Attenuated sarcomere lengthening of the aged murine left ventricle observed using two-photon fluorescence microscopy
Open accessAbstract
The Frank-Starling mechanism, whereby increased diastolic filling leads to increased cardiac output, depends on increasing the sarcomere length (Ls) of cardiomyocytes. Ventricular stiffness increases with advancing age, yet it remains unclear how such changes in compliance impact sarcomere dynamics in the intact heart. We developed an isolated murine heart preparation to monitor Ls as a function of left ventricular pressure and tested the hypothesis that sarcomere lengthening in response to ventricular filling is impaired with advanced age. Mouse hearts isolated from young (3-6 mo) and aged (24-28 mo) C57BL/6 mice were perfused via the aorta under Ca(2+)-free conditions with the left ventricle cannulated to control filling pressure. Two-photon imaging of 4-{2-[6-(dioctylamino)-2-naphthalenyl]ethenyl}1-(3-sulfopropyl)-pyridinium fluorescence was used to monitor t-tubule striations and obtain passive Ls between pressures of 0 and 40 mmHg. Ls values (in μm, aged vs. young, respectively) were 2.02 ± 0.04 versus 2.01 ± 0.02 at 0 mmHg, 2.13 ± 0.04 versus 2.23 ± 0.02 at 5 mmHg, 2.21 ± 0.03 versus 2.27 ± 0.03 at 10 mmHg, and 2.28 ± 0.02 versus 2.36 ± 0.01 at 40 mmHg, indicative of impaired sarcomere lengthening in aged hearts. Atomic force microscopy nanoindentation revealed that intact cardiomyocytes enzymatically isolated from aged hearts had increased stiffness compared with those of young hearts (elastic modulus: aged, 41.9 ± 5.8 kPa vs. young, 18.6 ± 3.3 kPa; P = 0.006). Impaired sarcomere lengthening during left ventricular filling may contribute to cardiac dysfunction with advancing age by attenuating the Frank-Starling mechanism and reducing stroke volume.
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Increased Fpassive has been observed in HFpEF patient biopsies, and increased cardiac stiffening is associated with aging.
“Increased Fpassive has been observed in HFpEF patient biopsies, and increased cardiac stiffening is associated with aging.38,39”
From The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF (2023) · cites this paper as [38]
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The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF
Withaar, C., Meems, L. M. G., Nollet, E. E., Schouten, E. M., Schroeder, M. A., Knudsen, L. B., Niss, K., Madsen, C. T., Hoegl, A., Mazzoni, G., et al. (2023) · JACC: Basic to Translational Science · doi:10.1016/j.jacbts.2023.05.012 · Cited by 74 · see citing works
- Authors
- Nance, M. E., Whitfield, J. T., Zhu, Y., Gibson, A. K., Hanft, L. M., Campbell, K. S., Meininger, G. A., McDonald, K. S., Segal, S. S., & Domeier, T. L.
- Affiliations
- University of Missouri (US)
- University of Kentucky (US)
- Corresponding author
- Domeier, Timothy L.
- ORCID
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2015-09
- Volume
- 309
- Issue
- 5
- Pages
- H918-H925
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- PMC
- PMC4591408
- OpenAlex
- W2174961023
- Cited by
- 17
- References
- 36
- Citations by year
- 2025: 2 · 2023: 4 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 1
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000117)
- National Institute on Aging (K01AG041208)
- National Heart, Lung, and Blood Institute (R01HL086483, R01HL057852, R37HL041026, P01HL095486, R01HL090749)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Keywords
- cardiac aging, Frank-Starling mechanism, left ventricular filling, ventricular stiffness, cardiomyocyte stiffness, two-photon imaging, isolated perfused heart, atomic force microscopy nanoindentation, C57BL/6 mice
- MeSH terms
- Age Factors, Animals, Fluorescent Dyes, Heart Ventricles, Mice, Inbred C57BL, Sarcomeres, Microscopy, Fluorescence, Multiphoton, Mice, Elastic Modulus
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