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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. [ABSTRACT FROM AUTHOR]

Keywords: muscle kinetics; thick filament; X-ray diffraction EN muscle kinetics thick filament X-ray diffraction 5001 5002 2 11/16/20 20201115 NES 201115 Muscle contraction is the product of highly coordinated intricate interplay between the actin-based thin filament and the myosin-based thick filament, both key components of the sarcomere, the smallest contractile unit in muscle. This exposes myosin binding sites on the actin filament, so that myosin heads can bind and subsequently pull on actin to generate force. Overall, the data presented by Ma I et al i . are in line with the previous findings in frog muscle and indicate that during the first phase of muscle relaxation myosin heads detach from actin but remain in the proximity of actin. [Extracted from the article]