@article {doi:10.1161/CIRCRESAHA.123.322588,
	title = {Stretch Harmonizes Sarcomere Strain Across the Cardiomyocyte},
	journal = {Circulation Research},
	year = {2023},
	month = {07/2023},
	publisher = {American Heart Association},
	abstract = {BACKGROUND:Increasing cardiomyocyte contraction during myocardial stretch serves as the basis for the Frank-Starling mechanism in the heart. However, it remains unclear how this phenomenon occurs regionally within cardiomyocytes, at the level of individual sarcomeres. We investigated sarcomere contractile synchrony and how intersarcomere dynamics contribute to increasing contractility during cell lengthening.METHODS:Sarcomere strain and Ca2+\&nbsp;were simultaneously recorded in isolated left ventricular cardiomyocytes during 1 Hz field stimulation at 37\&thinsp;\&deg;C, at resting length and following stepwise stretch.RESULTS:We observed that in unstretched rat cardiomyocytes, differential sarcomere deformation occurred during each beat. Specifically, while most sarcomeres shortened during the stimulus, \&asymp;10\% to 20\% of sarcomeres were stretched or remained stationary. This nonuniform strain was not traced to regional Ca2+\&nbsp;disparities but rather shorter resting lengths and lower force production in systolically stretched sarcomeres. Lengthening of the cell recruited additional shortening sarcomeres, which increased contractile efficiency as less negative, wasted work was performed by stretched sarcomeres. Given the known role of titin in setting sarcomere dimensions, we next hypothesized that modulating titin expression would alter intersarcomere dynamics. Indeed, in cardiomyocytes from mice with titin haploinsufficiency, we observed greater variability in resting sarcomere length, lower recruitment of shortening sarcomeres, and impaired work performance during cell lengthening.CONCLUSIONS:Graded sarcomere recruitment directs cardiomyocyte work performance, and harmonization of sarcomere strain increases contractility during cell stretch. By setting sarcomere dimensions, titin controls sarcomere recruitment, and its lowered expression in haploinsufficiency mutations impairs cardiomyocyte contractility.},
	url = {https://www.ahajournals.org/doi/abs/10.1161/CIRCRESAHA.123.322588},
	author = {Li, Jia and Sundnes, Joakim and Hou, Yufeng and Laasmaa, Martin and Ruud, Marianne and Unger, Andreas and Terje R. {Kolstad} and Frisk, Michael and Per A. {Norseng} and Yang, Limin and Ingunn E. {Setterberg} and Estela S. {Alves} and Kalakoutis, Michaeljohn and Ole M. {Sejersted} and Johanna T. {Lanner} and Wolfgang A. {Linke} and Ida G. {Lunde} and Pieter P. {de Tombe} and William E. {Louch}}
}
@article {Simula.simula.2258,
	title = {Variable T-Tubule Organization and Ca2+ Homeostasis Across the Atria},
	journal = {Heart and Circulatory Physiology},
	volume = {307},
	number = {4},
	year = {2014},
	month = {August},
	pages = {H609-H620},
	publisher = { },
	abstract = {Rationale: Although t-tubules have traditionally been thought to be absent in atrial cardiomyocytes, recent studies suggest that t-tubules exist in the atria of large mammals. However, it is unclear whether regional differences in t-tubule organization exist, which define cardiomyocyte function across the atria. Objective: We sought to investigate regional t-tubule density in pig and rat atria, and the consequences for cardiomyocyte Ca2+ homeostasis. Methods and Results: In contrast to previous reports that t-tubules are absent in rat atria, we observed t- tubules in approximately one third of rat atrial cardiomyocytes, both in tissue cryosections and in isolated cardiomyocytes. In a minority (\approx10\%) of atrial cardiomyocytes, the t-tubular network was well organized, with a transverse structure resembling that of ventricular cardiomyocytes. In both rat and pig atrial tissue, we observed higher t-tubule density in the epicardium than endocardium. Consistent with high variability in the distribution of t-tubules and Ca2+ channels among cells, L-type Ca2+ current amplitude was also highly variable, and steeply dependent on capacitance and t-tubule density. Accordingly, Ca2+ transients showed great variability in Ca2+ release synchrony. Simultaneous imaging of the cell membrane and Ca2+ transients confirmed t-tubule functionality. Results from mathematical modeling indicated that a transmural gradient in t-tubule organization and Ca2+ release kinetics supports synchronization of contraction across the atrial wall, and may underlie transmural differences in refractory period. Conclusions: T-tubule density is highly variable across the atria. We propose that higher t-tubule density in cells localized in the epicardium promotes synchronization of contraction across the atrial wall.},
	author = {Frisk, Michael and Koivum{\"a}ki, Jussi and Per A. {Norseng} and Maleckar, Molly and Ole M. {Sejersted} and William E. {Louch}}
}
