title: Tropomodulin 1 directly controls thin filament length in both wild-type and tropomodulin 4-deficient skeletal muscle.
abstract: The sarcomeric tropomodulin (Tmod) isoforms Tmod1 and Tmod4 cap thin filament pointed ends and functionally interact with the leiomodin (Lmod) isoforms Lmod2 and Lmod3 to control myofibril organization, thin filament lengths, and actomyosin crossbridge formation in skeletal muscle fibers. Here, we show that Tmod4 is more abundant than Tmod1 at both the transcript and protein level in a variety of muscle types, but the relative abundances of sarcomeric Tmods are muscle specific. We then generate Tmod4(-/-) mice, which exhibit normal thin filament lengths, myofibril organization, and skeletal muscle contractile function owing to compensatory upregulation of Tmod1, together with an Lmod isoform switch wherein Lmod3 is downregulated and Lmod2 is upregulated. However, RNAi depletion of Tmod1 from either wild-type or Tmod4(-/-) muscle fibers leads to thin filament elongation by ∼15%. Thus, Tmod1 per se, rather than total sarcomeric Tmod levels, controls thin filament lengths in mouse skeletal muscle, whereas Tmod4 appears to be dispensable for thin filament length regulation. These findings identify Tmod1 as the key direct regulator of thin filament length in skeletal muscle, in both adult muscle homeostasis and in developmentally compensated contexts.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA dgokhin@scripps.edu velia@scripps.edu.
authors.forename: David S
authors.initials: DS
authors.lastname: Gokhin
authors.affiliation: Centre of Human and Aerospace Physiological Sciences, King's College London, London SE1 1UL, UK.
authors.forename: Julien
authors.initials: J
authors.lastname: Ochala
authors.affiliation: Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA Rehabilitation Institute of Chicago, Chicago, IL 60611, USA.
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Domenighetti
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA dgokhin@scripps.edu velia@scripps.edu.
authors.forename: Velia M
authors.initials: VM
authors.lastname: Fowler
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D010641:Phenotype; D020033:Protein Isoforms / Q000378:metabolism; D034622:RNA Interference; D012518:Sarcomeres / Q000378:metabolism; D051348:Tropomodulin / Q000172:deficiency* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D008840:Microfilament Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms; C495831:Tmod1 protein, mouse; C495840:Tmod4 protein, mouse; D051348:Tropomodulin; C000598980:leiomodin-3 protein, mouse; C035620:nebulin
keywords: Actin filament; Leiomodin; Myofibril; Pointed-end capping; Sarcomere