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Sarcolemmal structure and function revert to an immature phenotype in failing cardiomyocytes
Lipsett DB1, Frisk M1, Aronsen JM1,2, Sejersted OM1, Sjaastad I1, Christensen G1, Louch WE1
1
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo,
Oslo, Norway
2
Bjørknes College, Oslo, Norway
The myocardium undergoes pathological remodeling during heart failure (HF). Of the many different
signaling mechanisms that have been implicated, re-activation of the fetal gene program is believed to
control many aspects of these detrimental changes. Here we hypothesized that pathological
phenotypes characteristic of failing cardiomyocytes resemble both structural and functional features of
immature cells. In order to compare surface topography, isolated cardiomyocytes were fixed in a 2.5%
glutaraldehyde/4% paraformaldehyde solution and imaged via scanning electron microscopy (SEM).
With the high resolution of SEM, we were not only able to observe Z-grooves and t-tubules, but also
ridge like structures, herein referred to as “Z-ridges”, that align with t-tubule openings in the valleys of
the Z-grooves. Immature rat cardiomyocytes were found to have a relatively flat membrane, although
ring-like Z-ridges were observed around the transverse axis as early as 15 days after birth. Z-grooves
appeared at later developmental time points corresponding to the appearance of t-tubules at the
surface. Interestingly, the surface membrane of failing cells isolated from hearts 6 weeks after
coronary ligation had fewer Z-grooves, while Z-ridges were preserved. Intracellularly, t-tubules
developed after birth and originally appeared as chaotic, primarily-longitudinal structures that became
more transverse with age. During HF, transverse tubules were lost, however, growth of compensatory
longitudinal elements resulted in no change to the overall t-tubule density, as compared to SHAMoperated controls. Additionally, the ratio of transverse to longitudinal t-tubules was similar to early
developmental time points. Via 2D confocal videos, we measured Ca2+ release patterns across the
cardiomyocyte. Ca2+ transients in both immature and failing cardiomyocytes were slower and more
dyssynchronous than their respective controls. Cardiomyocyte structure and function are dynamic, and
reversion to an immature phenotype may reveal novel therapeutic targets that prevent or reverse
pathological remodeling in patients.