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Mechanical Load Regulates Cardiomyocyte T-tubular Structure and Ca2+ Homeostasis
Ruud M1,2, Frisk M1,2, Aronsen JM1,2, Dahl CP3,4, Jølle GF1,2, Aakhus S3,4, Lunde IG1,2, Almaas V3,4,
Gullestad L3,4, Sjaastad I1,2, Tønnesen T1,2,5, Sejersted OM1,2, Norseng PA1,2, Christensen G1,2, Louch
WE1,2
1
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo,
Norway
2
K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo,
Oslo, Norway
3
Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
4
Research Institute for Clinical Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
5
Department of Cardiothoracic Surgery, Oslo University Hospital Ullevål, Oslo, Norway
T-tubules are critical for efficient excitation-contraction coupling in cardiomyocytes and their
disorganization during heart failure weakens contraction. The precise mechanisms underlying t-tubular
remodeling are largely unknown, but emerging data indicate that t-tubule integrity is regulated by
ventricular workload (Ibrahim et al., J Cell Mol Med, 2012). Indeed, we have recently shown that
increased preload (diastolic wall stress) during ventricular dilation is a specific trigger for t-tubular
remodeling (Frisk et al., Cardiovasc Res, 2016). We presently hypothesized that increased afterload
may have opposite effects on t-tubule structure/function, since wall stress is maintained during nondilated hypertrophy (Grossman et al., J Clin Invest, 1975). We specifically compared t-tubule structure
in patients with non-dilated hypertrophy (hypertrophic cardiomyopathy and aortic stenosis) and dilated
hypertrophy. Parallel experiments were performed in mice which developed hypertrophic or dilated
ventricular remodeling following aortic banding. Both human and murine data confirmed that increased
diastolic wall stress in dilated ventricles was associated with t-tubule loss and impaired Ca2+ release.
However, non-dilated hypertrophic remodeling was associated with increased t-tubule density and
maintained Ca2+ release. To test whether such effects were the result of increased afterload following
aortic stenosis, we employed isolated rat papillary muscles stimulated in a myobath system (0.5 Hz
stimulation, 48 hours). Exposure to large afterload (isometric contraction) resulted in higher t-tubule
density than in muscles stimulated with lower afterload (values set at 30% of peak developed force, tindex = 0.21 vs 0.16, P < 0.05). These results support the findings in patients and mice, and indicate a
compensatory mechanism triggered by increased afterload. Such adaptations are expected to
contribute to maintained systolic function in the hypertrophic heart, while t-tubule degradation during
ventricular dilation contributes to declining systolic function.