Mechanisms of enhanced force production in lengthening (eccentric) muscle contractions

Abstract

In contrast to isometric and shortening contractions, many observations made on actively lengthening muscles cannot be readily explained with the sliding filament and cross-bridge theory. Specifically, residual force enhancement, the persistent increase in force following active muscle lengthening, beyond what one would expect based on muscle length, has not been explained satisfactorily. Here, we summarize the experimental evidence on residual force enhancement, critically evaluate proposed mechanisms for the residual force enhancement, and propose a mechanism for residual force enhancement that explains all currently agreed upon experimental observations. The proposed mechanism is based on the engagement of the structural protein titin upon muscle activation and an increase in titin's resistance to active compared with passive stretching. This change in resistance from the passive to the active state is suggested to be based on 1) calcium binding by titin upon activation, 2) binding of titin to actin upon activation, and 3) as a consequence of titin-actin binding--a shift toward stiffer titin segments that are used in active compared with passive muscle elongation. Although there is some experimental evidence for the proposed mechanism, it must be stressed that much of the details proposed here remain unclear and should provide ample research opportunities for scientists in the future. Nevertheless, the proposed mechanism for residual force enhancement explains all basic findings in this area of research.

Shiver me titin! Elucidating titin's role in shivering thermogenesis

“…Leonard and Herzog (2010) and Powers et al (2014) observed that titinbased muscle stiffness increases upon activation. It is plausible that the mechanism by which titin increases active muscle stiffness is affected by the mdm mutation (Nishikawa et al, 2012;Herzog, 2014). Our observations of lower tremor frequency and reduced active stiffness in mutant muscle are consistent with the hypothesis that titin is an important modulator of active muscle stiffness.…”

“…Historically, titin was considered to have a static contribution to muscle stiffness as this protein is too compliant to substantially contribute to active muscle stiffness. However, Nishikawa et al (2012) and Herzog (2014) have suggested that titin's contribution to muscle stiffness may increase upon muscle activation by binding to the thin filament. Leonard and Herzog (2010) and Powers et al (2014) have shown that titin-based stiffness increases during muscle activation.…”

Eccentric contraction: unraveling mechanisms of force enhancement and energy conservation

“…Several hypotheses have attempted to explain the increased steadystate force that persists following muscle eccentric contractions Minozzo and Lira, 2013;Herzog, 2014). Broadly, these mechanisms include increased cross-bridge force, non-uniformities in sarcomere (Morgan, 1990(Morgan, , 1994 or halfsarcomere length, and engagement of structural elements upon muscle activation (Edman et al, 1982;Herzog and Leonard, 2002;.…”

“…Whereas force enhancement during active stretch has been observed consistently across a wide range of experimental preparations Herzog, 2014), the evidence in support of increased cross-bridge force during eccentric contraction is less robust (Minozzo and Lira, 2013;Herzog, 2014). Because of the technical impossibility of measuring cross-bridge force directly, changes in cross-bridge force are typically inferred from indirect measures.…”

“…Yet, the mechanisms for increased force and reduced energy cost during eccentric contractions have long evaded explanation (Minozzo and Lira, 2013;Herzog, 2014). Finding the solution to this puzzle will likely have important implications for understanding not only muscle contraction but also control of movement (Nishikawa et al, 2013).…”