title: Altered contractility of skeletal muscle in mice deficient in titin's M-band region.
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 Ca(2+) handling, as indicated by analysis of Ca(2+) transients in intact myofibers and expression of Ca(2)(+)-handling proteins, but can be explained by the reduced myofilament Ca(2+) 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 Ca(2+) 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.
authors.affiliation: Department of Physiology, Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Coen A C
authors.initials: CA
authors.lastname: Ottenheijm
authors.forename: Carlos
authors.initials: C
authors.lastname: Hidalgo
authors.forename: Katharina
authors.initials: K
authors.lastname: Rost
authors.forename: Michael
authors.initials: M
authors.lastname: Gotthardt
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis; D064211:Connectin; D005091:Exons; D051379:Mice; D008954:Models, Biological; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000172:deficiency*; D018482:Muscle, Skeletal / Q000502:physiology*; D011494:Protein Kinases / Q000172:deficiency*; D011995:Recombination, Genetic; D017384:Sequence Deletion; D000099163:Myosin Binding Protein C
chemical_list: D002118:Calcium; D002352:Carrier Proteins; D064211:Connectin; D009124:Muscle Proteins; D011494:Protein Kinases; D000099163:Myosin Binding Protein C
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