title: Cardiomyocyte Ca2+ handling and structure is regulated by degree and duration of mechanical load variation.
abstract: Cardiac transverse (t)-tubules are altered during disease and may be regulated by stretch-sensitive molecules. The relationship between variations in the degree and duration of load and t-tubule structure remains unknown, as well as its implications for local Ca(2+)-induced Ca(2+) release (CICR). Rat hearts were studied after 4 or 8 weeks of moderate mechanical unloading [using heterotopic abdominal heart-lung transplantation (HAHLT)] and 6 or 10 weeks of pressure overloading using thoracic aortic constriction. CICR, cell and t-tubule structure were assessed using confocal-microscopy, patch-clamping and scanning ion conductance microscopy. Moderate unloading was compared with severe unloading [using heart-only transplantation (HAHT)]. Mechanical unloading reduced cardiomyocyte volume in a time-dependent manner. Ca(2+) release synchronicity was reduced at 8 weeks moderate unloading only. Ca(2+) sparks increased in frequency and duration at 8 weeks of moderate unloading, which also induced t-tubule disorganization. Overloading increased cardiomyocyte volume and disrupted t-tubule morphology at 10 weeks but not 6 weeks. Moderate mechanical unloading for 4 weeks had milder effects compared with severe mechanical unloading (37% reduction in cell volume at 4 weeks compared to 56% reduction after severe mechanical unloading) and did not cause depression and delay of the Ca(2+) transient, increased Ca(2+) spark frequency or impaired t-tubule and cell surface structure. These data suggest that variations in chronic mechanical load influence local CICR and t-tubule structure in a time- and degree-dependent manner, and that physiological states of increased and reduced cell size, without pathological changes are possible.
authors.affiliation: Heart Science Centre, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Ibrahim
authors.forename: Punam
authors.initials: P
authors.lastname: Kukadia
authors.forename: Urszula
authors.initials: U
authors.lastname: Siedlecka
authors.forename: James E
authors.initials: JE
authors.lastname: Cartledge
authors.forename: Manoraj
authors.initials: M
authors.lastname: Navaratnarajah
authors.forename: Sergiy
authors.initials: S
authors.lastname: Tokar
authors.forename: Carin
authors.initials: C
authors.lastname: Van Doorn
authors.forename: Victor T
authors.initials: VT
authors.lastname: Tsang
authors.forename: Julia
authors.initials: J
authors.lastname: Gorelik
authors.forename: Magdi H
authors.initials: MH
authors.lastname: Yacoub
authors.forename: Cesare M
authors.initials: CM
authors.lastname: Terracciano
mesh_terms: D000818:Animals; D001011:Aorta / Q000601:surgery; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D006321:Heart; D006333:Heart Failure / Q000473:pathology; D016027:Heart Transplantation; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D011917:Rats, Inbred Lew; D012519:Sarcoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D013312:Stress, Physiological
chemical_list: D020746:Calcium Channels, L-Type; D002118:Calcium