Residual force enhancement: the neglected property of striated muscle contraction

Abstract

As pointed out by Dr Edman in his thoughtful review (Edman, 2012), residual force enhancement in striated muscles has been observed consistently over the past half-century, its properties have been well described, and its lack of explanation within the framework of the cross-bridge theory has been acknowledged. However, and this is the topic of Dr Edman's review, the primary mechanism producing force enhancement remains a matter of scientific debate. On the one hand, there is the classic explanation of the development of non-uniformities that develop upon muscle stretch; on the other hand, there is the idea of the ‘engagement’ of a passive structural element upon activation that produces the enhanced force following active muscle stretching. In his review, Dr Edman favours the idea that residual force enhancement is primarily a consequence of (half-) sarcomere length non-uniformities (e.g. [residual force enhancement]…‘is ultimately based on non-uniform sarcomere behaviour with the result that populations of sarcomeres, or half-sarcomeres, actually acquire a greater amount of filament overlap than expected from the overall sarcomere length recorded after stretch’; Edman, 2012). Here, we would like to make the argument that ‘the role of a passive structural element’, the second idea mentioned above, should not be dismissed prematurely. First, Dr Edman mentions the advantages of single fibre preparations over myofibril preparations, and all the points he makes are perfectly valid. However, the great advantage of myofibrils over single fibre preparations is that single myofibrils consist of serially arranged sarcomeres. Therefore, the forces measured at the ends of a myofibril reflect directly the force in each sarcomere. Furthermore, the instantaneous lengths of each and all sarcomeres of a myofibril can easily be quantified. In contrast, in a single fibre, sarcomeres are connected partly in parallel and partly in series forming a highly redundant network of force transmission and individual sarcomere lengths cannot be measured, thus making any inferences to sarcomere dynamics highly suspect. Regarding the involvement of a passive structural element in force enhancement, Dr Edman makes several statements that we do not agree with. For example, he states that: ‘It seems quite clear, however, that the phenomenon “force enhancement after stretch” is entirely limited to the active period of the fibre. It disappears completely as the fibre relaxes after the stimulation period.’ (Edman, 2012). This statement ignores the well-described passive force enhancement observed following active stretches of muscles (e.g. Herzog & Leonard, 2002), fibres (e.g. Lee et al. 2007) and myofibrils (e.g. Joumaa et al. 2007, 2008) which persists long after muscle stimulation has ceased. Dr Edman also mentions that: ‘Another strong indication that strain of elastic elements does not by itself determine the measured force is given by the fact that the force recorded during stretch is quite independent of the amplitude of the stretch ramp.’ (Edman, 2012). Again, we disagree; there is ample evidence that the forces during stretch increase with increasing stretch magnitudes, and that the forces at the end-length following stretches of different magnitudes are well correlated with the residual force enhancement (e.g. Bullimore et al. 2007). The sarcomere length non-uniformity theory, favoured in Dr Edman's review, also provides testable predictions. Arguably the most important of these is that a muscle cannot produce enhanced force that exceeds the maximal isometric force at optimal length (Edman et al. 1982). However, there are numerous studies showing peak force enhancements well in excess of 10% above the plateau forces (Lee & Herzog, 2008), and most importantly, force enhancement in single sarcomeres has been shown to exceed 35% on average, with peak values exceeding 50%, above the plateau of the force–length relationship (Leonard et al. 2010). These values cannot be attributed to random fluctuations or artifacts. In summary, we agree with Dr Edman that the mechanisms underlying residual force enhancement remain unknown. However, inferring single sarcomere mechanics from fibre experiments appears impossible. Myofibrils offer an elegant preparation to measure the mechanics of isolated sarcomeres directly and accurately, and have revealed enhanced forces exceeding 50% of the maximal isometric forces in single sarcomeres (Leonard et al. 2010). These results cannot be explained with increased myofilament overlap due to (half-) sarcomere length non-uniformities, but are consistent with the idea of the ‘engagement’ of a passive structural element upon activation. In agreement with Dr Edman, we speculate that titin might play a crucial role in this ‘passive’ force regulation (Herzog et al. 2012).