Figure 3. The inter-filament spacing hypothesis.

Modulation of myofilament inter-filament spacing has been proposed as a unifying mechanism for myofilament length dependent activation. Stretch of the sarcomere (top left) is expected to result in a closer approximation of the thick and filaments within the sarcomere (dashed arrows) resulting in a more favorable disposition of myosin heads to interact with actin (illustrated by red myosin heads on the right). Direct measurement[59, 68] of inter-filament spacing by x-ray diffraction has confirmed an inverse relationship between inter-filament spacing and sarcomere length (bottom left). A short sarcomere length is associated with a large inter-filament spacing and low myofilament Ca²⁺ sensitivity (green), while the opposite is true for a long sarcomere length (orange). Compression of the myofilament lattice (e.g. by dextran) at a short sarcomere length is expected, within the framework of the inter-filament spacing hypothesis, to lead to matched myofilament Ca²⁺ sensitivity[56, 74] even though sarcomere length has not changed (cf. blue arrow). The bar graphs (lower right) show the results of such an experiment: inter-filament spacing, as measured by x-ray diffraction, was varied by either a change in sarcomere length (long SL, orange; short SL, green) or by compression with 1% dextran (blue). Even though compression resulted in an inter-filament spacing that was matched to that attained at the long sarcomere length (top bars), myofilament Ca²⁺ sensitivity (as indexed by EC₅₀) was not affected by the osmotic compression (bottom bars). These data, and other data discussed in the text, suggest that inter-filament spacing may not be primary mechanism that underlies myofilament length dependent activation (modified from [71]).