Abstract
The contractile machinery of heart and skeletal muscles has as an essential component the thick filament, comprised of the molecular motor myosin. The thick filament is of a precisely controlled length, defining thereby the force level that muscles generate and how this force varies with muscle length. It has been speculated that the mechanism by which thick filament length is controlled involves the giant protein titin, but no conclusive support for this hypothesis exists. Here we show that in a mouse model in which we deleted two of titin’s C-zone super-repeats, thick filament length is reduced in cardiac and skeletal muscles. In addition, functional studies reveal reduced force generation and a dilated cardiomyopathy (DCM) phenotype. Thus, regulation of thick filament length depends on titin and is critical for maintaining muscle health.
Highlights
Justin Kolb[1,2], The contractile machinery of heart and skeletal muscles has as an essential component the thick filament, comprised of the molecular motor myosin
A popular but untested theory is that in vertebrate animals titin functions as a thick filament template that is responsible for determining thick filament length
To test the role of titin in thick filament length regulation, homologous recombination was used to delete from the mouse titin gene exons 305–325
Summary
Justin Kolb[1,2], The contractile machinery of heart and skeletal muscles has as an essential component the thick filament, comprised of the molecular motor myosin. Structural studies in both cardiac and skeletal muscles of TtnΔC1-2 mice reveal a reduced thick filament length, in line with the concept of a 2 × 43 nm shortened titin ruler.
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