Extreme sarcoplasmic reticulum volume loss and compensatory T-tubule remodeling after Serca2 knockout
2012
Swift, Fredrik | Franzini-Armstrong, Clara | Ãyehaug, Leiv | Enger, Ulla Helene | Andersson, Kristin Brevik | Christensen, Geir | Sejersted, Ole M. | Louch, William E.
Cardiomyocyte contraction and relaxation are controlled by Ca2+ handling, which can be regulated to meet demand. Indeed, major reduction in sarcoplasmic reticulum (SR) function in mice with Serca2 knockout (KO) is compensated by enhanced plasmalemmal Ca2+ fluxes. Here we investigate whether altered Ca2+ fluxes are facilitated by reorganization of cardiomyocyte ultrastructure. Hearts were fixed for electron microscopy and enzymatically dissociated for confocal microscopy and electrophysiology. SR relative surface area and volume densities were reduced by 63% and 76%, indicating marked loss and collapse of the free SR in KO. Although overall cardiomyocyte dimensions were unaltered, total surface area was increased. This resulted from increased T-tubule density, as revealed by confocal images. Fourier analysis indicated a maintained organization of transverse T-tubules but an increased presence of longitudinal T-tubules. This demonstrates a remarkable plasticity of the tubular system in the adult myocardium. Immunocytochemical data showed that the newly grown longitudinal T-tubules contained Na+/Ca2+-exchanger proximal to ryanodine receptors in the SR but did not contain Ca2+-channels. Ca2+ measurements demonstrated a switch from SR-driven to Ca2+ influx-driven Ca2+ transients in KO. Still, SR Ca2+ release constituted 20% of the Ca2+ transient in KO. Mathematical modeling suggested that Ca2+ influx via Na+/Ca2+-exchange in longitudinal T-tubules triggers release from apposing ryanodine receptors in KO, partially compensating for reduced SERCA by allowing for local Ca2+ release near the myofilaments. T-tubule proliferation occurs without loss of the original ordered transverse orientation and thus constitutes the basis for compensation of the declining SR function without structural disarrangement.
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