Altered Contractility of Skeletal Muscle in Mice Deficient in Titin's M-Band Region

Coen A.C. Ottenheijm, Carlos Hidalgo, Katharina Rost, Michael Gotthardt, Henk Granzier

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

We investigated the contractile phenotype of skeletal muscle deficient in exons MEx1 and MEx2 (KO) of the titin M-band by using the cre-lox recombination system and a multidisciplinary physiological approach to study skeletal muscle contractile performance. At a maximal tetanic stimulation frequency, intact KO extensor digitorum longus muscle was able to produce wild-type levels of force. However, at submaximal stimulation frequency, force was reduced in KO mice, giving rise to a rightward shift of the force-frequency curve. This rightward shift of the force-frequency curve could not be explained by altered sarcoplasmic reticulum Ca2+ handling, as indicated by analysis of Ca2+ transients in intact myofibers and expression of Ca2+-handling proteins, but can be explained by the reduced myofilament Ca2+ sensitivity of force generation that we found. Western blotting experiments suggested that the excision of titin exons MEx1 and MEx2 did not result in major changes in expression of titin M-band binding proteins or phosphorylation level of the thin-filament regulatory proteins, but rather in a shift toward expression of slow isoforms of the thick-filament-associated protein, myosin binding protein-C. Extraction of myosin binding protein-C from skinned muscle normalized myofilament Ca2+ sensitivity of the KO extensor digitorum longus muscle. Thus, our data suggest that the M-band region of titin affects the expression of genes involved in the regulation of skeletal muscle contraction.

Original languageEnglish (US)
Pages (from-to)10-26
Number of pages17
JournalJournal of Molecular Biology
Volume393
Issue number1
DOIs
StatePublished - Oct 16 2009

Keywords

  • Ca sensitivity
  • M-band
  • skeletal muscle
  • titin

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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