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Nemaline myopathy, a disease of the actin-based thin filament, is one of the most frequent congenital myopathies. To date, no specific therapy is available to treat muscle weakness in nemaline myopathy. We tested the ability of  tirasemtiv , a fast skeletal troponin activator that targets the thin filament, to augment muscle force—both  in vivo  and  in vitro —in a nemaline myopathy mouse model with a mutation (H40Y) in  Acta1 . In  Acta1 H40Y   mice, treatment with  tirasemtiv  increased the force response of muscles to submaximal stimulation frequencies. This resulted in a reduced energetic cost of force generation, which increases the force production during a fatigue protocol. The inotropic effects of  tirasemtiv  were present in locomotor muscles and, albeit to a lesser extent, in respiratory muscles, and they persisted during chronic treatment, an important finding as respiratory failure is the main cause of death in patients with congenital myopathy. Finally, translational studies on permeabilized muscle fibers isolated from a biopsy of a patient with the  ACTA1 H40Y   mutation revealed that at physiological Ca 2+  concentrations,  tirasemtiv  increased force generation to values that were close to those generated in muscle fibers of healthy subjects. These findings indicate the therapeutic potential of fast skeletal muscle troponin activators to improve muscle function in nemaline myopathy due to the  ACTA1 H40Y   mutation, and future studies should assess their merit for other forms of nemaline myopathy and for other congenital myopathies.

Acute and chronic tirasemtiv treatment improves in vivo and in vitro muscle performance in actin-based nemaline myopathy mice