Myosin Filaments of Vertebrate Skeletal and Cardiac Muscle are Highly Similar, but not Identical

Abstract Striated muscles consist of two filament types, one composed mostly of actin and the other composed mostly of myosin1,2. Actin filaments are highly similar across different muscle types and species both invertebrate and vertebrate3. Myosin filaments of vertebrate striated muscle are quite homogeneous in structure having identical lengths, governed by the giant protein titin4,5, and rotational symmetries while varying mostly in the isoforms of its proteins. Conversely, myosin filaments from invertebrate striated muscle are highly heterogeneous in multiple ways even within a single organism. Myosin filaments from vertebrate cardiac muscle have been shown to be highly similar in structure between mice and humans6-8. Conversely, thick filaments from the highly specialized insect indirect flight muscle have been shown to be highly variable in structure9-14. Here we used the drug mavacamten to stabilize a myosin head conformation known as the interacting heads motif in a fast skeletal muscle of rabbits, a highly studied model system. We show that the structure of relaxed rabbit skeletal muscle thick filaments is highly similar to those of relaxed human and mouse cardiac muscle, differing primarily in the positioning of some domains of myosin binding protein C vis-à-vis titin. In the context of the very different structures from indirect flight muscle, the result highlights different solutions to the same problems, control of muscle force and the requirements of endothermy, the internal generation of heat. In mammals, thick filaments are poised for varying levels of myosin activation15, while indirect flight muscle is poised for narrowly defined, high frequency contraction. In mammals, endothermy is a continuous problem; in insects, endothermy is primarily necessary for flight16. Competing Interest Statement The authors have declared no competing interest.