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Elevated Ventricular Wall Stress Disrupts Cardiomyocyte T-tubular Structure and Ca2+ Homeostasis Ruud M1,2, Frisk M1,2, Espe EK 1,2, Aronsen M1,2,3, Norseng PA1,2, Sjaastad I1,2,3, Sejersted O1,2, 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 Bjørknes College, Oslo, Norway T-tubules are critical for efficient excitation-contraction coupling in cardiomyocytes, and their disorganization during heart failure weakens contraction. The precise mechanism and signaling underlying such t-tubular remodeling are largely unknown, but increased ventricular load has been suggested to be centrally involved (Ibrahim et al., Cardiovasc Res, 2013). We presently hypothesized that ventricular wall stress is a specific trigger regulating t-tubule remodeling. In failing post-infarction rat hearts, we employed MRI-imaging and blood pressure measurements to estimate wall stress across the heart. Wall stress was higher in failing hearts than sham-operated controls, and was particularly elevated proximal to the infarct. Wall stress measurements were closely correlated with disruption of cardiomyocyte t-tubule structure and function, as marked disruption of t-tubule organization, Ca2+ homeostasis, and local contractility were observed near the infarct. Regional ttubule loss was associated with downregulation of Junctophilin-2 (JP2), an established t-tubule anchor (Wei et al., Circ Res, 2010). To investigate whether wall stress directly triggers t-tubule remodeling we mounted left ventricular rat papillary muscles in a myobath system and stretched to mimic in vivo wall stress levels (0.5 Hz stimulation, 48 hours). Muscles exposed to modest stretch (low diastolic wall stress ≈ 4 kN/m2) exhibited well-maintained t-tubule organization during culture. Exposure to high stretch (wall stress ≈ 15-20 kN/m2) approximating that observed proximal to the infarction of failing hearts triggered significant downregulation of JP2 and t-tubule loss. Although the calcineurin-NFAT pathway has been suggested to regulate JP2 expression via miR-24 (Xu et al., Circ Res, 2012), we did not observe wall stress-dependent regulation of miR-24 or RCAN1. This suggests the involvement of a new unknown signaling pathway in mediating wall stress-induced t-tubule remodeling which contributes to heart failure progression. Our findings also suggest a possible mechanism by which unloading of the heart is beneficial in heart failure patients.