Contribution of titin and extracellular matrix to passive pressure and measurement of sarcomere length in the mouse left ventricle

Charles S. Chung, Henk L. Granzier

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

It remains to be established to what degree titin and the extracellular matrix (ECM) contribute to passive pressure in the left ventricle (LV). Thus, we aimed to elucidate the contribution of major molecular determinants of passive pressure in the normal mouse LV. Furthermore, we determined the working sarcomere length (SL) range of the LV to bridge our findings to earlier work in skinned muscle fibers. We utilized Frank-Starling type protocols to obtain diastolic pressure-volume relationships (PVR) in Langendorff perfused isolated LVs. To quantify the molecular contribution of titin and ECM, we innovated on methods of fiber mechanics to chemically permeabilize intact LVs and measure a fully passive PVR. To differentially dissect the contributions of the ECM and titin, we utilized myofilament extraction techniques in permeabilized LVs, measuring passive PVRs at each stage in the protocol. Myofilament extraction suggests that titin contributes ~80% of passive pressures in the heart. Langendorff perfusion was also used to chemically fix passive and BaCl2 activated hearts at specific volumes to determine that the maximal working SL range of the midwall LV fibers is approximately 1.8-2.2μm. A model of the passive SL-volume relationship was then used to estimate the pressure-SL relationships, indicating that the ECM contribution does not exceed titin's contribution until large volumes with SLs >~2.2μm. In conclusion, within physiological volumes, titin is the dominant contributor to LV passive pressure, and ECM-based pressures dominate at larger volumes.

Original languageEnglish (US)
Pages (from-to)731-739
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume50
Issue number4
DOIs
StatePublished - Apr 1 2011

Keywords

  • Collagen
  • Diastole
  • Extracellular matrix
  • Skinned
  • Titin/connectin

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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