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First published online June 13, 2008
Journal of Experimental Biology 211, 2005-2013 (2008)
Published by The Company of Biologists 2008
doi: 10.1242/jeb.003145

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The Frank–Starling mechanism in vertebrate cardiac myocytes

Holly A. Shiels^1,* and Ed White²

¹ Faculty of Life Sciences, Core Technology Facility, 46 Grafton Street, University of Manchester, Manchester M13 9NT, UK
² Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, UK

View larger version (43K): [in this window] [in a new window]   Fig. 1. (A) The sarcomere length (SL)–tension relationship for striated muscle, showing how the degree of thick (myosin) and thin (actin) filament overlap determines the potential availability of cross-bridges and thus tension. Details of the cardiac sarcomeric filaments are given in C and are drawn schematically here in the insets a–d, where the thick line with cross hatching is myosin and the thin line is actin. (a) The position of actin and myosin at short SLs, when myosin comes in contact with the Z-line. There is a rapid decline in tension as SLs decreases (to the left of the arrow). The region between b and c is the range of SLs where the potential availability of cross-bridges remains constant during sarcomere stretch because the central cross-bridge head-free zone of the myosin filament (M-line) is progressively uncovered. SLs to the left of b show how tension decreases when the thin filaments from opposite ends of the sarcomere overlap at the M-line. (d) Tension declines toward zero when the sarcomere is stretched such that there is no overlap between thick and thin filaments. A key feature of the cardiac SL–tension ascending limb is that it is shifted in relation to the skeletal curve, and that force increases over the SL range where myofilament overlap remains constant. This means mechanisms other than overlap play an important role in cardiac muscle tension (see text). The figure is adapted from Gordon et al. (Gordon et al., 1966) and Bers (Bers, 2002). (B) Illustration of a cross section through striated muscle showing the effect of stretch on myofilament lattice spacing. Light grey circles represent thick (myosin) filaments and black circles represent thin (actin) filaments. (C) Schematic diagram of a cardiac sarcomere. The sarcomere is the fundamental unit of contraction and is defined as the region between two Z-lines. Each sarcomere consists of a central A-band (thick filaments) and two halves of the I-band (thin filaments). The I-band from two adjacent sarcomeres meet at the Z-line. The central portion of the A-band is the M-line, which does not contain actin. Also shown are the positioning of titin, actin (thin) and myosin (thick) filaments. The coloured bars at the top indicate key segments of the titin molecule and show the regions bound to the contractile filaments and the extensible region. Figure is adapted from Granzier and Labeit (Granzier and Labeit, 2004).

View larger version (24K): [in this window] [in a new window]   Fig. 2. (A) Stretch increases force in the absence of an increase in the amplitude of the [Ca2+]i transient. [Ca2+]i (upper traces, measured by aqueorin, expressed in nA) and tension (lower traces, expressed in mN mm–2) in an intact cat trabeculae at 100% (peak of length–tension relationship) and 81% (on ascending limb of length–tension relationship) of Lmax (length at which force is maximal). Figure is from Allen and Kurihara (Allen and Kurihara, 1982), with permission. (B) Simultaneous measurement of changes in tension (upper panel) and [Ca2+]i (lower panel) in a ventricular myocyte from the rainbow trout at resting length (dotted line) and after a stretch (solid line), showing the increase in force without an increase in [Ca2+]i. Figure is from Shiels et al. (Shiels et al., 2006), with permission. (C) Force [pCa (–log10 Ca mol–1)] curves in skinned frog ventricular myocytes. As sarcomere length (SL) is increased there is a leftward shift in the curve indicating an increase in myofilament Ca2+ sensitivity. SL: circles, 2.2–2.3 µm; triangles, 2.6–2.7 µm; squares, 3.0–3.1 µm) Figure is from Fabiato and Fabiato (Fabiato and Fabiato, 1978b), with permission.

View larger version (12K): [in this window] [in a new window]   Fig. 3. Illustration of passive tension in striated muscle showing the effect of titin isoform expression (N2A, N2BA and/or combination thereof as indicated by shaded area between lines) and modulation of titin by Ca2+ binding or phosphorylation on passive tension in mammalian cardiac muscle. Redrawn from Granzier and Labeit (Granzier and Labeit, 2004). Passive tension data measured from isolated rainbow trout ventricular myocytes [replotted from Shiels et al. (Shiels et al., 2006)] showing the low level of passive force generated by fish heart, even at long sarcomere lengths.

View larger version (60K): [in this window] [in a new window]   Fig. 4. (A) Stretch of single rat (top) and single trout (bottom) ventricular myocytes held between carbon fibres with resting and stretched sarcomere length (SL) shown on the image. Scale bars, 10 µm. (B) Mean SL– active tension relationships for trout (blue) and mammalian (red) ventricular myocytes where 1.0=1.84±0.02 µm for x-axis and 1.0=0.19±0.03 nN µm–2 for y-axis. The red square (ferret) and red triangle (rat) are data extrapolated to the peak of the mammalian length–tension relationship (2.2 µm). Boxes show the operating range of SLs over which each species act and the corresponding changes in force [adapted from Shiels et al. (Shiels et al., 2006)]. Mammalian data (rat and ferret) are replotted from Cazorla et al. (Cazorla et al., 2000a).

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