Striated muscle
myosin is a multidomain
ATP-dependent molecular motor. Alterations to various domains affect the chemomechanical properties of the motor, and they are associated with skeletal and cardiac
myopathies. The
myosin transducer domain is located near the
nucleotide-binding site. Here, we helped define the role of the transducer by using an integrative approach to study how Drosophila melanogaster transducer mutations D45 and Mhc(5) affect
myosin function and skeletal and cardiac muscle structure and performance. We found D45 (A261T)
myosin has depressed
ATPase activity and in vitro actin motility, whereas Mhc(5) (G200D)
myosin has these properties enhanced. Depressed D45
myosin activity protects against age-associated dysfunction in metabolically demanding skeletal muscles. In contrast, enhanced Mhc(5)
myosin function allows normal skeletal myofibril assembly, but it induces degradation of the myofibrillar apparatus, probably as a result of contractile disinhibition. Analysis of beating hearts demonstrates depressed motor function evokes a dilatory response, similar to that seen with vertebrate
dilated cardiomyopathy myosin mutations, and it disrupts contractile rhythmicity. Enhanced
myosin performance generates a phenotype apparently analogous to that of human
restrictive cardiomyopathy, possibly indicating
myosin-based origins for the disease. The D45 and Mhc(5) mutations illustrate the transducer's role in influencing the chemomechanical properties of
myosin and produce unique pathologies in distinct muscles. Our data suggest Drosophila is a valuable system for identifying and modeling mutations analogous to those associated with specific human
muscle disorders.