Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 02 2023
06 02 2023
Historique:
received:
14
01
2022
accepted:
19
01
2023
entrez:
6
2
2023
pubmed:
7
2
2023
medline:
9
2
2023
Statut:
epublish
Résumé
Polyglutamine expansion in the androgen receptor (AR) causes spinobulbar muscular atrophy (SBMA). Skeletal muscle is a primary site of toxicity; however, the current understanding of the early pathological processes that occur and how they unfold during disease progression remains limited. Using transgenic and knock-in mice and patient-derived muscle biopsies, we show that SBMA mice in the presymptomatic stage develop a respiratory defect matching defective expression of genes involved in excitation-contraction coupling (ECC), altered contraction dynamics, and increased fatigue. These processes are followed by stimulus-dependent accumulation of calcium into mitochondria and structural disorganization of the muscle triads. Deregulation of expression of ECC genes is concomitant with sexual maturity and androgen raise in the serum. Consistent with the androgen-dependent nature of these alterations, surgical castration and AR silencing alleviate the early and late pathological processes. These observations show that ECC deregulation and defective mitochondrial respiration are early but reversible events followed by altered muscle force, calcium dyshomeostasis, and dismantling of triad structure.
Identifiants
pubmed: 36746942
doi: 10.1038/s41467-023-36185-w
pii: 10.1038/s41467-023-36185-w
pmc: PMC9902403
doi:
Substances chimiques
Androgens
0
Calcium
SY7Q814VUP
Receptors, Androgen
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
602Subventions
Organisme : NINDS NIH HHS
ID : R01 NS119873
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR069107
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS055746
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
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