Mutation-specific effects on thin filament length in thin filament myopathy

• Published in: Annals of neurology Vol. 79; no. 6; pp. 959 - 969
• Main Authors: Winter, Josine M. de, Joureau, Barbara, Lee, Eun-Jeong, Kiss, Balázs, Yuen, Michaela, Gupta, Vandana A., Pappas, Christopher T., Gregorio, Carol C., Stienen, Ger J. M., Edvardson, Simon, Wallgren-Pettersson, Carina, Lehtokari, Vilma-Lotta, Pelin, Katarina, Malfatti, Edoardo, Romero, Norma B., Engelen, Baziel G. van, Voermans, Nicol C., Donkervoort, Sandra, Bönnemann, C. G., Clarke, Nigel F., Beggs, Alan H., Granzier, Henk, Ottenheijm, Coen A. C.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-06-2016; Wiley Subscription Services, Inc
• Subjects: Actins - genetics; Animals; Case-Control Studies; Confocal microscopy; Cytoskeleton - genetics; Cytoskeleton - physiology; Disorders; Fibers; Filaments; Genotypes; Humans; Mice, Knockout; Microscopy; Muscle contraction; Muscle Contraction - genetics; Muscle Contraction - physiology; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle Proteins - physiology; Muscle, Skeletal - metabolism; Muscular Diseases - genetics; Muscular Diseases - physiopathology; Mutation; Myopathy; Patients; Proteins; Rodents; Sarcomeres; Sarcomeres - genetics; Sarcomeres - physiology; Skeletal muscle
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.24654

Objective
Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation.
Methods
We investigated the sarcomere length‐dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41.
Results
Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in NEB and ACTA1, the lower force was associated with downward shifted force–sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional Neb knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin–thick filament overlap.
Interpretation
These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths. Ann Neurol 2016;79:959–969