A myosin-based mechanism for stretch activation and its possible role revealed by varying phosphate concentration in fast and slow mouse skeletal muscle fibers

Abstract

Stretch activation (SA) is a delayed increase in force following a rapid muscle length increase. SA is best known for its role in asynchronous insect flight muscle, where it has replaced calcium’s typical role of modulating muscle force levels during a contraction cycle. SA also occurs in mammalian skeletal muscle but has previously been thought to be too low in magnitude, relative to calcium-activated (CA) force, to be a significant contributor to force generation during locomotion. To test this supposition, we compared SA and CA force at different Piconcentrations (0–16 mM) in skinned mouse soleus (slow-twitch) and extensor digitorum longus (EDL; fast-twitch) muscle fibers. CA isometric force decreased similarly in both muscles with increasing Pi, as expected. SA force decreased with Piin EDL (40%), leaving the SA to CA force ratio relatively constant across Piconcentrations (17–25%). In contrast, SA force increased in soleus (42%), causing a quadrupling of the SA to CA force ratio, from 11% at 0 mM Pito 43% at 16 mM Pi, showing that SA is a significant force modulator in slow-twitch mammalian fibers. This modulation would be most prominent during prolonged muscle use, which increases Piconcentration and impairs calcium cycling. Based upon our previous Drosophila myosin isoform studies and this work, we propose that in slow-twitch fibers a rapid stretch in the presence of Pireverses myosin’s power stroke, enabling quick rebinding to actin and enhanced force production, while in fast-twitch fibers, stretch and Picause myosin to detach from actin.