Single histidine-substituted cardiac troponin I confers protection from age-related systolic and diastolic dysfunction.
OBJECTIVE
Contractile dysfunction associated with myocardial ischaemia is a significant cause of morbidity and mortality in the elderly. Strategies to protect the aged heart from ischaemia-mediated pump failure are needed. We hypothesized that troponin I-mediated augmentation of myofilament calcium sensitivity would protect cardiac function in aged mice.


RESULTS
To address this, we investigated transgenic (Tg) mice expressing a histidine-substituted form of adult cardiac troponin I (cTnI A164H), which increases myofilament calcium sensitivity in a pH-dependent manner. Serial echocardiography revealed that Tg hearts showed significantly improved systolic function at 4 months, which was sustained for 2 years based on ejection fraction and velocity of circumferential fibre shortening. Age-related diastolic dysfunction was also attenuated in Tg mice as assessed by Doppler measurements of the mitral valve inflow and lateral annulus Doppler tissue imaging. During acute hypoxia, cardiac contractility significantly improved in aged Tg mice made evident by increased stroke volume, end systolic pressure, and +dP/dt compared with non-transgenic mice.


CONCLUSIONS
This study shows that increasing myofilament function by means of a pH-responsive histidine button engineered into cTnI results in enhanced baseline heart function in Tg mice over their lifetime, and during acute hypoxia improves survival in aged mice by maintaining cardiac contractility.
Palpant
Nathan J
NJ
Department of Molecular and Integrative Physiology, University of Michigan Medical School, 1301 E. Catherine Street, 7727 Medical Science II, Ann Arbor, MI 48109-0622, USA.
Day
Sharlene M
SM
Herron
Todd J
TJ
Converso
Kimber L
KL
Metzger
Joseph M
JM
D008841:Actin Cytoskeleton / Q000378:metabolism; D000367:Age Factors; D000375:Aging; D019943:Amino Acid Substitution; D000818:Animals; D020013:Calcium Signaling; D015150:Echocardiography, Doppler; D006639:Histidine; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D013318:Stroke Volume; D019210:Troponin I / Q000235:genetics / Q000378:metabolism*; D018754:Ventricular Dysfunction / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D017725:Ventricular Pressure
D019210:Troponin I; D006639:Histidine