title: Tropomodulin isoforms regulate thin filament pointed-end capping and skeletal muscle physiology.
abstract: During myofibril assembly, thin filament lengths are precisely specified to optimize skeletal muscle function. Tropomodulins (Tmods) are capping proteins that specify thin filament lengths by controlling actin dynamics at pointed ends. In this study, we use a genetic targeting approach to explore the effects of deleting Tmod1 from skeletal muscle. Myofibril assembly, skeletal muscle structure, and thin filament lengths are normal in the absence of Tmod1. Tmod4 localizes to thin filament pointed ends in Tmod1-null embryonic muscle, whereas both Tmod3 and -4 localize to pointed ends in Tmod1-null adult muscle. Substitution by Tmod3 and -4 occurs despite their weaker interactions with striated muscle tropomyosins. However, the absence of Tmod1 results in depressed isometric stress production during muscle contraction, systemic locomotor deficits, and a shift to a faster fiber type distribution. Thus, Tmod3 and -4 compensate for the absence of Tmod1 structurally but not functionally. We conclude that Tmod1 is a novel regulator of skeletal muscle physiology.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Gokhin
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Lewis
authors.forename: Caroline R
authors.initials: CR
authors.lastname: McKeown
authors.forename: Roberta B
authors.initials: RB
authors.lastname: Nowak
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kim
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Littlefield
authors.forename: Richard L
authors.initials: RL
authors.lastname: Lieber
authors.forename: Velia M
authors.initials: VM
authors.lastname: Fowler
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051348:Tropomodulin / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; C495831:Tmod1 protein, mouse; C495837:Tmod3 protein, mouse; C495840:Tmod4 protein, mouse; D051348:Tropomodulin