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

Autor: Nicol C. Voermans, Balázs Kiss, Eun Jeong Lee, Alan H. Beggs, Christopher T. Pappas, Carina Wallgren-Pettersson, Michaela Yuen, Sandra Donkervoort, Vandana Gupta, Nigel F. Clarke, Edoardo Malfatti, Ger J.M. Stienen, Barbara Joureau, Katarina Pelin, Norma B. Romero, Henk Granzier, Josine M. de Winter, Carol C. Gregorio, Carsten G. Bönnemann, Baziel G.M. van Engelen, Simon Edvardson, Vilma Lotta Lehtokari, Coen A.C. Ottenheijm
Rok vydání: 2016
Předmět:
Zdroj: Annals of Neurology. 79:959-969
ISSN: 0364-5134
DOI: 10.1002/ana.24654
Popis: Nemaline myopathy and congenital fiber type disproportion are among the most common nondystrophic congenital muscular disorders.1 Genes that are implicated in these myopathies encode proteins that are either components of the skeletal muscle thin filament, including nebulin (NEB), skeletal muscle alpha-actin1 (ACTA1), beta-tropomyosin 2 (TPM2), alpha-tropomyosin 3 (TPM3), troponin T type 1 (TNNT1), cofilin-2 (CFL2), and leiomodin-3 (LMOD3), or are thought to contribute to stability or turnover of thin filament proteins, such as kelch repeat and BTB (POZ) domain containing 13 (KBTBD13), and kelchlike family members 40 (KLHL40) and 41 (KLHL41).2–6 Hence, muscle diseases caused by mutations in these genes are here referred to as thin filament myopathies. For a schematic of the thin filament and its associated proteins, see Figure 1. Patients with thin filament myopathy suffer from muscle weakness, but the underlying mechanisms are poorly understood. FIGURE 1 Schematic of the skeletal muscle thin filament. The thin filament is an essential structure in the sarcomere, the smallest contractile unit in skeletal muscle. The actin-based backbone of the thin filament is decorated with proteins that are involved ... The thin filament is a major constituent of the sarcomere, the smallest contractile unit in muscle, and is essential for force generation; its length determines the overlap between the thin and thick filament, and thereby the number of force-generating interactions that can be formed between actin and myosin. In healthy human muscle, the length of the thick filament is 1.6μm and that of the thin filament is regulated at 1.1 to 1.3μm.7 Accordingly, force depends on sarcomere length, with increasing force as the overlap between thick and thin filaments increases (up to a sarcomere length of ~2.6μm; ie, the ascending limb of the force–sarcomere length relation), and decreasing force at longer sarcomere lengths as the overlap between thick and thin filaments decreases (ie, the descending limb; Fig 2A8,9). Hence, appropriate length of the thin filament is important for muscle fiber strength; a shorter length causes lower force generation by shifting the descending limb of the force–sarcomere length relation downward. FIGURE 2 The force–sarcomere length relation in muscle fibers from thin filament myopathy patients and control (CTRL) subjects. (A) The shape of the force–sarcomere length relation is determined by the amount of overlap between the thick and thin ... Whether mutations in genes implicated in thin filament myopathy contribute to force loss by affecting thin filament length is unclear. Mouse models with mutations in Neb exhibit a shorter thin filament length associated with lower force generation that becomes more prominent as sarcomere length increases.10–12 Preliminary studies on a small number of human biopsies were largely in agreement with this observation.13,14 Whether these findings translate to a large group of patients, and whether shorter thin filament length is a general mechanism underlying force loss in thin filament myopathies with a variety of different gene defects, is unknown. Therefore, we studied muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41. In these fibers, we determined the sarcomere length-dependence of force, a functional assay that provides insight into the contractile strength of muscle fibers as well as the length of the thin filaments. In a novel, conditional Neb knockout mouse model that recapitulates thin filament myopathy—including shorter thin filament length—we studied whether muscle possesses mechanisms that compensate for shorter thin filament length, and we specifically focused on the addition of sarcomeres in series.
Databáze: OpenAIRE
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