The titin N2B and N2A regions: biomechanical and metabolic signaling hubs in cross-striated muscles

Robbert J. van der Pijl, Andrea A. Domenighetti, Farah Sheikh, Elisabeth Ehler, Coen A.C. Ottenheijm*, Stephan Lange

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


Muscle specific signaling has been shown to originate from myofilaments and their associated cellular structures, including the sarcomeres, costameres or the cardiac intercalated disc. Two signaling hubs that play important biomechanical roles for cardiac and/or skeletal muscle physiology are the N2B and N2A regions in the giant protein titin. Prominent proteins associated with these regions in titin are chaperones Hsp90 and αB-crystallin, members of the four-and-a-half LIM (FHL) and muscle ankyrin repeat protein (Ankrd) families, as well as thin filament-associated proteins, such as myopalladin. This review highlights biological roles and properties of the titin N2B and N2A regions in health and disease. Special emphasis is placed on functions of Ankrd and FHL proteins as mechanosensors that modulate muscle-specific signaling and muscle growth. This region of the sarcomere also emerged as a hotspot for the modulation of passive muscle mechanics through altered titin phosphorylation and splicing, as well as tethering mechanisms that link titin to the thin filament system.

Original languageEnglish
Pages (from-to)653-677
Number of pages25
JournalBiophysical Reviews
Issue number5
Early online date9 Sept 2021
Publication statusPublished - Oct 2021


  • Mechanosensor
  • Muscle
  • Muscle mechanics
  • Sarcomere
  • Signaling
  • Titin


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