M line-deficient titin causes cardiac lethality through impaired maturation of the sarcomere

J Cell Biol. 2006 May 22;173(4):559-70. doi: 10.1083/jcb.200601014. Epub 2006 May 15.

Abstract

Titin, the largest protein known to date, has been linked to sarcomere assembly and function through its elastic adaptor and signaling domains. Titin's M-line region contains a unique kinase domain that has been proposed to regulate sarcomere assembly via its substrate titin cap (T-cap). In this study, we use a titin M line-deficient mouse to show that the initial assembly of the sarcomere does not depend on titin's M-line region or the phosphorylation of T-cap by the titin kinase. Rather, titin's M-line region is required to form a continuous titin filament and to provide mechanical stability of the embryonic sarcomere. Even without titin integrating into the M band, sarcomeres show proper spacing and alignment of Z discs and M bands but fail to grow laterally and ultimately disassemble. The comparison of disassembly in the developing and mature knockout sarcomere suggests diverse functions for titin's M line in embryonic development and the adult heart that not only involve the differential expression of titin isoforms but also of titin-binding proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Connectin
  • Female
  • Gene Expression Regulation, Developmental / genetics
  • Genes, Lethal / genetics*
  • Heart / embryology
  • Heart Defects, Congenital / embryology
  • Heart Defects, Congenital / genetics*
  • Male
  • Mice
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Muscle Proteins / chemistry
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism*
  • Mutation / genetics
  • Myocardium / metabolism*
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / ultrastructure
  • Phosphorylation
  • Protein Binding / physiology
  • Protein Kinases / chemistry
  • Protein Kinases / genetics*
  • Protein Kinases / metabolism*
  • Protein Structure, Tertiary / genetics
  • Sarcomeres / metabolism*
  • Sarcomeres / ultrastructure

Substances

  • Connectin
  • Muscle Proteins
  • Protein Kinases