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
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.

Auteurs

Ricardo A Galli (RA)

Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology , Amsterdam, The Netherlands.
Amsterdam Movement Sciences, Musculoskeletal Health and Tissue Function and Regeneration, Amsterdam, The Netherlands.

Tamara C Borsboom (TC)

Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology , Amsterdam, The Netherlands.

Charlotte Gineste (C)

Aix-Marseille University, CNRS, CRMBM , Marseille, France.

Lorenza Brocca (L)

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Maira Rossi (M)

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Darren T Hwee (DT)

Research and Early Development, Cytokinetics Inc. , South San Francisco, CA, USA.

Fady I Malik (FI)

Research and Early Development, Cytokinetics Inc. , South San Francisco, CA, USA.

Roberto Bottinelli (R)

Department of Molecular Medicine, University of Pavia, Pavia, Italy.
IRCCS Mondino Foundation , Pavia, Italy.

Julien Gondin (J)

Aix-Marseille University, CNRS, CRMBM , Marseille, France.
Institut NeuroMyoGène, Unité Physiopathologie et Génétique du Neurone et du Muscle, Université Claude Bernard Lyon 1, CNRS UMR 5261, INSERM U1315, Université Lyon , Lyon, France.

Maria-Antonietta Pellegrino (MA)

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Josine M de Winter (JM)

Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology , Amsterdam, The Netherlands.
Amsterdam Movement Sciences, Musculoskeletal Health and Tissue Function and Regeneration, Amsterdam, The Netherlands.
Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, The Netherlands.

Coen A C Ottenheijm (CAC)

Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology , Amsterdam, The Netherlands.
Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Atherosclerosis, Amsterdam, The Netherlands.
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA.

Classifications MeSH