Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 46, Issue 1, Pages 39-46Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2008.10.004
Keywords
Diastolic dysfunction; Ventricular stiffness; Myosin; Ventricular function; Mathematical modeling; Detergent skinned muscle; Contractile proteins
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Funding
- American Heart Association Scientist Development Grant [0630079N]
- NIH [AG021862, HL 090749]
- University of Kentucky Research Challenge Trust Fund
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL090749] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R03AG028162] Funding Source: NIH RePORTER
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The mechanical properties of triton-permeabilized ventricular preparations isolated from 4, 18 and 24-month-old F344 rats were analyzed to provide information about the molecular mechanisms that lead to age-related increases in diastolic myocardial stiffness in these animals. Passive stiffness (measured in solutions with minimal free Ca2(+)) did not change with age. This implies that the aging-associated dysfunction is not due to changes in titin or collagen molecules. Ca2(+)-activated preparations exhibited a characteristic short-range force response: force rose rapidly until the muscle reached its elastic limit and less rapidly thereafter. The elastic limit increased from 0.43+/-0.01% l(o) (where l(0) is the initial muscle length) in preparations from 4-month-old animals to 0.49+/-0.01% l(0) in preparations from 24-month-old rats (p<0.001, ANOVA). Relative short-range force was defined as the maximum force produced during the short-range response normalized to the prevailing tension. This parameter increased from 0.110+/-0.002 to 0.142+/-0.002 over the same age-span (p<0.001, ANOVA). Analytical gel electrophoresis showed that the maximum stiffness of the preparations during the short-range response and the relative short-range force increased (p=0.031 and p=0.005 respectively) with the relative content of slow beta myosin heavy chain molecules. Elastic limit values did not correlate with myosin isoform content. Simulations based on these results suggest that attached beta myosin heavy chain cross-bridges are stiffer than links formed by alpha myosin heads. In conclusion, elevated content of stiffer beta myosin heavy chain molecules may contribute to aging-associated increases in myocardial stiffness. (C) 2008 Elsevier Inc. All rights reserved.
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