease, prior to the manifestation of muscle deficits. However, treatment with bortezomib (0.8 mg/kg every 72 h) for 3 weeks did not rescue SERCA levels. No change in muscle proteasome activity was observed in bortezomib-treated animals, suggesting that higher bortezomib doses are needed to rescue SERCA levels in this model. Overall, our results lay the foundation for exploring inhibition of the ubiquitin-proteasome as a new therapeutic target to treat LGMDR1 patients. Moreover, patients carrying missense mutations in CAPN3 and presumably other genes may benefit from proteasome inhibition by rescuing mutant protein levels. Further studies in suitable models will be necessary to demonstrate the therapeutic efficacy of proteasome inhibition for different missense mutations. Frontiers Media S.A. 2022-03-02 /pmc/articles/PMC8924035/ /pubmed/35309930 http://dx.doi.org/10.3389/fcell.2022.822563 Text en Copyright © 2022 Lasa-Elgarresta, Mosqueira-Martín, González-Imaz, Marco-Moreno, Gerenu, Mamchaoui, Mouly, López de Munain and Vallejo-Illarramendi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Lasa-Elgarresta, Jaione
Mosqueira-Martín, Laura
González-Imaz, Klaudia
Marco-Moreno, Pablo
Gerenu, Gorka
Mamchaoui, Kamel
Mouly, Vincent
López de Munain, Adolfo
Vallejo-Illarramendi, Ainara
Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations
title Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations
title_full Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations
title_fullStr Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations
title_full_unstemmed Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations
title_short Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations
title_sort targeting the ubiquitin-proteasome system in limb-girdle muscular dystrophy with capn3 mutations
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8924035/
https://www.ncbi.nlm.nih.gov/pubmed/35309930
http://dx.doi.org/10.3389/fcell.2022.822563
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