Pharmacological activation of SERCA ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice.
Animals
Calcium
/ metabolism
Disease Models, Animal
Dystrophin
/ deficiency
Humans
Mice
Mice, Inbred mdx
Muscle Contraction
/ genetics
Muscle Weakness
/ genetics
Muscular Atrophy
/ genetics
Muscular Dystrophy, Duchenne
/ genetics
Phenotype
Sarcoplasmic Reticulum
/ metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases
/ genetics
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
31 05 2021
31 05 2021
Historique:
received:
17
02
2021
revised:
30
03
2021
accepted:
31
03
2021
pubmed:
7
4
2021
medline:
4
3
2022
entrez:
6
4
2021
Statut:
ppublish
Résumé
Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscular weakness because of the loss of dystrophin. Extracellular Ca2+ flows into the cytoplasm through membrane tears in dystrophin-deficient myofibers, which leads to muscle contracture and necrosis. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) takes up cytosolic Ca2+ into the sarcoplasmic reticulum, but its activity is decreased in dystrophic muscle. Here, we show that an allosteric SERCA activator, CDN1163, ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice. The administration of CDN1163 prevented exercise-induced muscular damage and restored mitochondrial function. In addition, treatment with CDN1163 for 7 weeks enhanced muscular strength and reduced muscular degeneration and fibrosis in mdx mice. Our findings provide preclinical proof-of-concept evidence that pharmacological activation of SERCA could be a promising therapeutic strategy for DMD. Moreover, CDN1163 improved muscular strength surprisingly in wild-type mice, which may pave the new way for the treatment of muscular dysfunction.
Identifiants
pubmed: 33822956
pii: 6210386
doi: 10.1093/hmg/ddab100
pmc: PMC8170845
doi:
Substances chimiques
Dmd protein, mouse
0
Dystrophin
0
Sarcoplasmic Reticulum Calcium-Transporting ATPases
EC 3.6.3.8
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1006-1019Informations de copyright
© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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