Huxleys' Missing Filament: Form and Function of Titin in Vertebrate Striated Muscle

Stan Lindstedt, Kiisa Nishikawa

Research output: Contribution to journalReview articlepeer-review

29 Scopus citations


Although superthin filaments were inferred from early experiments on muscle, decades passed before their existence was accepted. Phylogenetic analyses suggest that titin, the largest known protein, first appeared in the common ancestor of chordates and nematodes and evolved rapidly via duplication. Twitchin and projectin evolved later by truncation. Sallimus mutants in Drosophila exhibit disrupted sarcomere and chromosome structure, suggesting that giant proteins may have evolved as chromosomal scaffolds that were co-opted for a similar purpose in striated muscles. Though encoded by only one gene, titin comprises hundreds of exons and has the potential for enormous diversity. Shorter isoforms typically confer greater passive stiffness associated with smaller in vivo muscle strains. Recent studies demonstrate unequivocally that titin stiffness increases upon muscle activation, but the mechanisms are only now being uncovered. Although some basic principles have been established, a vast opportunity remains to extend our understanding of titin function in striated muscle.

Original languageEnglish (US)
Pages (from-to)145-166
Number of pages22
JournalAnnual Review of Physiology
StatePublished - Feb 10 2017


  • Connectin
  • Evolution
  • Force enhancement
  • Giant sarcomeric proteins
  • Muscle passive tension
  • Titin activation

ASJC Scopus subject areas

  • Physiology


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