Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy.
Journal
The Journal of general physiology
ISSN: 1540-7748
Titre abrégé: J Gen Physiol
Pays: United States
ID NLM: 2985110R
Informations de publication
Date de publication:
01 Apr 2024
01 Apr 2024
Historique:
received:
22
08
2023
revised:
01
12
2023
accepted:
30
01
2024
medline:
20
2
2024
pubmed:
20
2
2024
entrez:
20
2
2024
Statut:
ppublish
Résumé
Nemaline myopathies are the most common form of congenital myopathies. Variants in ACTA1 (NEM3) comprise 15-25% of all nemaline myopathy cases. Patients harboring variants in ACTA1 present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, in severe cases, respiratory failure and death. To date, no specific treatments are available. Since NEM3 is an actin-based thin filament disease, we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3, harboring the patient-based p.Asp286Gly variant in Acta1. Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo. Additionally, long-term tirasemtiv treatment in NEM3 mice resulted in a decreased respiratory rate with preserved minute volume, suggesting more efficient respiration. Altogether, our data support the therapeutic potential of fast skeletal muscle troponin activators in alleviating skeletal muscle weakness in a mouse model of NEM3 caused by the Acta1:p.Asp286Gly variant.
Identifiants
pubmed: 38376469
pii: 276571
doi: 10.1085/jgp.202313471
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Netherlands Organisation for Health Research and Development
ID : 91819613
Informations de copyright
© 2024 Galli et al.